Insulin 1Q11

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Insulin_1Q11_1 Page 1

These materials are intended strictly for referential use by Washington Prescription Drug Program. Any other use, or use by

any other party is strictly forbidden and requires the written consent of Washington Prescription Drug Program.

Insulin Therapeutic Class Review MonographPHARMACY & THERAPEUTICS COMMITTEE

Summary information provided. Consult package insert for full prescribing information.

Conflict of Interest InformationThis monograph may contain discussion of products or components from the following manufacturers:

NovoLog/Novolin/FlexPen/Levemir (Novo Nordisk), Humalog/Humulin (Eli Lilly),Lantus/SoloStar/Apidra (Sanofi-Aventis)

DRUG APPROVALS AND SIGNIFICANT EVENTS:

New Drug Approvals Inhaled insulin (Exubera) January 2006 (discontinued January 2008)40

Detemir (Levemir) June 200541

Glulusine (Apidra) April 200442

Pending Drug Approvals Technosphere inhaled insulin (Afrezza) expected 2013+

FDA Safety A lerts

Lantus (glargine) July 2009

The FDA issued a statement notifying health care professionals that it is aware of the fourrecent observational studies published in the European Association for the Study of Diabetes(EASD) journal, Diabetologia; that looked at cancer risk in patients taking Lantus, of which threereported a positive association.1

Consensus statements from the Federal Drug Administration (FDA), American DiabetesAssociation (ADA), American Association of Clinical Endocrinologists (AACE), and the EASDcautioned against the interpretation of these inconclusive results and recommended thatpatients do not discontinue their insulin therapy, without speaking with their physician, sinceuncontrolled blood sugar levels can have deleterious immediate and long-term adverse effects.2, 3, 4

IntroductionThe purpose of this review is to provide a literature update on new insulin treatment and thecomparative efficacy and safety of human and insulin analogues in managing diabetes mellitus.In particular, the monograph will review glulusine (Apidra), detemir (Levemir), and a new inhaledinsulin pending FDA approvalAfrezza.

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Background

The Centers for Disease Control and Prevention (CDC) estimate that nearly 24 million people

(8% of the population) in the US have diabetesan increase of more than three million over theprevious two years; another 57 million people are at-risk for developing diabetes. 5

The projections for 2050 are a three- to four- fold increase in prevalence in the US, attributablein part to the aging population and growth in minority populations both of which aredisproportionately affected by diabetes.6 Other major contributing factors for the prevalenceprojections include obesity and physical inactivity.

The chronicity and sequelae of the disease gravely impacts health care dollarscosting inexcess of $170 billion annually to treat. The adjusted per capita medical expenditure for peoplewith diabetes is 2.4 times greater than those without diabetes.7

Ninety-five percent of patients with diabetes have Type 2 diabetes, which is characterizedprimarily by defects in insulin sensitivity at the peripheral cells where glucose uptake occurs.Other metabolic defects evident in Type 2 diabetes include: decreased insulin secretion,increased glucagon secretion, and impaired incretin effect. The etiology of Type 2 diabetes isbelieved to be genetic and linked with obesity.8

Type 1 diabetes is less common and is, in contrast to Type 2 diabetes, characterized by adefect in insulin secretion secondary to dysfunction in hepatic beta-cells where insulin is made.Furthermore, the etiology of Type 1 diabetes is believed to be autoimmune in nature.8

Gestational diabetes mellitus (GDM) occurs in less than 5% of all pregnancies and resolvesafter pregnancy; however the risk of developing overt diabetes later in life increases for both

mother and child.8

Two landmark trialsthe Diabetes Control and Complications Trial (DCCT) and the UnitedKingdom Prospective Diabetes Study (UKPDS)demonstrated that intensive blood glucosecontrol can decrease the incidence of microvascular complications, diabetes-related mortality,and MI, thereby providing the case to strive as closely as possible to mimic the serum levels ofinsulin produced in a healthy person.9, 10

In 2006, the ADA and the EASD published a consensus statement on the management ofhyperglycemia in individuals with type 2 diabetes to include a call for earlier intervention withinsulin therapy as a means to achieving and maintaining glycemic goals.11

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Table 1: Criteria for Diagnosing Diabetes Mellitus

Blood TestNormal PlasmaGlucose Level

(mg/dl)

Elevated PlasmaGlucose Levels

(mg/dl)

Diabetes Mellitus(mg/dl)

Fasting 110 110 and 1261 / = 126

2-hr Plasma Glucose 140 140 and 2002 / = 200

Table 2: Treatment Goals

1HbA1c = Glycosylated Hemoglobin Concentration. Elevated risk of microvascular and macrovascular

complications begins at HbA1c levels of 6.5% and above.

