references: obesity management for the treatment of type 2 ...2016 in the areas of obesity...

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


of type 2 diabetes





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


Goal setting Group sessionsTelephone coachingMedical supervision

682

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


Self-monitoring

1-on-1 counselingOnline coaching

424

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


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.


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.


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)


Complication rates

Estimates, % 17.00 (11.00-23.00)


Reoperation rates

Estimates, % 6.95 (3.27-12.04)


SH Chang. JAMA Surg 149:275, 2014


of type 2 diabetes





Algorithm for AntihyperglycemicTherapy 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

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


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


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



of type 2 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


*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

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.


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


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


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


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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of type 2 diabetes





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


of type 2 diabetes





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


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



of type 2 diabetes





references: obesity management for the treatment of type 2 ...2016 in the areas of obesity...

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