Obesity, Diabetes, & Diet

Home , Amylin Pharmaceuticals

Obesity, Diabetes, & Diet COMBINING EVIDENCE FOR ALL THREE INTO IMPROVED PATIENT CARE Case Study Louis J. Aronne, MD, FACP Weill Cornell Medical College Columbia University College of Physicians and Surgeons Louis J. Aronne, MD, FACP Disclosures

!! Research/Grants: Amylin Pharmaceuticals, Inc.; Arena Pharmaceuticals, Inc.; F. Hoffmann-La Roche, Ltd.; Metabolous Pharmaceuticals, Inc.; Norvo Nordisk; Orexigen Therapeutics, Inc.; Pfizer Inc.; TransTech Pharma, Inc. !! Speakers Bureau: None !! Consultant: Allergan, Inc.; Amylin Pharmaceuticals, Inc.; GI Dynamics, Inc.; GlaxoSmithKline Consumer Healthcare, LP; Johnson & Johnson Pharmaceutical Research & Development, LLC; NeuroSearch, Inc.; Novo Nordisk; Orexigen Therapeutics, Inc.; Roche Laboratories, Inc.; VIVUS, Inc.; Wyeth Pharmaceuticals, Inc. !! Stockholder: Cardiometabolic Support Network, LLC !! Other Financial Interest: None !! Advisory Board: Allergan, Inc.; Amylin Pharmaceuticals, Inc.; GI Dynamics, Inc.; GlaxoSmithKline Consumer Healthcare, LP; Johnson & Johnson Pharmaceutical Research & Development, LLC; NeuroSearch, Inc.; Novo Nordisk; Orexigen Therapeutics, Inc.; Roche Laboratories, Inc.; VIVUS, Inc.; Wyeth Pharmaceuticals, Inc. Father A.V. 04May09: 378 lbs, 5’ 11”, BMI = 53

!! Dx w/ DMII in 2004 !! Long history of obesity !! Can’t control his eating, binges !! HbA1c = 8.4% !! FPG = 166 !! TG = 241 !! UA Microalbumin = 973 !! “Can’t tolerate metformin” !! Considering RYGB, but afraid to have surgery

DMII = diabetes mellitus type II; Hb = hemoglobin; FPG = fasting plasma glucose; TG = triglycerides; UA = urinalysis; RYGB = Roux-en-Y gastric bypass Father A.V. 04May09: 378 lbs, 5’ 11”, BMI = 53

!!Medications !!Insulin glargine 100 u QPM !!Insulin aspart 160 u BID !!Candesartan and hydrochlorothiazide 32/12.5 mg !!Pravastatin !!Pantoprazole Management Plan

!!Low glycemic diet !!Start exenatide 5 mcg BID (" hour a.c.) !!Start slow-release metformin 500 mg QD to see if tolerable !!Cut short-acting insulin in half !!Sleep study Results

!!Loses 20 lbs in 1 month !!Increase exenatide to 10 mcg BID !!Tolerates slow-release metformin, increase to 500 ER BID !!Titrate down insulin as he loses weight !!Sleep apnea–won’t use mask but sleeps better because of weight loss !!Good compliance with low glycemic diet Medication Changes Timeline

