What’s New in the ADA Standards of Medical Care in Diabetes...What’s New in the ADA Standards of...

What’s New in the ADA Standards of

Medical Care in Diabetes William H. Herman, MD, MPH

Stefan S. Fajans/GlaxoSmithKline Professor of Diabetes Professor of Internal Medicine and Epidemiology

University of Michigan Director, Michigan Center for Diabetes Translational Research

Chair, American Diabetes Association Professional Practice Committee

Speaker Financial Disclosure Information

Dr. Herman serves on Data Safety Monitoring Boards for

Merck and Lexicon

Outline • Obesity management in the treatment of

type 2 diabetes • The role of SGLT-2 inhibitors and GLP-1

receptor agonists in the treatment of type 2 diabetes

• Controversies in lipid management in diabetes

Medical Nutrition Therapy There is no one-size-fits-all eating pattern for individuals with diabetes.

ADA. Standards of Care, 2016

Goals of Medical Nutrition Therapy for Adults with Diabetes • To promote and support healthful eating

patterns, emphasizing a variety of foods in appropriate portion sizes, in order to improve overall health and to ‒ Attain individualized glycemic, blood

pressure, and lipid goals ‒ Delay or prevent complications of diabetes ‒ Achieve and maintain body weight goals

ADA. Standards of Care, 2016

Diet Recommendations • Diet, physical activity, and behavioral

therapy designed to achieve 5% weight loss should be prescribed for overweight and obese patients with type 2 diabetes ready to achieve weight loss.

• Interventions should be high intensity (≥16 sessions in 6 months) and offer long-term weight maintenance counseling.

ADA. Diabetes Care 39(Suppl 1):S47, 2016

Components and Costs of High Intensity Commercial or Proprietary Weight-Loss Programs

Program Nutrition Physical Activity

Behavioral Strategies Support

Monthly Cost, $

Weight Watchers

Low-calorie conventional foods

Activity tracking

Self-monitoring

Group sessions Online coaching Online community forum

43

Jenny Craig Low-calorie meal replacements

Encourages increased activity

Goal setting Self-monitoring

1-on-1 counseling 570

Nutrisystem Low-calorie meal replacements

Exercise plans Self-monitoring

1-on-1 counseling Online community forum

280

HMR Very-low-calorie or low-calorie meal replacements


Goal setting Group sessions Telephone coaching Medical supervision

682

Medifast Very-low-calorie or low-calorie meal replacements


Self-monitoring

1-on-1 counseling Online coaching

424

OPTIFAST Very-low-calorie or low-calorie meal replacements


Problem solving

1-on-1 counseling Group support Medical supervision

665

Adapted from KA Gudzune. Ann Int Med 162:501, 2015

Differences in Mean Percentage of Weight Change with Low Calorie* and Very Low Calorie**

Weight-Loss Programs over Time

2.7 4.1

2.8 2.9

9.3 8.2

3.0

0

10

3 mos 6 mos 12 mos 24 mos

Difference in

Mean % Weight Change

LCDVLCD

Adapted from KA Gudzune. Ann Int Med 162:501, 2015

* Weight Watchers ** HMR or Optifast

Look AHEAD • RCT that examined whether weight loss in

overweight and obese individuals with type 2 diabetes reduces cardiovascular morbidity and mortality over 11 years (median 9.6 yrs)

• Randomized 5,145 overweight or obese individuals to: – Intensive lifestyle intervention – Diabetes support and education (control)

The Look AHEAD Research Group. NEJM 2013;369:145

Intensive Lifestyle Intervention participants had greater weight loss at every time point

Diabetes Support & Education

Intensive Lifestyle Intervention

-2.1%

-3.5%

-8.5%

-4.66% -4.7% -6.0%


Intensive Lifestyle Intervention participants had greater improvements in HbA1c


Diabetes Support & Education

Intensive Lifestyle Intervention

Intensive Lifestyle Intervention did not reduce cardiovascular morbidity and mortality


But… the Intensive Lifestyle Intervention had other positive effects: • Partial remission of diabetes • Improvements in physical functioning,

mobility, and quality-of-life • Reductions in urinary incontinence, sleep

apnea, and depression


Pharmacotherapy Recommendations • Weight loss medications may be effective as

adjuncts to diet, physical activity, and behavioral counseling for selected patients with type 2 diabetes and BMI ≥27 kg/m2.

