AUGUST 2012 VOL 5, NO 5 SPECIAL ISSUE

CARDIOMETABOLIC IMPLICATIONS . . . . . . . . . . . . . . . . .6Sustained glycemic control reduces cardiometabolic risk factorsPediatric diabetes rising with obesityepidemic

HEALTH ECONOMICS . . . . . . . . . .10Medical costs increase as CKD worsensValue-based benefit design reduceslow-value therapies

INCRETIN THERAPIES . . . . . . .14Exenatide versus glimepirideRole of GLP-1 and DPP-4 in type 2 diabetes

INSULIN UPDATE . . . . . . . . . . . .171 in 4 patients using insulin inappropriately Head-to-head comparisons of insulin therapies

DIABETES MANAGEMENT . . . .22Novel risk factors for diabetesNew data in young patients with diabetesQuality improvement programs enhance diabetes care

EMERGING THERAPIES . . . . . .28Diabetes pipeline is promisingNovel basal insulin reduces weightNew long-acting insulin degludec

INS IDE

AUGUST 2012, VOL 5, NO 5, SPECIAL ISSUE

Medical Spending for Diabetes,1987-2008: Where Does the Money Go?By Mary Mosley

Continued on page 6

AMERICAN DIABETES ASSOCIATION 2012 HIGHLIGHTS÷

The Diabetes Epidemic Is Likea Tsunami Hitting in WavesCardiometabolic health highlighted at ADA 2012By Wayne Kuznar

©2012 Engage Healthcare Communications, LLC

Reducing hemoglobin (Hb) A1clevels as soon as possible afterthe diagnosis of type 2 diabetes

results in a reduction in the diabetes-related complications, including myo -cardial infarction (MI) and all-causemortality. This early reduction in theHbA1c level explains the so-calledlegacy effect found in the UKPDS(United Kingdom Prospective DiabetesStudy), stated Marcus Lind, MD, ofthe Department of Molecular and Clin-ical Medicine, Institute of Medicine,Sahlgrenska Academy, University ofGothenburg, Sweden, who presentedan analysis in a late-breaking abstract

session at the 2012 ADA meeting.The legacy effect refers to the signif-

icantly lower risk for diabetes-relatedcomplications found in patients ran-domized to intensive glycemic controlcompared with patients randomizedto conventional glucose control, al-though the HbA1c levels were virtu-ally the same in both groups duringthe 10-year observational follow-up ofthe original UKPDS. The legacy effect,which is the continuing benefit ofearly improvements in glucose con-trol, is similar to the “metabolic mem-ory” described in type 1 diabetes, saidDr Lind.

Philadelphia, PA—The epidemic ofdiabetes is like a tsunami that willstrike in waves, said Geralyn R. Spol-lett, MSN, ANP-CS, CDE, Presidentof Health Care & Education, AmericanDiabetes Association (ADA), Alex -

andria, VA, and Associate Director ofthe Yale Diabetes Center, Yale Schoolof Medicine, New Haven, CT, at the2012 ADA annual meeting. The resultwill be 380 million people worldwidein 2025 with diagnosed diabetes,

Three incretin-based therapies—exenatide, liraglutide, and sita -gliptin—are associated with a

reduction in cardiovascular (CV) riskscores, “an effect more clearly ob-served in patients using glucagon-likepeptide-1 agonists,” said ChristopherJ. Smith, MD, Department of Diabetesand Endocrinology, Glasgow RoyalInfirmary, Scotland, during the 2012ADA annual meeting.

Incretin-based therapies are not sim-ply “glucocentric” but also confer ben-efits with respect to weight control andpossibly blood pressure (BP) reduc-tion, Dr Smith said.Dr Smith presented the results of a

planned observational analysis of therelative CV risk and benefit of theseagents in routine care in a universityhospital–based diabetes center. Dr Smith and his colleagues ana-

Incretin Therapies LowerCardiovascular Risk ScoreBy Wayne Kuznar

UKPDS Follow-Up: Early HbA1cReductions Linked to a Decreasein MI, All-Cause MortalityMajor benefits of sustained control are seen 5-10 years laterBy Mary Mosley

Continued on page 7

*This publication is not endorsed by nor associated with the American Diabetes Association.

Medical expenditures for dia-betes have increased over thepast 2 decades, along with

improvements in the management ofthe disease and the availability of new

drugs. But the major increase seen from1987 to 1997 slowed thereafter through2008, said Xiaohui Zhuo, PhD, HealthEconomist, Division of Diabetes Trans-lation, Centers for Disease Control

Continued on page 12


THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

www.AHDBonline.com

Focusing on what mattersImproving glycemic control for adult patients with type 2 diabetes

Indication and Important Limitations of Use

TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

TRADJENTA has not been studied in combination with insulin.

Important Safety Information

CONTRAINDICATIONSTRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema or bronchial hyperreactivity.

WARNINGS AND PRECAUTIONS USE WITH MEDICATIONS KNOWN TO CAUSE HYPOGLYCEMIAInsulin secretagogues are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in

a clinical trial. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA.

MACROVASCULAR OUTCOMESThere have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug.

ADVERSE REACTIONSAdverse reactions reported in ≥5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis.

Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 of 791 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea.

TRADJENTA (LINAGLIPTIN) TABLETS: THE ONLY ONCE-DAILY 1-DOSE DPP-4 INHIBITOR

FOR ADULT PATIENTS WITH TYPE 2 DIABETES

U

M

Copyright © 2012 Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (03/12) TJ184308PROFB

In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient-years of exposure [1 per 538 person-years]) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient-years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

DRUG INTERACTIONSThe effi cacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments to TRADJENTA is strongly recommended.

USE IN SPECIFIC POPULATIONSThere are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed.

It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human

milk, caution should be exercised when TRADJENTA is administered to a nursing woman.

The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established.

TJ PROF ISI FEB132012

References: 1. Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle H-J, Dugi K. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13:258-267. 2. Data on fi le. Boehringer Ingelheim Pharmaceuticals, Inc. 3. Taskinen M-R, Rosenstock J, Tamminen I, et al. Safety and effi cacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74. 4. Barnett AH. Linagliptin: a novel dipeptidyl peptidase 4 inhibitor with a unique place in therapy. Adv Ther. 2011;28:447-459.

Please see brief summary of full Prescribing Information on the adjacent page.

TRADJENTA delivers proven glycemic control

TRADJENTA: Experience dosing simplicity

No dose adjustment required, regardless of declining renal function or hepatic impairment4

TRADJENTA is primarily nonrenally excreted: 80% eliminated via the bile and gut and 5% eliminated via the kidney within 4 days of dosing

One dose, once daily for adult patients with type 2 diabetes

TRADJENTA: A safety and tolerability profile demonstrated in more than 4000 patients

† A randomized, double-blind, placebo-controlled, parallel-group study of adult patients with type 2 diabetes (aged 18-80) with insuffi cient glycemic control despite metformin therapy who were randomized to TRADJENTA 5 mg/day (n=524; mean baseline A1C=8.1%) or placebo (n=177; mean baseline A1C=8.0%) in combination with metformin ≥1500 mg/day for 24 weeks. Primary endpoint was change from baseline in A1C at 24 weeks. Results are adjusted for a 0.15% mean A1C increase for placebo and 0.5% mean decrease for TRADJENTA in add-on combination with metformin. 18.9% of patients in the placebo group required rescue therapy vs 7.8% of patients in the TRADJENTA group. Full analysis population using last observation on study.

Find out more about TRADJENTA and the Savings Card program at www.tradjenta.com

Signifi cant A1C reductions from baseline at 24 weeks

* A randomized, multicenter, double-blind, placebo-controlled study of adult patients with type 2 diabetes (aged 18-80) who were randomized to TRADJENTA 5 mg/day (n=336; mean baseline A1C=8.0%) or placebo (n=167; mean baseline A1C=8.0%) for 24 weeks. Primary endpoint was change from baseline in A1C at 24 weeks. 20.9% of patients in the placebo group required rescue therapy vs 10.2% of patients in the TRADJENTA group. Results adjusted for a 0.3% mean A1C increase for placebo and 0.4% mean decrease for TRADJENTA monotherapy. Full analysis population using last observation on study.

Plac

ebo-

adju

sted

mea

n ch

ange

in

A1C

at 2

4 w

eeks

(%)

-0.6%-0.7%

TRADJENTAmonotherapy1,2*

(n=333)

TRADJENTA + metformin2,3†

(n=513)

P<0.0001

P<0.0001

-0.8

-0.6

-0.4

-0.2

0

TRADJENTA is primarily nonrenally excreted: 80% eliminated via the bile and gut

TRADJENTA: A safety and tolerability profile demonstrated in more than 4000 patients

TRADJENTA

5 MG #30

Sig:i PO QD

x2 REFILLS

Tradjenta™ (linagliptin) tablets

BRIEF SUMMARY OF PRESCRIBING INFORMATION

Please see package insert for full Prescribing Information.

INDICATIONS AND USAGETRADJENTA tablets are indicated as an adjunct to diet and exercise to improve gly-cemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use: TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. TRADJENTA has not been studied in combination with insulin.

CONTRAINDICATIONSTRADJENTA is contraindicated in patients with a history of a hypersensitivity reac-tion to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity [see Adverse Reactions].

WARNINGS AND PRECAUTIONSUse with Medications Known to Cause Hypoglycemia: Insulin secretagogues are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions]. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglyce-mia when used in combination with TRADJENTA. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets or any other antidiabetic drug.

ADVERSE REACTIONSClinical Trials Experience: Because clinical trials are conducted under widely vary-ing conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of linagliptin has been evaluated in over 4000 patients with type 2 diabetes in clinical trials, including 12 placebo-controlled studies and 1 active-controlled study with glimepiride. TRADJENTA 5 mg once daily was studied as monotherapy in two placebo-controlled trials of 18 and 24 weeks’ duration. Five placebo-controlled trials investigated linagliptin in combination with other oral antihyperglycemic agents: two with metformin (12 and 24 weeks’ treat-ment duration); one with a sulfonylurea (18 weeks’ treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment duration); and one with piogli-tazone (24 weeks’ treatment duration). In placebo-controlled clinical trials, adverse reactions that occurred in 5% of patients receiving TRADJENTA (n = 2566) and more commonly than in patients given placebo (n = 1183) included nasopharyn-gitis (5.8% vs 5.5%). Adverse reactions reported in 2% of patients treated with TRADJENTA 5 mg daily as monotherapy or in combination with pioglitazone, sulfo-nylurea, or metformin and at least 2-fold more commonly than in patients treated with placebo are shown in Table 1. Following 52 weeks’ treatment in a controlled study comparing linagliptin with glimepiride in which all patients were also receiving metformin, adverse reactions reported in 5% patients treated with linagliptin (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were arthralgia (5.7% vs 3.5%), back pain (6.4% vs 5.2%), and headache (5.7% vs 4.2%).Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity), and myalgia. In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient years of exposure) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.Hypoglycemia: In the placebo-controlled studies, 195 (7.6%) of the total 2566 patients treated with TRADJENTA 5 mg reported hypoglycemia compared to

49 patients (4.1%) of 1183 placebo-treated patients. The incidence of hypoglyce-mia was similar to placebo when linagliptin was administered as monotherapy or in combination with metformin, or with pioglitazone. When linagliptin was adminis-tered in combination with metformin and a sulfonylurea, 181 of 791 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered pla-cebo in combination with metformin and a sulfonylurea.Laboratory Tests: Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo. Changes in labora-tory values that occurred more frequently in the TRADJENTA group and 1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group). No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA.

DRUG INTERACTIONSInducers of P-glycoprotein or CYP3A4 Enzymes: Rifampin decreased linagliptin exposure suggesting that the efficacy of TRADJENTA may be reduced when admin-istered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be adminis-tered with a P-gp or CYP3A4 inducer.

USE IN SPECIFIC POPULATIONSPregnancy: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.Linagliptin administered during the period of organogenesis was not teratogenic at doses up to 30 mg/kg in the rat and 150 mg/kg in the rabbit, or approximately 49 and 1943 times the clinical dose based on AUC exposure. Doses of linagliptin causing maternal toxicity in the rat and the rabbit also caused developmental delays in skel-etal ossification and slightly increased embryofetal loss in rat (1000 times the clinical dose) and increased fetal resorptions and visceral and skeletal variations in the rabbit (1943 times the clinical dose). Linagliptin administered to female rats from gestation day 6 to lactation day 21 resulted in decreased body weight and delays in physical and behavioral development in male and female offspring at maternally toxic doses (exposures >1000 times the clinical dose). No functional, behavioral, or reproductive toxicity was observed in offspring of rats exposed to 49 times the clinical dose. Lina-gliptin crossed the placenta into the fetus following oral dosing in pregnant rats and rabbits. Nursing Mothers: Available animal data have shown excretion of linagliptin in milk at a milk-to-plasma ratio of 4:1. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. Pediatric Use: Safety and effectiveness of TRADJENTA in pediatric patients have not been estab-lished. Geriatric Use: Of the total number of patients (n= 4040) in clinical studies of TRADJENTA, 1085 patients were 65 years and over, while 131 patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. While this and other reported clinical experience have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. No dose adjustment is recommended in this population. Renal Impairment: No dose adjustment is recommended for patients with renal impairment. Hepatic Impairment: No dose adjustment is recommended for patients with hepatic impairment.

OVERDOSAGEDuring controlled clinical trials in healthy subjects, with single doses of up to 600 mg of TRADJENTA (equivalent to 120 times the recommended daily dose) there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointes-tinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Linagliptin is not expected to be eliminated to a thera-peutically significant degree by hemodialysis or peritoneal dialysis.

Table 1 Adverse Reactions Reported in 2% of Patients Treated with TRADJENTA and at Least 2-Fold Greater than with Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination Therapy

Monotherapy*n (%)

Combination with Metformin# n (%)

Combination with SU n (%)

Combination with Metformin + SU n (%)

Combination with Pioglitazone n (%)

TRADJENTA n = 765

Placebon = 458

TRADJENTA n = 590

Placebon = 248

TRADJENTAn = 161

Placebon = 84

TRADJENTAn = 791

Placebon = 263

TRADJENTAn = 259

Placebon = 130

Nasopharyngitis – – – – 7 (4.3) 1 (1.2) – – – –Hyperlipidemia – – – – – – – – 7 (2.7) 1 (0.8)Cough – – – – – – 19 (2.4) 3 (1.1) – –Hypertriglyceridemia† – – – – 4 (2.4) 0 (0.0) – – –Weight increased – – – – – – – – 6 (2.3) 1 (0.8)

SU = sulfonylurea *Pooled data from 7 studies #Pooled data from 2 studies †Includes reports of hypertriglyceridemia (n = 2; 1.2%) and blood triglycerides increased (n = 2; 1.2%)

Copyright © 2011 Boehringer Ingelheim Pharmaceuticals, Inc.

Revised: July 2011 TJ-BS (7-11) TJ104305PROF

5AUGUST 2012 AMERICAN HEALTH & DRUG BENEFITS

In This Issue

EDITORIAL BOARD

EDITOR-IN-CHIEFDavid B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N.Grandon Professor, Jefferson School ofPopulation Health, Philadelphia, PA

DEPUTY EDITORSJoseph D. Jackson, PhDProgram Director, Applied Health Economics and Outcomes Research, Jefferson University School of Population Health, Philadelphia, PALaura T. Pizzi, PharmD, MPH, RPhAssociate Professor, Department of Pharmacy Practice, Jefferson School ofPharmacy, Philadelphia, PA

AGING AND WELLNESSEric G. Tangalos, MD, FACP,AGSF, CMDProfessor of MedicineMayo Clinic, Rochester, MN

CANCER RESEARCHAl B. Benson, III, MD, FACPProfessor of Medicine, Associate Directorfor Clinical InvestigationsRobert H. Lurie Comprehensive CancerCenter, Northwestern University, ILPast President, ACCCPast Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FASCOProfessor of Internal Medicine Hematology/OncologyAssistant Dean for ResearchAssociate Director, Faculty Group Practice, University of Michigan Medical School, MI

EMPLOYERSArthur F. Shinn, PharmD, FASCPPresident, Managed Pharmacy Consultants, LLC, Lake Worth, FLF. Randy Vogenberg, RPh, PhDPrincipal, Institute for Integrated Healthcare and BentteligenceSharon, MA

ENDOCRINOLOGY RESEARCHJames V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans AffairsMedical Center, Phoenix, AZ

EPIDEMIOLOGY RESEARCHJoshua N. Liberman, PhDExecutive Director, Research, Development & DisseminationSutter Health, Concord, CA

GOVERNMENTKevin B. “Kip” Piper, MA, FACHEPresident, Health Results Group, LLCWashington, DC

HEALTH INFORMATION TECHNOLOGY Kelly Huang, PhDPresident, HealthTronics, Inc.Austin, TX J. B. Jones, PhD, MBAResearch Investigator, Geisinger Health System, Danville, PA

Victor J. Strecher, PhD, MPHProfessor and Director for Innovation and Social EntrepreneurshipUniversity of Michigan, School of Public Health and MedicineAnn Arbor, MI

HEALTH OUTCOMES RESEARCH Diana Brixner, RPh, PhDProfessor and ChairDepartment of PharmacotherapyExecutive Director, Outcomes ResearchCenter, Director of Outcomes Personalized Health Care Program University of UtahSalt Lake City, UTJoseph Couto, PharmD, MBAClinical Program ManagerCigna Corporation, Bloomfield, CT Steve Miff, PhDSenior Vice PresidentVHA, Inc., Irving, TXKavita V. Nair, PhDAssociate Professor, School of PharmacyUniversity of Colorado at Denver, COGary M. Owens, MDPresident, Gary Owens AssociatesGlen Mills, PAAndrew M. Peterson, PharmD, PhDDean, Mayes School of Healthcare Business and Policy, Associate ProfessorUniversity of the SciencesPhiladelphia, PASarah A. Priddy, PhDDirector, Competitive Health AnalyticsHumana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPhExecutive Director, Strategic Accounts Xcenda, Palm Harbor, FLVincent J. Willey, PharmDAssociate Professor, Philadelphia School of Pharmacy, University of the SciencesPhiladelphia, PADavid W. Wright, MPHPresident, Institute for Interactive PatientCare, Bethesda, MD

HEALTH & VALUE PROMOTION Craig Deligdish, MDHematologist/OncologistOncology Resource NetworksOrlando, FLThomas G. McCarter, MD, FACPChief Clinical OfficerExecutive Health Resources, PAAlbert Tzeel, MD, MHSA, FACPENational Medical DirectorHumanaOne, Waukesha, WI

MANAGED MARKETS Jeffrey A. Bourret, RPh, MS, FASHPSenior Director, Medical Lead, Payer andSpecialty Channel Strategy, Medical Affairs, Pfizer Specialty Care Business Unit, PA

Richard B. Weininger, MDChairman, CareCore National, LLCBluffton, SC

PATIENT ADVOCACY William E. Fassett, BSPharm, MBA,PhD, FAPhAProfessor of Pharmacy Law & EthicsDept. of Pharmacotherapy, College of Pharmacy, Washington State University, Spokane, WAMike PucciSr VP, Commercial Operations and Business Development, PhytoChem PharmaceuticalsLake Gaston, NC

PERSONALIZED MEDICINEEmma Kurnat-Thoma, PhD, MS, RNDirector, Research ServicesURAC, Washington, DC

PHARMACOECONOMICSJosh FeldsteinPresident & CEOCAVA, The Center for Applied Value Analysis, Inc., Norwalk, CTJeff Jianfei Guo, BPharm, MS, PhDProfessor of Pharmacoeconomics& Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

PHARMACY BENEFIT DESIGN Joel V. Brill, MD, AGAF, CHCQMChief Medical Officer, Predictive Health, Phoenix, AZTeresa DeLuca, MD, MBASenior VP, PBM LeaderHumana Solutions, Louisville, KYLeslie S. Fish, PharmDVice President of Clinical ProgramsFallon Community Health Plan, MAJohn Hornberger, MD, MSCedar Associates, LLCCHP/PCOR Adjunct Associate Menlo Park, CA Michael S. Jacobs, RPhVice President, National AccountsTruveris, Inc., New York, NYMatthew Mitchell, PharmD, MBAManager, Pharmacy ServicesSelectHealth, Salt Lake City, UTPaul Anthony Polansky, BSPharm,MBASenior Field Scientist, Health Outcomesand PharmacoEconomics (HOPE) Endo Health Solutions, Chadds Ford, PAChristina A. Stasiuk, DO, FACOISenior Medical DirectorCigna, Philadelphia, PA Scott R. Taylor, BSPharm, MBAExecutive Director, Industry RelationsGeisinger Health System, Danville, PA

POLICY & PUBLIC HEALTH Joseph R. Antos, PhDWilson H. Taylor Scholar in Health CareRetirement Policy, American Enterprise Institute, Washington, DCRobert W. Dubois, MD, PhDChief Science OfficerNational Pharmaceutical Council Washington, DCJack E. Fincham, PhD, RPh Professor of Pharmacy Practice and Administration, School of Pharmacy University of Missouri Kansas City, MOWalid F. Gellad, MD, MPHAssistant Professor of Medicine University of Pittsburgh, Staff Physician,Pittsburgh VA Medical Center, AdjunctScientist, RAND HealthPaul Pomerantz, MBAExecutive DirectorDrug Information Association Horsham, PAJ. Warren Salmon, PhDProfessor of Health Policy & AdministrationSchool of Public HealthUniversity of Illinois at ChicagoRaymond L. Singer, MD, MMM, CPE, FACSChief, Division of Cardiothoracic SurgeryVice Chair, Department of Surgery forQuality & Patient Safety and OutreachLehigh Valley Health Network, PA

RESEARCH & DEVELOPMENT Frank Casty, MD, FACPChief Medical OfficerSenior VP, Clinical Development Medical ScienceEndo Pharmaceuticals, Chadds Ford, PAMichael F. Murphy, MD, PhDChief Medical Officer and Scientific OfficerWorldwide Clinical TrialsKing of Prussia, PA

SPECIALTY PHARMACYAtheer A. Kaddis, PharmDSenior Vice PresidentManaged Markets/Clinical ServicesDiplomat Specialty Pharmacy Flint, MIJames T. Kenney, Jr, RPh, MBAPharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MAMichael KleinrockDirector, Research DevelopmentIMS Institute for Healthcare InformaticsCollegeville, PA

CARDIOMETABOLIC IMPLICATIONSSustained glycemic control reduces cardiometabolic risk factorsDiabetes rates surging in youth with rising obesity More…..

HEALTH ECONOMICSMedical spending for diabetes, 1987-2008Medical costs increase as CKD worsensValue-based benefit design maximizes returnon investment Paying patients to change behavior is effective More…..

INCRETIN THERAPIESIncretin therapies reduce cardiovascular risk factorsExenatide versus glimepirideRole of GLP-1 and DPP-4 in type 2 diabetes More…..

INSULIN UPDATE1 in 4 diabetic patients not using insulin asprescribed Head-to-head comparison of insulin therapiesNinety years of insulin therapyMore…..

DIABETES MANAGEMENTNovel risk factors for type 2 diabetesNew data in young patients with diabetesQuality improvement programs enhance diabetes care More…..

EMERGING THERAPIESDiabetes pipeline is promisingEmpagliflozin safe, effective, reduces weightNovel basal insulin reduces weightLong-acting insulin degludec shows promiseMore…..

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN


PublisherNicholas [email protected] DirectorDalia [email protected] PublisherMaurice [email protected] EditorLara J. [email protected] Accounts ManagerZach [email protected] Vice PresidentEngage Managed MarketsChuck [email protected] AssistantJennifer [email protected] Production ManagerLynn HamiltonQuality Control DirectorBarbara MarinoBusiness ManagerBlanche Marchitto

Founding Editor-in-ChiefRobert E. Henry

Mission StatementAmerican Health & Drug Benefits is founded on theconcept that health and drug benefits have under-gone a transformation: the econo metric value of adrug is of equal importance to clinical outcomes as itis to serving as the basis for securing coverage in for-mularies and benefit designs. Because benefit designsare greatly affected by clinical, business, and policyconditions, this journal offers a forum for stakeholderintegration and collaboration toward the improve-ment of healthcare.This publication further provides benefit design de -cision makers the integrated industry informationthey require to devise formularies and benefit designsthat stand up to today’s special healthcare deliveryand business needs.Contact Information:For subscription information and edi torial queries,please contact: [email protected]: 732-992-1892; F: 732-992-1881American Health & Drug Benefits, ISSN 1942-2962(print); ISSN 1942-2970 (online), is published 8 timesa year by Engage Healthcare Communica tions, LLC,1249 South River Rd, Suite 202A, Cranbury, NJ08512. Copyright © 2012 by Engage Healthcare Com-munications, LLC. All rights reserved. American Health& Drug Benefits and The Peer-Reviewed Forum for Evi-dence in Benefit Design are trademarks of Engage Health-care Communications, LLC. No part of this publicationmay be reproduced or transmitted in any form or by anymeans now or hereafter known, electronic or mechan-ical, including photocopy, recording, or any informa-tional storage and retrieval system, without writtenpermission from the Publisher. Printed in the UnitedStates of America. The ideas and opinions expressed in American Health& Drug Benefits do not necessarily reflect those of theEditorial Board, the Editors, or the Publisher. Publi-cation of an advertisement or other product men-tioned in American Health & Drug Benefits should notbe construed as an endorsement of the product or themanufacturer’s claims. Readers are encouraged tocontact the manufacturers about any features or lim-itations of products mentioned. Neither the Editorsnor the Publisher assume any responsibility for anyinjury and/or damage to persons or property arisingout of or related to any use of the material mentionedin this publication.For permission to reuse material from American Health& Drug Benefits (ISSN 1942-2962), please access www.copyright.com <http://www.copyright.com/> or contactthe Copyright Clearance Center, Inc. (CCC), 222Rosewood Drive, Danvers, MA 01923, 978-750-8400.

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6 AMERICAN HEALTH & DRUG BENEFITS AUGUST 2012

Cardiometabolic Implications

lyzed the effect of exenatide, liraglu-tide, and sitagliptin on hemoglobin(Hb) A1c level, weight, systolic BP, andlipid profile over 12 months. CV riskwas calculated with the United King-dom Prospective Diabetes Study(UKPDS) calculator, using a fixed-effects model that corrected for sex, age,diabetes duration, heart rhythm, andsmoking status. The UKPDS risk en-gine is a validated CV risk assessmenttool for patients with type 2 diabetes.“The benefits of exenatide and lira -

glutide were slightly better than forsitagliptin,” said Dr Smith.In 102 patients, exenatide lowered the

mean HbA1c level from 9.41% to 9.08%and reduced weight from 110.35 kg to105.82 kg. Systolic BP was unchanged(134.76 mm Hg at baseline vs 134.11mm Hg) at 12 months. The UKPDS risk

score for coronary heart disease (CHD)was lowered from 18.5% to 16.3%.

A total of 30 patients used a combi-nation of insulin and exenatide. Themean daily insulin dosage in patientsreceiving exenatide declined from 83.1U to 77.5 U.