Date 5/4/09 6/2/09 6/9/09 8/12/09 9/28/09 4/28/10 7/28/10 Weight (lbs) 378 349 329 311 291 290 284 HbA1c (%) 8.4% 8.3% 7.1% FPG 166 207 Insulin 23.9 TG 241 417 UA Microalbumin 973 337 Medications Insulin aspart Insulin aspart Insulin aspart reduced to reduced to Insulin aspart d/c 80 u BID 40 u BID 20 u QD Insulin glargine 100 u QPM; Insulin glargine Insulin glargine reduced to reduced to reduced to 25 u QPM 10 u QPM 50 u QPM (5/27) Exenatide Inc Exenatide Exenatide Exenatide Exenatide 5 mcg BID 10 mcg BID 10 mcg BID 10 mcg BID 10 mcg BID Metformin ER Metformin ER Metformin ER 1250 mg 1000 mg BID 1000 mg BID Pramlintide Add Pramlintide increased to 60 mcg BID 120 mcg BID Ursodiol 300 mg BID Candesartan Candesartan Candesartan Candesartan cilexetil 32 mg (d/c HCT) 8 mg QD 8 mg QD 8 mg QD Glyburide Glyburide 1 mg BID 1 mg BID Pravastatin Pravastatin 40 mg QD 40 mg QD Hb = hemoglobin; FPG = fasting plasma glucose; TG = triglycerides; UA = urinalysis Are We Doing Enough in Patient Visits to Prevent and Manage Obesity? Robert F. Kushner, MD Northwestern University Feinberg School of Medicine Chicago, IL Robert F. Kushner, MD Disclosures

!!Research/Grants: None !!Speakers Bureau: None !!Consultant: Abbott Nutrition; Vivus, Inc. !!Stockholder: None !!Other Financial Interest: None !!Advisory Board: Allergan, Inc.; GI Dynamics; Orexigen Therapeutics, Inc. Medical Complications of Obesity

Mental health issues Depression, anxiety, insomnia Pulmonary disease Idiopathic intracranial Abnormal function hypertension Obstructive sleep apnea Stroke Hypoventilation syndrome Cataracts Nonalcoholic fatty liver Coronary heart disease disease Diabetes Steatosis Steatohepatitis Dyslipidemia Cirrhosis Hypertension Gall bladder disease Severe pancreatitis Gynecologic abnormalities Cancer Abnormal menses Breast, uterus, cervix Infertility Colon, esophagus, pancreas Polycystic ovarian syndrome Kidney, prostate Osteoarthritis Phlebitis Skin Venous stasis Gout What Should the Primary Care Provider Do?

!!Questions to consider: !!What is the role of the primary care provider? !!What resources do primary care clinicians need to provide effective obesity care? !!What is the best model for tackling the obesity epidemic?

Kushner RF. Arch Intern Med 2010;170:121-123. Tackling Obesity

!!Most assuredly, halting and reversing the obesity epidemic will require a comprehensive public health plan that addresses environmental, behavioral, and socioeconomic factors !!However, overweight and obese patients presenting to their primary care provider with comorbidities require treatment today

Kushner RF. Arch Intern Med 2010;170:121-123. Guidelines and Recommendations Regarding Obesity Care

!!Clinicians should screen all adult patients for obesity and offer intensive counseling and behavioral interventions to promote sustained weight loss for obese adults1 !!2010 HEDIS measures2 !!Adult body mass index (BMI) assessment !!Weight assessment !!Counseling for nutrition and physical activity for children/adolescents 1. US Preventive Services Task Force (USPSTF). Ann Intern Med 2003;139:930-932. 2. National Committee for Quality Assurance. Healthcare Effectiveness Data and Information Set (HEDIS) 2009. Mobilizing the Medical Community

!!Measure BMI and explain connection with increased risk for disease & disability !!Record physical activity levels and stress importance of daily activity !!Assess & record information on dietary patterns !!Work as a team !!Ensure that patients are referred to resources that will help meet their psychological, nutritional, and physical activity needs Office of the Surgeon General. The Surgeon General’s Vision for a Healthy and Fit Nation 2010. U.S. Department of Health and Human Services (HHS). 2010:1-21. Mobilizing the Medical Community (cont.)