Pharmacology

Insulin is a protein hormone produced in the beta-cells of the pancreas and whose action in theperiphery is essential for carbohydrate, protein, and fat metabolism. It stimulates the uptake ofglucose from plasma into cardiac muscle, skeletal muscle, and adipose tissue thereby loweringplasma glucose levels. Insulin also inhibits hepatic glucose production and facilitates theconversion of glucose to glycogen for storage.

In healthy adults, the body maintains insulin concentrations of 5 to 15 uU/mL sufficient to controlfasting plasma glucose levels. In response to the glucose surge after a meal insulinconcentrations peak at 60 to 80 uU/mL in.12 Post-prandial concentrations return to basal levelswithin one to two hours. Normal insulin secretion is characterized by this continuous low basalsecretion and rapidly-rising pulsed (bolus) secretions after meals.People with Type 1 diabetes do not produce enough insulin and therefore require exogenousinsulin replacement therapy for survival. In contrast, people with Type 2 diabetes may producesufficient levels of insulin in early disease but progressive loss of pancreatic beta cell functiontypically results in the need for insulin repletion therapy.

Insulin analog preparations have been designed to closely mimic physiologic human insulinprofile, in onset, peak, and duration of action, through recombinant DNA methods that allow forthe modification of key amino acids. The manipulations alter the pharmacokinetics of the insulinmolecules, thereby influencing the rate and extent of absorption and the rate of clearance.Insulin molecules dissociate into smaller units necessary for absorption, typically from itshexameric configuration into dimers then monomers; the self-association constant of the insulinmolecule dictates its action profile. Regular human insulin preparations have limitations

Biochemical Variable ADA Goal AACE Goal IDF Goal

Fasting plasma glucose (mg/dL) 90 to 130 < 110 < 110

Postprandial plasma glucose (mg/dL) < 180 < 140 < 145

A1c (%) < 7% 6.5% < 6.5%

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associated with time to peak action (2 to 4 hours after administration) requiring patients to inject30 to 60 minutes prior to a meal; however patients typically inject closer to the meal resulting inpost-prandial blood glucose excursions and between-meal hypoglycemia. Intermediate-actinginsulin neutral protamine Hagedorn (NPH) also has a delayed onset as well as variable peakand duration of action, potentiating wide glucose excursions.13

Insulin is categorized by its onset and duration of action. To date, all approved insulin productsare subcutaneous injections within vials or convenient delivery systems. Denaturation of theprotein in gastric pH has precluded oral formulations of insulin. Inhaled insulin preparationshave been explored; the first product Exubera was voluntarily discontinued by its manufacturer,Pfizer Inc., two years after coming to market due to meager sales against company projections.

Afrezza is pending FDA approval.

Table 3: Insul in Preparations.5-13

Onset ofAction

Brand Name Source/Types Descripti on

Short Acting Regular Insulin HumanPrepared by precipitation in presence of ZincChloride.

Humalog Insulin LisproFirst Insulin Analog: Biologic effects similar tounmodified insulin, but is absorbed more rapidlyafter SQ injection. *Pregnancy Category B

Rapid Acting NovoLog Insulin Aspart

Insulin analog produced from recombinant DNAmethods. Quicker absorption and more rapidonset compared to regular human insulin. Can be

used in an external infusion.

Apidra Insulin Glulisine

Differs in structure at 2 amino acid positions:Lysing instead of asparagines at B3 & glutamateinstead of lysine at B29. Allow for insulin todissociate more rapidly therefore having quickerabsorption rate.

IntermediateActing

NPHHumulin N/Novolin N

Crystalline suspension, using protamine tocomplex with R. The addition of protamine ionizesthe insulin molecule. Best for mimic ofendogenous basal insulin release.

Long ActingLantus Glargine

Mimics the normal basal secretion of endogenousinsulin with duration of action for 24 hours.

Levemir DetemirSynthetically derived from Saccharomycescerevisiae. Important not to mix with other insulin.

Therapeutic Indications

Insulin is indicated for the treatment of adults with type 1 diabetes mellitus or type 2 diabetesmellitus and pediatric patients with type 1 diabetes mellitus; it is also used to treat hyperkalemia,severe ketoacidosis, diabetic coma, and gestational diabetes. Insulin can be used asmonotherapy or in combination with other insulin and oral antihyperglycemic agents.