In 97 patients, liraglutide loweredthe mean HbA1c level from 9.94% to9.42%, weight from 107.97 kg to 104.07kg, and systolic BP from 138.36 mm Hgto 134.84 mm Hg. The UKPDS risk forCHD declined from 22.4% to 20.2%.A total of 42 patients used an insulin

and liraglutide combination. The meandaily insulin dosage was reduced from101.0 U to 94.7 U.In 102 patients, sitagliptin lowered

the HbA1c level from 9.22% to 8.95% at12 months (a change that was not sta-tistically significant) and had no effecton weight (93.30 kg to 92.72 kg) or sys-tolic BP (137.03 mm Hg to 139.81 mmHg). The UKPDS risk score decreasedfrom 18.5% to 17.3%.There were 12 patients who used a

combination of insulin and sitagliptin.In these patients, daily insulin dosage

increased significantly, from 62.8 U to76.0 U.“The reductions in the UKPDS risk

scores are signals that perhaps we’redoing the right thing for our patients,”said Dr Smith.Because the data for this analysis

came from a clinic database, “it’s notaccounting for variables like compli-ance,” he said.

Key Findings

• Liraglutide lowered HbA1c level,weight, systolic BP, CV risk score,and insulin dosage

• Exenatide lowered HbA1c level,weight, and CV risk score

• Sitagliptin lowered HbA1c level(nonsignificantly) and CV risk score,but the effect of this agent on weightwas neutral.�

“The benefits of exenatideand liraglutide were slightlybetter than for sitagliptin….The reductions in the UKPDSrisk scores are signals thatperhaps we’re doing the rightthing for our patients.”

—Christopher J. Smith, MD

Incretin Therapies Lower Cardiovascular... Continued from page 1

A2-year open-label study ofexen atide once weekly showedthat this medication was safe

when combined with a thiazolidine-dione (TZD) plus metformin, and thatit significantly lowered hemoglobin(Hb) A1c in patients with type 2 dia-betes. A second study of patients withtype 2 diabetes, the open-label exten-sion study of DURATION-1 (DiabetesTherapy Utilization: ResearchingChanges in A1c, Weight and Other Fac-tors Through Intervention with Exe-natide Once Weekly) trial, showed thatthe reductions in HbA1c in the trialwere sustained at 4 years, along withimprovements in cardio metabolicmeasures. Michael E. Trautmann, MD, Consult-

ant, Diabetes Drug Development at EliLilly, presented the results of these stud-ies at the 2012 ADA annual meeting.

Exenatide plus a TZD:

2-Year Results

In the 2-year, single-arm, open-labelstudy of the safety of exenatide in com-bination with a TZD, “there were nonew safety findings and no negativeinteraction between the drugs,” saidDr Trautmann. The known side effects for each drug

were seen at the same level as was al-ready known, he stated. For exenatide,these were the gastrointestinal (GI)-related side effect of nausea (17.2%)and injection-site nodule (11.9%). For

the TZDs, side effects included mildperipheral edema in 3 patients andedema in 1 patient, but no reports ofheart failure. No major hypoglycemicevents were reported, and minorhypoglycemic events were rare.

Of the 134 patients, 44 were exen -atide-naive and 90 were switched fromexenatide twice daily to the once-weekly 2-mg dose. The TZD pioglita-zone (≥30 mg daily) was taken by 90%of patients and the TZD rosiglitazone(24 mg daily) was taken by 10% (physi-cians were free to select the TZD), andmetformin by 90% of the patients. Noimpact was seen from the use of rosigli-

tazone, and its use was low, with manypatients switching to pioglitazone dur-ing the trial, because of cardiovascularconcerns, Dr Trautmann stated. To be included in the study, patients

had to have an HbA1c level between 7%and 10%. All patients had diabetes for 6years, most of them were white males,and the average age was 55 years. The HbA1c was significantly low-

ered in the overall intention-to-treat(ITT) analysis, from 7.2% at baseline to6.7%; a similar reduction, from 7.0% to6.6%, was seen in patients whoswitched from the twice-daily exe-natide dose to the once-weekly dose.The exenatide-naive patients had aslightly larger reduction in HbA1c—from 7.7% to 6.6% at study end. “Body weight was reduced despite

the continuous use of TZDs, which areknown to increase body weight quitesignificantly. Body weight was wellmaintained over the course of the 2years,” said Dr Trautmann. Overall baseline body weight was

98.1 kg; body weight was reduced themost in the exenatide-naive patients,by 2.7 kg, compared with reductions of0.6 kg and 0.5 kg in the ITT and theswitched groups, respectively.

DURATION-1: 4-Year Sustained

Benefits with Exenatide

The 4-year open-label extensionstudy of DURATION-1 that included295 patients showed the durability of

exenatide once weekly, resulting in asustained reduction of 1.7% in HbA1cand a 4-year maintenance of the 2.5-kgweight loss from baseline. In the randomized DURATION-1

trial, a significantly greater reductionwas seen in HbA1c level with exenatideonce weekly than with the twice-weekly administration of the drug—a 1.9% reduction compared with 1.5%(P = .002), respectively, at 30 weeks.Weight-loss level was similar in the 295patients in both groups.The patients had to have an HbA1c

level between 7.1% and 11% to be in-cluded in this study. At baseline, pa-tients (average age, 56 years) had anHbA1c of 8.2%, body weight of 100kg, and diabetes duration of 7 years.The management regimen includedexenatide once weekly, diet and exer-cise, and a TZD, metformin, or a sul-fonylurea. In the 176 patients who completed

the 4-year extension, 55% achievedan HbA1c of <7% and 36% achievedan HbA1c <6.5% (mean, 6.9%). Fast-ing plasma glucose was reduced by37 mg/dL. Blood pressure (BP) and lipid levels

were improved at 4 years. Reductionswere seen in:• Systolic BP, by 1.6 mm Hg• Total cholesterol, by 10.9 mg/dL• Low-density lipoprotein cholesterol,by 8.0 mg/dL.In addition, the mean change in

Sustained Glycemic Control with Once-Weekly ExenatideReduces Cardiometabolic Risk FactorsBy Mary Mosley

“Bodyweight wasreduceddespite thecontinuoususe ofTZDs,

which are known to increasebody weight quitesignificantly. Body weightwas well maintained over thecourse of the 2 years.”

—Michael E. Trautmann, MD

Continued on page 7

See also Incretin Therapies



This persistence in effect was seen forMI and for all-cause mortality. MI wasreduced by 16% with intensive HbA1ccontrol versus conventional control atthe end of the original study. At 10 yearsof follow-up, a 15% risk reduction wasfound with intensive control. All-cause mortality was reduced by

6% with intensive versus conventionalcontrol at the end of the original study,and the rate increased to a 13% riskreduction with intensive control at 10years (P = .006), with similar glycemiccontrol in both groups.

Benefits of Legacy

Effects Revealed

In the present analysis, the inves -tigators examined data from 3849patients assigned to intensive or con-ventional glycemic control in theUKPDS, using statistical models to de-termine the degree to which “histori-cal” HbA1c values contribute to laterreductions in the risks for MI and forall-cause mortality, and to elucidate thetime-dependent impact of an earlier re-

duction in HbA1c values on a year-by-year outcome.Older age, male sex, and HbA1c val-

ues, but not the treatment group, weresignificantly related to MI and all-cause mortality, according to the analy-sis by Dr Lind and his colleagues.

As the researchers learned from amodel to determine the year-by-yearbenefit of the legacy effect, the benefitof a 1% reduction in HbA1c will in-crease over time. For all-cause mortal-ity, the hazard ratio was 1 for years 0 to

10, but the risk reduction increased to21% at year 15 and to 24.7% at year 20.Furthermore, the earlier the HbA1c

level is lowered, the greater the benefit.If the HbA1c level is lowered from thetime of diagnosis of type 2 diabetes,there is a 15% risk reduction in all-cause mortality at year 15. This is cutnearly in half (7.1%) if HbA1c is notlowered until 10 years after the diseaseis diagnosed. Therefore, there is a 3-fold greater risk reduction in all-causemortality because of the legacy effectof early HbA1c reduction.An increased risk reduction in all-

cause mortality, to 24.7%, is seen after20 years if HbA1c level is lowered fromthe time of diagnosis versus a 14.1% re-duction if HbA1c level is not lowereduntil 10 years after the diagnosis. A similar pattern is seen in patients

with MI. At year 15, there is a 21.6%risk reduction in MI if HbA1c is low-ered 1% starting from the time of diag-nosis, but the risk reduction was only13.5% if lowering HbA1c was delayeduntil 10 years after diagnosis. At year

20, the risk reductions for the earlierand the delayed HbA1c lowering were27.8% and 23.9%, respectively. Using a fitted model, the benefit

of early reduction of HbA1c and thelegacy effect were illustrated by theexample of a 50-year-old man with an8% HbA1c at the time his type 2 dia-betes was diagnosed. An immediate1% HbA1c reduction will give him a19% risk reduction in all-cause mor-tality when he is aged 60 to 70 years,whereas a delayed 1% HbA1c reduc-tion will give him only a 6.6% risk re-duction. An early HbA1c reductionprovides a 3-fold greater effect onmortality.“Achieving and maintaining optimal

glycemic control is essential to mini-mize the long-term risk of diabeticcomplications,” said Dr Lind. Waitingto reduce glycemia will not recapturethe full benefits of immediate interven-tion. These models confirm that an ear-lier reduction in HbA1c levels continuesto contribute to reducing the risk ofdiabetic complications.�

UKPDS Follow-Up: Early HbA1c Reductions... Continued from page 1

“Achieving and maintainingoptimal glycemic control isessential to minimize thelong-term risk of diabeticcomplications,” including MIand all-cause mortality.

—Marcus Lind, MD

Glycemic Control in Patients with Type 2 DiabetesSignificantly Lowers Cardiovascular Disease RiskBy Wayne Kuznar

Improved glycemic control in pa-tients with type 2 diabetes lowersthe risk of adverse cardiovascular

(CV) events, reported Katarina Eeg-Olofsson, MD, from the University ofGothenburg in Sweden at the 2012ADA annual meeting. In this study by Dr Eeg-Olofsson and

colleagues, patients who reduced theirmean hemoglobin (Hb) A1c levels byalmost 1%—from 7.8% to 7%—had asignificant 45% reduction in their riskof CV death.In this observational study, Dr Eeg-

Olofsson and colleagues evaluated theassociation between improved glycemiccontrol during follow-up and the risk for

coronary heart disease (CHD), CV dis-ease (CVD), or total mortality in 18,035patients with type 2 diabetes from theSwedish National Diabetes Register. At baseline, participants (aged 30-75

years) were free of CVD and had anHbA1c level of 7% to 8.9%. The mean du-ration of diabetes since diagnosis was 8to 10 years; the patients were followedfrom 2004 to 2009 (mean, 5.7 years).The patients were divided into 2

groups based on their median changein HbA1c levels during follow-up—one group included 8923 patientswhose HbA1c level had decreased by≥0.1% from baseline to follow-up, andthe second group included 9112 pa-tients whose HbA1c level remainedstable or increased.

HbA1c Levels and CVD-

Associated Mortality Risk

After adjusting for covariates, the ab-solute risk for a death event from a CVcause was 9.9 events per 1000 person-years in patients with decreasing HbA1clevels compared with 17.8 events per1000 person-years in patients with sta-ble or increasing HbA1c levels. Superior glycemic control was also

associated with a significant 39% re-duction in the risk for fatal and non-fatal CHD events, and a significant37% reduction in the risk for fatal ornonfatal CVD events. The absolute risk of a first fatal or

nonfatal CHD event was 10.3 per 1000person-years for those patients whoseHbA1c levels declined versus 17.9 per1000 person-years for those whoselevels remained stable or increased.The rates for a first CV event were15.1 per 1000 person-years and 26.1events per 1000 person-years in the 2groups, respectively.The study demonstrates that tar-

geting HbA1c level to 7% can help re-duce the excess CVD risk seen inpatients with diabetes, said Dr Eeg-Olofsson. �

Patients who reduced their mean hemoglobin A1c levels byalmost 1%—from 7.8% to 7%—had a significant 45%reduction in their risk of CV death. Superior glycemic controlwas also associated with a significant 39% reduction in therisk for fatal or nonfatal CHD events, and a significant 37%reduction in the risk for fatal or nonfatal CVD events.

triglycerides was 13%. Improvementin beta-cell function was observed atthe end of the study, as shown by a26% increase in the homeostasismodel assessment-B score and a 13%increase in the homeostasis model as-sessment-S score (which are measuresof beta-cell function). Of note, mild nausea decreased

over time with exenatide onceweekly, from 85 events per 100-yearpatient exposure during weeks 1 to

30, to 15 events for the study dura-tion. Mild nausea is the most com-mon adverse event associated withthis regimen. Among patients receiv-ing exenatide once weekly, 6 discon-tinued the drug because of GIadverse events, and 21 patients with-drew overall. Few minor hypoglycemia events

were observed, most with a sulfony-lurea, and no major hypoglycemiaevent was observed. �

Sustained Glycemic Control... Continued from page 6


Cardiovascular (CV) outcomeswere not improved with eitheromega-3 fatty acids or with in-

sulin glargine in a 6-year study of 12,537patients with dysglycemia and otherCV risk factors. The multinational Out-come Reduction with an Initial GlargineIntervention (ORIGIN) trial showedthat insulin glargine had no effect oncancer, and that it reduced the progres-sion from dysglycemia to diabetes.Hertzel C. Gerstein, MD, MSc, FRCPC,Professor, Department of Clinical Epi-demiology and Biostatistics, McMasterUniversity, Ontario, Canada, presentedthe CV results of the ORIGIN trial at the2012 ADA annual meeting. The ORIGIN trial included patients

(mean age, 63.5 years) with type 2 dia-betes who had impaired fasting glucose(IFG) or impaired glucose tolerance(IGT), as well as CV risk factors. Usinga 2 × 2 factorial design, the patientswere randomized to insulin glargine orto standard care (without insulin), andto omega-3 fatty acids or to placebo. All the patients had CV risk factors,

82% had a previous diagnosis of dia-betes (average duration, 5 years), and6% had diabetes detected at the timethey were randomized. IFG or IGT wasfound in 12% of patients. At baseline, 40% of the patients were

not taking any glucose-loweringdrugs, 27% were taking metformin,and 30% were taking a sulfonylurea.The median fasting plasma glucosewas 125 mg/dL, and the medianhemoglobin A1c was 6.4%. The study questions were (1) does

insulin replacement therapy targetingfasting normoglycemia (≤95 mg/dL)with insulin glargine produce a greaterreduction of CV outcomes than stan-dard approaches, and (2) does addingomega-3 fatty acids reduce CV death?

CV Outcomes with

Insulin Glargine

“Basal insulin glargine has a neutraleffect on CV events and cancers, andreduces the progression of diabetes,”said Dr Gerstein. No difference was seen between the

insulin glargine and the standard-caregroups in the composite end point ofmyocardial infarction (MI), stroke, orCV death (adjusted hazard ratio [HR],1.02), or in the composite end point ofMI, stroke, CV death, revascularization,or heart failure (adjusted HR, 1.04). Inaddition, no difference was seen for all-cause death (adjusted HR, 0.98). Among the 1456 people without

diabetes at baseline, the developmentof new-onset diabetes was reduced by28%. This finding was durable at 3months when these individuals hadanother oral glucose tolerance test.The risk for severe hypoglycemia was

0.7% higher in the insulin group (1%vs 0.3% annually with standard care).

Overall, the rates of hypoglycemia werelow. With insulin glargine, 57% of pa-tients had ≥1 episodes of any hypo-glycemic event versus 25% of patients inthe standard group. The rate for any hy-poglycemia in the insulin group was 17per 100 person-years versus 5 per 100person-years. Patients taking insulin glargine

gained a mean of 1.6 kg of body weightcompared with a 0.5-kg weight losswith standard care.

CV Outcomes with Omega-3

Fatty Acids

No difference was found betweenthe patients taking omega-3 fatty acids(1 tablet daily) and those taking aplacebo in terms of the primary endpoint of CV death (HR, 0.98). For thesecondary composite end point of MI,stroke, or CV death, the finding wasalso neutral (HR, 1.01). However, triglycerides were signifi-

cantly reduced with omega-3 fattyacids, by 23.5 mg/dL compared with 9mg/dL with placebo (P <.001), fromthe baseline value of 142 mg/dL inboth groups. The baseline values and reductions

in low-density lipoprotein cholesterolwere similar in both groups, with re-ductions of approximately 12 mg/dLfrom baseline values of 112 mg/dL ineach group. Baseline high-density lipo -protein cholesterol values were alsosimilar—46 mg/dL in both groups—with nominal reductions occurring. Omega-3 supplementation was well

tolerated, and adherence was high(88%), said Jackie Bosch, MSc, Associ-ate Professor, School of RehabilitationScience, McMaster University, whopresented the omega-3 results fromORIGIN.

“There was neither benefit nor harmin the participants who were studied,”Ms Bosch commented. “However, theeffect of this treatment in other groups,and the effect of a diet rich in omega-3fatty acids, were not studied.”

Implications of the ORIGIN Trial

“People have been debating thequestion of whether there are adverseconsequences to long-term insulin usefor years,” Dr Gerstein said. “Thisstudy provides the clearest answer yetto that question: no, there are not.” He noted that insulin glargine is the

best studied of all glucose-loweringdrugs with respect to long-term CVoutcomes. Furthermore, “This is the longest

and most extensively conducted studyof the effect of insulin versus no insulinon cancers,” Dr Gerstein added, and itshowed that insulin glargine had no ef-fect on cancer (HR, 1.0). “There is noevidence whatsoever of an effect of thedrug on cancer or cancer death.” Coinvestigator Lars Rydén, MD,

PhD, Professor Emeritus, CardiologyUnit, Department of Medicine, Karo -linska Institutet, Sweden, said that

there are many people with coronaryartery disease or CV disease who ac-tually have disturbed glucose metab-olism. “Some of them walk aroundwith hidden diabetes. For a cardiolo-

gist, it is much more difficult to useinsulin than for an expert endo -crinologist. So for me, it is reassuringthat this type of insulin is safe to use,easy to use, does not cause my patienta lot of hypoglycemia, and does notcarry any risk of treatment-relatedcancer.” �


ORIGIN: Insulin Glargine and Omega-3 Do Not ImproveCardiovascular Outcomes in Patients with Type 2 DiabetesBut omega-3 fatty acids significantly reduce triglyceride levelsBy Mary Mosley

“Basal insulin glargine has aneutral effect on CV eventsand cancers, and reducesthe progression of diabetes.”

—Hertzel C. Gerstein, MD, MSc,FRCPC

“There was neither benefitnor harm [with omega-3 fattyacids] in the participants whowere studied. However, theeffect of this treatment inother groups, and the effectof a diet rich in omega-3fatty acids, were notstudied.”

—Jackie Bosch, MSc

Chronic kidney disease (CKD)is significantly underdiag-nosed in the population of pa-

tients with type 2 diabetes, sayinvestigators from a multisite, obser-vational, cross-sectional study con-ducted by the National KidneyFoundation, which was presentedby lead investigator Lynda Szczech,MD, President of the National KidneyFoundation, New York City, at the2012 ADA annual meeting.Dr Szczech and colleagues as-

sessed the prevalence and the propor-tion of patients with CKD and type 2diabetes who were treated within theprimary care setting. The study,

which was conducted at 466 primarycare provider sites and included 9307patients, used a clinician survey, a pa-tient physical examination and med-ical history, a single patient blooddraw to measure estimated glomeru-lar filtration rate (eGFR) and hemo-globin A1c, a urine dipstick to assessprotein, an albumin-creatinine ratio, 2patient quality-of-life questionnaires,and a 15-month patient medicalrecord review.

Early Stages of CKD

Not Recognized

Of the 9307 patients, 5036 (54.1%)had stage 1 to stage 5 CKD, based on

Primary Care PhysiciansUnderdiagnose Chronic Kidney Disease in DiabeticPatientsEarly diagnosis can reduce cardiovascular eventsBy Wayne Kuznar

Continued on page 9



The prevalence of both type 1 andtype 2 diabetes has increasedsubstantially among American

youth over the past decade, and, withthis rise, the rates of diabetes compli-cations have increased. This topic wasdiscussed in a session on pediatric obe-sity at the 2012 ADA annual meeting.The SEARCH for Diabetes in Youth

study is a project undertaken by theCenters for Disease Control and Pre-vention and the National Institutes ofHealth to explore the burden of thisdisease among young Americans. Thestudy is documenting the number ofchildren and youth under age 20years who are diagnosed with dia-betes in 5 geographically dispersedpopulations in the United States, re-ported Dana Dabelea, MD, PhD, As-sociate Professor, Department ofEpidemiology, University of Col-orado, Denver. Preliminary findings were presented

at the meeting. From 2001 to 2009, theprevalence of type 2 diabetes amongthe young (age <20 years) increased by21%, from 2.9 per 10,000 persons to 3.6per 10,000 persons; during the sameperiod, the prevalence of type 1 dia-betes increased by 23%, from 1.7 per

1000 persons to 2.1 per 1000 persons,reported Dr Dabelea.In 2009, the estimated number of

young Americans under age 20 yearswho had diabetes was approximately189,000; of those, approximately 168,000young patients had type 1 diabetes,and 19,373 young patients had type 2diabetes.Only 2% of the cases of type 2 dia-

betes occurred in youth aged <10years; however, the prevalence is risingrapidly among young Americans, withincreasing age.Although blacks and American In-

dians still have the highest prevalenceof type 2 diabetes in all age-groups,the increase in the prevalence of type2 diabetes in American youth waslargest among non-Hispanic whitesand Hispanics.

The Pediatric Obesity Epidemic

The surge in type 2 diabetes amongyoung Americans is believed to be theresult of the obesity epidemic in thatage-group, as well as “fetal overnutri-tion,” in which the developing fetus isexposed to maternal obesity and gesta-tional diabetes associated with preg-nancy, said Dr Dabelea. The risk for

type 2 diabetes in early life strongly in-creases with being exposed to maternaldiabetes or obesity while in the womb.

“The vicious cycle of obesity createsa transgenerational problem,” DrDabelea said, “as the offspring ofwomen who are obese or who havetype 2 diabetes during pregnancy are

more likely to develop diabetes earlyin life.”

Long-Term Implication

The consequences of the increase indiabetes prevalence among Americanyouth include signs of early diabetescomplications, even after a relativelyshort duration of the disease. Thesecomplications include: • Neuropathy, which may be relatedto complications of heart diseaselater in life; “almost 12% of youthwith type 1 diabetes and 26% withtype 2 show signs and symptoms ofneuropathy,” said Dr Dabelea, and“glucose control correlates stronglywith these symptoms”

• In addition, albuminuria is presentin 22% of the young patients withtype 2 diabetes and 9% of those withtype 1 diabetes

• Furthermore, young patients withtype 2 diabetes are likely to have pro-teinuria, which may predispose themto kidney disease later in life. “All of these data provide evidence

that diabetes in youth is not benign,”Dr Dabelea said, noting that more dataare needed on this disease amongyoung Americans. �

Diabetes Rates Surging Among American YouthLinked to the pediatric obesity epidemic By Wayne Kuznar

“The viciouscycle of obesitycreates atransgenerationalproblem, as the

offspring of women who areobese or who have type 2diabetes during pregnancyare more likely to developdiabetes early in life….All ofthese data provide evidencethat diabetes in youth is not benign.”

—Dana Dabelea, MD, PhD

eGFR and albuminuria; however,only 607 (12.1%) of the patients withCKD had been identified by theirphysicians as having the disease. Cli-nicians were more successful in diag-nosing more advanced CKD—stages3 to 5—than stages 1 and 2.

Of the 445 clinicians who enrolledat least 10 patients, 14.3% had a 50%or better likelihood of identifying pa-tients with CKD, and 48.8% had alikelihood of less than 50%. Almosthalf (47.0%) of the physicians did not

identify any of their patients as hav-ing CKD. No differences were noted in the

clinicians’ likelihood of identifyingCKD based on practice setting, num-ber of years in practice, or number ofpatients seen weekly.“More than 26 million Americans

already have chronic kidney disease,which represents about 10% to 15%of the US population. Millions moreare at risk due to diabetes,” said DrSzczech, stating that diabetes is theleading cause of kidney disease. Shenoted, “Early detection and treat-ment of kidney disease in patientswith diabetes can help slow progres-sion, reduce cardiovascular events,and delay time to kidney failure.”CKD management guidelines are

relatively new compared with guide-lines for the management of diabetesor hypertension, and unfamiliaritywith the guidelines regarding CKDmay be a barrier in physicians recog-nizing the disease, she added.The data set from this study will be

undergoing further analysis. The re-

search will lead to further longitudi-nal studies to demonstrate that earlyrecognition and treatment of CKD inpeople with diabetes will improvelong-term health outcomes, includ-ing cardiovascular outcomes, DrSzczech pointed out.

A Call to Action

The hope is that the study will be aclarion call to improve recognition ofearly-stage CKD so that appropriatepreventive measures can be adoptedas routine clinical practice, said

Chester Fox, MD, Professor of FamilyMedicine, State University of NewYork at Buffalo, and a member of thestudy’s steering committee. These measures include using spe-

cific diabetes drugs in individualswith renal impairment, avoiding theuse of nonsteroidal anti-inflamma-tory drugs, and using renoprotectivemedications such as angiotensin-con-verting enzyme inhibitors and an-giotensin receptor blockers. �

“More than 26 millionAmericans already havechronic kidney disease,which represents about 10%to 15% of the US population.Millions more are at risk dueto diabetes.”

—Lynda Szczech, MD

“Early detection andtreatment of kidney diseasein patients with diabetes canhelp slow progression,reduce cardiovascularevents, and delay time tokidney failure.”

—Lynda Szczech, MD

Primary Care Physicians Underdiagnose... Continued from page 8

For more information

visitwww.AHDBonline.com


Health Economics

The Diabetes Epidemic Is Like a Tsunami... Continued from page 1

with 53.1 million of them from theUnited States.Tsunamis generally consist of a se-

ries of waves that arrive in a so-calledwave train, Ms Spollett said.

The Obesity Wave

The first wave in the diabetes epi-demic is an increasing incidence of obe-sity. Worldwide, 2.8 million people dieannually as a result of being overweightor obese. Between 1980 and 2008, theworldwide prevalence of obesity nearlydoubled, Ms Spollett noted.As with a natural tsunami, expect

significant financial distress and de-struction with the surge in diabetes,Ms Spollett pointed out. The impact ofdiabetes will be felt at the state andfederal levels in the form of higherhealthcare costs, and, as the costs forinsurance increase, it will be felt at thesmall business level as well. Diabetes will also place an increased

burden on the primary care health sys-tem and will diminish the availabilityof specialty services. The most dire ofthese predictions asserts that annualmedical and societal costs will increaseby 72%, to a total of $514 billion.

The Hyperglycemic Wave

The second wave of the diabetestsunami is the alarming increase in therate of hyperglycemia.

A 3-Step Process to

Survive a Tsunami

Surviving a tsunami is a 3-stepprocess. The first step is to warn thepublic by sounding an alarm. Dia-betes educators must “heighten ournation’s sense of urgency for thegrowing diabetes epidemic,” Ms Spol-lett said, by convincing the public thatit must take diabetes very seriously,because the disease is potentiallydeadly. Diabetes kills more Americansannually than breast cancer and AIDScombined, she said.The second step in survival is for cli-

nicians and educators to help reducethe impact of diabetes by promotingincreased allocation of resources forresearch into the pre vention, care, andcure of diabetes.The third step in surviving a tsunami

is “taking” to higher ground. “Majorchange is usually driven from the bot-tom up, by an informed and assertivepublic,” she explained.“My dream is that in understand-

ing and responding to the crisis of di-abetes, a national diabetes preventionplan will be seen as important, withthe help of all of our citizens, and thatthe work we have done becomes abeacon for the broader future of

healthcare,” said Ms Spollett.A national diabetes prevention plan

would include building communityawareness of diabetes, improving nu-trition from farm to table, and fostering

activities to prevent an increase in dia-betes (ie, supporting physical educa-tion, bike paths/exercise courses, andpublic transportation), Ms Spollettsaid, and would offer financial reim-bursement for counseling and educa-tion for those at risk.