!! Encourage clinicians & staff to practice healthy lifestyle behaviors and be role models !! Use best practice guidelines on how to counsel patients !! Promote effective prenatal counseling about maternal weight gain, breastfeeding !! Advocate for community strategies that improve nutrition and physical activity resources for patients !! Promote innovative ways to advocate for policy changes at local, state, and federal levels

Office of the Surgeon General. The Surgeon General’s Vision for a Healthy and Fit Nation 2010. U.S. Department of Health and Human Services (HHS). 2010:1-21. Trends in Obesity-Related Counseling in Primary Care: 1995-2004

† 25 Any (p = .152 ) Diet (p = .085) 20 Exercise (p = .123) 15

% of Visits % of Visits 10 Weight (p = .009) 5

0 1995-1996 1997-1998 1999-2000 2001-2002 2003-2004 Data from the National Ambulatory Medical Care Survey (NAMCS) * Information about weight loss counseling not collected between 1997 and 2000 † p-value based on test for linear trend McAlpine DD, et al. Medical Care 2007;45:322-329. Percent of Patients Receiving PCP Advice By Obesity Classification

100 Specific Advice 90 84 80 Told Overweight 75 70 62 60 48 48 50 46

Percent 40 32 28 30 20 10 0 Overweight Obesity I Obesity II Obesity III (BMI 27.0-29.9) (BMI 30.0-34.9) (BMI 35.0-39.9) (BMI # 40.0) Told overweight: X2 (test for linear trend) = 16.5, p = .001 Gave weight loss advice: X2 (test for linear trend) = 5.5, p = .019 Simkin-Silverman LR, et al. Prev Med 2005;40:71-82. A Catch-22 Managing Obesity in Primary Care

!!The phrase "Catch-22" is common idiomatic usage meaning "a no-win situation" or "a double bind” of any type 1 !!Uncommonly the chief complaint !!Limited insurance coverage !!Minimal to no physician training !!Few therapeutic options !!Sense of futility and avoidance !!No to minimal RD coverage !!Few office tools & resources 1. Heller J. Catch-22;1961. Barriers to Optimal Obesity Management

Bardia A, et al. Mayo Clin Proc 2007;82:927-932. Overweight & Obese Treatment Multiple Options

Self-help books/fad diets Community/park district/ church-based programs Over-the-counter medication/dietary supplements Internet programs Commercial programs Worksite programs Registered Dietitian Primary care provider Obesity medicine specialist Bariatric surgeon Obesity Treatment Pyramid

Surgery

BMI Pharmacotherapy Lifestyle Modification

Diet Physical Activity A Guide to Selecting Obesity Treatment

BMI Category

Treatment 25-26.9 27-29.9 30-34.9 35-39.9 # 40

Diet, physical With activity, and comorbidity + + + + behavior therapy

With Pharmacotherapy comorbidity + + +

With Surgery comorbidity +

NHLBI Obesity Education Initiative. The Practical Guide. 2001:1-94. Suggested Reading

Roadmaps for Clinical Practice: Case Studies in Disease Prevention and Health Promotion. Assessment and Management of Adult Obesity: A Primer for Physicians

Kushner RF. American Medical Association; Robert Wood Johnson Foundation. 2003. Developing a Chronic Care Model (CCM) of Care A Systems Approach

!!Put Prevention Into Practice !!AHRQ !!http://www.ahrq.gov !!Improving Chronic Illness Care* !!http://www.improvingchroniccare.org !!Chronic care training manual !!ICIC Improving your practice manual !!Tools

* Supported by The Robert Wood Johnson Foundation. Chronic Care Model (CCM)

2. Health System Health Care Organization 1. Community Resources 3. Self- 4. Delivery 5. Decision 6. Clinical and Policies Mgmt System Support Information Support Design Systems

Informed, Prepared, Activated Productive Proactive Patient Interactions Practice Team

Improved Outcomes Improving Chronic Illness Care. http://www.improvingchroniccare.org; Supported by The Robert Wood Johnson Foundation. Essential Elements of Good Chronic Illness (Obesity) Care

Informed, Productive Prepared Activated Interactions Practice Patient Team

Improving Chronic Illness Care. http://www.improvingchroniccare.org; Supported by The Robert Wood Johnson Foundation. Essential Elements of Good Chronic Illness (Obesity) Care

Informed, Productive Prepared Activated Interactions Practice Patient Team

At the time of the visit, the team has the patient information, decision support, people, equipment, and time required to deliver evidence-based clinical management and self-management support.