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Rapid-acting Insulins

Humalog [insulin lispro]14, NovoLog [insulin aspart]15, and Apidra [insulin glulusine]16 are allrapid-acting human insulin analogues, available by prescription only and FDA-approved forsubcutaneous injection and infusion. Novolog and Apidra are approved for intravenous infusionfor inpatient settings. Humalog, Novolog, and Apidra are FDA-approved for use in insulinpumps. Humalog, Novolog, and Apidra all have a more rapid onset and shorter duration ofaction than regular human insulin. They are approved for use in adult patients with type 1 ortype 2 diabetes mellitus and pediatric patients with type 1 diabetes mellitus. Humalog, Novolog,and Apidra can be mixed with NPH for SC injection only and only by drawing the rapid-actinginsulin analogue into the syringe first then injecting immediately upon mixing.

Short-acting Insulins19

Humulin R [regular human insulin] and Novolin R [regular human insulin] are both short-actinghuman insulins, available without a prescription (except the concentrated 500 units/mL HumulinR). Humulin R is FDA-approved for SC injection; Novolin R is approved for SC injection and IMor IV infusion in an inpatient setting; the use of the short-acting insulins by SC infusion is off-labeled. They are approved for use in adult patients with type 1 or type 2 diabetes mellitus andpediatric patients with type 1 diabetes mellitus. Humulin R and Novolin R can be mixed withNPH for SC injection only and only by drawing the short-acting insulins into the syringe first theninjecting immediately upon mixing.

Intermediate-acting Insulin

Humulin N38 [human isophane suspension; NPH] and Novolin N39 [human isophane suspension;NPH] are both intermediate-acting human insulins and are available without a prescription andFDA-approved for SC injection only. They are approved for use in adult patients with type 1 ortype 2 diabetes mellitus and pediatric patients with type 1 diabetes mellitus. NPH insulins canbe mixed with aspart, glulisine, lispro, and regular insulins.

Long-acting Insulins

Lantus [insulin glargine]17 and Levemir [insulin detemir]18 are both long-acting human insulinanalogues, available by prescription only. Lantus is FDA-approved for once-daily SC injection;Levemir is FDA-approved for once- or twice- daily SC injection. They are approved for use inadult patients with type 1 or type 2 diabetes mellitus and pediatric patients >6 years of age with

type 1 diabetes mellitus. The long-acting insulins cannot be mixed with other insulins.

High potency U-500 insulin

U-50019 is non-modified regular human insulin, five times more potent than the more commonlyused U-100 insulin. Its pharmacokinetics, however, resembles NPH in duration of effectgenerally active for 8 hours and up to 24 hours. Its onset of action and time to peak action issimilar to U-10030 minutes and 1 to 3 hours, respectively. Based on its unique properties, it

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confers both prandial and basal coverage; due to its potency, it has traditionally been reservedfor patients who require >200 total units of insulin per day20, 21

Insulin pre-mixturesNovolog Mix 70/3022, Humalog Mix 75/2523, and Humalog Mix 50/5024 [human insulin analogsolution / human insulin analog protamine suspension] are all mixtures of a rapid-acting analogand intermediate-acting protamine suspension, thereby conferring both basal and prandialcoverage when administered once- or twice- daily. They are all available by prescription onlyand FDA-approved for SC injection only.Humulin 70/3025 and Novolin 70/3026 [human insulin solution / isophane suspension] are bothmixtures of a short-acting regular insulin and intermediate-acting isophane suspension, therebyconferring both basal and prandial coverage when administered once- or twice- daily. They areboth available without a prescription and FDA-approved for SC injection only.

Comparative Efficacy Data

Apidra vs. Regular human insulin34

Type 2 Diabetes Adult. In a 26-week randomized, open-label, active-control study (N=876), thesafety and efficacy of Apidra was compared to regular human insulin (RHI). Both groupsreceived twice daily NPH as basal insulin. At end of treatment, Apidra achieved greaterchanges in A1c from baseline compared to RHI (-0.46 vs. -0.30, respectively; 95% CI 0.26 to -0.05; p

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Apidra Add-on27

Type 2 Diabetes Adult. Owens et al. treated 135 type 2 diabetic subjects with Lantus and oralagents, titrating to fasting glucose

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kg; p

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Safety ConsiderationsThe most common adverse event reported in studies on insulin is hypoglycemia. Othercommonly reported adverse events are weight gain, injection-site reactions, and infections ofthe upper respiratory tract. Serious adverse events are uncommon.