ADA’s Response to

Hurricane Katrina

In a separate address, Vivian Fon-

seca, MD, ADA’s President of Medi-cine & Science and Chief of the Sec-tion of Endocrinology at TulaneUniversity School of Medicine, NewOrleans, LA, noted that the ADA wasunprepared for the devastation thatHurricane Katrina brought to NewOrleans and to the surrounding GulfCoast in 2005.“There were no physicians, no

nurses, and no pharmacists availableafter the hurricane,” said Dr Fonseca.“This had an immediate effect on thelives of people with diabetes.”Interruptions of care meant that

hemoglobin (Hb) A1c levels went un-controlled, and the interruptions af-fected those with private insurance aswell as those with public coverage orno insurance. Some of the uninsuredwent without diabetes care for as longas 2 years.Most healthcare facilities in New

Orleans, including research facilities,were destroyed by Hurricane Katrina.The ADA responded with emergencygrants to locate patients who had toabandon the city after the storm, saidDr Fonseca.The ADA also created a task force

that developed first responders’ bestpractices, which include diabetes care.Disaster preparedness is now part of theADA’s standard of care.A strategic plan by the ADA de-

mands new research priorities andtransformational approaches to treat-ment. A new series of grants shifts thefocus away from specific compounds toindividual investigators, in the hopes ofencouraging more risk taking in re-search, he said.

Discovery of a Third Type

of Adipose Tissue

After Dr Fonseca’s address, BruceSpiegelman, PhD, Professor of Cell Bi-ology, Harvard Medical School, Boston,

chronicled the discovery of irisin, a keyregulatory hormone in glucose metab-olism, and beige fat cells, a third typeof adipose tissue in addition to brownfat and white fat.Beige fat, which can burn off calories

unlike white fat, is genetically distinctfrom brown fat, which is found in smallmammals and human infants, affordingthem protection from the cold. Highlevels of the adipose tissue regulatorPRDM 16 (PR domain containing 16)can turn white fat into beige fat. Genet-ically manipulated mice that createmore brown or beige fat have increasedglucose tolerance and antiobesity ac-tions, explained Dr Spiegelman. “Beige fat can improve the meta-

bolic health of an animal,” he said. “Inhuman beings, this same browning islinked with exercise.”Exercise induces an improvement

in glucose metabolism. Recent studiesshow that peroxisome proliferator-activated receptor γ coactivator-1α�(PGC-1α), a regulator of mitochon -drial biogenesis that is upregulated byvigorous exercise, plays an importantrole in converting white fat intobrown fat. In tissue culture, PGC-1α�stimulates glucose uptake and angio-genesis, thus mimicking the beneficialeffects of exercise.Exercise is thought to produce the se-

cretion of irisin, a molecule that in-creases the amount of beige fat. In obesehumans, the expression of circulatinglevels of irisin increases by 40% to 60%after 4 weeks of exercise training. “Irisin causes a browning reaction to

protect against metabolic disease,” saidDr Spiegelman. Although irisin is amolecule at the proof-of-concept stagethat is not appropriate for use in humanbeings, the hope is that an understand-ing of its actions can lead to the de -velopment of a new generation oftherapeutics, he noted. �

“My dream is that inunderstanding andresponding to the crisis ofdiabetes, a national diabetesprevention plan will be seenas important, with the help ofall of our citizens, and thatthe work we have donebecomes a beacon for thebroader future of healthcare.”

—Geralyn R. Spollett, MSN, ANP-CS, CDE

Curtailing the progression of es-tablished chronic kidney dis-ease (CKD) could contribute

to controlling its costs. New datashow a 2-fold increase in medicalcosts in patients whose CKD pro-gresses to a higher stage. An esti-mated 12% of patients with type 2

diabetes progress to CKD, and ap-proximately 40% have some form ofdiabetic nephropathy. These new data, which were pre-

sented by Suma Vupputuri, PhD,Kaiser Permanente Center for HealthResearch, GA, at the 2012 ADA meet-ing, come from patients with type 2

diabetes and CKD in a real-worldmanaged care setting, and reveal con-siderable worsening of CKD over time. In this retrospective, observational,

cohort study of patients in the KaiserPermanente Northwest and Georgiahealth systems, 12% of 21,018 patients

Medical Costs Increase as ChronicKidney Disease WorsensManaged care analysis highlights disease burden on US healthcareBy Mary Mosley


in stages 0 to 2 CKD progressed to ahigher stage, with 327 patients reach-ing stage 4 and 76 reaching end-stagerenal disease (ESRD). Approximately27% of the 3885 patients in stage 3CKD progressed, with 930 patientsreaching stage 4 CKD and 217 reach-ing ESRD. Progression to ESRD wasfound in 30% of the 683 patients instage 4 CKD.

The incidence of CKD progressionfrom one stage to a higher stage, per1000 person-years, was 26 in stages 0to 2, 74 in stage 3, and 78 in stage 4. Therates were adjusted for age, sex, andduration of diabetes. The costs for CKD and diabetes are

increasing rapidly. The current annualexpenditure for CKD and diabetes isapproximately $18 billion, which isapproximately 11 times higher thanin 1993. Approximately 26% of theMedicare expenditure for diabetes isfor patients (aged ≥65 years) whohave CKD and diabetes, according tothe US Renal Data System. The baseline pharmacy, outpatient,

and inpatient costs, by CKD stage,were $6551 for stages 0 to 1, $8206for stage 2, $12,529 for stage 3, and$23,229 for stage 4. In each CKD stage,the outpatient nonpharmacy cost waspredominant, at approximately 60%in stages 0 to 1 and 40% to 43% inthe other stages. Pharmacy costs ac-counted for approximately 21% to24% of the total costs, except in stage4 CKD, for which it was 15%. A nearly 2-fold increase for inpa-

tient costs occurred when CKD pro-gressed from stage 3 to stage 4. Costswere annualized and standardized to2010 dollars.Even when adjusted for demo-

graphics and clinical characteristics,disease progression was associatedwith significantly greater costs in eachstage, stated Dr Vupputuri. Medicalcosts were 2 times higher in the pa-tients with stage 2 CKD who pro-gressed to a higher stage, 3 timeshigher for stage 3 CKD, and 4 timeshigher in patients who had ESRD atbaseline. Compared with the patientswho did not progress to CKD, the costs

were $16,642 for stages 0 to 2 CKD,$34,698 for stage 3, and $57,509 forstage 4. The study population of 25,586 pa-

tients, with a mean age of 60 years, hada 5.1-year duration of diabetes, and

51% were men. Men and blacks wereless likely to be in the more severestages of CKD, noted Dr Vupputuri.Age progressively increased across theCKD stages, from 53 years in stage 1 to71 years in stage 4. Comorbidities also

increased with higher CKD stages. The medical costs of only the pa-

tients whose CKD worsened showedthat their costs doubled, from $12,937before progression to $23,233 afterCKD progression. �


Health Economics

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Medical Costs Increase as Chronic Kidney Disease... Continued from page 10

Approximately 26% of theMedicare expenditure fordiabetes is for patients whohave CKD and diabetes,according to the US RenalData System.


Health Economics

and Prevention, Atlanta, GA, who pre-sented results of the first study docu-menting the US cost trend for diabetesat the 2012 ADA annual meeting.Dr Zhuo noted the changing face of

diabetes in his presentation—morecases of diabetes are being diagnosedat younger ages, and in more minoritypatients, and patients are living longerwith diabetes. There has also beenprogress in diabetes management, in-cluding new medications and im-proved glucose measurement andself-management.Dr Zhuo and colleagues analyzed

medical expenditures and healthcareutilization for diabetes for 3 periods—1987, 1997-1998, and 2007-2008—usingcost data from the National MedicalExpenditure Survey and Medical Ex-penditure Panel Survey. Dr Zhuo and colleagues adjusted

the data for sex, race, ethnicity, age, ed-ucation, income, marital status, andgeographic region, as well as for healthinsurance coverage and major healthconditions other than diabetes. Overall, the analysis showed an ex-

cess annual expenditure and health-care utilization for patients withdiabetes compared with those withoutthe disease. All expenditures were ad-justed to 2008 dollars. An average of $3050 more was spent

on medical care by a typical patientwith diabetes than a patient without

diabetes in 1987 (Table). This gap incost increased to $4560 during 1997-1998 and to $4670 during 2007-2008,noted Dr Zhuo.

Although inpatient costs increased inabsolute terms from 1987 to 2007-2008,the proportion of the total inpatient costs

decreased from 52% in 1987 to 30% in2007-2008. A modest decline was seen inthe proportion of outpatient costs, from24% in 1987 to 16% in 2007-2008.Of note, there was a substantial in-

crease in the costs for prescriptionmedications, stated Dr Zhuo, resultingin a greater proportion of costs for pre-scription drugs, from 15% in 1987 to31% in 1997-1998 and to 46% in 2007-2008. (The average cost for prescriptiondrugs was approximately $2100 in2007-2008 compared with approxi-mately $474 in 1987.)

Annual Healthcare Utilization

Patients with diabetes had 3 morephysician office visits in 1987 and 3.9more than patients without diabetes.Despite a slight dip to a 3.4-visit gap in2007-2008, this number was still in-creased compared with in 1987. In line with the increase in spending

for prescription medications, the num-bers of additional prescription medi -cations purchased also significantlyincreased, from 7.5 per person in 1987to 16.5 per person in 1997-1998 and to

20.2 in 2007-2008. There were significantly fewer hos-

pital admissions for diabetes in 2007-2008 compared with in 1987.

CVD Adds Significant Cost

to Diabetes

The combination of cardiovasculardisease (CVD) and diabetes progres-sively increased costs compared withcosts for patients without diabetes.The excess medical expenditure forCVD plus diabetes was $6000 in 1987,$8000 in 1997-1998, and $9000 in 2007-2008. By contrast, the cost increase forpatients with CVD only was muchsmaller—from $2000 in 1987 to $3000in 2007-2008. Among patients with diabetes, the

annual medical cost increased by 13%for patients with macrovascular compli-cations compared with a 29% decreasein patients without macrovascular com-plications, according to Dr Zhuo.Dr Zhuo noted that the expenditures

do not represent actual resource costs,and that nursing home and long-termcare were not included. �

Among patients withdiabetes, annual medicalcost increased by 13% forpatients with macrovascularcomplications compared witha 29% decrease in patientswithout macrovascularcomplications.

Table Medical Costs for Patients with and without Diabetes

Cost1987, $

1997-1998, $

2007-2008, $

Patients with diabetes 8864 10,726 11,091

Patients without diabetes 5814 6166 6421

Medical Spending for Diabetes, 1987-2008... Continued from page 1

Value-based insurance design(VBID) that reduces patient co-payments to encourage the use

of high-value therapies is cost-effec-tive, because the cost of the additionaluse of high-value drugs encouragedby such a design may be offset by a re-duction in the use of nondrug healthser vices, said Allison B. Rosen, MD,MPH, ScD, Associate Professor, De-partment of Quantitative Health Sci-ences, University of MassachusettsMedical School, Worcester, at the 2012ADA annual meeting.

Provide Incentives to Encourage

Use of High-Value Therapies

The silo-based approach to cost ver-sus quality trade-offs defies commonsense, said Dr Rosen. Increasing out-

of-pocket costs to consumers createsincentives for them to curb healthcareuse, and at the same time the pay-for-performance approach creates incen-tives for providers to improve qualityof care. These incentives can be con-flicting in cases in which consumersare asked to pay an increasing share ofthe cost of a therapy with proven ben-efits, such as beta-blockers for somepatients with heart disease. If patients were discerning users of

healthcare, they would curb the useonly of low-value therapies. Unfortu-nately, Dr Rosen argues, cost-sharingreduces excess use as well as essentialmedication use alike. As such, in-creased cost-sharing may lead to ad-verse health outcomes. “For some chronic diseases, copay-

related underuse actually results inhigher cost of care,” said Dr Rosen.

“Value-based insurance design hasbeen proposed to realign incentives forvalue,” she added.

When applying a value-based bene-fit design strategy, drugs associatedwith greater benefit would have alower copay rather than a copay that isbased on acquisition cost.Value is the amount of health gained

per dollar spent on healthcare services,Dr Rosen suggested. VBID reduces thecopay for specific services or specificpatients, “or some combination of the2,” she said.In the case of beta-blockers, for ex-

ample, the clinical benefit is highestfor patients with diabetes who havehad 4-vessel coronary artery bypassgraft surgery.

Socioeconomic Status Affects VBID

One of the earliest controlled studiesof VBID was conducted at a large non-

Value-Based Benefit Design: Reducing Copayment forHigh-Value Services Maximizes Return on InvestmentTherapies with proven benefit should have low or no cost-sharing By Wayne Kuznar

“For some chronic diseases,copay-related underuseactually results in higher costof care. Value-basedinsurance design has beenproposed to realignincentives for value.” —Allison B. Rosen, MD, MPH, ScD


—Xiaohui Zhuo, PhD


Health Economics

Financial incentives to patients areincreasingly being used, and theycan be effective in driving better

health behaviors, but their design iscrucial to their success in motivatingchange, said Kevin G.M. Volpp, MD,PhD, Director of the Center for HealthIncentives at the University of Penn-sylvania, Philadelphia, during the 2012ADA annual meeting.The use of incentives by large em-

ployers to improve health has in-creased from slightly more than 30% oflarge employers in 2009 to approxi-mately 70% in 2012. But the design ofthe reward programs is important, saidDr Volpp.“Rewards once a year ignore my-

opia,” he said, citing one employer’soffer to rebate $150 to employees whojoin and regularly use a fitness center.Such one-time incentives, especially ifthey occur at the end of a calendaryear, may not prompt long-termchange, because people tend to focuson the present. In addition, an incen-tive in the form of a discounted em-ployee insurance premium will not beas effective in changing behavior as adirect payment. These lessons are gleaned from stud-

ies of behavioral economics, in whichimmediacy is important. The impacttends to be greater with immediate re-wards, he said. The use of frequent,small rewards tends to work betterthan single awards to promote positivebehavior. The amount of the reward isnot as critical as immediacy either.As an example, he used his own

randomized, controlled study inwhich “long-term smoking-cessationrates tripled in the incentive group.”The study followed 878 General Elec-tric employees from 85 worksites.

Half of the employees were offered$100 to complete a community-basedsmoking-cessation program, another$250 if they refrained from smoking

for 6 months after finishing the pro-gram, and $400 more if they remainedsmoke-free for an additional 6months. The other half was asked toenroll in a smoking-cessation pro-gram without incentives.Enrollment in the smoking-cessation

program was more than double in thegroup that was offered incentives. Fur-thermore, smoking cessation rates at 12months were 14.7% in the incentivegroup and 5% in the controls. At the lastfollow-up (at 15-18 months), 9.4% in theincentive group remained smoke-freecompared with 3.6% of the controls.

Playing the Lottery

Other types of incentive programshave been examined for their effec-tiveness in promoting behaviorchange, and lottery systems appear tobe a winner, said Dr Volpp. A studythat he coauthored showed that aDutch lottery system added to a well-ness program motivated individualsto complete health risk assessment(HRA) questionnaires.

In this study, 3 types of incentiveswere compared. The first was a $25cash award to an employee for com-pleting an HRA, the second was a $25

cash award combined with a $25 gro-cery gift card, and the third was assign-ment to workforce groups of 4 to 8members with a chance to win prizes(a Dutch lottery). Among those in theDutch lottery, 1 group was chosen ran-domly each week. Each member of thechosen group who had completed anHRA received $100. The groups inwhich at least 80% of the members hadcompleted HRAs had their cash prizesincreased to $125. The study was conducted among 1299

employees from 14 offices of a healthcaremanagement company. Some 64% ofthe employees in the lottery groupscompleted HRAs compared with 42% inthe $50 cash or grocery gift card groupand 40% in the $25 cash–only group.Similar success was achieved with

enhancing compliance to warfarin,using a lottery in which patients couldwin money daily if they had takentheir warfarin the previous day.Because humans discount the future,

they are not as motivated by far-off re-wards, said Dr Volpp. This concept was

illustrated in a study of weight-lossprograms. The patients who were ran-domly assigned to a deposit contract inwhich they had to put up their ownmoney, which was matched by re-searchers monthly if they met theirweight-loss goal, lost an average of14.0 lb during the study. Those whowere assigned to a lottery lost 13.1 lb,and those assigned to a control grouplost only 3.9 lb.Loss aversion was a powerful incen-

tive for those in the deposit group, be-cause they stood to lose money, DrVolpp pointed out.

Peer Mentoring Works Well

Peer mentorship worked well to im-prove glucose control, more so than fi-nancial incentive or usual care. Over6 months, patients assigned to speakwith a peer mentor at least weekly hada mean hemoglobin A1c level declineof >1% from baseline to 6 months com-pared with a 0.46% decline in the fi-nancial-incentive group and 0.01% inthe usual-care group.Because Americans spend only 1 to

2 hours annually with their physicians,monitoring their behaviors beyond theexamination room may be key to theirengagement in healthy behaviors. Automated hovering is the principle

of using wireless or electronic tech-nologies to engage patients while theyare away from a healthcare setting, of-fering constant reinforcement. In thestudy of warfarin mentioned above,electronic pill boxes were used to au-tomatically enter patients into a lotteryeach time they took their warfarin. Theuse of the electronic pill dispenser in-creased the time spent in the therapeu-tic range and decreased the number ofincorrect doses. �

Paying Patients to Change Their Health Behavior Is EffectiveLong-term change requires carefully planned immediate incentives By Wayne Kuznar

The use of incentives by large employersto improve health has increased fromslightly more than 30% of largeemployers in 2009 to approximately 70%in 2012; but the reward program designis important: “Rewards once a yearignore myopia.” —Kevin G.M. Volpp, MD, PhD

profit employer with more than 60,000employees and dependents. In thatprogram, patients with diabetes hadcopays reduced for angiotensin-con-verting enzyme (ACE) inhibitors orangiotensin receptor blockers (ARBs),other antihypertensive agents, glucose-control agents, statins, and other lipid-lowering agents. The largest reduction in copay was

for the use of tier 1 (ie, generic) drugs,when possible, for which the entirecopay was waived. Copays were re-duced by 50% for tier 2 (preferredbrand-name) drugs, and by 25% for tier3 (nonpreferred brand-name) drugs.

The institution of VBID increased theuptake of medications in all classescompared with the control group. Theuptake of metformin increased by >4%,ACE inhibitors and ARBs by >8%, andstatins by approximately 9%.During 18 months, pharmacy spend -

ing increased by $28 per member perquarter in the intervention group com-pared with the controls, but nonphar-macy spending decreased by $14 permember per quarter in the interven-tion group versus the controls. Over-all, the intervention was only slightlymore costly over the 18-month period,said Dr Rosen.

There was a differential impact of theVBID by income, Dr Rosen pointedout. The uptake of glycemic agents andantihypertensive drugs in the interven-tion group was greater in those patientswith a socioeconomic status lower thanthe median compared with those witha socioeconomic status above themedian, she said. Those in the intervention group with

incomes below the mean had signifi-cantly greater uptake of metformin,ACE inhibitors or ARBs, and selectiveserotonin reuptake inhibitors com-pared with patients in the interventiongroup with incomes above the mean.

Value-based interventions “may bea useful adjunct to efforts aimed at in-creasing patient initiation of and ad-herence to high-value medications andpossibly an avenue for addressing dis-parities,” Dr Rosen noted.The data show that the incremental

costs of increased use of high-valueservices can be subsidized by medicalcost offsets and higher cost-sharingfor services of lower value. In addi-tion, the financial impact of stand-alone VBIDs—those that focus onremoving barriers to evidence-basedcare services for chronic conditions—are cost-neutral. �

Value-Based Benefit Design: Reducing Copayment for... Continued from page 12


Health Economics

Real-time continuous glucosemonitoring improved glycemiccontrol compared with self-

monitoring of blood glucose at 1 year ina recent clinical trial; real-time continu-ous glucose monitoring was cost-effec-tive for providing modest increases inlife expectancy and improved qualityof life based on 2 statistical models.Coinvestigator Stephanie J. Fonda,PhD, Walter Reed National MilitaryMedical Center, Bethesda, MD, pre-sented the data at the 2012 ADA an-nual meeting. “We used the data from a study we

completed that showed a sustained re-duction of 1.1% in hemoglobin A1cwithreal-time continuous glucose monitor-ing at 1 year compared to a smaller (ie,0.5%) reduction with self-monitoring ofblood glucose to develop 2 differentmodels to project cost-effectiveness, costof complications, and quality of life,”explained Dr Fonda. In the recently published study

(Vigersky RA, et al. Diabetes Care. 2012;35:32-38) of patients with type 2 dia-betes, 50 patients wore a continuousloop monitor for the real-time contin-uous glucose monitoring and 50 pa-tients performed self-monitoring ofblood glucose during the 3-month in-tervention period. All patients werethen followed until week 52.The volunteer participants are repre-

sentative of the motivated populationof patients with type 2 diabetes. The

volunteers were typically middle-aged(mean age, 57.8 years), overweight orobese (mean body mass index, 32kg/m2), and mostly men (60%), andthey had poorly controlled type 2 dia-betes (mean baseline hemoglobin [Hb]A1c , 8.3%). Approximately 35% to 40%

of participants were black, reflectingthe population in the military medicalcenter. Most of the patients were takingan oral antidiabetic drug, insulin, orboth, and the duration of their diabeteswas approximately 9 years.

The 2 Analyses

The base-case analysis determinedthe costs at 5 years for using the inter-vention exactly as it was used in theclinical trial. The scenario analysislooked at the 5-year costs for adding asecond “dose” of real-time continuousglucose monitoring in year 2 as a re-fresher for the participant. Assump-tions included the convergence ofHbA1c within 21 months of the inter-vention and that patients would betaking insulin by year 5. The validatedIMS CORE Diabetes model was usedto predict economic outcomes and es-timated health outcomes in terms ofquality-adjusted life-years (QALYs). The researchers used a US payer

perspective to calculate costs and in-cluded only direct costs obtained frompublished sources that were inflated to2011 US dollars. In the base-case analysis, an incre-

mental increased cost of $250 versusself-monitoring of blood glucose wasassociated with a 1.03-month increasein life expectancy and a 0.8-month im-provement of QALY with real-timecontinuous glucose monitoring.

Incremental Cost Reductions in

Treating Complications

The incremental cost-effectivenessratio (ICER) was $2903 for each life-year gained and $3735 for each QALYgained. The following reductions wereseen with real-time continuous glucose

monitoring in the cost of treating dia-betes complications: • –$177 for cardiovascular diseases• –$141 for renal disease• –$212 for diabetic foot complications.In the scenario analysis, a greater in-

crease was found in life expectancy—2 additional quality-adjusted life-months—than in the base-case analy-sis. The incremental cost was $1217 for2 episodes of real-time continuous glu-cose monitoring (1 each in year 1 andyear 2) more than self-monitoring ofblood glucose, and the ICER was$10,071 per QALY. Dr Fonda noted that the cost of the

interventions is low, which contributesto the cost-efficacy, and that behavioralinterventions are known to have amodest impact when used withoutfeedback from the clinician. A big im-provement in glycemic control overthe intervention period is being seen,she pointed out. But the refresher dose of real-time

continuous glucose monitoring isneeded, because patients begin toregress after approximately a year. Fur-thermore, feedback from the clinicianto enable patients to see the relation-ships between their eating and exercisehabits and their HbA1c levels wouldlikely give greater benefits, she said. The real-time continuous glucose

monitoring could be used for only 2weeks, because the response is seen inthis time frame. �

“We used the data from astudy we completed thatshowed a sustainedreduction of 1.1% inhemoglobin A1c with real-time continuous glucosemonitoring at 1 yearcompared to a smaller, 0.5% reduction with self-monitoring of blood glucoseto develop 2 different modelsto project cost-effectiveness,cost of complications, andquality of life.”

—Stephanie J. Fonda, PhD

Real-Time Continuous Glucose Monitoring Cost-Effectivein Patients with Type 2 DiabetesBy Mary Mosley

Incretin Therapies

In a recent head-to-head compari-son, glycemic control was betterwith the glucagon-like peptide-1

(GLP-1) exenatide twice daily thanwith the sulfonylurea glimepirideonce daily in patients with type 2 di-abetes who are inadequately con-trolled with metformin, said GuntramSchernthaner, MD, Head of the De-partment of Medicine, RudolfstiftungHospital, Vienna, Austria, at the 2012ADA annual meeting. Dr Schern-thaner reported the results of the

European Exenatide trial known asEUREXA, which was simultaneouslypublished in the Lancet (Gallwitz B, etal. Lancet. 2012;379:2270-2278).

Comparing Sulfonylurea and GLP-1

A sulfonylurea is a common choiceas second-line therapy after metforminfailure in many countries in patientswith type 2 diabetes, because sulfony-lureas are inexpensive and have arapid effect, Dr Schernthaner noted.Glycemic control subsequently deteri-

orates with a sulfonylurea, however,because its effect is not glucose-depen-dent, and the risk for hypo glycemiamay limit the dosage of the sulfony-lurea used in clinical practice, he said.The EUREXA trial was conducted

at 128 centers in 14 European coun-tries and included 1029 adults withtype 2 diabetes who were overweightor obese and whose hemoglobin (Hb)A1c level was between 6.5% and 9.0%,despite stable and maximally toler-ated doses of metformin.

The study tested the following 2hypotheses: (1) that exenatide is non-inferior to glimepiride on time totreatment failure, and (2) if nonin -feriority is demonstrated, exenatidewould prove superior to glimepiride.Treatment failure was defined as

treatment with the maximally toler-ated dose of antidiabetic agents and 1of 2 situations—the HbA1c level re-mains above 7% at 2 consecutive of-fice visits 3 months apart, or theHbA1c level is more than 9% at any

Head-to-Head Comparison: Exenatide Outperforms Glimepiridein Controlling Glycemic Levels after Failing Metformin TherapyBy Mark Knight

See also Cardiometabolic Implications



Incretin Therapies

Researchers analyzing trial datafor 2 oral dipeptidyl peptidase(DPP)-4 inhibitors—sitagliptin

and saxagliptin—have found themboth to provide effective glycemiccontrol in elderly patients with type 2diabetes.Controlling hypoglycemia is of

great concern in this population, be-cause of potential accidents or falls. Inaddition, elderly patients are at in-creased risk for adverse events associ-ated with drug therapy; therefore,treatment must be chosen carefully,pointed out Barry Goldstein, MD,PhD, Vice President of Diabetes andEndocrinology Clinical Development,Merck & Co, who presented the re-sults at the 2012 ADA annual meeting.

Similar Glucose Reductions with

Sitagliptin and a Sulfonylurea

A post hoc pooled analysis of 3double-blind clinical trials in whicholder patients (aged ≥65 years) weretreated with 100 mg of oral sitagliptin,a once-daily DPP-4 inhibitor, showedthat these patients achieved bloodglucose reductions similar to the re-ductions seen in patients managedwith a sulfonylurea (glipizide orglimepiride). The investigators com-pared the changes from baseline inthe level of hemoglobin (Hb) A1c, fast-ing plasma glucose, body weight, and

the proportion of patients who expe-rienced ≥1 episodes of symptomatichypoglycemia.