Improving Chronic Illness Care. http://www.improvingchroniccare.org; Supported by The Robert Wood Johnson Foundation. Essential Elements of Good Chronic Illness (Obesity) Care

Informed, Productive Prepared Activated Interactions Practice Patient Team

Patient understands the disease process, and realizes his/her role as the daily self-manager. Family and caregivers are engaged in the patient’s self-management. The provider is viewed as a guide or agent of change.

Improving Chronic Illness Care. http://www.improvingchroniccare.org; Supported by The Robert Wood Johnson Foundation. Activities of Self- Management

!!Encouraging people to become active participants !!Teaching condition-specific skills !!Promoting healthy behaviors !!Teaching problem-solving skills !!Assisting with the emotional impact of having a chronic condition !!Regular and sustained follow-up

Chen E, Bodenheimer T. Obesity Management 2008;4:227-231. Weight Control in the Physician’s Office

3 Group 1 Group 2 Group 3 2 RD classes RD classes Brief MD 1 + MRs + MRs 0 -1 -2 -3 -4 Weight Change (kg) Weight -5 -6 -7 0 5 10 15 20 25 30 35 40 45 50 Time (Weeks) RD = registered dietician; MR = meal replacement Ashley JM, et al. Arch Intern Med 2001;161:1599-1604. Using a Pedometer Increases Physical Activity

Sample Size Difference in Change in Steps/Day, Mean Source Intervention Control (95% CI) p-value Eastep et al, 2004 12 9 945 (-1,656 to 3,546) .476 Huitquist et al, 2005 31 27 2,226 (1,488 to 2,964) < .001 Araiza et al, 2006 15 15 3,189 (905 to 5,473) .006 de Blok et al, 2006 8 8 567 (-1,872 to 3,006) .649 Talbot et al, 2003 17 17 1,498 (-300 to 3,296) .102 Moreau et al, 2001 15 9 5,066 (4,003 to 6,129) < .001 Izawa et al, 2005 24 21 3,254 (1,851 to 4,657) < .001 Randsell et al, 2004 28 9 3,994 (1,050 to 6,938) .008 and Ormes et al, 2005 Summary Difference 150 115 2,705 (1,566 to 3,845) < .001

-2,500 0 2,500 5,000 7,500 Difference in Change in Steps/Day, Mean (95% CI)

!! Pedometer use increased physical activity by 27% over baseline !! Pedometer users significantly decreased BMI by 0.38 Bravata DM, et al. JAMA 2007;298:2296-2304. Internet & Smart Phone Programs Clinical Connections

!!We are not adequately addressing obesity care in the office practice environment !!Provision of obesity care in the office setting requires an organized systems approach, i.e., chronic care model !!Use of readily available resources – EMR, handouts, pedometers, internet & smart phone applications – should aid in obesity care Internet Resources for Dietary Change and Physical Activity !!Aim for a Healthy Weight !!http://www.nhlbi.nih.gov/health/public/heart/ obesity/lose_wt/index.htm !!MyPyramid !!http://www.mypyramid.gov !!Physical Activity for Everyone !!http://www.cdc.gov/nccdphp/dnpa/physical/ !!Be Active Your Way: A Guide for Adults !!http://www.health.gov/paguidelines/ Resources Obesity Care

!!U.S. Preventive Services Task Force – Recommendations !!http://www.annals.org/content/ 139/11/930.long !!2010 HEDIS Measures !!http://www.ncqa.org/Portals/0/HEDISQM/ HEDIS2010/2010_Measures.pdf The Incretin Effect: Examining its Role in Diabetes and Obesity Louis J. Aronne, MD, FACP Weill Cornell Medical College Columbia University College of Physicians and Surgeons Louis J. Aronne, MD, FACP Disclosures