• If a patient’s response to weight loss medications is <5% after 3 months or if there are safety or tolerability issues at any time, the medication should be discontinued and alternative medications or treatment approaches should be considered.


FDA-Approved Medications for the Long-Term Treatment of Obesity

1-Year weight change status Adverse effects

Drug name Adult dosing

Average wholesale price

(per month)

Average weight loss relative to

placebo

% Patients with ≥5% loss of

baseline weight Common Serious

Orlistat (Xenical)

120 mg t.i.d. $670 3.4 kg 35-73% Abdominal pain, fecal urgency, fat malabsorption

Liver failure and oxalate nephropathy

Lorcaserin (Belviq)

10 mg b.i.d. $263 3.2 kg 38-48% Headache, fatigue

Serotonin syndrome, heart valve disorders (<2.4%)

Phentermine/ topiramate ER

(Qsymia)

Maximum dose: 15 mg/92 mg q.d.

$239 8.9 kg 45-70% Paresthesia, xerostomia, constipation, headache

Topiramate is tertogenic (cleft lip/ palate)

Naltrexone/ bupropion

(Contrave)

Maximum dose: 16 mg/180 mg b.i.d.

$251 2.0-4.1 kg 36-57% Nausea, constipation, headache

Depression, mania, contra-indicated in seizure disorders

Liraglutide (Saxenda)

Maintenance dose: 3 mg s.c. q.d.

$1,385 5.8-5.9 kg 51-73% Nausea, vomiting, diarrhea, constipation, headache

Pancreatitis, acute renal failure, contraindicated with MTC or MEN2

Adapted from ADA. Diabetes Care 39(Suppl 1):S47, 2016

Bariatric Surgery Recommendations • Metabolic surgery should be recommended to treat type 2

diabetes in surgical candidates with BMI ≥40 kg/m2 (BMI ≥37.5 kg/m2 in Asian Americans), regardless of the level of glycemic control or complexity of glucose-lowering regimens, and in patients with BMI 35.0-39.9 kg/m2 (32.5-37.4 kg/m2 in Asian Americans) when hyperglycemia is inadequately controlled despite lifestyle and optimal medical therapy.

• Metabolic surgery should be considered for patients with type 2 diabetes and BMI 30.0-34.9 kg/m2 (27.5-32.4 kg/m2 in Asian Americans) if hyperglycemia is inadequately controlled despite optimal treatment with oral and/or injectable medications (including insulin).

F Rubino. Diabetes Care 39:861, 2016

Bariatric Surgery Recommendations • Metabolic surgery should be performed in high-

volume centers with multidisciplinary teams that are experienced in the management of diabetes and gastrointestinal surgery.

• Long-term support and annual medical monitoring of micronutrient and nutritional status must be provided to patients after surgery.

F Rubino. Diabetes Care 39:861, 2016

Metabolic Surgery: Baseline Characteristics of the STAMPEDE

Population with Type 2 Diabetes

Parameter

Intensive Medical Therapy (N=40)

Gastric Bypass (N=48)

Sleeve Gastrectomy

(N=49) Age – yrs 50 ± 8 48 ± 8 48 ± 8 Female sex (%) 68 58 78 Caucasian race (%) 73 75 74 Body-mass index – (kg/m2) 36.4 ± 3.0 37.1 ± 3.4 36.1 ± 3.9 Body-mass index <35 kg/m2 (%) 45 27 37 Duration of diabetes – yrs 8.8 ± 5.38 8.0 ± 5.36 8.3 ± 4.49 Insulin users (%) 43 44 43