In 2 of the studies, patients withdiabetes whose disease had beenmanaged with diet alone or with met-formin were randomized to receivesitagliptin or glipizide (each as mono -therapy or in combination with met-formin) for 104 weeks. In the thirdstudy, patients were randomized toreceive sitagliptin or glimepiride for30 weeks. The pooled analysis focused on re-

sults at or close to 30 weeks in each ofthe 3 trials and included 373 patientswho completed the trials through thistime point. Among this older patient popula-

tion, 178 patients who were taking

sitagliptin had a 0.73% mean reduc-tion in HbA1c from baseline, whichwas similar to the 195 patients whotook a sulfonylurea (0.78% meanHbA1c reduction). In the patients re-ceiving a sulfonylurea, 28.2% experi-enced ≥1 episodes of symptomatichypoglycemia compared with 6.2% ofpatients receiving sitagliptin, a signif-icant difference.

Comparing Saxagliptin Use in

Older and Younger Patients

The second post hoc analysis ofsaxagliptin was led by Bernard Char-bonnel, MD, Professor of Endocrinol-ogy and Metabolic Diseases, CentreHospitalier Universitaire de Nantes,France. In this analysis, the re-searchers conducted a subanalysis ofoutcomes from a 24-week, placebo-controlled trial of treatment withsaxagliptin in 104 older patients (aged≥65 years) and in 351 younger pa-tients (aged <65 years). All the patients had type 2 diabetes

and an inadequate response to insulinalone or to insulin in combinationwith metformin. This trial showedthat adding saxagliptin at a 5-mgdaily dose improved glycemic con-trol, regardless of metformin use, andthe drug was generally well tolerated.This subanalysis showed that im-

provement in glycemic control from

baseline to week 24 with saxagliptinadd-on therapy was similar in the el -derly and nonelderly groups (interac-tion of treatment by age, P = .942 forHbA1c; P = .184 for fasting plasmaglucose; and P = .291 for 120-minutepostprandial glucose), demonstrating

that saxagliptin added to insulin, withor without metformin, was just as ef-fective in older patients as it was inyounger populations. At week 24, the overall incidence

rates of adverse events with saxa -gliptin and placebo were 54.9% and57.6%, respectively, in the older pa-tients. No older patients discontinuedthe study because of adverse events,whereas 1.7% and 2.5% of theyounger patients discontinued thestudy in the saxagliptin and placebogroups, respectively. �

DPP-4 Inhibitors Improve Glycemic Control in Elderly Patients with DiabetesSitagliptin and saxagliptin investigated in 2 post hoc analyses By Wayne Kuznar

Patients aged ≥65 years whowere receiving 100 mg ofsitagliptin achieved bloodglucose reductions similar to the reductions seen inpatients managed with asulfonylurea.

visit after 3 months of treatment.In this open-label study, participants

were assigned to receive exenatide in-jected subcutaneously within 60 min-utes before breakfast and eveningmeals—starting at 5 mcg twice dailyfor 5 weeks and followed by 10 mcgtwice daily for the remaining studyperiod—or to glimepiride 1 mg dailyimmediately before breakfast.

“Exenatide twice daily was associ-ated with lower A1c levels over timecompared with glimepiride,” said DrSchernthaner.Treatment failure occurred in 41% of

patients in the exenatide group versus54% of those in the glimepiride group,a risk difference of 12.4%, which corre-sponded to a 25% reduction in the riskof treatment failure with exenatide.

Exenatide met the criterion for nonin-feriority and separately showed superi-ority over glimepiride as an add-ontreatment to metformin.

Reduced HbA1c Levels and Weight

The median time to inadequateglycemic control was 180 weeks in theexenatide group versus 142 weeks inthe glimepiride group. Overall, 45% ofthe patients assigned to exenatideachieved an HbA1c concentration <7%compared with 31% of the patients as-signed to glimepiride.Fasting plasma glucose concentration

was significantly lower in the exenatidegroup at years 1, 2, and 3 compared withthe glimepiride group. Glucose levelsduring oral glucose tolerance tests werealso significantly lower with exenatide

versus glimepiride at these time points.“Exenatide-treated patients experi-

enced significantly greater weight lossover time,” said Dr Schernthaner. Pa-

tients in the exenatide group lost3.32 kg of body weight from baselinethrough the last visit compared with again of 1.15 kg in those randomized toglimepiride.The incidence of hypoglycemia was

lower in patients receiving exenatidetwice daily than in those receivingglimepiride, he said. Hypoglycemia ofany type was reported by 36% of pa-tients in the exenatide group and by 67%in the glimepiride group; documentedsymptomatic hypoglycemia occurred in7% of the exenatide group versus 12%of the glimepiride group. Gastrointestinal and injection-site

reactions were more common in pa-tients receiving exenatide twice dailythan in patients receiving glimepirideonce daily. �

“Exenatide twice daily wasassociated with lower A1c

levels over time comparedwith glimepiride….Exenatide-treated patients experiencedsignificantly greater weightloss over time.”

—Guntram Schernthaner, MD

Saxagliptin 5-mg daily doseadded to insulin, with orwithout metformin, was justas effective in older patientsas it was in youngerpopulations.

Head-to-Head Comparison: Exenatide Outperforms Glimepiride... Continued from page 14


Incretin Therapies

The contribution of incretin im-pairment to type 2 diabetes isthe focus of ongoing research,

and many questions remain to be an-swered. Preliminary data from severalongoing studies have provided in-sights into the role of glucagon-likepeptide-1 (GLP-1) and dipeptidylpeptidase (DPP)-4 in relation to therole of the incretin system in type 2 di-abetes. These data were reviewed byRichard Pratley, MD, Medical Directorof the Florida Hospital Diabetes Insti-tute and Professor at the Sanford-Burnham Medical Research Institute,Orlando, at the 2012 American DiabetesAssociation (ADA) annual meeting.A number of metabolic defects con-

tribute to the complexity of type 2 di-abetes and its management. Some ofthese defects are insulin resistance inadipose tissue and skeletal muscle,decreased insulin secretion from pan-creatic beta-cells, overproduction ofglucagon (which drives hepatic glu-cose production), abnormalities inglucose absorption in the kidneys,and effects in the stomach and brain.

Impact of Incretin Impairment

in Type 2 Diabetes

GLP-1 is a natural hormone that is se-creted in the gut during meals. Foodtriggers the release of the incretin hor-mones GLP-1 and glucose-dependentinsulinotropic polypeptide (GIP) fromthe intestines into the blood. GLP-1 haseffects on the pancreas to decreaseglucagon and increase insulin secretion.DPP-4 is an enzyme that inactivates

GLP-1. The levels of GLP-1 can be en-hanced for their beneficial effects byinhibiting the action of DPP-4 througha DPP-4 inhibitor, resulting in en-hanced levels of endogenous secre-tion of GLP-1 and GIP. The use of aGLP receptor agonist bypasses in-cretin secretion but results in pharma-cologic levels of GLP, which worksthrough its receptor in the pancreas todecrease glucagon, increase insulin,and lower blood glucose.Native GLP-1 increases insulin se-

cretion from the beta-cell in a glucose-dependent fashion. It decreasesglucagon secretion from the alpha-cell, and, at pharmacologic levels, itdecreases gastric emptying. In con-trast, the DPP-4 enzyme inactivates na-tive GLP-1, and this contributes to theregulation of glucose homeostasis byinactivating the incretin hormonesGLP-1 and GIP. The incretin effect is the enhanced

glucose-stimulated insulin secretion

from the beta-cells in response to anoral glucose challenge compared withan intravenous challenge in patientswith type 2 diabetes.

It is not yet known whether an in-cretin defect in patients with type 2 di-abetes is related to impaired incretinsecretion or to impaired incretin action.Abnormalities in the incretin systemhave been shown to contribute to pro-gressive beta-cell failure.

The mechanisms of the incretin de-fect are not completely understood,and various investigations have shownmultiple defects that contribute to this.There are slight decreases in the se -cretion of GLP-1, a possible reducedinsulinogenic response to GLP-1, im-paired activity of GLP-1, and beta-cellresistance to GIP.

Strategies to Overcome

the Incretin Defect

Increase GLP-1 LevelsOne strategy to overcome an im-

paired incretin effect is to give higherlevels of GLP-1. A physiologic infusionof GLP-1 over 2 hours under hyper-glycemic conditions resulted in a veryrobust insulin secretory response inhealthy controls, although it wasmarkedly blunted in patients withtype 2 diabetes. In contrast, a higher dose of GLP-1

(double that of the infusion) restored

the insulin secretory response in pa-tients with type 2 diabetes to nearlythe same level as in the healthy con-trols who had normal glucose toler-ance. Thus, pharmacologic levels ofGLP-1 can restore the insulin secre-tory effect of GLP-1 in patients withtype 2 diabetes, as shown in the studydiscussed by Dr Pratley.Another study has shown that na-

tive GLP-1 stimulates insulin secre-tion and inhibits glucagon secretion ina glucose-dependent manner. In pa-tients with poorly controlled type 2diabetes (fasting plasma glucose, 220mg/dL), the infusion of native GLP-1markedly decreased the glucose re-sponse to a normal fasting glucoselevel at approximately 4 hours com-pared with placebo. The prompt increase in the secre-

tion of insulin and the prompt sup-pression of glucagon with the GLP-1infusion were the mechanisms con-tributing to the improved glucose re-sponse. The long-term effect of GLP-1to improve glucose control and im-prove beta-cell function was shown inanother study.DPP-4 inhibition relies on an en-

dogenous secretion of GLP-1 and GIP,which enhances insulin secretion anddecreases glucagon secretion. But thistends to be with levels in the highphysiologic range, which gives clearimprovements over baseline in pa-tients with type 2 diabetes, but doesnot achieve pharmacologic levels.To obtain the full pharmacologic ef-

fect, exogenous GLP-1 must be giventhrough an infusion of a GLP-1 ago-nist. This provides some additional ef-fects (eg, decreased gastric emptying,increased satiety, decreased energy in-take, decreased body weight, and in-creased nausea and vomiting). A proof-of-concept study in patients

with type 2 diabetes showed that sub-cutaneous infusion of GLP-1 in 10 pa-tients compared with saline infusion in9 patients over 6 weeks resulted in anapproximate 4-lb reduction of bodyweight with GLP-1 versus an approxi-mate 1.5-lb loss with saline.

DPP-4 InhibitionImpaired incretin effect is a key com-

ponent of dysregulation of glucose inpatients with type 2 diabetes, said DrPratley. DPP-4, an enzyme foundthroughout the body, rapidly inacti-vates GLP-1 and GIP, and modulatesendogenous, physiologic GLP-1 activ-ity levels. The effects of GLP-1 whengiven at pharmacologic levels include

restoration of the insulin response andreduced body weight.GLP-1 and DPP-4 interact with the

GLP-1 receptor by slightly differentmechanisms. These actions are:� GLP-1 activation: • Directly stimulates GLP-1 receptor• Markedly increases GLP-1 activity• Markedly decreases glucagon secretion

• Increases insulin response• Delays gastric emptying• Decreases appetite and energy intake

� DPP-4 inhibition:• Indirectly stimulates GLP-1 receptor

• Modestly increases endogenousGLP-1 and GIP levels

• Modestly decreases glucagon secretion

• Increases insulin response• No effect on gastric emptying• No effect on appetite and energyintake.The recent ADA and the European

Association for the Study of DiabetesPosition Statement for managing hy-perglycemia in patients with type 2diabetes calls for initiating treatment

with lifestyle changes and metformin,said Dr Pratley. In patients who arenot achieving goals within 3 months,the second-line options include sul-fonylureas, thiazolidinediones (TZDs),DPP-4 inhibitors, GLP-1 receptor ag-onists, and insulin. The next steps in treatment would be

the use of 3-drug combinations andmore complex insulin strategies. The clinical question is how to select

from these different options. To main-tain glycemic control without promot-ing hypoglycemia, we are limited toTZDs, DPP-4 inhibitors, or GLP-1 re-ceptor agonists, said Dr Pratley. To avoid weight gain, we want to

avoid sulfonylureas, TZDs, and in-sulin; incretin therapies have the ad-vantages of low rates of hypoglycemiaand low or no weight gain. �

Incretin Impairment: The Role of GLP-1 and DPP-4 in Type 2 Diabetes ManagementBy Mary Mosley

A number of metabolicdefectscontributeto thecomplexityof type 2

diabetes and its management.Impaired incretin effect is akey component ofdysregulation of glucose inpatients with type 2 diabetes.

One strategy to overcome animpaired incretin effect is togive higher levels of GLP-1.

To avoid weight gain, wewant to avoid sulfonylureas,TZDs, and insulin; incretintherapies have theadvantages of low rates ofhypoglycemia and low or no weight gain.

Richard Pratley, MD


Insulin Update

1 in 4 Patients with Type 2 Diabetes Does Not Take Basal Insulin as PrescribedIn addition to skipping doses, many patients self-treat a hypoglycemic eventBy Wayne Kuznar

Among patients with type 2 dia-betes, 1 in 4 patients did nottake the prescribed doses of

basal insulin correctly in the past 30days, and more than 33% of the pa-tients treated themselves for hypo-glycemia, according to the results ofthe Global Attitudes of Patients andPhysicians (GAPP2) survey.“Despite clinical awareness of hypo-

glycemia and dosing irregularities,type 2 diabetes patients using insulinanalogs still need further support toimprove medication-taking behaviorand reduce rates of self-treated hypo-glycemia,” said Meryl Brod, PhD, Pres-ident of the Brod Group, a healthoutcomes and phase 4 strategic plan-ning consultancy in Mill Valley, CA,who reported the study results at the2012 ADA annual meeting.

The study included data on the fre-quency and effect of basal insulin–tak-ing behavior and hypoglycemia from3042 patients with type 2 diabeteswho use insulin analogs and 1653healthcare professionals (primary carephysicians, diabetes specialists, anddiabetes nurses and educators). The GAPP2 was an online survey

conducted in 6 countries (UnitedStates, Canada, Japan, Germany,United Kingdom, and Denmark) be-tween January 2012 and March 2012.The results showed that dosing irreg-ularities were common. As many as 22% of the surveyed pa-

tients reported missing taking a basalinsulin dose (mean, 3 times) in the past30 days, 24% took their prescribedbasal insulin more than 2 hours beforeor after the scheduled time (mean, 4times), and 14% reduced the pre-scribed dose (mean, 4.2 times). Ofthese patients, 39% worried when theymissed an insulin dose and 37% feltguilty about missing a dose.

By contrast, 48% of the patients saidthat they never missed a dose, 51%took a dose more than 2 hours laterthan prescribed, 38% reduced a dose,

and 80% self-treated for a hypo-glycemic event; within the past year,these percentages were 10%, 10%, 9%,and 16%, respectively.

A correlation was seen between hy-poglycemia and dosing irregularities.Significantly more patients who misseda basal insulin injection in the previous

Karen’s doctor said taking Levemir ® (insulin detemir [rDNA origin] injection)

once-daily may get her the control she needs & more

Low rates of hypoglycemia

In 1 study, approximately 45% of patients in each treatmentarm achieved A1C <7% with no hypoglycemic events

within the last 4 weeks of observation.1

A single major hypoglycemic event was reported in the 70-90 mg/dL group; no major hypoglycemic events in the 80-110 mg/dL group

Minor hypoglycemia rates were 5.09 (70-90 mg/dL) and 3.16 (80-110 mg/dL) per patient-year*

From a 20-week, randomized, controlled, multicenter, open-label, parallel-group, treat-to-target trial using a self-titration algorithm in insulin-naïve patients with type 2 diabetes, A1C ≥7% and ≤9% on OAD therapy randomized to Levemir® and OAD (1:1) to 2 different fasting plasma glucose (FPG) titration targets (70-90 mg/dL [n=121] or 80-110 mg/dL [n=122]). At study end, in the 80-110 mg/dL group, 55% of patients achieved goal (A1C <7%) with A1C decrease of 0.9%. The mean A1C was 7%.1

24/7 GLUCOSE CONTROL

For your patients with type 2 diabetes who need more than A1C control, choose Levemir ® (insulin detemir [rDNA origin] injection)

Covered on more than 90% of managed care plans2 †

hypoglycemia usually reflects the time action profile of the administered insulin formulations. Glucose monitoring is essential for all patients receiving insulin therapy. Any changes to an insulin regimen should be made cautiously and only under medical supervision.Needles and Levemir® FlexPen® must not be shared.Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Levemir®. Adverse reactions associated with Levemir® include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, rash and pruritus. Careful glucose monitoring and dose adjustments of insulin, including Levemir®, may be necessary in patients with renal or hepatic impairment.Levemir® has not been studied in children with type 2 diabetes, and in children with type 1 diabetes under the age of six.

Please see brief summary of Prescribing Information on adjacent page.Needles are sold separately and may require a prescription in some states.

Indications and UsageLevemir® (insulin detemir [rDNA origin] injection) is indicated to improve glycemic control in adults and children with diabetes mellitus.

Important Limitations of Use: Levemir® is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting orshort-acting insulin is the preferred treatment forthis condition.

Important Safety InformationLevemir® is contraindicated in patients hypersensitive to insulin detemir or one of its excipients. Do not dilute or mix Levemir® with any other insulin solution, or use in insulin infusion pumps. Do not administer Levemir® intravenously or intramuscularly because severe hypoglycemia can occur.Hypoglycemia is the most common adverse reaction of insulin therapy, including Levemir®. The timing of

On your iPhone®

Scan the QR code to download the NovoDose™ app to knowhow to optimally dose Levemir®

* Minor=SMPG <56 mg/dL and not requiring third-party assistance.† Intended as a guide. Lower acquisition costs alone do not necessarily refl ect a

cost advantage in the outcome of the condition treated because othervariables affect relative costs. Formulary status issubject to change.

iPhone® is a registered trademark of Apple, Inc.FlexPen® and Levemir® are registered trademarks and NovoDose™ is a trademark of Novo Nordisk A/S.© 2012 Novo Nordisk Printed in the U.S.A. 0911-00005042-1 April 2012

References: 1. Blonde L, Merilainen M, Karwe V, Raskin P; TITRATE™ Study Group. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets - the TITRATE™ study. Diabetes Obes Metab. 2009;11(6):623-631. 2. Data on fi le. Novo Nordisk Inc, Princeton, NJ.

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“Despite clinical awarenessof hypoglycemia and dosingirregularities, type 2 diabetespatients using insulinanalogs still need furthersupport to improvemedication-taking behaviorand reduce rates of self-treated hypoglycemia.”

—Meryl Brod, PhD


Insulin Update

30 days reported a hypoglycemic event(41%) compared with those who didnot (34%). Overall, 36% of the patientsreported a hypoglycemic event in thepast 30 days. Hypoglycemic eventswere nocturnal in 26% of the patients;42% of patients worried about noctur-nal events compared with 23% of

patients who worried about daytimehypoglycemic events.Although 74% of the healthcare pro-

fessionals surveyed said that they rou-tinely discuss basal insulin dosingirregularities with their patients, in-cluding hypoglycemic events, only ap-proximately 33% of the healthcare

professionals reported always dis-cussing these events with their patientswho were taking basal insulin only(27%) or basal-bolus (37%).The researchers concluded that

injection nonadherence and self-treated hypoglycemia are continuedmanagement challenges in insulin-

treated patients with type 2 diabetes.Patient support should focus on inter-ventions that address both the rea-sons for poor regular insulin-takingand the risk entailed by self-manage-ment of hypoglycemia “given thelink between these 2 issues,” accord-ing to Dr Brod. �

LEVEMIR® (insulin detemir [rDNA origin] injection)Rx ONLYBRIEF SUMMARY. Please consult package insert for full prescribing infor-mation.INDICATIONS AND USAGE: LEVEMIR® is indicated to improve glycemic control in adults and children with diabetes mellitus. Important Limitations of Use: LEVEMIR® is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting or short-acting insulin is the preferred treatment for this condition.CONTRAINDICATIONS: LEVEMIR® is contraindicated in patients with hypersensi-tivity to LEVEMIR® or any of its excipients. Reactions have included anaphylaxis.WARNINGS AND PRECAUTIONS: Dosage adjustment and monitoring: Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin regimen should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in the insulin dose or an adjustment of concomitant anti-diabetic treatment. As with all insulin preparations, the time course of action for LEVEMIR® may vary in different individuals or at different times in the same indi-vidual and is dependent on many conditions, including the local blood supply, local temperature, and physical activity. Administration: LEVEMIR® should only be administered subcutaneously. Do not administer LEVEMIR® intravenously or intra-muscularly. The intended duration of activity of LEVEMIR® is dependent on injection into subcutaneous tissue. Intravenous or intramuscular administration of the usual subcutaneous dose could result in severe hypoglycemia. Do not use LEVEMIR® in insulin infusion pumps. Do not dilute or mix LEVEMIR® with any other insulin or solution. If LEVEMIR® is diluted or mixed, the pharmacokinetic or pharmacodynamic profile (e.g., onset of action, time to peak effect) of LEVEMIR® and the mixed insulin may be altered in an unpredictable manner. Hypoglycemia: Hypoglycemia is the most common adverse reaction of insulin therapy, including LEVEMIR®. The risk of hypoglycemia increases with intensive glycemic control. Patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia can lead to unconscious-ness or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person or parenteral glucose infusion, or glucagon administration has been observed in clinical trials with insulin, including trials with LEVEMIR®. The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), exercise, and concomitant medications may also alter the risk of hypoglycemia. The prolonged effect of subcutaneous LEVEMIR® may delay recovery from hypoglycemia. As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food intake). The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or intensified glycemic control. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia. Hypersensitivity and allergic reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including LEVEMIR®. Renal Impairment: No difference was observed in the pharmacokinetics of insulin detemir between non-diabetic individuals with renal impairment and healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with renal impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR®, may be necessary in patients with renal impairment. Hepatic Impairment: Non-diabetic individuals with severe hepatic impairment had lower systemic exposures to insulin detemir compared to healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with liver impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR®, may be necessary in patients with hepatic impairment. Drug interac-tions: Some medications may alter insulin requirements and subsequently increase the risk for hypoglycemia or hyperglycemia.ADVERSE REACTIONS: The following adverse reactions are discussed elsewhere: Hypoglycemia; Hypersensitivity and allergic reactions. Clinical trial experience: Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. The frequencies of adverse reactions (excluding hypoglycemia) reported during LEVEMIR® clinical trials in patients with type 1 diabetes mellitus and

type 2 diabetes mellitus are listed in Tables 1-4 below. See Tables 5 and 6 for the hypoglycemia findings.Table 1: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and 24 weeks duration in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)

LEVEMIR®, % (n = 767)

NPH, % (n = 388)

Upper respiratory tract infection 26.1 21.4Headache 22.6 22.7Pharyngitis 9.5 8.0Influenza-like illness 7.8 7.0Abdominal Pain 6.0 2.6

Table 2: Adverse reactions (excluding hypoglycemia) in a 26-week trial comparing insulin aspart + LEVEMIR® to insulin aspart + insulin glargine in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)

LEVEMIR®, % (n = 161)

Glargine, % (n = 159)

Upper respiratory tract infection 26.7 32.1Headache 14.3 19.5Back pain 8.1 6.3Influenza-like illness 6.2 8.2Gastroenteritis 5.6 4.4Bronchitis 5.0 1.9

Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and 24 weeks duration in adults with type 2 diabetes (adverse reactions with incidence ≥ 5%)

LEVEMIR®, % (n = 432)

NPH, % (n = 437)

Upper respiratory tract infection 12.5 11.2Headache 6.5 5.3

Table 4: Adverse reactions (excluding hypoglycemia) in a 26-week clinical trial of children and adolescents with type 1 diabetes (adverse reactions with incidence ≥ 5%)

LEVEMIR®, % (n = 232)

NPH, % (n = 115)

Upper respiratory tract infection 35.8 42.6Headache 31.0 32.2Pharyngitis 17.2 20.9Gastroenteritis 16.8 11.3Influenza-like illness 13.8 20.9Abdominal pain 13.4 13.0Pyrexia 10.3 6.1Cough 8.2 4.3Viral infection 7.3 7.8Nausea 6.5 7.0Rhinitis 6.5 3.5Vomiting 6.5 10.4

Hypoglycemia: Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LEVEMIR®. Tables 5 and 6 summarize the incidence of severe and non-severe hypoglycemia in the LEVEMIR® clinical trials. Severe hypogly-cemia was defined as an event with symptoms consistent with hypoglycemia requiring assistance of another person and associated with either a blood glucose below 50 mg/dL or prompt recovery after oral carbohydrate, intravenous glucose or glucagon admin-istration. Non-severe hypoglycemia was defined as an asymptomatic or symptomatic plasma glucose < 56 mg/dL (<50 mg/dL in Study A and C) that was self-treated by the patient. The rates of hypoglycemia in the LEVEMIR® clinical trials (see Section 14 for a description of the study designs) were comparable between LEVEMIR®-treated patients and non-LEVEMIR®-treated patients (see Tables 5 and 6).

1 in 4 Patients with Type 2 Diabetes Does Not Take... Continued from page 17

Of 713 patients in a pooledanalysis, approximately 45%were at target hemoglobin

(Hb) A1c levels (ie, <7%) after 6 monthsof basal-plus treatment compared with

20% at baseline when taking oral anti -diabetic drugs and insulin glargine(P <.001). Stefano Del Prato, MD, Pro-fessor of Endocrinology and Metabo-lism (School of Medicine) and Chief of

the Section of Diabetes, University ofPisa, Italy, presented the data at the2012 ADA annual meeting. The patients had poorly controlled

type 2 diabetes (HbA1c >7%) when tak-

ing oral antidiabetic drugs and insulinglargine. The mean baseline HbA1cwas7.6%, and the overall prevalence of se-vere hypoglycemia was 1.7%.For the basal-plus regimen, insulin

glulisine once daily at mealtime wasadded to insulin glargine for up to 6months. The investigators pooled datafrom 4 previously reported clinical tri-als using this basal-plus regimen.Dr Del Prato said the basal-plus

regimen is becoming an increasinglycommon step when it is necessary to in-tensify insulin therapy, and that a singlemealtime injection of a rapid-acting in-sulin analog, such as insulin glulisine,is added to antidiabetic drugs andonce-daily basal insulin. This is thoughtto more closely mimic physiologic in-sulin levels and achieve good glycemiccontrol with fewer daily injections. Treatment guidelines recommend

adding a prandial insulin, whenneeded, to reduce peaks of postpran-dial glucose (PPG).In this analysis, the basal-plus regi-

men was associated with significant re-ductions in HbA1c and PPG (P <.001).Over 6 months, mean HbA1c levels werereduced by nearly 0.5% (from 7.6% atbaseline to 7.1%), and mean PPG levelswere reduced by almost 55 mg/dL. Although the doses of insulin

glargine and glulisine increased signif-icantly from baseline, no significant in-creases in body weight or body massindex were observed.The insulin glargine dose increased

from 36.8 to 41.9 U daily, and the in-sulin glulisine dose increased from 4.9to 13.2 U daily.These results suggest that patients

with type 2 diabetes who were previ-ously uncontrolled with an antidia-betic drug and insulin glargine wouldhave improved glycemic control by theaddition of once-daily insulin gluli-sine, said Dr Del Prato. �

Insulin Initiation and Intensification of Glucose Control: Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy. Lipodystrophy: Long-term use of insulin, including LEVEMIR®, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin adsorption. Rotate insulin injection sites within the same region to reduce the risk of lipodystrophy. Weight Gain: Weight gain can occur with insulin therapy, including LEVEMIR®, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Peripheral Edema: Insulin, including LEVEMIR®, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Allergic Reactions: Local Allergy: As with any insulin therapy, patients taking LEVEMIR® may experience injection site reactions, including localized erythema, pain, pruritis, urticaria, edema, and inflammation. In clinical studies in adults, three patients treated with LEVEMIR® reported injection site pain (0.25%) compared to one patient treated with NPH insulin (0.12%). The reports of pain at the injection site did not result in discontinuation of therapy. Rotation of the injection site within a given area from one injection to the next may help to reduce or prevent these reactions. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Most minor reactions to insulin usually resolve in a few days to a few weeks. Systemic Allergy: Severe, life-threatening, gener-alized allergy, including anaphylaxis, generalized skin reactions, angioedema, bron-chospasm, hypotension, and shock may occur with any insulin, including LEVEMIR®, and may be life-threatening. Antibody Production: All insulin products can elicit the formation of insulin antibodies. These insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical trials of LEVEMIR®, antibody development has been observed with no apparent impact on glycemic control. Postmarketing experience: The following adverse reactions have been identified during post approval use of LEVEMIR®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Medication errors have been reported during post-approval use of LEVEMIR® in which other insulins, particularly rapid-acting or short-acting insulins, have been accidentally administered instead of LEVEMIR®. To avoid medication errors between LEVEMIR® and other insulins, patients should be instructed always to verify the insulin label before each injection.