!! Research/Grants: Amylin Pharmaceuticals, Inc.; Arena Pharmaceuticals, Inc.; F. Hoffmann-La Roche, Ltd.; Metabolous Pharmaceuticals, Inc.; Norvo Nordisk; Orexigen Therapeutics, Inc.; Pfizer Inc.; TransTech Pharma, Inc. !! Speakers Bureau: None !! Consultant: Allergan, Inc.; Amylin Pharmaceuticals, Inc.; GI Dynamics, Inc.; GlaxoSmithKline Consumer Healthcare, LP; Johnson & Johnson Pharmaceutical Research & Development, LLC; NeuroSearch, Inc.; Novo Nordisk; Orexigen Therapeutics, Inc.; Roche Laboratories, Inc.; VIVUS, Inc.; Wyeth Pharmaceuticals, Inc. !! Stockholder: CardioMetabolic Support Network, LLC !! Other Financial Interest: None !! Advisory Board: Allergan, Inc.; Amylin Pharmaceuticals, Inc.; GI Dynamics, Inc.; GlaxoSmithKline Consumer Healthcare, LP; Johnson & Johnson Pharmaceutical Research & Development, LLC; NeuroSearch, Inc.; Novo Nordisk; Orexigen Therapeutics, Inc.; Roche Laboratories, Inc.; VIVUS, Inc.; Wyeth Pharmaceuticals, Inc. Type 2 Diabetes The Role of Incretin-Based Therapies

!!Leveraging the incretin effect !!Glucoregulatory effects of GLP-1 !!Therapeutic approaches to GLP-1 analog therapy !!Short-acting GLP-1 analog therapy !!Longer-acting GLP-1 analog therapy !!DPP-4 inhibitor therapy !!Other effects of GLP-1 therapy !!Effects on body weight !!Beta cell function !!CVD risk factors

GLP-1 = Glucagon-like peptide-1; DPP-4 = Dipeptidyl peptidase-4 The Pathophysiology of Type 2 Diabetes

Incretin “Defect”

Insulin Relative Insulin Resistance Deficiency

Hyperglycemia T2 Diabetes and Pre-diabetes

International Diabetes Center 2008. Pathogenesis of T2DM Multiple Risk Factors Involved

Jin W, Patti ME. Clin Sci (Lond) 2009;116:99-111. Natural History of Type 2 Diabetes

350 Post-Meal Glucose 300 Diabetes 250 Diagnosis 200 Fasting Glucose 150 100

Glucose (mg/ dL ) 5 0

250 200 Insulin Resistance 150 Incretin Effect 100 Insulin Level 5 0 ! cell function

Relative Amount Relative Amount 0 -15 -10 -5 0 5 10 15 20 25 30 Onset Diabetes Years Kendall DM, Cuddihy RM, Bergenstal RM. Am J Med. In press. Copyright © 2009 International Diabetes Center. All rights reserved. Usual Mechanism of GLP-1 in Gut

Nauck MA, et al. Diabetes Care 2009;32:S223-S231. Leveraging the Incretin Effect1-4 The Therapeutic Potential of GLP-1

Excess food intake CNS: promotes satiety and reduction of appetite

Excess glucose production Liver: Impaired beta-cell function " glucagon reduces Beta cell: hepatic glucose output enhances glucose-dependent insulin secretion and beta-cell functional mass Glucagon excess Stomach: Alpha cell: regulates gastric " glucagon secretion emptying post-meal Rapid gastric emptying See supplemental bibliography for full references. Approved Incretin Therapies* Summary of Clinical Effects

A1C = glycosylated hemoglobin; MET = metformin; SU = sulfonylurea; TZD = thiazolidinedione; * Approved by the FDA as an adjunct to diet and exercise to improve glycemic control in adults with T2DM Garber AJ. Am J Manag Care 2010;16:S187-S194. 2-Hour Postprandial Active Plasma GLP1 Concentrations Baseline and After 2 Wks of Treatment