PR Schauer. N Engl J Med 370:2002, 2014


Mean Change in BMI by Treatment Group, STAMPEDE Study


Mean Change in Glycated Hemoglobin by Treatment Group, STAMPEDE Study


Polar Chart of Scores of Quality-of-Life at 3-years by Treatment Group, STAMPEDE Study

Meta-analysis of Risks of Bariatric Surgery from Randomized Controlled Trials, 2002-2012

Mean (95% CI) Mortality ≤30 d Estimates, % 0.08 (0.01-0.24) Study/arm/No. of patients 15/30/1803 Mortality >30 d Estimates, % 0.31 (0.01-0.75) Study/arm/No. of patients 15/30/1703 Complication rates Estimates, % 17.00 (11.00-23.00) Study/arm/No. of patients 16/30/1778 Reoperation rates Estimates, % 6.95 (3.27-12.04) Study/arm/No. of patients 12/23/1322

SH Chang. JAMA Surg 149:275, 2014

Algorithm for Antihyperglycemic Therapy in Type 2 Diabetes


Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study

(GRADE)

• to compare the effectiveness of four medications combined with metformin to achieve and maintain HbA1c <7%

Specific Aim

DM Nathan. Diabetes Care 36:2254, 2013

Screening Type 2 diabetes

Treated with metformin alone HbA1c >6.8% at screening

Less than 10 years duration at randomization

Metformin run-in Titrate metformin to 1000 (min) – 2000 (goal) mg/day

Randomization n=6000 eligible subjects

Sulfonylurea (glimepiride)

n=1500

DPP-IV inhibitor (sitagliptin)

n=1500

GLP-1 analog (liraglutide)

n=1500

Insulin (glargine) n=1500

HbA1c 6.8-8.5% at final run-in visit

DM Nathan. Diabetes Care 36:2254, 2013

Where do the SGLT-2 inhibitors fit into the algorithm for antihyperglycemic therapy?

• Empagliflozin is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

Jardiance (empagliflozin) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2016

Results of 24-week placebo-controlled trials of empagliflozin

Trial Baseline A1c %

10 mg ∆ A1c %

∆ weight (kg)

25 mg ∆ A1c %

∆ weight (kg)

Monotherapy versus Pbo

7.9 -0.7 -2.5 -0.9 -2.8

Combination with metformin

7.9 -0.6 -2.0 -0.6 -2.5

Sulfonylurea 8.1 -0.6 -2.4 -0.6 -2.7 DPP-4I N.S. * * * * TZD 8.1 -0.5 -2.6 -0.6 -2.4

Baseline 10 mg 25 mg Trial A1c % ∆ A1c % ∆ weight (kg) ∆ A1c % ∆ weight (kg) Monotherapy 7.9 -0.7 -2.5 -0.9 -2.8 Combination therapy with: Metformin 7.9 -0.6 -2.0 -0.6 -2.5 Sulfonylurea 8.1 -0.6 -2.4 -0.6 -2.7 DPP-IV 8.0 -0.7 -2.5 -0.6 -3.2 TZD 8.1 -0.5 -2.6 -0.6 -2.4 Insulin* 8.3 -0.5 -3.0 -0.7 -3.0

* 78 weeks

Jardiance (empagliflozin) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2016

Summary In placebo controlled trials, empagliflozin is: • moderately effective (~0.6% HbA1c ↓) • associated with weight loss (~3 kg ↓) • not associated with hypoglycemia • associated with GU infections • expensive (AWP $470 / mo)

Red Book, 2016

The EMPA-REG Outcome Trial compared the impact of empagliflozin and placebo when added to standard care on cardiovascular death, nonfatal MI, and nonfatal stroke in patients with type 2 diabetes and established cardiovascular disease.