For information about LEVEMIR® contact: Novo Nordisk Inc., 100 College Road West Princeton, NJ 08540 1-800-727-6500 www.novonordisk-us.comManufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd, DenmarkRevised: 1/2012Novo Nordisk®, Levemir®, NovoLog®, FlexPen®, and NovoFine® are registered trademarks of Novo Nordisk A/S.LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930 and other patents pending.FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,400 and other patents pending.© 2005-2012 Novo Nordisk 0212-00007333-1 2/2012

More detailed information is available upon request.

Table 5: Hypoglycemia in Patients with Type 1 DiabetesStudy A

Type 1 Diabetes Adults

16 weeks In combination with insulin aspart

Study B Type 1 Diabetes

Adults 26 weeks

In combination with insulin aspart

Study C Type 1 Diabetes

Adults 24 weeks

In combination with regular insulin

Study D Type 1 Diabetes

Pediatrics 26 weeks

In combination with insulin aspartTwice-Daily LEVEMIR® Twice-Daily NPH Twice-Daily

LEVEMIR®Once-Daily

GlargineOnce-Daily LEVEMIR® Once-Daily NPH Once- or Twice

Daily LEVEMIR®Once- or Twice

Daily NPHSevere hypo-glycemia

Percent of patients with at least 1 event (n/total N)

8.7 (24/276)

10.6 (14/132)

5.0 (8/161)

10.1 (16/159)

7.5 (37/491)

10.2 (26/256)

15.9 (37/232)

20.0 (23/115)

Event/patient/year 0.52 0.43 0.13 0.31 0.35 0.32 0.91 0.99Non-severe hypoglycemia

Percent of patients (n/total N)

88.0 (243/276)

89.4 (118/132)

82.0 (132/161)

77.4 (123/159)

88.4 (434/491)

87.9 (225/256)

93.1 (216/232)

95.7 (110/115)

Event/patient/year 26.4 37.5 20.2 21.8 31.1 33.4 31.6 37.0

Table 6: Hypoglycemia in Patients with Type 2 DiabetesStudy E

Type 2 Diabetes Adults

24 weeks In combination with oral agents

Study F Type 2 Diabetes

Adults 22 weeks

In combination with insulin aspartTwice-Daily LEVEMIR® Twice-Daily NPH Once- or Twice Daily LEVEMIR® Once- or Twice Daily NPH

Severe hypo-glycemia

Percent of patients with at least 1 event (n/total N)

0.4 (1/237)

2.5 (6/238)

1.5 (3/195)

4.0 (8/199)

Event/patient/year 0.01 0.08 0.04 0.13Non-severe hypoglycemia

Percent of patients (n/total N)

40.5 (96/237)

64.3 (153/238)

32.3 (63/195)

32.2 (64/199)

Event/patient/year 3.5 6.9 1.6 2.0


Insulin Update

More Patients Reach Target HbA1c with an Approach Combining Insulin Glargine and GlulisineBy Mary Mosley Patients

with type 2diabeteswho werepreviouslyuncontrolledwith anantidiabetic

drug and insulin glarginewould have improvedglycemic control by the addition of once-dailyinsulin glulisine.

Stefano Del Prato, MD

An insulin analog formulatedwith recombinant human hy -aluronidase (rHuPH20) was

noninferior to lispro in a comparatorcrossover study and had a similarsafety and tolerability profile, saidIrl B. Hirsch, MD, University of Wash-ington, Seattle. He presented the studyresults at the 2012 ADA meeting. rHuPH20 is a genetically engi-

neered soluble version of the natu-rally occurring human hyaluronidaseenzyme, and there are more than 60years of clinical use to support thesafety of hyaluronidase, Dr Hirschsaid. rHuPH20 is the first and onlyUS Food and Drug Administration–approved recombinant human hyal -uronidase enzyme.“Current rapid-acting analog insulin

products are too slow to mimic thephysiologic insulin mean response,”said Dr Hirsch. Postprandial glucosecontrol is improved with rHuPH20,because it accelerates the absorptionand action of insulin. Dr Hirsch and colleagues compared

a rapid-acting insulin plus rHuPH20with insulin lispro alone to determinethe effects on glycemic control parame-ters, safety, and tolerability in an inten-sive basal-bolus insulin therapy regimenin patients with type 1 diabetes. In this randomized, double-blind

trial, after a 4- to 6-week run-in periodwhen all patients received insulinglulisine for their prandial insulin and

twice-daily insulin glargine, patientswere randomized to 1 of 2 cohorts. Inone cohort, patients were randomizedto initiate a regimen of insulin aspart(100 U/mL) plus rHuPH20 (5 mcg) orinsulin lispro alone (100 U/mL). In theother cohort, the patients were ran-domized to start insulin lispro (100U/mL) plus rHuPH20 (5 mcg) or in-sulin lispro alone (100 U/mL). The study involved two 12-week in-

tensive management periods; the pa-tients were crossed over to the otherregimen in their cohort for the secondmanagement period. Prandial doseswere taken immediately before meals. Dr Hirsch noted that only patients

who met the aggressive fasting bloodglucose targets of 80 to 120 mg/dLwere included in the trial. Of the 117randomized patients, 113 completedthe trial. They were aged 42 years onaverage, 61 were women, and mostwere white. The mean body massindex was 27.3 kg/m2. “The prespecified noninferiority mar -

gin of 0.4% was met, with a differencein the change of A1c from baseline of0.05% with rHuPH20,” said Dr Hirsch.In both the lispro and analog-rHuPH20groups, the 7.43% hemoglobin A1c atscreening was reduced to 7.02% at ran-domization, and was reduced furtherto 6.83% with lispro and 6.88% withanalog-rHuPH20. Prandial control was better with

analog-rHuPH20 compared with

lispro throughout the study. The gly -cemic excursion was reduced by 73%at breakfast, 34% at lunch, and by219% at dinner. The overall reductionin the glycemic excursion was a signif-icant 82%. “The glucose profile was flatter in

the analog-rHuPH20 group,” comparedwith lispro, as measured by a 10-pointglucose profile at the end of the study,said Dr Hirsch.

Overall hypoglycemia rates weresignificantly reduced with analog-rHuPH20 compared with lispro. Theprespecified hypoglycemia criterionfor overall hypoglycemic events, ≤70mg/dL, was reduced by 5%, and thecriterion of <56 mg/dL by 7% withanalog-rHuPH20. One severe hypoglycemic episode

occurred in 1 patient in the analog-rHuPH20 group, and 5 episodes oc-curred in 5 patients in the lispro group. Two favorable trends were seen

with analog-rHuPH20. Compared withlispro, there was a small reduction of2.5 U/mL in the total daily insulindose and a small difference in weight(a slight reduction of 0.25 lb with ana-log-rHuPH20 and a gain of 0.10 lbwith lispro alone). Adverse events were similar be-

tween the groups for all system-organclasses. Treatment-phase severe ad-verse events were limited to severehypoglycemia, which occurred in 2patients treated with lispro alone. Nodifference was seen for injection-sitepain between groups, with approxi-mately 70% of patients reporting noneand 30% minimal injection-site pain. Immunogenicity profiles were not

changed, regardless of the sequence inwhich the patient received analog-rHuPH20 or lispro. The anti-insulinantibodies were at 86% at baseline andat 81% at the end of the second treat-ment period for patients receiving ana-log-rHuPH20 first and then lispro, andwere 76% at baseline and 71% at theend of the second treatment period inthe patients receiving lispro and thenanalog-rHuPH20. Positive anti-rHuPH20 antibodies

were found in 13 patients at baselineand in 12 patients at the end of the sec-ond treatment period. �


Insulin Update

rHuPH20 Added to Rapid-Acting Insulin Noninferior to Lispro in Type 1 DiabetesSimilar safety and tolerability, improved postprandial glycemic controlBy Mary Mosley

“Current rapid-acting analoginsulin products are too slowto mimic the physiologicinsulin mean response.”Postprandial glucose controlis improved with rHuPH20,because it accelerates theabsorption and action of insulin. —Irl B. Hirsch, MD

Insulin glargine as a second-linetreatment after metformin in pa-tients with type 2 diabetes is supe-

rior to adding the dipeptidyl peptidase(DPP)-4 inhibitor sitagliptin to achieveglycemic control, according to a firstrandomized head-to-head comparisonof a DPP-4 and basal insulin presentedat the 2012 ADA annual meeting. The study showed that the reduc-

tion in hemoglobin (Hb) A1c wasgreater with insulin glargine than withthe DPP-4 sitagliptin, reported princi-pal investigator Pablo J. Aschner, MD,MSc, Professor, Department of Endo -crinology, Javeriana Pontificia Univer-sity, Colombia. The results of this study

were simultaneously published in theLancet (Aschner PJ, et al. Lancet. 2012;379:2262-2269).

Long-Term Benefits with

Early Basal Insulin

“The results of this study supportthe option of introducing basal insulin

(glargine) in patients with type 2 dia-betes who are inadequately controlledby metformin, with the potential forlong-term benefits arising from theachievement of optimum glycemiccontrol early in the course of the dis-ease,” Dr Aschner said.This open-label study demonstrated

that patients assigned to insulin glarginewere 60% more likely to achieve anHbA1c level <7% than those assigned tositagliptin, “with concurrently lowerfasting and postprandial blood glucose.”The trial included 515 metformin-

treated patients with type 2 diabeteswhose HbA1c level was between 7%and 11% while receiving metformin.The patients were randomized toinsulin glargine, starting at 0.2 U/kginjected at dinner or bedtime, or tositagliptin 100 mg daily. The dosage ofinsulin glargine was adjusted accord-ing to patients’ self-monitored fastingplasma glucose (FPG) concentrationto maintain FPG between 4.0 mmol/Land 5.5 mmol/L.

“The results of this study support the option of introducingbasal insulin (glargine) in patients with type 2 diabetesinadequately controlled by metformin, with the potential forlong-term benefits arising from the achievement of optimumglycemic control early in the course of the disease.”

—Pablo J. Aschner, MD, MSc

Head-to-Head Comparison: Early Insulin Glargine Can Help Achieve Glycemic Target in Type 2 DiabetesDPP-4 inhibitor versus basal insulin as add-on therapy to metforminBy Wayne Kuznar



Insulin Update

The introduction of insulin glar -gine in 2000 and of insulin de-temir in 2004 responded to some

of the problems associated with neutralprotamine Hagedorn (NPH) insulin,introduced 90 years ago. Continuoussubcutaneous insulin infusion (CSII)delivered through an insulin pump be-came the gold standard replacement ofinsulin for type 1 diabetes in 1978. Yet,improved basal insulins are needed,said Geremia B. Bolli, MD, Universityof Perugia, Italy, in a session providingan update on insulin therapy at the 2012ADA annual meeting. Dr Bolli said that NPH is not appro-

priate when beta-cell function is lost,as in the case of patients with type 1diabetes, or worsens, as in patientswith type 2 diabetes. Also, as bodymass index decreases, NPH is less in-dicated because of the increased riskfor hypoglycemia.

Insulin Glargine versus Detemir

The merits of insulin glargine, thefirst long-acting insulin analog, includeits relatively peakless pharmacody-namic profile, solubility that makes itsabsorption more reproducible, and asteady-state duration of action beyond24 hours. In patients with type 1 dia-betes, glargine is noninferior to CSII, issuperior to NPH because of less hypo-glycemia, particularly nocturnal, andresults in the achievement of a loweror similar hemoglobin (Hb) A1c. Theseimprovements with insulin glargine“make intensive treatment in type 1diabetes much safer,” said Dr Bolli. Insulin detemir, by contrast, is solu-

ble, and therefore its absorption is lessvariable than that of glargine, it isnearly as peakless as glargine, and it isprotective against hypoglycemia; how-ever, detemir’s duration of action isshorter than glargine’s, and detemirhas a weaker efficacy in obesity. Dr Bolli reviewed several studies

that showed the benefits of thesedrugs; however, he noted that glargineand detemir have limitations. For glargine, the duration of action is

not sufficient, and the day-to-day vari-ability is too great in approximately20% of patients with type 1 diabetes.For detemir, the duration of actionneeds to be longer in the majority of pa-tients with type 1 diabetes, and greaterpotency is needed in obese patients (pri-marily those with type 2 diabetes).

Novel Basal Insulins on the Horizon

Dr Bolli also reviewed 2 investiga-tional basal insulins—insulin de -gludec and PEGylated insulin lispro(LY2605541).

Insulin degludec. Insulin degludec,a second-generation agent, has a sus-tained release, with an approximate25-hour duration of action in patientswith type 1 diabetes. Its pharmaco -kinetic profile predicts that degludecwill have a sustained effect for morethan 24 hours, low variability in sub-cutaneous absorption, and a low rateof hypoglycemia.

In one study, degludec had a 4-foldlower day-to-day variability in its glu-cose-lowering effect compared with in-sulin glargine; however, a crossoverstudy is needed to confirm this obser-vation, said Dr Bolli.A noninferiority trial in patients

with type 1 diabetes showed thatdegludec was noninferior to glargineat a similar dose, showing a 25% riskreduction in nocturnal hypoglycemiawith degludec, translating to 1.5 fewerevents per patient-year. In a noninferiority trial in patients

with type 2 diabetes, degludec, at asimilar dose as glargine, produced asimilar reduction in HbA1c at 1 year,with an 18% risk reduction in hypo-glycemia and a 25% reduction in noc-turnal hypoglycemia. An interesting possibility with a

long-acting insulin such as degludec,noted Dr Bolli, is the ability to vary thetiming of the dosing, without excessivedisruption of glucose control or diff -erences in HbA1c or nocturnal hypo-glycemia, as shown in 2 studies.

PEGylated insulin lispro. PEGylatedinsulin lispro (LY2605541) has a pro-longed duration of action because itdelays insulin absorption and reducesclearance. In vitro studies have shownthat this agent is safe. In patients with type 1 diabetes, a

short phase 2 study showed thatLY2605541 was noninferior to glargineon daily mean blood glucose, HbA1c,and fasting plasma glucose (FPG) vari-ability. Dr Bolli said that these resultswere obtained with a prandial dose ofLY2605541 that was 24% lower thanthe glargine dose, which could be in-

terpreted as a “better provision of basalinsulin” with LY2605541. In this study, patients lost weight

with LY2605541 but gained weightwith glargine. Although there wasmore hypoglycemia overall with thenew insulin, the nocturnal hypo-glycemia was reduced. Other findings included an eleva-

tion in hepatic enzymes and triglyc-erides, an increase in low-densitylipoprotein cholesterol (LDL-C), and adecrease in high-density lipoproteincholesterol (HDL-C), although thisvalue remained in the normal range. Another study of patients with

type 2 diabetes demonstrated thatLY2605541 was noninferior to glargineon FPG and HbA1c after 12 weeks. Theweight loss was consistent with that inthe study in patients with type 1 dia-betes. Hypoglycemia (including noc-turnal) was reduced with LY2605541.Continuous glucose monitoring re-vealed that there was less time spentin hypoglycemia (24-hour, nocturnal)and lower blood glucose variability.The increase in hepatic enzymes withLY2605541 was within the normalrange, triglycerides were higher, andLDL-C and HDL-C did not change.Further work is needed to answer

remaining questions about degludecand LY2605541, including questions onthe day-to-day variability at doses rel-evant to clinical practice, titration, andprotection against hypoglycemia.

Bolus Insulin Analogs

The bolus (prandial) insulin analogslispro, aspart, and glulisine address thelimitations seen with regular human in-sulin. These analogs are more physiolog-ically active in terms of their appearanceand disappearance from the circulationthan regular insulin, said Luigi F.Meneghini, MD, MBA, University ofMiami, FL. Key advantages of rapid-acting insulins are listed in the Table.

Bolus Insulin in the Pipeline

An insulin formulated with a syn-thetic hyaluronidase, analog-rHuPH20,is under development. Combining arapid-acting insulin with rHuPH20 re-sults in higher insulin concentrations at1 hour after injection and lower insulinconcentrations at 2 hours after injectioncompared with rapid-acting insulin

alone. The biologic activity of therapid-acting insulin or the rapid-act-ing insulin analog is enhanced byrHuPH20, making it more physio-logic, stated Dr Meneghini.Inhaled insulin is currently under

development. Technosphere-inhaled in -sulin is in phase 3 clinical trials. Com-pared with subcutaneous insulin,technosphere-inhaled insulin produceda slightly better clinically relevant im-provement in HbA1c in patients withtype 1 diabetes, according to a meta-analysis published in 2006. A greater reduction in fasting FPG

was found with inhaled insulin, and nodifference was seen in hypoglycemia orweight; however, one study of patientswith type 2 diabetes showed lessweight gain with inhaled insulin. Pa-tient satisfaction was higher with in-haled insulin, and quality of life wasimproved in 2 studies.However, pulmonary issues with in-

haled insulin were found in the meta-analysis. Nonproductive cough is 3- to4-fold higher with inhaled insulin butis not associated with changes in pul-monary function. The cough beginsimmediately after inhalation and tendsto improve after the first month. Firstexpiratory volume in 1 second (FEV1)progressively decreases for the first 6months and then stabilizes, which isseen more in patients with type 1 dia-betes. Diffusion capacity is slightly de-creased, mostly in patients with type 1diabetes, but this has been seen only inshort-term studies. A 52-week study in patients with

uncontrolled type 2 diabetes showed asimilar reduction in HbA1c with pran-dial inhaled insulin plus insulinglargine compared with twice-daily bi-aspart insulin. The inhaled insulin wasassociated with less weight gain, lowerFPG, lower postprandial glucose ex-cursions after a meal challenge, andless hypoglycemia. In patients with type 1 diabetes,

inhaled technosphere insulin plusglargine produced a similar HbA1creduction at 1 year as aspart plusglargine. FPG was lower with techno -sphere-inhaled insulin. But fewer than20% of patients reached an HbA1clevel <7.0% with the inhaled insulin,which is a criticism of inhaled insulins,said Dr Meneghini. �

Ninety Years of Insulin: What’s Needed? What’s New? By Mary Mosley

An interesting possibility witha long-acting insulin such asdegludec is the ability to varythe timing of the dosing,without excessive disruptionof glucose control ordifferences in HbA1c levels.

—Geremia B. Bolli, MD

Table Advantages and Benefits of Rapid-Acting Insulin Analogs vs Regular Insulin

Advantages Benefits

Earlier onset and peak of biologic activity Lower prandial glucose

Shorter duration of action Less late prandial hypoglycemia

Less biologic activity Fewer hypoglycemic fluctuations

Several presentations at the 2012ADA annual meeting focused onnew risk factors for diabetes, in-

dependent of obesity, that were foundin recent studies; these risk factors areobstructive sleep apnea (OSA), expo-sure to second-hand smoking, and thehepatokines fetuin-A.

Obstructive Sleep Apnea

and Diabetes

OSA and type 2 diabetes are majorobesity-associated diseases that coexistin the same individuals with insulin re-sistance. A recent meta-analysis showeda positive relationship between OSAand the risk for diabetes, independentof obesity. Furthermore, OSA wasshown to cause diabetes, said KazuyaFujihara, MD, Department of InternalMedicine, University of Tsukuba Insti-tute of Clinical Medicine, Japan. Because of the strength of the asso-

ciation between OSA and type 2 dia-betes, Dr Fujihara and colleaguesconducted a systematic review ofcross-sectional and longitudinal stud-ies to investigate whether this associa-tion is dependent on obesity. Inaddition, the causal nature of this rela-tionship was not clear from the avail-able cohort studies. A total of 41,813 patients were in-

cluded in the 17 cross-sectional studies

identified for this systematic review; ofthese, 2513 patients had type 2 diabetesand 6524 had OSA. Compared withmild OSA, the patients with severeOSA had a 91% increased risk of type2 diabetes. Even after adjusting for obesity, the

risk for diabetes in people with OSAremained high (odds ratio [OR], 2.03).When instrumentation rather thanquestionnaires was used to ascertainOSA, the risk for diabetes was evenhigher (OR, 2.59 vs 1.56, respectively). To determine the causal relationship

between diabetes and OSA, Dr Fuji-hara and colleagues examined the datafrom 11 studies with nearly 38,500patients. Results showed that severeOSA significantly predicted the risk ofdeveloping type 2 diabetes (OR, 1.99).However, having diabetes did not sig-nificantly predict the risk of futureOSA (OR, 1.03). Based on these data, said Dr Fuji-

hara, incident diabetes is caused by se-vere OSA. Conversely, diabetes did notcause OSA. The proposed mechanismsfor OSA as causing diabetes includeintermittent hypoxia, unhealthy life -styles, or a change in endocrine hor-mones that contribute to increasedinsulin resistance, decreased insulinsensitivity, and, ultimately, to a wors-ening of glycemic control.

All patients with OSA should there-fore be screened for diabetes, sug-gested Dr Fujihara, to facilitate earlydetection of the disease and initiationof appropriate management.

Second-Hand Smoking

and Diabetes

A second study presented at themeeting showed that exposure to sec-ond-hand smoking, as measured byserum cotinine levels in never-smokers,is associated with type 2 diabetes inadults in the general population, saidOmayma O. Alshaarawy, MBBS, WestVirginia University, Morgantown. Several studies have reported an

association between active smokingand diabetes among smokers, but onlya few studies have investigated therelationship between environmentaltobacco smoking and diabetes innever-smokers. The present studyused an objective measure of exposurerather than a self-report as was usedin previous studies.Using data from the National Health

and Nutrition Examination Survey(NHANES), Alshaarawy and col-leagues studied 8407 participants; ofthese, 57% were women and 68%were non-Hispanic whites. Their weightwas equally distributed across all partsof the spectrum.Diabetes was identified in 6.5% of

the participants, and the geometricmean serum cotinine was 0.07 ng/mL.NHANES is a nationally representa-

tive sample of US adults aged >20years. The data were adjusted for age,sex, race, and physical activity. Thedata represented 5 time periods be-tween 1999 and 2008. Persons whowere pregnant, had cardiovascular dis-ease, were former or current smokers,or who had missing data on serum co-tinine were excluded from the study.Serum cotinine levels were signifi-

cantly associated with glycohemo -globin, and the mean change in

glycohemoglobin increased with ele-vations in the cotinine levels. A significant relationship was found

between serum cotinine levels and thedevelopment of diabetes; the risk fordiabetes increased with elevations inthe cotinine levels in the blood. Cotinine levels in the middle range

were associated with a 28% increasedrisk for diabetes, whereas the highestrange of cotinine was associated with a56% increased risk for diabetes.The association between second-

hand smoke exposure and diabetes riskwas stronger in women, non-Hispanicwhites, and nonobese persons. Whetherthis association represents a preventablerisk factor requires prospective study.

Fetuin-A, a Hepatokine,

and Diabetes

Fetuin-A was identified as a risk fac-tor for diabetes in data from the Nurses’Health Study in an analysis presentedby Qi Sun, MD, SCD, Research Associ-ate, Department of Nutrition, HarvardSchool of Public Health, Boston. The liver plays a pivotal role in glu-

cose metabolism. Accumulating evi-dence shows that the liver produces agroup of molecules called hepatokines,including fetuin-A, selenoprotein P, andangiopoietin-like protein 4, which di-rectly regulate glucose sensitivity. Fetuin-A, also called alpha-2HS-

glycoprotein, inhibits insulin receptoractivity. A total of 3 previous studieshave shown an association betweenfetuin-A levels and an increased risk oftype 2 diabetes, said Dr Sun.The present study was a prospective,

nested, case-control study within theNurses’ Health Study. The average pa-tient age was 65 years. In 470 womenwith diabetes, the body mass index washigher at baseline (30 kg/m2), and phys-ical activity was lower than in 470women without diabetes. The levels offetuin-A and the liver enzymes alanineaminotransferase (ALT) and gamma-glutamyl peptidase were also elevatedin the women with diabetes. Dr Sun and colleagues found that

high plasma fetuin-A levels were sig-nificantly associated with an increasedrisk for developing type 2 diabetes.This association was independent ofthe established risk factors for diabetesand from the levels of ALT andgamma-glutamyl peptidase.Overall, the existing data from

prospective studies, including the pres-ent study, consistently support thehypothesis that fetuin-A is a novelindependent risk factor for type 2 dia-betes, according to Dr Sun. �

Novel Risk Factors for Type 2 DiabetesSleep apnea, second-hand smoking exposure, and fetuin-ABy Mary Mosley

Severe OSA, independent ofobesity, significantly predictsthe risk of developing type 2 diabetes, but havingdiabetes does notsignificantly predict the riskof future OSA. Exposure tosecond-hand smoking andfetuin-A are 2 additionalnovel, independent riskfactors for type 2 diabetes.


Diabetes Management

At 24 weeks, the adjusted mean re-duction in HbA1c level in the modi-fied intent-to-treat patient populationwas 1.72% in the patients assigned toinsulin glargine and 1.13% in those as-signed to sitagliptin, with a final meanHbA1c concentration of 6.8% in the in-sulin glargine group versus 7.4% inthe sitagliptin group.At the last available visit during

study treatment in which HbA1c levelwas measured, 68% of insulin glargineusers versus 42% of sitagliptin usersachieved a target of <7% HbA1c.The adjusted mean difference in self-

monitored FPG between the 2 groupswas 2.3 mmol/L (41 mg/dL) in favorof insulin glargine.

Advantages of DPP-4 Inhibitors

“As expected, the estimated rate ofhypoglycemia per patient-year was 8times higher with glargine, but therisk of severe events, although also 3times higher, was not significantly dif-ferent from that with sitagliptin,” saidDr Aschner.