75 75 Baseline 2-Hour Plasma Exenatide Exenatide 63.8 Sitagliptin

50 50 ( pM )

GLP-1 ( pM ) 25 25

15.1

2-Hour Postprandial Plasma 7.2 7.9 0 0

Plasma GLP-1 Plasma Exenatide Patients with T2DM; Evaluable population n = 61 for all treatment groups; Mean ±SE; 2-week post-treatment concentration data DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952. Relative Effect of GLP-1 Agonists1-6 Summary of Clinical Trial Data

GLP-1 Agonist Dose A1C Reduction Mean Weight Loss Exenatide BID 0.8-1.5% 0.9-3.6 kg Liraglutide QD 0.9-1.6% 0.8-3.0 kg Exenatide QW 1.6-2.0% 2.0-3.7 kg

Taspoglutide QW 1.1% (8 weeks) 1.2-3.0 kg (8 weeks) Albiglutide QW Not known Not known

AVE-0010 QD 0.3-0.7% (13 weeks) 2.1-3.9 kg (13 weeks) !! A1C change is range of response reported in clinical trials (ITT and evaluable) !! Mean weight loss from baseline –12-52 week trials See supplemental bibliography for full references. Glucose-Dependent Actions of GLP-1 Effect in Subjects with Type 2 Diabetes

Placebo GLP-1

Glucose (mmol/L) Insulin (pmol/L) Glucagon (pmol/L)

17.5 350 25 GLP-1/Placebo Infusion GLP-1/Placebo Infusion GLP-1/Placebo Infusion 15.0 300 20 12.5 250 15 10.0 * 200 * * 7.5 * 150 * * 10 * * * * * 5.0 100 * * * * * 5 2.5 50 * * * 0.0 0 0 -30 0 60 120 180 240 -30 0 60 120 180 240 -30 0 60 120 180 240 Time (Minutes) Time (Minutes) Time (Minutes)

Data are mean ± standard error of the mean (SE); * p < .05 Adapted from: Nauck MA, et al. Diabetologia 1993;36:741-744. Glucose-Dependent Actions of GLP-11,2 Effect in Patients with Type 2 Diabetes

Placebo Placebo GLP-1 Exenatide (0.10 mcg/kg) 17.5 GLP-1/Placebo Infusion Exenatide 15.0 270 12.5

10.0 * * * 180 7.5 * * * 5.0 *

Glucose ( mmol /L) 90

2.5 Glucose (mg/ dL )

0.0 Mean (+ SEM)Plasma -30 0 60 120 180 240 0 2 4 6 8 Time (Minutes) Time (Hours) Data are mean ± SE; * p < .05 1. Kolterman OG, et al. J Clin Endocrinol Metab 2003;88:3082-3089. 2. Nauck MA, et al. Diabetologia 1993;36:741-744. Effects of Exenatide on 1st and 2nd Phase Insulin Response

Exenatide/Placebo Infusion 3 0 Healthy Control Patients 2 5 Type 2 Diabetes 2 0 Type 2 Diabetes + Exenatide

1 5

/kg/min] [ pmol /kg/min] 1 0 Insulin Secretion Insulin Secretion 5 IV Glucose 0 -180 -90 0 3 0 6 0 9 0 120 Time (Minutes)

Fehse F, et al. J Clin Endocrinol Metab 2005;90:5991-5997. Exenatide vs. Glargine Over 1 Year Impact on C-Peptide Secretion During Hyperglycemic Clamp

p < .0001 1 0 AIRarg 9 4 8 3 7 2 Exenatide (n = 36) 6 1 5 3.19 1.31 Ratio to Baseline 4 0 3 Glargine (n = 33)