Special Populations

Geriatric43 Higher insulin AUC levels (up to 35%) in the elderly have been reported from a clinical

trial comparing young versus elderly subjects due to a reduced clearance. Information on theeffect of age on the pharmacokinetics of other insulin preparations is unavailable; however,subgroup analyses based on age did not show differences in safety and efficacy betweengroups. All insulin preparations should be titrated to individual requirements; no pre-specifiedadjustments for renal or hepatic impairment are required.

Gestational43 Screening and diagnosis of Gestational Diabetes Mellitus (GDM) is standard at 24-28 weeks of gestation. Two approaches may be followed for GDM screening. Initial screening isperformed by measuring plasma or serum glucose 1 hour after a 50-g load of 140 mg/dl. Thisthreshold identifies approximately 80% of women with GDM. Using a threshold of130 mg/dl,approximately 90% of women with GDM are identified. On a separate day, a diagnostic 100-goral glucose tolerance test (OGTT) is performed in women who have exceeded the selectedthreshold (i.e., either140 mg/dl or130 mg/dl).At least two of the following plasma glucose valuesmust be found to arrive at a diagnosis of GDM: Fasting glucose 95 mg/dl: 1-h glucose 180 mg/dl;2-h glucose 155 mg/dl; 3-h glucose 140 mg/dl. Due to the risk of GDM both to the mother andneonate, screening and diagnosis are warranted.

Cost Considerations33

The short-acting insulins (Humulin R, Novolin R) and the insulin mixtures Humulin 70/30 andNovolin 70/30 are available without a prescription; the cost per 10 mL vial ranges fromapproximately $62 to $73 AWP.

The intermediating-acting insulins (Humulin N, Novolin N) are comparable in cost to the short-acting insulins, ranging from $62 to $73 per 10 mL vial.

In comparing AWP of the rapid-acting insulins, Apidra is less costly per vial, per boxedcartridges, and per pre-filled disposable SoloStarpen ($105, $203, and $201 respectively) thanHumalog and Novolog.

In comparing AWP of the long-acting insulins, Levemir is less costly per vial and per pre-filled

disposable Flexpen ($110 and $199 respectively) than Lantus ($111/vial; $202/SoloStar pen). In comparing AWP of the insulin mixturesNovolog Mix 70/30, Humalog Mix 75/25, and

Humalog Mix 50/50the Humalog Mixes are less costly per vial and pre-filled disposableKwikPen ($111 and $215, respectively) than Novolog Mix ($117/vial and $221/FlexPen)

U-500 is not available without a prescription. U-500 is only available in 20 mL vials; the cost pervial is approximately $284 AWP. However, although U-500 is more expensive per mL,economic analysis demonstrates cost-savings per unit compared to U-100 (owing to thereduced volume required per injection).

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Conclusions

Diabetes is an epidemic with grave impact on patient health status and economic dollars. Thepast trend and the current projections for the growth in the prevalence of diabetes havewarranted dutiful attention to the current options available for cost-effective treatment. Since2006, with the ADA and AACE consensus statement on the management of diabetes, insulinhas gained a place in first-line therapy for certain patients, along with metformin andnonpharmacologic lifestyle changes. Promoting early use of insulin is believed to conferbenefits in the preservation of pancreatic function, a well known sequelae of patients withdiabetes.

Advent of insulin analogues provide considerable advantages over regular human insulin andNPH, notably in regards to convenience of timed administration relative to meals, reducedvariability in glucose excursions, and in effect reduced risk for hypoglycemia.

Since the last insulin therapeutic class review, another option for rapid-acting insulin has beenintroduced to the market, with comparable pharmacokinetic and pharmacodynamic properties tothe other rapid-acting analogues. No advantage has been demonstrated in clinical trials for theuse of Apidra over the other available rapid-acting analogues.

Since the last insulin therapeutic class review, another option for long-acting insulin has beenintroduced to the market, with some studies reporting the following advantages over Lantus:less weight gain associated with Levemir compared to Lantus and less between subjectvariability in fasting blood glucose. However, most studies also report increased daily doserequirements, twice-daily dosing, and increased injection site reactions for Levemir.