The rates of hypoglycemia were46% with insulin glargine comparedwith 13% for sitagliptin. Symptomatichypoglycemia occurred more often inthe insulin glargine recipients, and se-vere symptomatic hypoglycemia wasrare in either group—1% of the insulinglargine group and <1% in thesitagliptin group. The risk for severenocturnal hypoglycemia was <1% ineach group.Body weight declined by a mean

of 1.08 kg from baseline in thesitagliptin group but increased by amean of 0.44 kg in the insulinglargine group, for an adjusted meandifference of 1.51 kg (P <.001).There were no new safety signals

observed with insulin glargine in thestudy.“Results show that if people learn to

titrate basal insulin and do not haveepisodes of severe hypoglycemia, moreof them might continue over time toreach their glycemic goal with the com-bination of insulin glargine plus met-formin,” concluded Dr Aschner. �

Head-to-Head Comparison... Continued from page 20

See also Insulin Update

Reversing prediabetes and re-turning to a normal state of glu-cose regulation, even transiently,

significantly reduces future risk of de-veloping diabetes, reported investiga-tors from the Diabetes PreventionProgram Research Group at the 2012ADA annual meeting.Data were analyzed from partici-

pants in the 1990 Diabetes PreventionProgram who were randomized to in-tensive lifestyle intervention (N = 736),to metformin (N = 647), or to placebo(N = 607) and who then continued fol-low-up in the observational, postinter-vention Diabetes Prevention ProgramOutcomes Study (DPPOS). The pri-mary outcome was the proportion ofpatients who progressed to diabetesduring the DPPOS.

Patients who had at least 1 annualoral glucose tolerance test during theDiabetes Prevention Program and hadnormal glucose regulation (fastingplasma glucose [FPG] <100 mg/dL ora 2-hour glucose <140 mg/dL) low-ered their risk for developing diabetesby 56% compared with those whocontinued to have prediabetes, inde-pendent of how the reduction wasachieved, said principal investigatorLeigh Perreault, MD, a physician inthe department of endocrinology andmeta bolism, and a clinical researcherat the University of Colorado DenverSchool of Medicine, Aurora.“The treatment arm did not affect

the reduction in diabetes onset inDPPOS in those who reached normalglucose regulation in the Diabetes Pre-vention Program,” Dr Perreault noted.

Diabetes Prevention

Risk reduction was strongly associ-ated with the number of times normalglucose regulation was achieved.Those who achieved normal glucoseregulation once had a 47% reductionin the risk of progression to diabetes,those who achieved it twice had a60.7% reduction in risk, and those who

achieved it 3 times had a 66.9% reduc-tion in risk.Prediabetes, defined as an FPG con-

centration of 5.6 mmol/L to 6.9 mmol/L

or 2-hour plasma glucose of 7.8 mmol/Lto 11.0 mmol/L, is itself a very highrisk factor for development of type 2diabetes and carries with it the risk ofdiabetes complications, Dr Perreaultpointed out.

Several clinical trials have shownthat the incidence of diabetes can beprevented or delayed in people withprediabetes through diet, physical ac-tivity, and drugs. Together, studieshave shown incidence reductions be-


Diabetes Management


“The treatment arm did notaffect the reduction indiabetes onset in DPPOS inthose who reached normalglucose regulation in theDiabetes PreventionProgram.” —Leigh Perreault, MD

Achieving Normoglycemia, Even Once, SignificantlyReduces Diabetes Risk in Patients with PrediabetesRestoring normal glucose regulation provides long-term benefits By Wayne Kuznar


Diabetes Management

The rise of diabetes in Americanyouth was the focus of a sessionat the 2012 ADA annual meet-

ing that was devoted to the TreatmentOptions for Type 2 Diabetes in Ado-lescents and Youth (TODAY) study.Philip S. Zeitler, MD, PhD, SectionHead, Endocrinology, University ofColorado, Denver, presented updateddata from new analyses released afterthe publication of the key results inApril 2012.The TODAY trial, which was

sponsored by the National Instituteof Diabetes and Digestive and KidneyDiseases, followed 699 young individ-uals who were between the ages of 10and 17 years at study entry (mean age,14 years).The average duration of diabetes

among study participants was 7.8months; the average body mass index(BMI) was 34.9 kg/m2; and the averagehemoglobin (Hb) A1c was 6.0% at base-line. Nearly 90% of the participantshad a family history of diabetes; 65%of the participants were female, 41%Hispanic, 32% black, 20% white, and6% were American Indian.The 3 treatment groups were (1)

metformin-alone, (2) metformin-plus-lifestyle, and (3) metformin-plus-rosiglitazone; participants were fol-lowed for 2 to 6 years. (Rosiglitazone isnot approved by the US Food andDrug Administration for the treatmentof type 2 diabetes in young patients.)Nearly 46% met the primary end

point of failure to maintain HbA1c <8%for 6 months.

Outcomes and Implications

Metformin monotherapy is inade-quate in 50% of young patients withtype 2 diabetes, said Dr Zeitler, basedon the TODAY study. This percentageis greater than has been shown in stud-ies of metformin in adults. The addi-tion of rosiglitazone did not change themedian time to failure. Lifestyle inter-vention increased weight reduction at6 months but did not improve sus-tained glycemic control. Early addition of a second agent to

metformin may be required in this pa-tient population, but additional studies

are needed to determine the best agentfor this purpose. The role of intensive lifestyle inter-

vention in young patients with type 2diabetes is uncertain. Despite increasedweight loss at 6 months in the met-formin-plus-lifestyle group, glycemiccontrol was not improved. Dr Zeitler noted that treatment as-

signment did not affect long-term con-trol of HbA1c, which was nearly thesame in each arm in the almost 50%of young patients who maintainedglycemic control over the course of thestudy. Furthermore, the onset of ele-vated HbA1c is quick and thereforecannot be predicted before HbA1c lev-els are first elevated. Treatment of type 2 diabetes in

youth may need to be individualized.There were “very intriguing race andgender differences that need furtheranalysis, including adherence, socio -economic status, and other predictors”of treatment failure, said Dr Zeitler.Slightly more males (48%) than fe-males (44%) failed to maintain HbA1ccontrol. In addition, failure rates were53% in non-Hispanic blacks, 45% inHispanics, 37% in non-Hispanic whites,and 40% in American Indians.

Furthermore, the response to treat-ment differed: the metformin-plus-rosiglitazone combination was moreeffective in controlling HbA1c in fe-males, and greater improvement wasseen in males with metformin plus alifestyle intervention. In non-Hispanic blacks, there was a

“strikingly poor response to met-formin,” said Dr Zeitler, with 50% los-ing glycemic control by 6 months. Notreatment difference was found amongHispanics.

TODAY’s Comorbidities

A snapshot of the comorbidities inthe TODAY study raises concerns. Co-

morbidities were apparent early in thecourse of type 2 diabetes, within 2 to 6years of the initial diagnosis, said NeilH. White, MD, CDE, Professor of Pedi-atrics, Washington University Schoolof Medicine in St. Louis, MO.Between 10% and 30% of partici-

pants had dyslipidemia (low-densitylipoprotein cholesterol ≥130 mg/dLand triglycerides ≥150 mg/dL), and34% had hypertension, which was de-fined as a blood pressure (BP) of ≥95thpercentile, systolic BP ≥130 mm Hg, ordiastolic BP ≥80 mm Hg. In addition,17% had microalbuminuria (defined asan albumin-creatinine ratio ≥30 mg/gcreatinine), a risk factor for nephropa-thy along with hypertension. The predictive factors for hyperten-

sion were sex, age at baseline, and anincrease in BMI over time, and for mi-croalbuminuria, a predictive factorwas an increase in HbA1c over time.The only difference in adverse

events between the treatment groupswas hepatotoxicity, which was lowerin the metformin-plus-rosiglitazonegroup (3.1 events per person-year)than in the metformin-only (8.1 events)and the metformin-plus-lifestyle (5.9events) groups.Fundus photography revealed a

14% rate of nonproliferative diabeticretinopathy, Dr White noted, after anaverage of 4 to 5 years of diabetes. Increased levels of echocardiogra-

phy measures were found as well: 85%to 90% for left ventricular (LV) massand 75% for left atrial (LA) diameter.LV mass and LA diameter did not dif-fer between the treatment arms. “Overall, these findings show that

these young people with type 2 dia-betes have large hearts, suggestive ofrisk for cardiovascular disease,” saidDr White. “Glycemic control appearsto matter in the development of left-ventricular hypertrophy.”

Factors Predicting Poor

Glycemic Control

Increased obesity and HbA1c levels,as well as lower insulinogenic index(IGI) levels at baseline, were associatedwith failing to maintain glucose con-trol for 6 months, according to ananalysis of 2 subsets of patients, saidKenneth C. Copeland, MD, AssociateDirector, University of Oklahoma Dia-betes Center. (IGI is an indicator of in-sulin secretion.)The HbA1c rate increase (even

within the normal range) was the onlylongitudinal factor associated with theprimary end point.

TODAY Study: New Data, Implications for YoungPatients with DiabetesBy Mary Mosley

Treatment oftype 2diabetes inyouth mayneed to beindividualized.

There were “very intriguingrace and gender differencesthat need further analysis,including adherence,socioeconomic status, andother predictors” oftreatment failure.

—Philip S. Zeitler, MD, PhD

“Overall,thesefindingsshow thatthese youngpeople withtype 2

diabetes have large hearts,suggestive of risk forcardiovascular disease.”

—Neil H. White, MD, CDE

Achieving Normoglycemia... Continued from page 23

tween 25% and 72%, but most partic-ipants remain with prediabetes. Some trial results mention the 20%

to 50% of participants who did notprogress to diabetes and in fact re-gressed to normoglycemia; however,these studies offer little in the way ofexplaining predictive factors.

Restoring Normal

Glucose Regulation

This analysis outlined 3 factors thathad significant associations with theachievement of normal glucose regu-lation during the DPPOS: • Previous normal glucose regula-tion during the Diabetes Preven-tion Program

• Increased beta-cell function• Insulin sensitivity. One surprise finding was that pa-

tients from the Diabetes Prevention

Program who were randomized to in-tensive lifestyle intervention but re-mained persistently prediabetic had a31% greater risk of progressing to di-abetes and a 41% lower risk of achiev-ing normal glucose regulation duringthe DPPOS than did participants ran-domized to placebo.This finding emphasizes a particu-

lar susceptibility for this group, whomay benefit from additional interven-tions. These results suggest that themanagement strategy is unimportant,as long as the lifestyle intervention oc-curs early and can restore normal glu-cose regulation.The analysis supports aggressive

glucose-lowering treatments to achievenormal glucose levels in people withprediabetes to maximize long-termslowing or preventing the progres-sion to diabetes. �


See also Insulin Update


Diabetes Management

The changes from baseline valuesover time were evaluated to deter-mine their relationship to durableglycemic control in 172 participantswho maintained glycemic control forat least 48 months and in 305 partici-pants who lost glycemic control be-fore that time point.Treatment assignment was not sig-

nificantly associated with maintainingor losing glycemic control. Race/eth-nicity predicted durable glycemiccontrol, said Dr Copeland. A lowerfailure rate was found in non-His-panic whites (16%), and a higher fail-ure rate was seen in non-Hispanicblacks (38%).Failure rates for glycemic control de-

creased with increases in income andeducation. Only 20% of participantsfailed to maintain glycemic control inthe >$50,000 category compared with45% in the <$25,000 category and 35%in the $25,000 to $49,999 category.A significantly higher HbA1c at base-

line predicted failure. Participants witha 6.4% HbA1c at baseline failed com-pared with participants with an HbA1cof 5.7%, who maintained glycemic con-trol. In addition, a significantly lowerIGI (1.12 vs 2.04) predicted failure. Factors that were associated with

failure over time were a rise in HbA1c,a lower IGI at baseline, and a higherBMI. Baseline HbA1c, even within thenondiabetic range, was the best predic-tor of failure to maintain glycemic con-trol for 6 months, regardless of thetreatment arm. During treatment, arapidly rising HbA1c, even within thenormal range, is associated with failureand may suggest the need to intensifytreatment early.

Combination Therapy

Combination treatment may be re-quired for young patients with type 2diabetes “to address the profound de-gree of insulin resistance observed inthe study,” said Sonia Caprio, MD,

Professor of Pediatrics (Endocrinol-ogy), Yale School of Medicine, NewHaven, CT.

Beginning aggressive therapy veryearly may slow the decline in beta-celladaptation and may achieve moredurable glycemic control.Dr Caprio presented results from an

analysis of 674 participants in the

TODAY study who had a slower rateof decline in beta-cell function in themetformin-plus-rosiglitazone group,which was relatively stable from 6months to 24 months compared withthe metformin-alone or the metformin-plus-lifestyle cohorts. This favorablechange accounts for the lower rate ofglycemic control loss observed in themetformin-plus-rosiglitazone group,she said.Treatment with metformin plus

rosiglitazone resulted in a 20% signifi-cant increase in insulin sensitivity inthe first 6 months, but no change wasfound in the other 2 groups. However,insulin sensitivity decreased thereafterto approximately 10%, and no differ-ence was seen between the groups atthe end of the study.The metformin-alone and metformin-

plus-lifestyle groups had no significanteffect on insulin sensitivity or beta-celladaptation, both of which decreasedprogressively across 48 months. �

Combinationtreatment maybe requiredfor youngpatients withtype 2

diabetes “to address theprofound degree of insulinresistance observed in the study.” —Sonia Caprio, MD

TODAY Study: New Data, Implications for Young... Continued from page 24

Quality Improvement Programs Enhance Diabetes Care,Especially When Baseline Measures Are PoorThese interventions can improve cardiometabolic healthBy Wayne Kuznar

Results of a meta-analysis thatlooked at the effectiveness ofquality improvement (QI) strate-

gies beyond controlling hemoglobin(Hb)A1c levels indicate that many trialsof such strategies show improvementsin patient care for diabetes.“QI strategies significantly im-

proved intermediate disease outcomes,including HbA1c, low-density lipopro-tein cholesterol, systolic blood pres-sure, and diastolic blood pressure,”said the study’s principal investigator,Andrea C. Tricco, PhD, MSc, Instructor,Systematic Reviews and Meta-Analy-sis, King Saud University Medical Re-search at the Li Ka Shing KnowledgeInstitute of St. Michael’s Hospital, On-tario, Canada. “These effects are important on a

population level, and the effects werelarger with poor baseline control,” saidDr Tricco, who presented the results ofthis meta-analysis at the 2012 ADA an-nual meeting; the study was simulta-neously published in the Lancet (TriccoAC, et al. Lancet. 2012;379:2252-2261).Through a systematic review of pub-

lished trial data, the investigators as-sessed the effects of QI strategies onHbA1c levels, vascular risk manage-ment, microvascular complicationmonitoring, and smoking cessation inpatients with diabetes. A total of 142 clinical trials were re-

viewed, which included 38,664 pa-tients from patient-randomized trialsand 84,865 patients from cluster-ran-domized trials. In addition, predefinedQI strategies or financial incentives tar-geting health systems, providers, andpatients were also assessed.The QI strategies targeting health

systems were case management, teamchanges, electronic patient registries,facilitated relay of information to clini-cians, and continuous QI. Strategies assessing providers were

audit and feedback, clinician educa-tion, clinician reminders, and financialincentives. For patients, the strategieswere education, promotion of self-management, and reminder systems.


Overall, compared with usual care,implementing QI strategies was asso-ciated with reductions in:• HbA1c levels (mean reduction,0.37%)

• Low-density lipoprotein cholesterol(LDL-C; 0.10 mmol/L)

• Systolic blood pressure (BP; 3.13mm Hg)

• Diastolic BP (1.55 mm Hg).Implementing QI strategies increased

the likelihood that patients receivedaspirin by 33%, antihypertensive drugsby 17%, screenings for retinopathy by22%, screenings for renal function by

28%, and screenings for foot abnormal-ities by 27%. The results for some cardiovascular

outcomes were not as robust, becausestatin use, hypertension control, andsmoking cessation were not increasedsignificantly with QI strategies versususual care. Few studies reported harm-ful outcomes, said Dr Tricco.

Larger effects on outcomes werenoted when baseline concentrationswere >8% for HbA1c, 2.59 mmol/L forLDL-C, and 80 mm Hg and 140 mmHg for diastolic BP and systolic BP, re-spectively. For lowering HbA1c levels,the most effective QI strategies werepromotion of self-management, teamchanges, case management, and pa-tient education, which accounted for areduction of approximately 0.60%.

The effectiveness of QI interventionstrategies targeting providers and pa-tients varied, depending on baselineHbA1c control. According to the re-searchers, the results show that thestrategies involving interventions tar-geting the entire system of chronic dis-ease management were associatedwith the best results, regardless ofbaseline HbA1c levels. Interventions aimed only at patients

may be beneficial regardless of base-line HbA1c , whereas interventionssolely targeting providers are benefi-cial only if baseline HbA1c control waspoor (>8%). Therefore, optimization ofall of the systems of care should be in-cluded in programs to improve dia-betes management, said Dr Tricco.If these quality indicators are

widely adopted, the population ben-efits would be potentially important.Data from the United KingdomProspective Diabetes Study showedthat a 1% reduction in mean HbA1c re-sults in 21% fewer deaths, 14% fewermyocardial infarctions (MIs), and a37% decrease in microvascular com-plications at the population level.Using these data, the reduction inmean HbA1c shown in this meta-analysis could translate into 7% fewerdeaths, 5% fewer MIs, and 12% fewermicrovascular complications at thepopulation level. �

“QI strategies significantlyimproved intermediatedisease outcomes, includingHbA1c, low-densitylipoprotein cholesterol,systolic blood pressure, anddiastolic blood pressure.”

—Andrea C. Tricco, PhD, MSc


Diabetes Complications

Intensive therapy initiated in newlydiagnosed patients with type 2 dia-betes can preserve beta-cell function,

according to data released by IldikoLingvay, MD, Assistant Professor of In-ternal Medicine at the University ofTexas Southwestern Medical Center,Dallas, at the 2012 ADA annual meeting.Progression of type 2 diabetes

hinges on a progressive decline in beta-cell function over time, and Dr Ling-vay recommended that “we try toachieve glycemic normalization asquickly as possible after diagnosis. Inaddition, I recommend we maintainglycemic control long-term.”Dr Lingvay and colleagues sought to

study the effects of a treatment strategythey devised, with the intent of pre-serving beta-cell function. The studystarted with a run-in period of 3months in which 63 newly diagnosed,treatment-naive patients aged 21 to 70years were treated with insulin (70/30aspart premix) and metformin (500 mgdaily, which was titrated weekly to1000 mg twice daily). The run-in pe-riod was designed to remove any pre-existing glucotoxicity and associated

temporary beta-cell stunning. Patients were then randomized to

either continuation of insulin andmetformin or to triple oral therapy—glyburide 1.25 mg twice daily, whichwas titrated throughout the study;metformin 1000 mg twice daily; andpioglitazone 15 mg daily, titratedmonthly to a final dosage of 45 mgdaily). A total of 58 patients finished the3-month run-in and were randomized.

A mixed-meal challenge test wasused to assess beta-cell function atrandomization and at 6, 12, 18, 30, and42 months.Treatment failure was predefined as

a hemoglobin (Hb) A1c level >8%. Ifpatients in the triple oral arm achievedthis target, they were transitioned toinsulin and metformin. Those assignedto the insulin group who achieved thistarget remained on insulin, with theoption to change the frequency or typeof treatment.Treatment failure occurred in 3 pa-

tients in the insulin group and 5 pa-tients in the triple oral therapy group.At the time of diagnosis, the average

HbA1c was 10.6%. After the 3-monthrun-in period, the HbA1c was reducedto 5.9% and all participants achievedan HbA1c level <7%.After 3.5 years, 83% of patients re-

ceiving insulin plus metformin and72% of those receiving triple oral ther-apy had completed the study.Beta-cell function was preserved in

both groups, with no significant changeover time in beta-cell function betweenor within groups, as calculated by C-peptide area under the curve (AUC) orglucose AUC, said Dr Lingvay. There was an increase in body

weight in both groups, with no signif-

icant difference between groups.Mild hypoglycemia, defined as home

glucose measurement of <70 mg/dLassociated with any symptoms sugges-tive of hypoglycemia, occurred at a rateof 1 monthly during the first 4 months.The rate decreased significantly overtime, to <0.5 events monthly by the endof the study, and did not differ signifi-cantly between groups.“This is a very important finding, in

light of a very low HbA1c achieved andmaintained throughout the study,”noted Dr Lingvay.Because diabetes is a multifactorial

disease, monotherapy may not be ade-quate to change the course of the dis-ease, she pointed out. “I recommendcombination treatment with comple-mentary mechanisms of action….Treat-ment intensification should be donewhile the patient’s glycemic control isstill within the target range. I wouldnot recommend waiting until HbA1cgoes above target before intensifyingtreatment.”Because of the design of the study, it

is not known whether the beta-cellpreservation effect could be attributedto the initial insulin-based therapyduring the run-in phase or to the ongo-ing therapy received after randomiza-tion, Dr Lingvay noted. �

“Treatmentintensificationshould bedone whilethe patient’sglycemic

control is still within thetarget range. I would notrecommend waiting untilHbA1c goes above targetbefore intensifyingtreatment.” —Ildiko Lingvay, MD

Diabetes Management

The dipeptidyl peptidase (DPP)-4inhibitor linagliptin was shownto have a protective effect on the

microvasculature of the diabetic retina,most likely as a result of a combined ef-fect on the neurovascular unit, accord-ing to data presented at the 2012ADA annual meeting by Hans-PeterHammes, MD, PhD, of the Universityof Heidelberg, Germany.The effect of DPP-4 inhibitors on the

diabetic vasculature is still being stud-ied. DPP-4 inhibition could have ef-fects on oxidation, apoptosis, andvasoprotection, but it has also beenshown to be proangiogenic, whichcould be an untoward effect in the di-abetic eye.Glucose and hemoglobin (Hb) A1c

levels were reduced by 10% to 15%with linagliptin in the diabetic rats.Diabetes was induced in the rats withstreptozotocin. One group of diabeticrats was fed food containing linagliptin

(0.083 g/kg) for 26 weeks, and anotherdiabetic group and the control groupwere fed regular food.

DPP-4 activity was reduced by 75%with linagliptin. Surprisingly, activeglucagon-like peptide (GLP)-1 was in-creased by more than 12-fold withlinagliptin; Dr Hammes said that thismay contribute to the benefits seen inthis study. Methylglyoxal, a major factor in the

reduction of vascular damage, wassignificantly reduced by 50% in the di-abetic rats receiving linagliptin com-pared with a 4-fold increase in thediabetic rats who did not (P = .01).Regarding the retinal morphology,

for the first time, the researchers dis-criminated between the superficiallayer of the retina and the layer proxi-mal to the large vessels. Notably, theyfound a >80% reduction of acellularcapillaries with linagliptin, primarilyin the deep capillary layer proximal tothe photoreceptors. In neurodegenera-tive models, this layer is the site wherecapillary degeneration starts. Diabeticretinopathy is thought to be a neurode-generative disease. Dr Hammes and colleagues estab-

lished 4 years ago that pericyte loss oc-curs in the diabetic retina of mostmodels of hyperglycemia, and thatpericyte migration is an important con-tributing mechanism to this loss. In the

present study, the usual 25% rate ofpericyte loss was found in the diabeticrats, but this was normalized withlinagliptin. Pericyte migration, whichoccurs when endothelial cells are dam-aged, was normalized.No proangiogenic effect of lina -

gliptin was found in the diabetic retina.Stromal-derived factor concentrationswere not changed, indicating that therewas no signal to recruit more stem cellsto the diabetic retina for repair. The major effect of DPP-4 inhibition

on the vasculature was seen in theganglion-cell layer, the location of thelarge neurons, of the diabetic retina.Linagliptin increased active GLP-1 andphospho-Akt and reduced capillarydamage. The reduction in reactive oxy-gen species and methylglyoxal foundin the present study has since beenconfirmed by the investigators in an-other experimental model that con-tained only neurons. �

DPP-4 inhibition could haveeffects on oxidation,apoptosis, andvasoprotection, but it hasalso been shown to beproangiogenic, which couldbe an untoward effect in thediabetic eye.

Diabetic Retinopathy: Beneficial Effects Shown inExperimental Model with LinagliptinBy Mary Mosley

Early Intensive Therapy in Type 2 Diabetes PreservesBeta-Cell FunctionBy Wayne Kuznar

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Emerging Therapies

Anumber of promising oral andinjectable agents for diabetesare currently in late-stage de-

velopment and were featured inposters, oral abstract presentations,and symposia during the 2012 ADAannual meeting. The following is asampling of new medications with po-tentially important implications for thetreatment of patients with diabetes.

Lixisenatide is an injectable glucagon-like peptide-1 (GLP-1) receptor agonistcurrently in phase 3 clinical trials; in themultinational GetGoal-P study, lixisen-atide was able to lower hemoglobin(Hb) A1c levels further in patients withtype 2 diabetes who were already beingtreated with pioglitazone, with or with-out metformin, but who had failed toachieve glycemic control with pioglita-zone, with or without metformin (seearticle on page 31).The news was mixed regarding al-

biglutide, because this GLP-1 receptoragonist, currently in phase 3 clinicaltrials, was noninferior to insulin lisproin achieving glycemic control in pa-

tients with type 2 diabetes who werenot adequately controlled with in-sulin; however, albiglutide was notable to demonstrate noninferiority onthis end point in a comparative trialversus liraglutide.Several sodium glucose cotrans-

porter (SGLT)-2 inhibitors are in late-stage development. Canagliflozin is anSGLT-2 inhibitor that was superior toglimepiride and to sitagliptin in lower-ing HbA1c levels in 2 separate phase 3clinical studies of patients with type 2diabetes in whom metformin, withor without a sulfonylurea, failed toachieve glycemic control.Another investigational SGLT-2 in-

hibitor, empagliflozin, which is cur-rently in phase 2b clinical trials, showedsustained reductions in average HbA1clevels for up to 90 weeks in patients withtype 2 diabetes when used as monother-apy or as an add-on to metformin. Fur-thermore, empagliflozin was associatedwith significant reductions in fastingplasma glucose (FPG) and excess bodyweight (see article below).

A third SGLT-2 inhibitor, dapag -liflozin, improved glycemic control in2 clinical trials in patients with type 2diabetes, cardiovascular (CV) disease,and hypertension. Dapagliflozin hadno effect on CV safety. Another studyshowed no renal toxicity with dapag -liflozin. In addition, dapagli flozindemonstrated a long-term (up to 104weeks) reduction in HbA1c levels inpatients with type 2 diabetes and poorglycemic control despite previously re-ceiving high doses of insulin.

Ipragliflozin is yet another SGLT-2inhibitor in phase 3 clinical trials. In a24-week, placebo-controlled, random-ized study of 168 patients with type 2diabetes who were receiving a con-stant metformin dose for at least 12weeks before being randomized,ipragliflozin therapy lowered HbA1clevels by 1.3% compared with placebo.Significant reductions in FPG andblood pressure levels were also seenwith ipragliflozin.