/L) C-Peptide ( nmol /L) 2 1 Glucose 15 mmol/L 0 165 180 190 210 240 260 270 290 Time (Minutes) Exenatide Glucose Bolus Arginine Bolus Mean (SE) Bunck MC, et al. Diabetes Care 2009;32:762-768. Impact of DPP-4 Inhibitor on Glycemic Control and Beta Cell Function1,2

Placebo 0.0 1400 Sitagliptin 100 mg Baseline End Treatment Period -0.3 1200

1000 -0.6 Sitagliptin 100 mg 800 -0.9 Glipizide 600 Change in A1C (%) Change in Least Squares Mean -1.2 400 Pooled

Insulin Secretion ( pmol /min) monotherapy Baseline A1C: 7.7% studies -1.5 200 0 6 12 18 24 30 38 46 52 160 180 200 220 240 260 Week Glucose concentration (mg/dL) 1. Nauck MA, et al. Diabetes Obes Metab 2007;9:194-205. 2. Xu L, et al. Diabetes Obes Metab 2008;10:1212-1220. Reductions in PPG Concentrations Over Time

1º Endpoint GLP-1 agonist: 28 0 •! Greater insulin release •! Greater glucagon suppression •! Reduced food intake

24 0

20 0 Baseline

Sitagliptin PPG (mg/ dL ) 16 0 Exenatide

12 0 - 30 0 30 60 90 12 0 15 0 18 0 210 24 0 Standard Meal Time (Minutes) PPG = Postprandial glucose; Patients with T2DM; Evaluable population n = 61 for all treatment groups; Mean ± SE; * LS mean ± SE, p < .0001 DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952. Leveraging the Incretin Effect1-4 The Therapeutic Potential of GLP-1

Excess food intake CNS: promotes satiety and reduction of appetite

SC injection GLP-1 PBO GLP-1 500 Liquid meal " 400 * * 300 * 200 * 100 Gastric Volume ( mL ) * 0 -30 0 30 60 90 120 150 180 210 240 Time (Minutes) * p < .0001 Nauck MA, et al. Diabetologia 1996;39:1546-1553. GLP-1 Regulation of Food Intake1,2

" Daily ICV GLP-1 injections result

Food Intake g ) in reduced body weight

# GLP-1 Change in Body Weight ( Change in Body Weight GLP-1 Receptor Day of Study Distribution ICV Injection 7 * p < .05 6 ** p < .01 vs. 0.9% saline 5 4 * 3 * 2 1 **

2-Hour Food Intake 0 0 0.3 1 3 10 30 ICV GLP-1 (mcg) 1. Meeran K, et al. Endocrinology 1999;140:244-250. 2. Tuton MD, et al. Nature 1996;379:69-72. Regional Cerebral Blood Flow in Appetite Control Areas Related to Plasma GLP-1

Pannacciulli N, et al. Neuroimage 2007;35:511-517. GLP-1 and Hunger/ Appetite in Patients with Type 2 Diabetes

500 p = .034 1200 p = .034 600 p = .011

400 1000 500 800 400 300 600 300 200 400 200 Fluid Intake ( mL ) Calorie Intake (kcal) 100 200 100 Food Quantity Consumed ( g ) 0 0 0 PBO GLP-1 PBO GLP-1 PBO GLP-1

Gutzwiller JP, et al. Am J Physiol 1999;276:R1541-R1544. Effect of 6-Week Continuous GLP-1 Infusion on Mean Body Weight

1.0 Mean Change (%) in Weight from Baseline GLP-1 0.5 Saline 0.0 -0.5 -1.0 -1.5 -2.0 -2.5

Mean (SE) $ Weight (%) -3.0 -3.5 0 2 3 4 5 6 Time (Weeks) GLP-1: n = 10; Saline: n = 9; p = .02 (week 0 vs. week 6) Zander M, et al. Lancet 2002;359:824-830. Incretin-Based Therapy for Diabetes1-4