B Zinman. N Engl J Med 373:2117, 2015

Eligibility criteria for the EMPA-REG Outcome Trial

• Adults ≥18 years of age with type 2 diabetes and cardiovascular disease and BMI <45 kg/m2, eGFR ≥30 ml/min, and HbA1c 7.0-10.0%



Cumulative Incidence of Nonfatal MI, Nonfatal Stroke, or Cardiovascular Death by

Treatment Group, EMPA-REG

Baseline Characteristics of the EMPA-REG Study Population

Characteristic* Placebo (N=2333)

Pooled empagliflozin (N=4687)

Age – years ± SD 63 ± 9 63 ± 9

Sex (% male) 72 71

Race (% White) 72 73

Body mass index – kg/m2 30.7 ± 5.2 30.6 ± 5.3

>10 years since diagnosis of type 2 diabetes (%) 57 57

Insulin treated (%) 49 48

Glycated hemoglobin (%) 8.08 ± 0.84 8.07 ± 0.85

CV risk factor (%)

Coronary artery disease 76 76

History of myocardial infarction 46 47

Coronary artery bypass graft 24 25

Cardiac failure 11 10

History of stroke 24 23

Peripheral artery disease 21 21


The LEADER Trial compared the impact of liraglutide and placebo when added to standard care on cardiovascular death, nonfatal MI, and nonfatal stroke in patient with type 2 diabetes at high cardiovascular risk.

SP Marso. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827

Eligibility criteria for LEADER

• Adults ≥50 years of age with type 2 diabetes and cardiovascular disease or ≥60 with ≥1 cardiovascular risk factor and HbA1c ≥7.0%



Cumulative incidence of nonfatal MI, nonfatal stroke, or cardiovascular death by

treatment group, LEADER

Baseline Characteristics of the LEADER Study Population

Characteristic* Placebo (N=4672)

Liraglutide (N=4668)

Age – years ± SD 64 ± 7 64 ± 7

Sex (% male) 64 65

Body mass index – kg/m2 32.5 ± 6.3 32.5 ± 6.3

Diabetes duration, years 13 ± 8 13 ± 8

Glycated hemoglobin (%) 8.7 ± 1.5 8.7 ± 1.6

CVD risk factors (%)

Prior myocardial infarction 30 31

Prior revascularization 39 39

>50% stenosis of coronary, carotid, or lower extremity arteries

26 25

Documented asymptomatic cardiac ischemia 26 27

Documented symptomatic CHD 9 9

Prior stroke or transient ischemic attack 17 16


U.S. Population with diagnosed type 2 diabetes by age, 2010

0

5

10

20-44 45-64 65+

Mill

ions

with

dia

bete

s

Age in years

Total = 21 million

U.S. Population with diagnosed type 2 diabetes reporting any heart

disease or stroke by age, 2010

0

5

10

20-44 45-64 65+Mill

ions

with

CVD

or s

trok

e

Age in years

Total <7 million (30%)

EMPA-REG Outcome Trial: Baseline risk factors

Placebo Pooled EMPA HbA1c % 8.1 ± 0.8 8.1% ± 0.9 SBP mmHg 136 ± 17 135 ± 17 LDL-C mg/dl 85 ± 35 86 ± 36


EMPA-REG Outcome Trial: Differences in cardiovascular risk

factors at 2-years follow-up HbA1c -0.5% Weight -2 kg Waist circumference -1.5 cm Systolic BP -3 mmHg Diastolic BP -1 mmHg LDL-C +3 mg/dl HDL-C +2 mg/dl Uric acid -3 mg/dl


LEADER: Baseline risk factors

Placebo Liraglutide HbA1c % 8.7 ± 1.5 8.7 ± 1.6 SBP mmHg 136 ± 18 136 ± 18 LDL-C mg/dl ― ―


HbA1c -0.5% Weight -2.4 kg

Systolic BP -2 mmHg

LEADER: Differences in cardiovascular

risk factors at 2-years follow-up


Unresolved questions • What explains the cardiovascular

and survival benefits seen with empagliflozin and liraglutide? – Is it due to the combination of small

beneficial changes in multiple known cardiovascular risk factors?

– Is it due to unmeasured “off-target” effects?

