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What’s New in the Standards of Medical Care in Diabetes – 2016? William H. Herman, MD, MPH
Friday, March 4, 2016 1:00 p.m. – 1:45 p.m.
Caring for patients with diabetes is hard work. Each year, the American Diabetes Association updates the Standards of Medical Care in Diabetes to reflect new evidence, to organize the evidence to make it more useful to clinicians, and to assist clinicians in tailoring treatment to vulnerable populations with diabetes and making care more patient-centered. In this presentation, Dr. Herman highlights some of the important revisions to the Standards of Care in 2016 in the areas of obesity management for the treatment of type 2 diabetes, SGLT-2 inhibitors for the management of type 2 diabetes, lipid management in diabetes, the treatment of diabetic retinopathy, and the treatment of gestational diabetes mellitus.
References:
Obesity Management for the Treatment of Type 2 Diabetes
1. Gudzune KA, Doshi RS, Mehta AK, Chaudhry ZW, Jacobs DK, Vakil RM, Lee CJ, Bleich SN, Clark JM. Efficacy of commercial weight-loss programs: an updated systematic review. Ann Intern Med 2015;162:501-512. Review. Erratum in: Ann Intern Med. 2015 May 19;162(10):739-740.
2. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA 2014;311:74-86.
3. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, Lau DC, le Roux CW, Violante Ortiz R, Jensen CB, Wilding JP; SCALE Obesity and Prediabetes NN8022-1839 Study Group. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med 2015;373:11-22.
4. Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Brethauer SA, Navaneethan SD, Aminian A, Pothier CE, Kim ES, Nissen SE, Kashyap SR; STAMPEDE Investigators. Bariatric surgery versus intensive medical therapy for diabetes--3-year outcomes. N Engl J Med 2014;370:2002-2013.
5. Chang SH, Stoll CR, Song J, Varela JE, Eagon CJ, Colditz GA. The effectiveness and risks of bariatric surgery: an updated systematic review and meta-analysis, 2003-2012. JAMA Surg 2014;149:275-287.
Approaches to Glycemic Treatment
1. Nathan DM, Buse JB, Kahn SE, Krause-Steinrauf H, Larkin ME, Staten M, Wexler D, Lachin JM; GRADE Study Research Group. Rationale and design of the glycemia reduction approaches in diabetes: a comparative effectiveness study (GRADE). Diabetes Care 2013;36:2254-2261.
2. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-2128.
Cardiovascular Disease and Risk Management
1. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM;
IMPROVE-IT Investigators. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015;372:2387-2397.
2. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM, Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR, Nakamura H, Ohashi Y, Mizuno K, Ray KK, Ford I. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735-742.
3. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 2012;380:565-571.
4. Richardson K, Schoen M, French B, Umscheid CA, Mitchell MD, Arnold SE, Heidenreich PA, Rader DJ, deGoma EM. Statins and cognitive function: a systematic review. Ann Intern Med 2013;159:688-697.
Microvascular Complications and Foot Care
1. Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, Gibson A, Sy J, Rundle AC, Hopkins JJ, Rubio RG, Ehrlich JS; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012;119:789-801.
Management of Diabetes in Pregnancy
1. Balsells M, García-Patterson A, Solà I, Roqué M, Gich I, Corcoy R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ 2015;350:h102.
What’s New in the 2016 Standards of
Medical Care in Diabetes
William H. Herman, MD, MPHStefan 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 DisclosureInformation
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 in the treatment of type 2 diabetes
• Controversies in lipid management in diabetes
• New treatments for diabetic retinopathy
• Pharmacologic treatments for gestational diabetes mellitus
Outline• Obesity management in the treatment
of type 2 diabetes
• The role of SGLT-2 inhibitors in the treatment of type 2 diabetes
• Controversies in lipid management in diabetes
• New treatments for diabetic retinopathy
• Pharmacologic treatments for gestational diabetes mellitus
DietRecommendations
• 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 NutritionPhysicalActivity
BehavioralStrategies Support
Monthly Cost, $
Weight Watchers
Low-calorie conventional foods
Activity tracking
Self-monitoring
Group sessionsOnline coachingOnline community forum
43
Jenny Craig Low-calorie mealreplacements
Encourages increased activity
Goal settingSelf-monitoring
1-on-1 counseling 570
Nutrisystem Low-calorie meal replacements
Exercise plans Self-monitoring
1-on-1 counselingOnline community forum
280
HMR Very-low-calorie or low-calorie meal replacements
Encourages increased activity
Goal setting Group sessionsTelephone coachingMedical supervision
682
Medifast Very-low-calorie or low-calorie meal replacements
Encourages increased activity
Self-monitoring
1-on-1 counselingOnline coaching
424
OPTIFAST Very-low-calorie or low-calorie meal replacements
Encourages increased activity
Problem solving
1-on-1 counselingGroup supportMedical 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
2.74.1
2.8 2.9
9.38.2
3.0
0
10
3 mos 6 mos 12 mos 24 mos
Difference in
Mean % Weight Change
LCD
VLCD
Adapted from KA Gudzune. Ann Int Med 162:501, 2015
* Weight Watchers** HMR or Optifast
PharmacotherapyRecommendations
• 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. $615 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.
$239 2.0-4.1 kg 36-57% Nausea,constipation, headache
Depression, mania
Liraglutide(Saxenda)
Maintenancedose: 3 mg s.c.q.d.
$1,282 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 SurgeryRecommendations
• Bariatric surgery may be considered for adults with BMI >35 kg/m2 and type 2 diabetes, especially if diabetes or associated comorbidities are difficult to control with lifestyle and pharmacological therapy.
• Patients with type 2 diabetes who have undergone bariatric surgery need lifelong lifestyle support and annual medical monitoring.