Since the last insulin therapeutic class review, an inhaled insulin (Exubera) was introduced tothe market and subsequently removed due to inadequate sales. Another inhaled insulin

formulation option with Afrezza has since been introduced and is pending FDA-approval.Clinical trials report an advantage over rapid-acting SC insulin in regards to more rapid onset ofaction, thereby closely mimicking physiologic post-prandial insulin release. Trials alsodemonstrate greater total insulin exposure but without the greater risk for hypoglycemia orweight gain. Inhaled insulin has been demonstrated in controlled trials to be well-tolerated butsafety concerns regarding pulmonary function remain to be further explicated. Manufacturers of

Afrezza have also addressed the issue of bulky packaging, a likely contributing factor to themarketing failure for Exubera.

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CostBrand

Name

Generic Name Dosage AWP-15% Cost/Unit

Rapid-Acting

NovoLog Insulin Aspart

Cartridge $204

Pen $212

Vial $86

HumalogInsulin Lispro, Human Rec.

Analog

Cartridge $204

Pen $212

Vial $110

Apidra Insulin Glulisine

Cartridge OBSOLETE

Vial $94.91

Pen $129.42

Short-Acting

Novolin R Insulin Reg Human Rec.Cartridge $119.47

Vial $55.28Pen OBSOLETE

Humulin R Insulin Regular Human Rec.Vial 100u/ml $55.28Vial 500u/ml $321.86

Intermediate-Acting

Novolin N Insulin NPH Human Recom.Cartridge $119.47

Vial $55.28Pen $104.89

Humulin N Insulin NPH Human Recom.

Vial $55.28Pen $175

Long-Acting

Levemir DetemirVial $102.73Pen $140.07

LantusInsulin Glargine, Hum. Rec.

Analogue

Vial $101.34

Pen $195.80

Cartridge $195.71

Mixed Preparations

Humalog Mix75/25

Insulin LisproProtamine/Insulin Lispro

Pen $212

Vial $109.75

NovoLog Mix70/30 Insulin Aspart Protamine/

Insulin Aspart

Cartridge OBSOLETEPen $212

Vial $109.75

Humalog Mix50/50

Insulin NPH/Ins LisproVial $109.75

Pen $212

Humulin 70/30Insulin NPH

Hu Rec/Ins Rg Hu Rec.Pen $175

Vial $55.28

Novolin 70/30Insulin NPH Hu Rec/Ins Rg

Hu Rec.

Cartridge $119.47

Vial $55.28

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REFERENCES

1 Food and Drug Administration. Early communication about safety of Lantus (insulin glargine).www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHealthcareProfessionals/ucm169722.htm (accessed 2010 Nov 20).

1 Food and Drug Administration. Early Communication about Safety of Lantus (insulin glargine).www.fda.gov/Drugs/DrugSafety/PotsmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHealthcareProfessionals/ucm169722.htm (accessed 2010 Nov 20).

2 American Diabetes Association. ADA statement on insulin glargine and cancer.http://forecast.diabetes.org/news/ada-statement-insulin-glargine-and-cancer (accessed 2010 Nov 20).

3

American Association of Clinical Endocrinologists. AACE response to insulin glargine cancer riskarticles in Diabetologia. http://media.aace.com/article_display.cfm?article_id=4932 (accessed 2010 Oct20).

4 European Association for the Study of Diabetes. EASD statement: Lantus insulin: a possible link withcancer which requires further investigation. http://webcast.easd.org/press/glargine/glargine.htm(access 2010 Oct20).

5 Centers for Disease Control and Prevention. Press release. Estimates of diagnosed diabetes nowavailable for all U.S. counties: 2008. www.cdc.gov/media/pressrel/2008/r080624.htm (accessed 2010Oct 28).

6 Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the USadult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. PopulationHealth Metrics 2010;8(29):1-12.

7 American Diabetes Association: economic costs of diabetes in the U.S. in 2007. Diabetes Care2008;32:596-615.

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9 The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment ofdiabetes on the development and progression of long-term complications in insulin-dependent diabetesmellitus. N Engl J Med 1998;339:229-34.

10 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control withsulphonylureas or insulin compared with conventional treatment and risk of complications in patientswith type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53.

11 Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: aconsensus algorithm for the initiation and adjustment of therapy: a consensus statement from the

American Diabetes Association and the European Association for the Study of Diabetes. DiabetesCare 2006;29:1963-72.

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12 Owens DR, Zinman B, Bolli GB. Insulins today and beyond. Lancet 2008;358:739-46.

13 White JR. Insulin analogs: what are the clinical implications of structural differences? Diabetes&Pharm Care 2010 May: 3-7.