Imeglimin is the first in a new,tetrahydrotriazine-containing class of

oral antidiabetes agents—the glimins.In a 12-week, multicenter, phase 2 clin-ical trial, imeglimin was shown to beeffective as add-on therapy to met-formin in reducing HbA1c levels andFPG in patients with type 2 diabetes.The ultra–long-acting insulin degludec

was as effective as insulin glargine interms of glycemic control in patientswith type 2 diabetes. Furthermore, in-sulin degludec resulted in lower ratesof severe hypoglycemia and nocturnalhypoglycemia than insulin glargine.The pharmacokinetic profile of insulindegludec suggests an effect in excessof 24 hours and low variability in sub-cutaneous absorption (see article onpage 32).The long-acting basal insulin

LY2605541 performed well comparedwith insulin glargine in studies of pa-tients with type 1 or type 2 diabetes,with mean reductions in HbA1c of0.6% with LY2605541 versus 0.4% withinsulin glargine. Of note, LY2605541also was associated with weight reduc-tion (see article on page 33). �

Diabetes Drug Pipeline: Promising Agents in Late Stages of DevelopmentBy Wayne Kuznar

Data presented from a phase2b study with empagliflozin,a sodium glucose cotrans-

porter-2, which increases renal glu-cose excretion, showed reductions inhemoglobin (Hb) A1c, fasting plasmaglucose (FPG), and body weight inpatients with type 2 diabetes at 90weeks. Hans-Juergen Woerle, MD,Vice President, Boehringer Ingelheim,Germany, presented this randomized,multinational, open-label extensionstudy in a late-breaking abstract ses-sion at the 2012 ADA annual meeting. A total of 659 adults with type 2 di-

abetes who had participated in 1 oftwo 12-week, blinded, dose-findingtrials of empagliflozin were treatedfor an additional 78 weeks with open-label empagliflozin (10 mg or 25 mg)alone or added to metformin, withmetformin alone, or with metforminplus sitagliptin. Empagliflozin showed sustained ef-

ficacy over 90 weeks, with a clearly sig-nificant and meaningful efficacy withboth doses, said Dr Woerle.

Average HbA1c was approximately8% at baseline. At 90 weeks, HbA1clevels were reduced with the 10-mgand 25-mg doses of empagliflozinmono therapy (–0.34% and –0.47%, re-spectively), metformin monotherapy(–0.56%), both doses of empagliflozin in

combination with metformin (–0.34%and –0.63%, respectively), and sitagliptinplus metformin (–0.40%).FPG was reduced with empa -

gliflozin 10 mg (–30.4 mg/dL) and 25mg (–27.8 mg/dL) compared withmetformin (–26 mg/dL). FPG reduc-tions were greater with both doses of

empagliflozin in combination withmetformin compared with sitagliptinplus metformin. Body weight ranged from 82 kg to

87 kg at baseline. Weight loss wasgreater in all empagliflozin groupscompared with the metformin alone orthe sitagliptin plus metformin groups;reductions were –2.24 kg with the 10-mg dose and –2.61 kg with the 25-mgdose of empagliflozin alone comparedwith –1.28 kg with metformin. Reduc-tions with sitagliptin plus metforminwere small compared with the 2 em-pagliflozin doses in combination withmetformin. Empagliflozin was generally well

tolerated. Adverse events (AEs) weremostly mild or moderate and reportedin 63.2% to 74.1% of patients takingempagliflozin, and in 69.6% of patientstaking metformin or sitagliptin plusmetformin. Hypoglycemic events were more

frequent with metformin or withsitagliptin plus metformin than withempagliflozin.

Patients with Liver Impairment

In a phase 1, open-label, parallel-group study presented by SreerajMacha, PhD, Boehringer Ingelheim,Ridgefield, CT, the drug was foundto be safe and well tolerated in pa-tients with varying degrees of liverimpairment. The increased exposure to em-

pagliflozin in patients with hepaticimpairment was less than 2-fold.Therefore, the investigators con-cluded that dose adjustment of em-pagliflozin is not required in thispatient population.The 36 patients in this study—8 each

with mild, moderate, or severe hepaticimpairment and 12 controls—weregiven a single dose of empagliflozin50 mg and were monitored for 5 daysin the study center. AEs were reportedin 5 subjects with hepatic impairmentand in 6 healthy persons.A phase 3 clinical trial with em-

pagliflozin is currently in develop-ment, with planned enrollment ofmore than 14,500 patients. �

Empagliflozin Safe and Effective with or withoutMetformin, Reduces WeightAlso safe in patients with liver impairmentBy Mary Mosley

Empagliflozin showedsustained efficacy and safetyover 90 weeks, with reducedHbA1c levels, and greaterweight loss with either dosecompared with metformin orwith sitagliptin.


Emerging Therapies

The anti-inflammatory agent sal-salate, used for decades as atreatment for rheumatoid arthri-

tis, also has glucose-lowering proper-ties, said Steven Shoelson, MD, PhD,Associate Director of Research at theJoslin Diabetes Center, Boston, andprincipal investigator of a placebo-controlled study of salsalate in patientswith type 2 diabetes.Salsalate lacks many of the side ef-

fects of aspirin; however, in the currentstudy, this drug was associated withweight gain and an increase in low-density lipoprotein cholesterol (LDL-C), said Dr Shoelson.

In 2012, a 12-week study demon-strated that salsalate reduced levels ofhemoglobin (Hb) A1c by approximately0.5% at the highest dose (4 g/day).“We now have to determine

whether the degree to which this druglowers blood glucose levels is largeenough to warrant using it as an addi-tion to the diabetes drug armamentar-ium,” Dr Shoelson said.The data he presented came from a

year-long trial sponsored by the Na-tional Institutes of Health. The re-searchers compared 3.5-g daily salsalatewith placebo in 286 patients with type2 diabetes who had a baseline HbA1c of7.5% despite anti diabetic treatment.Compared with placebo, salsalate re-

duced HbA1c levels by 0.24% and fast-ing blood glucose levels by 11 mg/dLover 48 weeks. These modest improve-ments occurred while patients requiredlower doses of other diabetes medica-tions compared with the control group.Salsalate did reduce inflammation—

white blood cell, neutrophil, and lym-phocyte counts decreased from highlevels to lower levels within the normalrange. Although the anti- inflammatoryeffects of salsalate have long beenknown, these particular effects have notbeen previously documented in clinicaltrials. In addition, those who took sal-salate saw an increase in levels ofadiponectin by 21% and a decrease inuric acid levels by 11%, which suggest

some cardiovascular protective quali-ties and a potential reduction in the riskfor gout.However, patients randomized to

salsalate gained a mean of 2.2 lb more

of body weight than those who re-ceived placebo, and their LDL-C levelsincreased by 8 mg/dL; by contrast,triglyceride levels declined. In addition, a small change in uri-

nary albumin of 1.8 mcg/mg of creati-nine was observed in the salsalategroup, which was reversed on discon-

tinuation of the drug. This suggeststhat it may have an impact on kidneyfunction; however, there was nochange in glomerular filtration ratewith salsalate.There were few gastrointestinal side

effects with salsalate, Dr Shoelson noted,which caused no discontinuations. �

“We now have to determinewhether the degree to whichthis drug lowers bloodglucose levels is largeenough to warrant using it asan addition to the diabetesdrug armamentarium.”

—Steven Shoelson, MD, PhD

© 2012 Novo Nordisk 1111-00006045-1 January 2012Victoza® is a registered trademark and VictozaCare™ is a trademark of Novo Nordisk A/S.

Help adult patients with type 2 diabetes gain greater access

Get to know Victoza®

on a deeper level.Powerful reductions in A1C from -0.8% to -1.5%*

To see how Victoza® works for your patients, visit VictozaPro.com/GLP1.

Indications and usageVictoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Because of the uncertain relevance of the rodent thyroid C-cell tumor fi ndings to humans, prescribe Victoza® only to patients for whom the potential benefi ts are considered to outweigh the potential risk. Victoza® is not recommended as fi rst-line therapy for patients who have inadequate glycemic control on diet and exercise.

In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators. Victoza® has not been studied suffi ciently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®. Use with caution in patients with a history of pancreatitis.

Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

The concurrent use of Victoza® and insulin has not been studied.

Important safety informationLiraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the fi ndings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum

calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors.

If pancreatitis is suspected, Victoza® should be discontinued. Victoza® should not be re-initiated if pancreatitis is confi rmed.

When Victoza® is used with an insulin secretagogue (e.g. a sulfonylurea) serious hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia.

Renal impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration, which may sometimes require hemodialysis. Use caution when initiating or escalating doses of Victoza® in patients with renal impairment.

There have been no studies establishing conclusive evidence of macrovascular risk reduction with Victoza® or any other antidiabetic drug.

The most common adverse reactions, reported in ≥5% of patients treated with Victoza® and more commonly than in patients treated with placebo, are headache, nausea, diarrhea, and anti-liraglutide antibody formation. Immunogenicity-related events, including urticaria, were more common among Victoza®-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials.

Victoza® has not been studied in type 2 diabetes patients below 18 years of age and is not recommended for use in pediatric patients.

Victoza® should be used with caution in patients with hepatic impairment.

Please see brief summary of Prescribing Information on adjacent page.

* Victoza® 1.2 mg and 1.8 mg when used alone or in combination with OADs. † Crossix ScoreBoard™ Report, September 2011. Adherence measured by number of actual Victoza® prescriptions fi lled for existing Victoza® patients enrolled in VictozaCare™ versus a match-pair control group not enrolled in VictozaCare™ through fi rst 8 months of enrollment.

Low rate ofhypoglycemia

May reduce weight— Victoza® is not indicated

for the management of obesity, and weight change was a secondary end point in clinical trials

Flexible dosing any time of day, independent of meals

VictozaCare™ helps patients stay on track with ongoing support— Patients enrolled in

VictozaCare™ were more adherent to Victoza® than those not enrolled†

1 1 4:33 PM

The Ancient Anti-Inflammatory Drug Salsalate Lowers Blood Glucose LevelsBy Wayne Kuznar


Several studies related to the Get-Goal Program involving the in-vestigational glucagon-like peptide

(GLP)-1 agonist lixisenatide were pre-

sented at the 2012 ADA annual meet-ing. Glycemic control was improved inpatients with type 2 diabetes withonce-daily lixisenatide added to vari-

ous antidiabetes medications, includ-ing basal insulin in the GetGoal-Lstudy, pioglitazone in the GetGoal-Pstudy, and insulin glargine and oral

agents in the GetGoal Duo 1 study. More patients achieved hemoglobin

(Hb) A1c target levels of <7.0% or≤6.5% with lixisenatide compared withplacebo in these studies. This novelGLP-1 agonist was safe and well toler-ated in these 24-week, randomized,double-blind, parallel-group, placebo-controlled, multicenter studies.

GetGoal-L Study

Ronnie Aronson, MD, of the LMCDiabetes & Endocrinology in Toronto,Canada, presented results of the Get-Goal-L study. Patients insufficientlycontrolled with basal insulin, with orwithout metformin, were randomizedto lixisenatide (20 mcg) to placeboonce daily after breakfast. The meanHbA1c was 8.4%, and the body massindex was 32.1 kg/m2. Previous in-sulin therapy (mean, 55 U/day) in-cluded glargine, neutral protamineHagedorn, detemir, and premix. Byprotocol, the insulin dose was to be re-duced by 20% for an HbA1c ≤7.5% tolimit hypoglycemia.At 24 weeks there was a significant

reduction in HbA1c, the primary endpoint, to 7.8% with lixisenatide com-pared with 8.1% with placebo, fromthe mean baseline level of 8.4% in bothgroups. Of the patients receiving lixi -senatide, 28% achieved an HbA1c<7.0% compared with 12% of the pa-tients receiving placebo. Greater reductions with lixisenatide

were also found in postprandial glu-cose (PPG) and body weight. The PPGlevel 2 hours after breakfast was re-duced by 5.54 mmol/L with lixisen-atide and by 1.72 mmol/L withplacebo, and weight was reduced by1.80 kg from 87.4 kg and by 0.52 kgfrom 89.1 kg, respectively. The frequency of adverse events

(AEs) and serious AEs was similar inthe 2 groups. Discontinuation becauseof an AE was 7.6% with lixisenatide,primarily because of gastrointestinal(GI) problems, and 4.8% with placebo.

GetGoal-P Study

The patient population was similar inthe GetGoal-P study; patients taking pi-oglitazone, with or without metformin,were randomized to lixisenatide or toplacebo. More than 80% of patientswere taking metformin at baseline. Thestudy was presented by Dr Aronsonand Michel Pinget, MD, UniversityHospital of Strasbourg in France. The HbA1c target <7.0% was achieved

by 52.3% of the patients taking lixisen-

Emerging Therapies


Constipation 5.3 0.9 1.7Dyspepsia 5.2 0.9 2.6

Add-on to Metformin + GlimepirideVictoza® 1.8 + Metformin +

Glimepiride N = 230

Placebo + Metformin + Glimepiride

N = 114

Glargine + Metformin + Glimepiride

N = 232Adverse Event Term (%) (%) (%)Nausea 13.9 3.5 1.3Diarrhea 10.0 5.3 1.3Headache 9.6 7.9 5.6Dyspepsia 6.5 0.9 1.7Vomiting 6.5 3.5 0.4

Add-on to Metformin + RosiglitazoneAll Victoza® + Metformin +

Rosiglitazone N = 355Placebo + Metformin

+ Rosiglitazone N = 175Adverse Event Term (%) (%)Nausea 34.6 8.6Diarrhea 14.1 6.3Vomiting 12.4 2.9Decreased Appetite 9.3 1.1Anorexia 9.0 0.0Headache 8.2 4.6Constipation 5.1 1.1Fatigue 5.1 1.7

Table 3: Treatment-Emergent Adverse Events in 26 Week Open-Label Trial versus Exenatide (Adverse events with frequency ≥5% and occurring more frequently with Victoza® compared to exenatide are listed)

Victoza® 1.8 mg once daily + metformin and/or

sulfonylurea N = 235

Exenatide 10 mcg twice daily + metformin and/or

sulfonylurea N = 232Preferred Term (%) (%)Diarrhea 12.3 12.1Dyspepsia 8.9 4.7Constipation 5.1 2.6

Gastrointestinal adverse events: In the five clinical trials of 26 weeks duration or longer, gastrointestinal adverse events were reported in 41% of Victoza®-treated patients and were dose-related. Gastroin-testinal adverse events occurred in 17% of comparator-treated patients. Events that occurred more commonly among Victoza®-treated patients included nausea, vomiting, diarrhea, dyspepsia and con-stipation. In a 26-week study of Victoza® versus exenatide, both in combination with metformin and/or sulfonylurea overall gastrointestinal adverse event incidence rates, including nausea, were similar in patients treated with Victoza® and exenatide. In five clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time. Approximately 13% of Victoza®-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment. In a 26 week study of Victoza® versus exenatide, both in combination with metformin and/or sulfonylurea, the proportion of patients with nausea also declined over time. Immunogenicity: Con-sistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with Victoza® may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza®-treated patients in the five clinical trials of 26 weeks duration or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Low titers (concentrations not requiring dilu-tion of serum) of anti-liraglutide antibodies were detected in 8.6% of these Victoza®-treated patients. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. Cross-reacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the Victoza®-treated patients in the 52-week monotherapy trial and in 4.8% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of the Victoza®-treated patients in the 52-week monotherapy trial and in 1.0% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. Among Victoza®-treated patients who developed anti-liraglutide antibodies, the most common category of adverse events was that of infections, which occurred among 40% of these patients compared to 36%, 34% and 35% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among Victoza®-treated antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred among 11% of Victoza®-treated antibody-positive patients; and among 7%, 7% and 5% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Among Victoza®-treated antibody-negative patients, the most common category of adverse events was that of gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Antibody formation was not associ-ated with reduced efficacy of Victoza® when comparing mean HbA1c of all antibody-positive and all antibody-negative patients. However, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1c with Victoza® treatment. In clinical trials of Victoza®, events from a compos-ite of adverse events potentially related to immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of Victoza®-treated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for Victoza®-treated patients. Patients who developed anti-liraglutide antibodies were not more likely to develop events from the immunogenic-ity events composite than were patients who did not develop anti-liraglutide antibodies. Injection site reactions: Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of Victoza®-treated patients in the five clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza®-treated patients discontinued due to injection site reactions. Papillary thyroid carcinoma: In clinical trials of Victoza®, there were 6 reported cases of papillary thyroid carcinoma in patients treated with Victoza® and 1 case in a comparator-treated patient (1.9 vs. 0.6 cases per 1000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screen-ing with serum calcitonin or thyroid ultrasound. Hypoglycemia: In the clinical trials of at least 26 weeks

duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza®-treated patients (2.6 cases per 1000 patient-years) and in two comparator-treated patients. Six of these 7 patients treated with Victoza® were also taking a sulfonylurea. One other patient was taking Victoza® in combination with metformin but had another likely explanation for the hypoglycemia (this event occurred during hospitalization and after insulin infusion) (Table 4). Two additional cases of hypo-glycemia requiring the assistance of another person for treatment have subsequently been reported in patients who were not taking a concomitant sulfonylurea. Both patients were receiving Victoza®, one as monotherapy and the other in combination with metformin. Both patients had another likely explanation for the hypoglycemia (one received insulin during a frequently-sampled intravenous glucose tolerance test, and the other had intracranial hemorrhage and uncertain food intake).Table 4: Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in the 52-Week Monotherapy Trial and in the 26-Week Combination Therapy Trials

Victoza® Treatment

Active Comparator

Placebo Comparator

Monotherapy Victoza® (N = 497)

Glimepiride (N = 248)

None

Patient not able to self−treat 0 0 —Patient able to self−treat 9.7 (0.24) 25.0 (1.66) —Not classified 1.2 (0.03) 2.4 (0.04) —Add-on to Metformin

Victoza® + Metformin (N = 724)

Glimepiride + Metformin (N = 242)

Placebo + Metformin (N = 121)

Patient not able to self−treat 0.1 (0.001) 0 0Patient able to self−treat 3.6 (0.05) 22.3 (0.87) 2.5 (0.06)Add-on to Glimepiride Victoza® +

Glimepiride (N = 695)

Rosiglitazone + Glimepiride

(N = 231)

Placebo + Glimepiride

(N = 114)Patient not able to self−treat 0.1 (0.003) 0 0Patient able to self−treat 7.5 (0.38) 4.3 (0.12) 2.6 (0.17)Not classified 0.9 (0.05) 0.9 (0.02) 0Add-on to Metformin + Rosiglitazone

Victoza® + Metformin +

Rosiglitazone (N = 355)

None

Placebo + Metformin +

Rosiglitazone (N = 175)

Patient not able to self−treat 0 — 0Patient able to self−treat 7.9 (0.49) — 4.6 (0.15)Not classified 0.6 (0.01) — 1.1 (0.03)Add-on to Metformin + Glimepiride

Victoza® + Metformin + Glimepiride

(N = 230)

Insulin glargine + Metformin + Glimepiride

(N = 232)

Placebo + Metformin + Glimepiride

(N = 114)Patient not able to self−treat 2.2 (0.06) 0 0Patient able to self−treat 27.4 (1.16) 28.9 (1.29) 16.7 (0.95)Not classified 0 1.7 (0.04) 0

In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neo-plasms (based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label study periods) was 10.9 for Victoza®, 6.3 for placebo, and 7.2 for active comparator. After excluding papillary thyroid carcinoma events [see Adverse Reactions], no par-ticular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication, six events among Victoza®-treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not been established. Laboratory Tests: In the five clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the refer-ence range) occurred in 4.0% of Victoza®-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. Post-Marketing Experience: The fol-lowing additional adverse reactions have been reported during post-approval use of Victoza®. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: nausea, vomiting and diarrhea sometimes resulting in dehydration [see Warnings and Precautions]. Renal and Urinary Disorders: increased serum creatinine, acute renal failure or worsening of chronic renal failure, which may sometimes require hemodialysis [see Warnings and Precautions].OVERDOSAGE: In a clinical trial, one patient with type 2 diabetes experienced a single overdose of Victoza® 17.4 mg subcutaneous (10 times the maximum recommended dose). Effects of the overdose included severe nausea and vomiting requiring hospitalization. No hypoglycemia was reported. The patient recovered without complications. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.More detailed information is available upon request. For information about Victoza® contact: Novo Nordisk Inc., 100 College Road West, Princeton, New Jersey 08540, 1−877-484-2869Date of Issue: May 18, 2011 Version: 3Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, DenmarkVictoza® is a registered trademark of Novo Nordisk A/S. Victoza® is covered by US Patent Nos. 6,268,343; 6,458,924; and 7,235,627 and other patents pending. Victoza® Pen is covered by US Patent Nos. 6,004,297; 6,235,004; 6,582,404 and other patents pending.© 2011 Novo Nordisk 140586-R3 6/2011

4:44 PM

Lixisenatide Continues to Show Good Results in GetGoal Program StudiesNovel GLP-1 receptor agonist provides significant glycemic reductionsBy Mary Mosley


Emerging Therapies

atide and by 26.4% taking placebo.More patients taking lixisenatide (28.9%)also achieved an HbA1c target <6.5%compared with placebo (10.1%). Other key findings with lixisenatide

in GetGoal-P include a significantlylarger reduction in fasting plasma glu-cose (FPG) by 1.16 mmol/L versus 0.32mmol/L with placebo. Patients receiv-ing lixisenatide lost 0.21 kg in bodyweight, but those using a placebogained 0.21 kg.There was less of a need for rescue

therapy by patients receiving lixisen-atide (3.8%) compared with 11.3% ofpatients receiving placebo. AEs and drug discontinuation were

similar in the 2 groups. GI eventswere the primary cause of the 2.8%drug discontinuation in the patientstaking lixisenatide compared with0.6% in those taking placebo; 6.5%and 5.0% of patients in these groups,respectively, stopped taking theirstudy drug.

GetGoal Duo 1 Study

In the GetGoal Duo 1 study reportedby Julio Rosenstock, MD, Director, Dal-las Diabetes and Endocrine Center,

Texas, targeting PPG glucose with theGLP-1 agonist in patients with uncon-trolled type 2 diabetes significantly im-proved HbA1c levels and reduced PPGlevel, without affecting weight. In this randomized, double-blind,

multicenter trial, lixisenatide was addedto insulin glargine and to oral antidia-betic agents. During the 12-week run-in phase, glargine was titrated toachieve a FPG of 80 to 100 mg/dL. Atotal of 446 patients with an HbA1c≥7.5% were evenly randomized tolixisenatide or to placebo once daily inthe morning and were followed for 24weeks. All patients were taking met-formin and 12% were receiving a thia-zolidinedione. Sulfonylurea therapywas stopped at randomization. During the randomized follow-up,

HbA1c was reduced to 6.96% withlixisenatide and to 7.30% with placebo(P <.001). More patients taking lixisen-atide achieved an HbA1c <7.0% (56%)than patients taking placebo (39%). At study end, FPG values were 6.56

mmol/L and 6.69 mmol/L in the lixisen -atide and placebo groups, respectively,and were reduced to 6.70 mmol/L and6.86 mmol/L, respectively.

A robust reduction in the PPG wasseen with lixisenatide, stated Dr Rosen-stock. PPG measured 2 hours after astandardized breakfast was reducedwith lixisenatide from 13.02 mmol/L atbaseline to 9.87 mmol/L at 24 weeksbut increased from 12.85 mmol/L to13.04 mmol/L with placebo.

There was a trend toward greaterweight loss with lixisenatide. Only asmall increase in the insulin dose wasfound in both arms, suggesting thatthe patients could not be titrated, orthat there was more potential effect

with more aggressive titration, DrRosenstock stated. AEs occurred more frequently (80%)

in the lixisenatide group versusplacebo (68%) and were the usualGLP-1–related events of nausea andvomiting, which abated as the studyprogressed. Drug discontinuation be-cause of AEs was higher in the lixisen-atide group. Hypoglycemia was morefrequent with lixisenatide, but theoverall numbers were low. After treatment, a blood glucose level

<60 mg/dL was measured in 26% of theplacebo group and in 45% of the lixise-natide group. The number of events perpatient annually was 0.44 in the placebogroup and 0.80 in the lixisenatide group.Severe hypoglycemia was reported inonly 1 patient (in the lixisenatide group). Dr Rosenstock noted that the com-

posite end points showed more benefitwith the GLP-1 receptor. More patientsin the lixisenatide than in the placebogroup achieved an HbA1c of <7% with-out hypoglycemia (44% vs 34%, re-spectively), an HbA1c of <7% withoutweight gain (34% vs 20%), and anHbA1c of <7% without hypoglycemiaor weight gain (28% vs 18%). �

Lixisenatide Continues to Show Good Results... Continued from page 31

More patients achievedHbA1c target levels of <7.0%or ≤6.5% with lixisenatidecompared with placebo. Inone study, patients receivinglixisenatide lost 0.21 kg inbody weight, but those usinga placebo gained 0.21 kg.

The investigational ultra–long-act-ing insulin degludec improveslong-term glycemic control in pa-

tients with type 2 diabetes similar to in-sulin glargine but with a reduced rateof nocturnal and severe hypoglycemia,and greater weight loss, said BernardZinman, MD, Director of the DiabetesCenter at Mount Sinai Hospital, Pro-fessor of Medicine, University ofToronto, and lead investigator of a ran-domized head-to-head comparison.In this randomized, open-label,

phase 3a, noninferiority, treat-to-targettrial, 1030 adults with insulin-naivetype 2 diabetes that was inadequatelycontrolled with oral antidiabetic med-ications were randomized in a 3:1 ratioto insulin degludec or to insulinglargine. Both insulins were used oncedaily and were titrated to achieve self-measured blood glucose targets cali-brated to plasma glucose values of 70mg/dL to 89 mg/dL. The mean baselinehemoglobin (Hb) A1c level was 8.2%.Completion rates were 79% with in-

sulin degludec and 77% with insulinglargine by week 52 (ie, study end), atwhich time the mean HbA1c level de-

clined by 1.06% with insulin degludecand by 1.19% with insulin glargine,meeting the study’s criterion for non-

inferiority. Reductions in fastingplasma glucose levels were signifi-cantly greater with insulin degludec(–67.7 mg/dL) compared with insulinglargine (–59.5 mg/dL).The rates of nocturnal hypoglycemia

were 36% lower with insulin degludecthan with insulin glargine (0.25 vs 0.39episodes per patient annually). “Thedifference in hypoglycemia rate corre-sponds to less than 8 patients neededto treat for a year with insulindegludec in place of insulin glargineto avoid 1 nocturnal hypoglycemicepisode,” said Dr Zinman.“Treating 100 patients for 1 year

with insulin degludec would result in13 fewer nocturnal hypoglycemicevents compared to treatment with in-sulin glargine,” he added.The overall rates of confirmed hy-

poglycemia were 1.52 versus 1.85episodes per patient annually for in-sulin degludec and insulin glargine,respectively. Overall severe hypo gly -cemia was infrequent in both groups,but it was significantly lower with in-sulin degludec.Adverse events occurring in >5% of

patients were bronchitis, gastroenteri-tis, nasopharyngitis, upper respiratorytract infection, headache, diarrhea,vomiting, back pain, and cough. Themean weight gain was similar betweenthe 2 groups.

In a separate meta-analysis compar-ing hypoglycemia between these 2agents in more than 4300 patients, therates of overall and nocturnal hypo-glycemia were significantly lowerwith insulin degludec at similar levelsof HbA1c, reported Robert E. Ratner,MD, Senior Research Scientist atMedStar Health Research Institute,Hyattsville, MD, and Professor ofMedicine, Georgetown University,Washington, DC.For this meta-analysis, hypo-

glycemia was defined as rates of self-reported confirmed hypoglycemia(plasma glucose <56 mg/dL or severehypoglycemia requiring assistance)and nocturnal confirmed hypogly -cemia (00:01 through 05:59 hours).Compared with insulin glargine, in-

sulin degludec resulted in a 17% lowerrate of overall hypoglycemia and a32% lower rate of nocturnal hypo-glycemia in patients with type 2 dia-betes, both of which were statisticallysignificant. In patients with type 1 dia-betes, there were 25% fewer episodesof nocturnal hypoglycemia in patientstreated with insulin degludec. �

New Long-Acting Insulin Degludec Lowers HypoglycemiaSignificantly versus Insulin GlargineHead-to-head comparison in insulin-naive patients with type 2 diabetesBy Wayne Kuznar

“Thedifference inhypoglycemiaratecorrespondsto less than

8 patients needed to treat fora year with insulin degludecin place of insulin glargine to avoid 1 nocturnalhypoglycemic episode.”

