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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
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
Encourages increased activity
Goal setting Group sessions Telephone coaching Medical supervision
682
Medifast Very-low-calorie or low-calorie meal replacements
Encourages increased activity
Self-monitoring
1-on-1 counseling Online coaching
424
OPTIFAST Very-low-calorie or low-calorie meal replacements
Encourages increased activity
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%
The Look AHEAD Research Group. NEJM 2013;369:145
Intensive Lifestyle Intervention participants had greater improvements in HbA1c
The Look AHEAD Research Group. NEJM 2013;369:145
Diabetes Support & Education
Intensive Lifestyle Intervention
Intensive Lifestyle Intervention did not reduce cardiovascular morbidity and mortality
The Look AHEAD Research Group. NEJM 2013;369:145
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
The Look AHEAD Research Group. NEJM 2013;369:145
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.
ADA. Diabetes Care 39(Suppl 1):S47, 2016
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
PR Schauer. N Engl J Med 370:2002, 2014
Mean Change in BMI by Treatment Group, STAMPEDE Study
PR Schauer. N Engl J Med 370:2002, 2014
Mean Change in Glycated Hemoglobin by Treatment Group, STAMPEDE Study
PR Schauer. N Engl J Med 370:2002, 2014
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
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
Algorithm for Antihyperglycemic Therapy in Type 2 Diabetes
ADA. Diabetes Care 39(Suppl 1):S52, 2016
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%
B Zinman. N Engl J Med 373:2117, 2015
B Zinman. N Engl J Med 373:2117, 2015
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
B Zinman. N Engl J Med 373:2117, 2015
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%
SP Marso. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827
SP Marso. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827
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
SP Marso. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827
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
B Zinman. N Engl J Med 373:2117, 2015
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
B Zinman. N Engl J Med 373:2117, 2015
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 ― ―
SP Marso. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827
HbA1c -0.5% Weight -2.4 kg
Systolic BP -2 mmHg
LEADER: Differences in cardiovascular
risk factors at 2-years follow-up
SP Marso. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827
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
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
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
ADA. Diabetes Care 39(Suppl 1):S60, 2016
*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
ADA. Diabetes Care 39(Suppl 1):S60, 2016
*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.
ADA. Diabetes Care 39(Suppl 1):S60, 2016
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.
ADA. Diabetes Care 39(Suppl 1):S60, 2016
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.
ADA. Diabetes Care 39(Suppl 1):S60, 2016
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
N Sattar. Lancet 375:735, 2010
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
N Sattar. Lancet 375:735, 2010
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
icha
rdso
n. A
nn In
tern
Med
159
:688
, 201
3
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