14 Humalog (insulin lispro injection, usp) prescribing information. Indianapolis, IN: Eli Lilly andCompany; 2007.

15 NovoLog (insulin aspart [rDNA origin] injection) prescribing information. Princeton, NJ: Novo NordiskA/S; 2007.

16 Apidra (insulin glulisine) prescribing information. Bridgewater, NJ: sanofi-aventis, LLC; 2008.

17 Lantus (insulin glargine) prescribing information. Bridgewater, NJ: sanofi-aventis, LLC; 2007.

18Levemir (insulin detemir [rDNA origin] injection) prescribing information. Princeton, NJ: Novo Nordisk;2007.

19 Humulin R insulin (U-500) package insert. Indianapolis, IN: Eli Lilly and Company; 2009.

20 Cochran E, Musso C, gorden P. The use of U-500 in patients with extreme insulin resistance.Diabetes Care 2005;28:1240-4.

21 Garg R, Johnston V, McNally P, et al. U-500 insulin: why, when and how to use in clinical practice.Diabetes Metab Res Rev 2007;23:265-8.

22 NovoLog Mix 70/30 ([rDNA origin] injection) prescribing information. Princeton, NJ: Novo NordiskA/S; 2010.

23 Humalog Mix 75/25 ([rDNA origin] injection) prescribing information. Indianapolis, IN: Eli Lilly andCompany; 2009.

24 Humalog Mix 50/50 ([rDNA origin] injection) prescribing information. Indianapolis, IN: Eli Lilly andCompany; 2009.

25 Humulin Mix 70/30. ([rDNA origin] injection) prescribing information. Indianapolis, IN: Eli Lilly andCompany; 2009.

26 Novolin Mix 70/30 ([rDNA origin] injection) prescribing information. Princeton, NJ: Novo Nordisk A/S;2010.

27 Bloomgarden ZT. Aspects of insulin treatment. Diabetes Care 2010;33:e1-6.

28 Plank J, Bodenlenz M, Sinner F, et al. A double-blind, randomized, dose-response studyinvestigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analogdetemir. Diabetes Care 2005;28:1107-12.

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29 Swinnen SG, Dain M-P, Aronson R, et al. A 24-week, randomized, treat-to-target trial comparinginitiation of insulin glargine once-daily with insulin detemir twice-daily in patients with type 2 diabetesinadequately controlled on oral glucose-lowering drugs. Diabetes Care 2010;33:1176-78.

30 Rosenstock J, Davie M, Home P, et al. A randomised, 52-week, treat-to-target trial comparinginsulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-nave people with type 2 diabetes. Diabetologia 2008;51:408-16.

31 Rave K, Heise T, Pfutzner A, et al. Coverage of postprandial blood glucose excursions with inhaledtechnosphere insulin in comparison to subcutaneously injected regular human insulin in subjects withtype 2 diabetes. Diabetes Care 2007;30:2307-8.

32

Rosenstock J, Lorber D, Gnudi L, et al. Prandial inhaled insulin plus basal insulin glargine versustwice daily biaspart insulin for type 2 diabetes: a multicentre randomised trial. Lancet2010;375:224453.

33 Comparison of insulins and injectable diabetes meds. Pharmacists Letter/Prescribers Letter2010;26:260304.

34 Dailey, George. Rosenstock J. Insulin Glulusine Provides Glycemic Control in Patients with Type 2Diabetes. Diabetes Care 2004 27:2363-2368.

35 Dreyer M, Prager R, Robinson A, et al. 2005. Efficacy and safety of insulin glulisine in patients withType 1 diabetes. Horm Metab Res, 37:702-7.

36 Home P, Bartley, P, et al. 2004. Insulin Detemir Offers Improved Glycemic Control Compared withNPH in People with Type 1 Diabetes. Diabetes Care 27:1081-1087.

37 Hermansen K, Davies M, et al. 2006. A 26-Week, Randomized, Parallel, Treat-to-Target TrialComparing Insulin Detemir with NPH Insulin as Add-On Therapy to Oral Glucose-Lowering Drugs inInsulin Nave People With Type 2 Diabetes. Diabetes Care 29:1269-1274.

38 Humulin N insulin (rDNA origin) Isophane Suspension prescribing information. Indinanapolis, IN: EliLilly and Company; 2009.

39 Novolin N insulin (recombinant DNA origin) prescribing information. Princeton, NJ: Novo Nordisk A/S;

2005.40 FDA Website, Drug Details Exubera Available at:http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails .

Accessed January 1, 2011.

41 FDA Website, Drug Details Levemir Available at:http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails .


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42 FDA Website, Drug Details Apidra Available at:http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails .


43 Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. Volume 34, Supplement 1, January2011.

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