—Bernard Zinman, MD

Call for Papers

American Health & Drug Benefits offers an open forum for all healthcare participants to exchangeideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit designmodels that meet the needs of all stakeholders—Distributors, Employers, Manufacturers, Patients, Payers,Providers, Purchasers, Regulators, and Researchers.

Readers are invited to submit articles that aim at improving the quality of patient care and patient well-beingwhile reducing or controlling costs, enhancing the health of communities and patient populations, as well as othertopics relevant to benefit design with specific implications to policymakers, payers, and employers.

Follow the Manuscript Instructions for Authors at www.AHDBonline.comFor more information, call 732-992-1892 or e-mail [email protected]

Areas of High Interest Include:

• Adherence Concerns

• Benefit Design

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Trends in Biologic Therapies for RA

91

www.AH

DBonline

.com l Am

erican He

alth & Dr

ug Benef

its l

Vol 5, N

o 2 l Ma

rch/Apri

l 2012

Biologic Therapies for Rheumatoid Arthritis: It’s All about Value

Value has

been defi

ned as th

e relation

ship betw

een

benefits

and costs

. Using

mathemat

ical conc

epts,

value ha

s been de

scribed as

“value =

benefits/

cost” or

the units

of benefit

derived

from a gi

ven num

ber of

units of c

osts. App

lying this

definitio

n, if we w

ish to

maximize

the valu

e of a ther

apy, there

are only 2

ways

to achie

ve it: ei

ther by

increasing

the ben

efits

obtained

from the

therapy, o

r by decr

easing the

cost

paid for t

hat thera

py.

Value in h

ealthcare

is also a fu

nction of

perspectiv

e.

What ma

y be con

sidered v

aluable to

an indiv

idual

patient u

ndergoin

g treatme

nt or to

a physici

an pre-

scribing t

hat treatm

ent to a s

imilar gro

up of pat

ients

may not n

ecessarily

be consid

ered valua

ble to the

same

extent by

a payer, w

ho must n

ot only pa

y for that

indi-

vidual’s t

reatment

but who

also has

to manag

e the

needs of

multiple

groups of

patients

and/or m

embers

with equa

lly compel

ling medi

cal condi

tions and

prior-

ities. Opt

imizing v

alue with

in the he

althcare s

ystem

means tha

t physici

ans and p

ayers mus

t be align

ed in

the way th

ey view t

he variou

s benefits

and costs

of a

given trea

tment.

Achievin

g such op

timization

is where

the artic

le by

Ms Green

apple in th

is issue of

American Health & Drug

Benefitsfits i

n. In her

article,

Ms Green

apple sho

ws

that prov

iders and

payers, at

least whe

n it comes

to the

use of bio

logics for

the treatm

ent of rhe

umatoid a

rthri-

tis, have m

uch more

in comm

on than n

ot when

look-

ing at val

ue within

this drug

class. Th

e finding

s from

this surve

y have s

everal im

portant im

plications

to

providers

, payers, a

nd patien

ts/plan me

mbers.

PROVIDERS: Providers

can p

ractice

more

autonom

ously in a

ddressing

the need

s of the p

atient

with rheu

matoid ar

thritis. T

hey can d

o this by

follow-

ing evide

nce-based

guideline

s as they

initiate

treat-

ment wit

h disease-

modifyin

g antirheu

matic dru

gs, and

only prog

ress to m

ore costly

biologic

therapies

when

they need

to improv

e treatme

nt benefit

s, thereby

opti-

mizing the

value of

treatmen

t. Such st

aged man

age-

ment is a

ligned wit

h payer c

overage p

olicies.

PAYERS: For paye

rs, this iss

ue is a ma

tter of exp

ec-

tation. Kn

owing tha

t provider

s practice

using the

same

specialty g

uidelines

that paye

rs follow w

ill allow p

ayers

to expect

that their

contract

ed provid

ers will “d

o the

right thin

g” when

it comes

to promo

ting evide

nce-

based med

icine whe

n treating

patients

with rheu

ma-

toid arthr

itis.

PATIENTS/PLAN MEMBERS: When

provider

practice i

s aligned

with plan

policy, p

atients or

plan

members

are the u

ltimate w

inners. A

s is descri

bed in

this artic

le, with 8

4% of pro

viders rep

orting app

roval

rates of at

least 61%

of reques

ts for rheu

matoid ar

thritis

biologics (

and 55%

reporting

approvals

of at least

81%

of such r

equests),

patients w

ho need

more inte

nsive

treatmen

t for thei

r arthriti

s can rece

ive it in

a more

timely an

d coordina

ted manne

r.

MEDICAL DIRECTORS: Does th

is mean

that

payers sh

ould stop

enforcing

step the

rapies or

other

such stra

tegies? Re

gretfully,

not yet; c

omplete

buy-in

to evide

nce-base

d medic

ine has

not yet

been

achieved

, and we c

ontinue to

see treat

ment irre

gular-

ities for c

ertain dis

ease state

s. Perhap

s one day

soon,

with the

advancem

ent of me

aningful

use param

eters

by provid

ers, alon

g with e

lectronic

medical

records

and decis

ion supp

ort system

s promoti

ng evide

nce-

based me

dicine, we

will be a

ble to get

there. Af

ter all,

reaching s

uch a go

al for rhe

umatoid

arthritis,

or any

other sig

nificant

condition

, would

not only

be

admirabl

e, but mo

re importa

nt, it wou

ld provid

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healthca

re.

Albert Tzeel,

MD, MHSA, FACPE

National

Medical D

irector, H

umanaOn

e

Milwauke

e, WI

STAKEHOLDER PERSPECTIVE

Continued

BUSINESS

271

www.AHDBonline.com l American Health & Drug Benefits l

Vol 4, No 5 l September 2011

I n forecasting the future of cardiovascular disease

(CVD), the American Heart Association calls for

preventive strategies, with particular attention to

obesity. 1 The facts related to the current obesity epi-

demic are familiar, stark, and bode bad news not only

for the physical health of the US population but also for

its economic health. Obesity is a common denominator

in and a risk factor for many chronic conditions,

including diabetes, coronary artery disease (CAD),

stroke, and hypertension. 2,3

Dr Colombi is Corporate Medical Director, PPG Industries,

Pittsburgh, PA; Mr Wood is a Senior Biostatistician, Center

for Health Research, Geisinger Clinic, Danville, PA.

ORIGINAL RESEARCHObesity in the Workplace: Impact on

Cardiovascular Disease, Cost, and

Utilization of CareAlberto M. Colombi, MD, MPH; G. Craig Wood, MS

Background: In forecasting the future of cardiovascular disease (CVD), the American Heart

Association calls for preventive strategies with particular attention to obesity. The association

between obesity and CVD, including coronary artery disease (CAD) and diabetes, is well

established. The rising prevalence of obesity in the workforce may have additional implications

for employers and employees besides the demonstrated effects on absenteeism and work-

ers’ compensation.Objective: This study was undertaken to determine the impact of population obesity on care

utilization and cost of cardiovascular conditions such as hypertension, CAD, and cerebrovas-

cular disease (or stroke) in a large US population of employees engaged in a major corporate

wellness program.Study sample: Using data from a single large industrial employer across 29 geographically

distinct worksites in the United States, 179,708 episodes of care from 2004 to 2007 for

10,853 employees were included.

Methods: The population-based economic impact of obesity was calculated on the basis of

the frequency of episodes of care per 1000 employees and on the amount eligible for pay-

ment per episode of care in US dollars. Data were obtained from a wellness program data-

bases, episode of illness inventories, and pharmacy and medical claims. High and low preva-

lence rates of obesity, by obesity quartile, were used to create linear mixed models to examine

associations with disease outcomes, while controlling for correlation within each worksite.

Results: Worksites with a high rate of obesity (ie, in the fourth quartile) had 348.4 more

episodes of care of any kind per 1000 employees (P <.001), 38.6 more hypertension episodes

of care per 1000 employees (P <.001), and 2.5 more cerebrovascular disease episodes of care

per 1000 employees (P = .017) compared with worksites in the lower 3 quartiles. A worksite

in the fourth obesity rate quartile had $223 greater cost per any kind of episode (P <.001), $169

greater cost per hypertension episode (P = .003), and $1620 more per CAD episode (P = .005)

compared with worksites in the lower 3 quartiles. The overall economic impact per 1000

employees was calculated by combining episode frequency and eligible amount for payment

per episode. For sites in the lower 3 quartiles of obesity, the eligible amount per 1000 employ-

ees for any kind of care was $4.01 million. However, for sites in the highest obesity quartile, the

eligible amount for payment per 1000 employees was $5.26 million. This translates into $1250

greater cost per employee. Similar calculations were used to evaluate the effect of obesity on

the amount eligible for payment per employee for hypertension, CAD, and cerebrovascular dis-

ease episodes, with an estimated $69, $89, and $8 greater cost, respectively, per employee.

Conclusion:Worksites with greater obesity prevalence rates were associated with numerically

more frequent and more expensive episodes of care than worksites with low obesity prevalence.

Am Health Drug Benefits.2011;4(5):271-278www.AHDBonline.comDisclosures are at end of text

Stakeholder Perspective,page 278

Alberto Colombi

EDITORIAL

American Health & Drug Benefits: Reflections on the First 5 YearsGary M. Owens, MD

The Business Case for Ending Homelessness: Having a Home ImprovesHealth, Reduces Healthcare Utilization and Costs Daniel G. Garrett, RPh, MS, FASHP

BUSINESS

Beyond the Cost of Biologics: Employer Survey Reveals Gap inUnderstanding Role of Specialty Pharmacy and Benefit DesignF. Randy Vogenberg, RPh, PhD; Cheryl Larson, BA; Margaret Rehayem, MA; Larry Boress, MPA

Stakeholder Perspective by Atheer A. Kaddis, PharmD

REGULATORY

Primary Care Shortages: Strengthening This Sector Is Urgently Needed, Nowand in Preparation for Healthcare Reform Sarah Collins, MBA

Stakeholder Perspective by Gary M. Owens, MD

CLINICAL

Daily Average Consumption of 2 Long-Acting Opioids: An Interrupted TimeSeries AnalysisR. Amy Puenpatom, PhD; Sheryl L. Szeinbach, PhD, MS, BSPharm; Larry Ma, PhD; Rami H. Ben-Joseph, PhD; Kent H. Summers, PhD, BSPharm

Stakeholder Perspective by Matthew Mitchell, PharmD, MBA

INDUSTRY TRENDS

Employers, Health Plans, and New Drug Benefit Designs: A Shifting Landscape

™

©2012 Engage Healthcare Communications, LLCwww.AHDBonline.com

JANUARY/FEBRUARY 2012 VOLUME 5, NUMBER 1

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™


Jentadueto™ (linagliptin and metformin hydrochloride) tablets

BRIEF SUMMARY OF PRESCRIBING INFORMATIONPlease see package insert for full Prescribing Information.

WARNING: RISK OF LACTIC ACIDOSISLactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and non-specific abdominal distress.Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately.

INDICATIONS AND USAGE: Indication: JENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate. Important Limitations of Use: JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effec-tive in these settings. JENTADUETO has not been studied in combination with insulin.

CONTRAINDICATIONS: JENTADUETO is contraindicated in patients with:Renal impairment (e.g., serum creatinine 1.5 mg/dL for men, 1.4 mg/dL for women, or abnormal creatinine clearance) which may also result from condi-tions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions]Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions]A history of hypersensitivity reaction to linagliptin (such as urticaria, angio-edema, or bronchial hyperreactivity) or metformin [see Adverse Reactions]

WARNINGS AND PRECAUTIONS: Lactic Acidosis: Metformin: Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumula-tion during treatment with JENTADUETO and is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels of >5 µg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, (with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medica-tions. Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demon-strates that renal function is not reduced. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking metformin, since alcohol potentiates the effects of metformin on lac-tate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may cause dose-dependent metabolic acidosis and may exacerbate the risk of metformin-induced lactic acidosis [see Drug Interac-tions]. The onset of lactic acidosis is often subtle, and accompanied by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. More severe acidosis may be associated with signs such as hypothermia, hypotension, and resistant bradyarrhythmias. Patients should be educated to recognize and promptly report these symptoms. If present, JENTADUETO should be discontinued until lactic acidosis is ruled out. Gastrointesti-nal symptoms, which are commonly reported during initiation of metformin therapy are less frequently observed in subjects on a chronic, stable, dose of metformin. Gastrointestinal symptoms in subjects on chronic, stable, dose of metformin could be caused by lactic acidosis or other serious disease. To rule out lactic acidosis, serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be due to other mechanisms, such as poorly-controlled diabetes or obesity, vigorous physical activity, or technical prob-lems in sample handling. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a

patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and supportive measures promptly instituted. Metformin is dialyzable (clearance of up to 170 mL/min under good hemodynamic conditions) and prompt hemodialysis is recommended to remove the accumulated metformin and correct the metabolic acidosis. Such management often results in prompt reversal of symp-toms and recovery [see Boxed Warning].Monitoring of Renal Function: Although linagliptin undergoes minimal renal excretion, metformin is known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Therefore, JENTADUETO is contraindicated in patients with renal impair-ment. Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified to be normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present. Linagliptin may be continued as a single entity tablet at the same total daily dose of 5 mg if JENTADUETO is discontinued due to evidence of renal impairment. No dose adjustment of linagliptin is recommended in patients with renal impairment.Use of concomitant medications that may affect renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or interfere with the disposition of metformin should be used with caution [see Drug Interactions]. Radiological studies and surgical procedures: Radiologic studies involving the use of intravascular iodin-ated contrast materials (e.g., intravenous urogram, intravenous cholangiography, angiography, and computed tomography) can lead to acute alteration of renal func-tion and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, JENTADUETO should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal. JENTADUETO should be temporarily discontinued for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal. Impaired Hepatic Function: Because impaired hepatic function has been associated with some cases of lactic acidosis with metformin therapy, JENTADUETO should generally be avoided in patients with clinical or laboratory evidence of hepatic disease [see Warnings and Precautions]. Hypoglycemia: Linagliptin: Insulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions]. Therefore, a lower dose of the insu-lin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO. Metformin: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as SUs and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particu-larly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs. Vitamin B12 Levels: In controlled, 29-week clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia or neurologic manifestations due to the short duration (<1 year) of the clinical trials. This risk may be more relevant to patients receiving long-term treatment with metformin, and adverse hematologic and neurologic reactions have been reported postmarketing. The decrease in vita-min B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on JENTADUETO and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inad-equate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurement at 2- to 3-year intervals may be useful. Alcohol Intake: Alco-hol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake while receiving JENTADUETO [see Warnings and Precautions]. Hypoxic States: Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly dis-continued [see Warnings and Precautions]. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with linagliptin or metformin or any other antidiabetic drug. ADVERSE REACTIONS: Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Linagliptin/Metformin: The safety of concomitantly administered linagliptin (daily dose 5 mg) and metformin (mean daily dose of approximately 1800 mg) has been evaluated in 2816 patients with type 2 diabetes mellitus treated for 12 weeks in clinical trials. Three placebo-controlled studies with linagliptin + metformin were conducted: 2 studies were 24 weeks in duration, 1 study was 12 weeks in duration. In the 3 placebo-controlled clinical studies, adverse events which occurred in 5% of patients receiving linagliptin + metformin (n=875) and were more common than in patients given placebo + metformin (n=539) included nasopharyngitis (5.7% vs 4.3%). In a 24-week factorial design study, adverse events reported in 5% of patients receiving linagliptin + metformin and were more common than in patients given placebo are shown in Table 1.

Table 1 Adverse Reactions Reported in 5% of Patients Treated with Linagliptin + Metformin and Greater than with Placebo in a 24-week Factorial-Design Study

Placebon=72

Linagliptin Monotherapyn=142

Metformin Monotherapyn=291

Combination of Linagliptin with Metforminn=286

n (%) n (%) n (%) n (%)

Nasopharyngitis 1 (1.4) 8 (5.6) 8 (2.7) 18 (6.3)

Diarrhea 2 (2.8) 5 (3.5) 11 (3.8) 18 (6.3)

Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyper-activity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis.Linagliptin Monotherapy: Nasopharyngitis was reported in 5% of patients treated with linagliptin and more commonly than in patients treated with placebo (5.8% vs 5.5%). In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient-years of exposure) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient-years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperactivity) and myalgia. Metformin Monotherapy: The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and head-ache. Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia) [see Warnings and Precautions]. Hypoglyce-mia: In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin, and 1 (1.4%) of 72 subjects treated with placebo. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 (22.9%) of 792 patients reported hypoglycemia compared with 39 (14.8%) of 263 patients administered placebo in combination with metformin and sulfonylurea. Laboratory Tests: Changes in laboratory findings were similar in patients treated with linagliptin + metformin compared to patients treated with placebo + metformin. Changes in laboratory values that occurred more frequently in the linagliptin + metformin group and 1% more than in the placebo group were not detected. No clinically meaningful changes in vital signs were observed in patients treated with linagliptin.DRUG INTERACTIONS: Drug Interactions with Metformin: Cationic Drugs: Cat-ionic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interac-tions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system [see Warnings and Precautions]. Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase [see Warnings and Precautions]. Drug Interactions With Linagliptin: Inducers of P-glycoprotein and CYP3A4 Enzymes: Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp inducer or CYP 3A4 inducer. As JENTADUETO is a fixed-dose combination of linagliptin and metformin, use of alternative treatments (not containing linagliptin) is strongly rec-ommended when concomitant treatment with a strong P-gp or CYP 3A4 inducer is necessary. Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, cal-cium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving JENTADUETO, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving JENTADUETO, the patient should be observed closely for hypoglycemia.USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category B: JENTADUETO: There are no adequate and well controlled studies in pregnant women with JENTADUETO or its individual components, and some clinical data is available for metformin which indicate that the risk for major malformations was not increased when metformin is taken during the first trimester in pregnancy. In addition, met-formin was not associated with increased perinatal complications. Nevertheless, because these clinical data cannot rule out the possibility of harm, JENTADUETO should be used during pregnancy only if clearly needed. JENTADUETO was not tera-togenic when administered to Wistar Han rats during the period of organogenesis at doses similar to clinical exposure. At higher maternally toxic doses (9 and 23 times the clinical dose based on exposure), the metformin component of the combination was associated with an increased incidence of fetal rib and scapula malformations. Linagliptin: Linagliptin was not teratogenic when administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg and 150 mg/kg, respectively. These doses represent approximately 943 times the clinical dose in rats and 1943 times the clinical dose in rabbits, based on exposure. No functional, behavioral, or reproductive toxicity was observed in off-spring of female Wistar Han rats when administered linagliptin from gestation day 6 to lactation day 21 at a dose 49 times the maximum recommended human dose,

based on exposure. Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits. Metformin Hydrochloride: Metformin has been studied for embryofetal effects in 2 rat strains and in rabbits. Metformin was not teratogenic in Sprague Dawley rats up to 600 mg/kg or in Wistar Han rats up to 200 mg/kg (2-3 times the clinical dose based on body surface area or exposure, respectively). At higher maternally toxic doses (9 and 23 times the clinical dose based on exposure), an increased incidence of rib and scapula skeletal malforma-tions was observed in the Wistar Han strain. Metformin was not teratogenic in rabbits at doses up to 140 mg/kg (similar to clinical dose based on body surface area). Met-formin administered to female Sprague Dawley rats from gestation day 6 to lactation day 21 up to 600 mg/kg/day (2 times the maximum clinical dose based on body surface area) had no effect on prenatal or postnatal development of offspring. Met-formin crosses the placenta into the fetus in rats and humans. Nursing Mothers: No studies in lactating animals have been conducted with the combined components of JENTADUETO. In studies performed with the individual components, both linagliptin and metformin were secreted in the milk of lactating rats. It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of JENTADUETO in pediatric patients have not been established. Geriatric Use: Linagliptin is minimally excreted by the kidney; however, metformin is substantially excreted by the kidney. Considering that aging can be associated with reduced renal function, JENTADUETO should be used with caution as age increases [see Warnings and Precautions]. Linagliptin: Of the total number of patients (n=4040) in clinical studies of linagliptin, 1085 patients were 65 years and over, while 131 patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. Therefore, no dose adjustment is recommended in the elderly population. While clinical studies of linagliptin have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. Metformin: Controlled clinical studies of metformin did not include sufficient num-bers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. The initial and maintenance dosing of metformin should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function [see Contraindications and Warnings and Precautions].

OVERDOSAGE: In the event of an overdose with JENTADUETO, employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Removal of linagliptin by hemodialysis or perito-neal dialysis is unlikely. However, metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful partly for removal of accumulated metformin from patients in whom JENTADUETO overdosage is suspected. Linagliptin: During controlled clinical tri-als in healthy subjects, with single doses of up to 600 mg of linagliptin (equivalent to 120 times the recommended daily dose), there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans. Metformin: Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Boxed Warning and Warnings and Precautions].

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA

Marketed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USAandEli Lilly and Company Indianapolis, IN 46285 USA

Licensed from: Boehringer Ingelheim International GmbH Ingelheim, Germany

Copyright 2012 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED

January 2012 JD/BS/01-12 JD148400PROF

Copyright © 2012, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (03/12) JD184306PROFB

LINAGLIPTIN AND METFORMIN IN A SINGLE TABLET

FOR ADULT PATIENTS WITH TYPE 2 DIABETES

Improving glycemic control for adult patients with type 2 diabetes

Significant A1C reductions (placebo-adjusted) at 24 weeks*†

Focusing on what matters

Indication and Important Limitations of UseJENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate.

JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, and has not been studied in combination with insulin.

Important Safety Information

CONTRAINDICATIONSJENTADUETO is contraindicated in patients with:

Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men or ≥1.4 mg/dL for women, or abnormal creatinine clearance).

Acute or chronic metabolic acidosis, including diabetic ketoacidosis. History of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin.

WARNINGS AND PRECAUTIONSLACTIC ACIDOSIS

Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases.

The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.

Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis.

The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. The risk of lactic acidosis may be significantly decreased by regular monitoring of renal function in patients taking metformin. Treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced.

Metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis.

MONITORING OF RENAL FUNCTIONBefore initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present.Radiological studies and surgical procedures: JENTADUETO should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal.

IMPAIRED HEPATIC FUNCTIONImpaired hepatic function has been associated with cases of lactic acidosis with metformin therapy. JENTADUETO tablets should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment.HYPOGLYCEMIAInsulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with

an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. A lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO.VITAMIN B12 LEVELSVitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Monitor hematologic parameters annually.ALCOHOL INTAKEAlcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving JENTADUETO.HYPOXIC STATESCardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) has been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued. MACROVASCULAR OUTCOMESThere have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JENTADUETO or any other antidiabetic drug.ADVERSE REACTIONS

In a 24-week factorial design study, adverse reactions reported in ≥5% of patients treated with JENTADUETO and more commonly than in patients treated with placebo were nasopharyngitis and diarrhea.

In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin and 1 (1.4%) of 72 subjects treated with placebo. In the placebo-controlled studies, hypoglycemia was more commonly reported in patients treated with the combination of linagliptin and metformin with SU (22.9%) compared with those treated with the combination of placebo and metformin with SU (14.8%).

Pancreatitis was reported more often in patients randomized to linagliptin (1 per 538 person-years versus 0 in 433 person-years for comparator).

DRUG INTERACTIONS Because cationic drugs eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems, careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

The efficacy of JENTADUETO may be reduced when administered in combination with a strong P-glycoprotein inducer and CYP3A4 inducer (e.g., rifampin). Use of alternative treatments is strongly recommended.

The concomitant use of carbonic anhydrase inhibitors (e.g., topiramate) and metformin may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase.

USE IN SPECIFIC POPULATIONS As there are no adequate and well-controlled studies in pregnant women, the safety of JENTADUETO in pregnant women is not known. JENTADUETO should be used during pregnancy only if clearly needed.

It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

The safety and effectiveness of JENTADUETO in patients below the age of 18 have not been established.

JENTADUETO should be used with caution as age increases, as aging can be associated with reduced renal function.

JD PROF ISI FEB272012

Please see adjacent pages for brief summary of full Prescribing Information and Boxed Warning regarding the risk of lactic acidosis.

WARNING: RISK OF LACTIC ACIDOSISLactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately.

NOW

APPROVED

*A randomized, double-blind, placebo-controlled, parallel-group study of drug-naïve or previously treated (4 weeks washout and 2 weeks placebo run-in) adult patients with type 2 diabetes and insufficient glycemic control (aged 18-80) who were randomized to placebo (n=72), linagliptin 5 mg once daily (n=142), metformin 500 mg twice daily (n=144), linagliptin 2.5 mg twice daily + metformin 500 mg twice daily (n=143), metformin 1000 mg twice daily (n=147), or linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily (n=143). Primary endpoint was change from baseline A1C at 24 weeks. Results adjusted for 0.1% mean A1C increase for placebo. 29.2% of patients in the placebo group required use of rescue therapy vs 11.1% of patients receiving linagliptin 5 mg once daily, 13.5% of patients receiving metformin 500 mg twice daily, 8.0% of patients receiving metformin 1000 mg twice daily, 7.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 500 mg twice daily, and 4.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily. Full analysis population using last observation on study.

† Superiority of both free combination therapies, consisting of the twice daily administration of linagliptin 2.5 mg and met-formin (500 mg or 1000 mg), was shown over the individual metformin components (500 mg and 1000 mg, both BID) and over linagliptin 5 mg QD for the change in A1C from baseline at Week 24. Linagliptin 2.5 mg BID + metformin 1000 mg BID was superior to metformin 1000 mg BID (P<0.0001); linagliptin 2.5 mg BID + metformin 1000 mg BID was superior to linagliptin 5 mg QD (P<0.0001); linagliptin 2.5 mg BID + metformin 500 mg BID was superior to metformin 500 mg BID (P<0.0001); linagliptin 2.5 mg BID + metformin 500 mg BID was superior to linagliptin 5 mg QD (P<0.0001).

‡ JENTADUETO studied as coadministered linagliptin and metformin tablets; total daily dose of linagliptin was equal to 5 mg.

Find out more about JENTADUETO and the Savings Card program at www.jentadueto.com

JENTADUETO was approved based on clinical trials that evaluated linagliptin and metformin as separate tablets. Bioequivalence of JENTADUETO to linagliptin and metformin coadministered as individual tablets was demonstrated in healthy subjects.

Plac

ebo-

adju

sted

mea

n ch

ange

in A

1C a

t 24

wee

ks (%

)

Linagliptin 5 mg QD

Metformin 500 mg BID

JENTADUETOLinagliptin 2.5 mg/Metformin 500 mg

BID‡

Baseline A1C:

Metformin 1000 mg BID

JENTADUETOLinagliptin 2.5 mg/

Metformin 1000 mg BID‡

8.7%0

-0.2

-0.4

-0.6

-0.8

-1.0

-1.2

-1.4

-1.6

-1.8

8.7% 8.7% 8.5% 8.7%

-0.6%

-1.2%-1.3%

-0.8%

-1.7%

(n=135)

(n=141)

(n=137)(n=138)

(n=140)

AUGUST 2012 VOL 5, NO 5 SPECIAL ISSUE

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Transcript of AUGUST 2012 VOL 5, NO 5 SPECIAL ISSUE