If the cardiovascular and survival benefits of newer therapies are due to the combination of small beneficial effects on known risk factors, what benefits could be achieved by intensifying risk factor control using other, less expensive, glucose, blood pressure, and lipid lowering agents?

Conclusions • Newer therapies are expensive

–Empagliflozin $4,884 / year –Liraglutide $9,972 / year

• The costs of diabetes treatments must be carefully weighed against their likely benefits

Conclusions • Empagliflozin or liraglutide in

combination with metformin are reasonable options for initial dual therapy for type 2 diabetes

• Empagliflozin or liraglutide may be preferred treatments for older adults with type 2 diabetes and high cardiovascular risk

Recommendation for Statin Treatment in People with Diabetes

Age Risk factors Recommended statin intensity <40 years None None

ASCVD risk factor(s)* Moderate or high ASCVD High

40-75 years None Moderate ASCVD risk factors High ASCVD High

>75 years None Moderate ASCVD risk factors Moderate or high ASCVD High


*ASCVD risk factors include LDL cholesterol ≥100 mg/dL (2.6 mmol/L), high blood pressure, smoking, overweight and obesity, and family history of premature ASCVD.

High-intensity and moderate-intensity statin therapy*

High-intensity statin therapy Moderate-intensity statin therapy Lowers LDL cholesterol by ≥50% Lowers LDL cholesterol by 30% to <50% Atorvastatin 40-80 mg Atorvastatin 10-20 mg Rosuvastatin 20-40 mg Rosuvastatin 5-10 mg

Simvastatin 20-40 mg Pravastatin 40-80 mg Lovastatin 40 mg Fluvastatin XL 80 mg Pitavastatin 2-4 mg


*Once-daily dosing.

Where do non-statin lipid lowering therapies fit into the management of dyslipidemia

in diabetes?

IMPROVE-IT

CP Cannon. N Engl J Med 372:2387, 2015

Efficacy of Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes

CP Cannon. N Engl J Med 372:2387, 2015

Lipid Management • The addition of exetimibe to moderate-

intensity statin therapy provides additional cardiovascular benefit compared with moderate-intensity statin therapy alone and may be considered for patients with a recent acute coronary syndrome with LDL cholesterol ≥50 mg/dL who cannot tolerate high-intensity statin therapy.


Lipid Management, continued • Combination therapy (statin/fibrate) has not

been shown to improve atherosclerotic cardiovascular disease outcomes and is generally not recommended. However, therapy with statin and fenofibrate may be considered for men and both triglyceride level ≥204 mg/dL and HDL cholesterol level ≤34 mg/dL.


Lipid Management, continued • Combination therapy (statin/niacin) has not

been shown to provide additional cardiovascular benefit above statin therapy alone and may increase the risk of stroke and is not generally recommended.


Does statin therapy increase the risk of type 2 diabetes?

Association Between Statin Therapy and Incident Diabetes in 13 Major Cardiovascular Trials

N Sattar. Lancet 375:735, 2010

Overall (P=11.2% [95% CI 0.0-50.2%]) 1.09 (1.02-1.17)

Association Between Different Statins and Development of Diabetes


Atorvastatin

Simvastatin Rosuvastatin Pravastatin Lovastatin

Overall 1.09 (1.02-1.17)

1.14 (0.89-1.46)

1.11 (0.97-1.26)

1.18 (1.04-1.33)

1.03 (0.90-1.19)

0.98 (0.70-1.38)

How do the benefits of statin therapy compare to the risks of

statin therapy?

Treating 255 nondiabetic patients with statins for 4 years will result in: • 1 additional case of diabetes • 5.1 fewer cardiovascular events


Do statins cause cognitive impairment?

Statins and Cognitive Function: A Systematic Review

Dementia

Alzheimer disease

Mild cognitive impairment

0.87 (0.82-0.92)

0.79 (0.63-0.99)

0.66 (0.51-0.86)

Favors Statin Users Favors Nonusers K R

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