ADA. Diabetes Care 39(Suppl 1):S47, 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 in the treatment of type 2 diabetes
• Controversies in lipid management in diabetes
• New treatments for diabetic retinopathy
• Pharmacologic treatments for gestational diabetes mellitus
Algorithm for AntihyperglycemicTherapy 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
ScreeningType 2 diabetes
Treated with metformin aloneHbA1c >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
Where do SGLT-2 Inhibitors Fit into the Algorithm for Antihyperglycemic Therapy?
• Interpreting the results of the EMPA-REG Outcome Trial that examined the effects of empagliflozin, as compared with placebo, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high risk for cardiovascular events who were receiving standard care.
B Zinman. N Engl J Med 373:2117, 2015
Cumulative Incidence of Nonfatal MI, Nonfatal Stroke, or Cardiovascular Death by
Treatment Group, EMPA-REG
Absolute Reductions in Incidence of Cardiovascular Outcomes in EMPA-REG
Placebo (N=2333)
Empagliflozin(N=4687) Rate difference
(95% CI)p-value
Rate/1000 patient-years
Rate/1000patient-years
Primary outcome cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke
43.9 37.4 -6.5 (-12.6, -0.4) 0.04
All-cause mortality 28.6 19.4 -9.1 (-13.8, -4.5) <0.001
Cardiovascular death
20.2 12.4 -7.7 (-11.6, -3.9) <0.001
Hospitalization for heart failure
14.5 9.4 -5.1 (-8.4, -1.8) 0.003
B Zinman. N Engl J Med 373:2117, 2015
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
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
Outline• Obesity management in the treatment
of type 2 diabetes
• The role of SGLT-2 inhibitors in the treatment of type 2 diabetes
• Controversies in lipid management in diabetes
• New treatments for diabetic retinopathy
• Pharmacologic treatments for gestational diabetes mellitus
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
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.
ADA. Diabetes Care 39(Suppl 1):S60, 2016
Recommendation for Statin and Combination Treatment in People with Diabetes
Age Risk factorsRecommended 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
ACS and LDL cholesterol >50 mg/dL in patients who cannot tolerate high-dose statins
Moderate plus ezetimibe
>75 years None Moderate
ASCVD risk factors Moderate or high
ASCVD High
ACS and LDL cholesterol >50 mg/dL in patients who cannot tolerate high-dose statins
Moderate plus ezetimibe
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
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
Cardiovascular Benefits and Diabetes Risks of Statin Therapy in Primary Prevention:
The JUPITER TrialNo Major Risk Factors for Diabetes
P Ridker. Lancet 380:565, 2012
CVD Diabetes
Cardiovascular Benefits and Diabetes Risks of Statin Therapy in Primary Prevention:
The JUPITER TrialOne or More Major Risk Factors for Diabetes
P Ridker. Lancet 380:565, 2012
CVD Diabetes 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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Outline• Obesity management in the treatment
of type 2 diabetes
• The role of SGLT-2 inhibitors in the treatment of type 2 diabetes
• Controversies in lipid management in diabetes
• New treatments for diabetic retinopathy
• Pharmacologic treatments for gestational diabetes mellitus
Diabetic Retinopathy: Macular Edema
Type 2Type 1 Hemorrhages
DiskDisk Hemorrhages
Hard exudates
Hard exudates
Macula
Diabetic macular edema
24-month controlled treatment period(monthly intravitreal/sham injections: rescue laser,
if eligible, beginning month 3)
Randomization (1 eye per patient)
Intravitreal Ranibizumab for the Treatment of Diabetic Macular Edema
QD Nguyen. Ophthalmology 119:789, 2012
Compared to sham-treated patients, those treated with intravitreal ranibizumab were:
• More likely to achieve VA 20/40 or better
• More likely to have improved visual acuity
• Less likely to have worsened visual acuity
• Less likely to require laser procedures
• No more likely to experience ocular or non-ocular harm
QD Nguyen. Ophthalmology 119:789, 2012
Outline• Obesity management in the treatment
of type 2 diabetes
• The role of SGLT-2 inhibitors in the treatment of type 2 diabetes
• Controversies in lipid management in diabetes
• New treatments for diabetic retinopathy
• Pharmacologic treatments for gestational diabetes mellitus
Management of GDM
• 70 to 85% of women diagnosed with GDM using Carpenter-Coustan or National Diabetes Data Group (NDDG) criteria can control GDM with lifestyle modifications alone.
• The proportion is even greater when the lower IADPSG diagnostic criteria are used.
Pharmacologic Therapy of GDM
• Medications should be added if required to achieve glycemic targets.
• Insulin is the first line agent recommended for the treatment of GDM in the U.S.
• Individual randomized controlled trials support the efficacy and short-term safety of metformin (pregnancy category B) and glyburide (pregnancy category B). However, both agents cross the placenta, and long-term safety data are not available for either agent.
Pharmacologic Treatments for GDM: Glyburide vs Insulin
• Effective (only 10% require supplemental insulin)
• >2-fold higher incidence of macrosomia
• 100 g higher mean birth weight
• 2-fold higher incidence of neonatal hypoglycemia
Balsells. BMJ 2015;350:h102
Pharmacologic Treatments for GDM: Metformin vs Insulin• Less effective (⅓ to ½ require
supplemental insulin)
• Less maternal weight gain
• Less pregnancy-induced hypertension
• Less severe neonatal hypoglycemia
• Lower gestational age at delivery and more preterm birth
Balsells. BMJ 2015;350:h102
Pharmacologic Treatments for GDM: Conclusions
• Insulin is the preferred treatment
• Metformin (plus insulin when required) performs slightly better than insulin alone
• Glyburide is inferior to both insulin and metformin
Balsells. BMJ 2015;350:h102