GLP-1 Analogs DPP-4 Inhibitors

•!A1C reduction ~0.8-1.9% •!A1C reduction 0.5-1.1% •!Significant and sustained weight loss •!Weight neutral •!Injected therapy •!Oral administration •!Potential GI side effects •!No significant GI side effects •!Low rates of hypoglycemia •!Low rates of hypoglycemia •!Improved CV risk factors – •!Limited data on CV risk factors lipids, blood pressure •!Improves islet function •!Multiple mechanisms of action •! % Insulin secretion •!% Insulin secretion, & glucagon release •! & Glucagon release •!& Food intake, slows gastric emptying

See supplemental bibliography for full references. Effects of # 3 Years Exenatide Therapy Change in A1C and Body Weight

Change in A1C (%)* Change in Body Weight (kg)*

10 1 9 0 -1 8 -1.1 ± 0.1% -1.0 ± 0.1% -2 7 -3 6 -4 -5.3 ± 0.4 kg -5 5 -6 54% % Achieving A1C 46% Baseline Weight: 99 kg 4 -7 0 26 52 78 104 130 156 0 26 52 78 104 130 156 Treatment (Weeks) Treatment (Weeks) ~70% of patients improved A1C and lost weight at 30 weeks and 3+ years N = 217; Mean ± SE; * p < .0001 Klonoff DC, et al. Curr Med Res Opin 2008;24:275-286. Weight and A1C Change Stratified by 3-Year Weight Change Quartile

Weight Change A1C Change by 3-Year Weight Change Quartiles by 3-Year Weight Change Quartiles

Quartile I II III IV Quartile I II III IV 0.0 0 -0.5 -5 -1.0

-10 Change from Baseline (kg) Change from Baseline (kg) -1.5

-15 -2.0

N = 217; Mean ± SE Klonoff DC, et al. Curr Med Res Opin 2008;24:275-286. Klonoff DC,etal. * Statisticallysignificant, as95%CIdidnotcross 0 Factors Over3.5 Years Improvements inCVRisk % Lipid and BP Changes From Baseline -50 -40 -30 -20 -10 10 0 -44.4mg/dL Curr MedRes Opin TG * -10.8 mg/dL

TC * + 8.5mg/dL HDL-C 2008;24:275-286. *

-11.8 mg/dL LDL-C * -3.5 mmHg Systolic BP BP * -3.3 mmHg Diastolic BP BP * Incretin therapy TZD Metformin Weight Loss Incretin -$ Insulin & Activity Secretagogue 350 Post-Meal Glucose 300 Diabetes 250 Diagnosis 200 Fasting Glucose 150 100

Glucose (mg/ dL ) 5 0

250 200 Insulin Resistance 150 Incretin Effect 100 Insulin Level 5 0 ! cell function

Relative Amount Relative Amount 0 -15 -10 -5 0 5 10 15 20 25 30 Onset Diabetes Years

Kendall DM, et al. Am J Med 2009;122:S37-S50. Kendall DM, Cuddihy RM, Bergenstal RM. Am J Med. In press. Copyright © 2009 International Diabetes Center. All rights reserved. Beyond Lifestyle Modification: Current and Emerging Treatment Strategies Holly Wyatt, MD University of Colorado Denver Denver, CO Holly Wyatt, MD Disclosures

!!Research/Grants: National Institutes of Health; Orexigen Therapeutics, Inc. !!Speakers Bureau: Scienta Healthcare Education !!Consultant: Allergan, Inc.; Arena Pharmaceuticals; Vivus, Inc.; Wellspring !!Stockholder: None !!Other Financial Interest: UpToDate, Inc. !!Advisory Board: None Obesity Management

!!Where are we now? !!What can patients expect with current treatment options? !!What are the emerging treatment strategies? Standard of Care Current Treatment Strategies

Surgery

Pharmacotherapy

Lifestyle Modification

Diet Physical Activity State of the Art

0 2 4 6 8 Sibutramine alone Lifestyle modification alone 10 Sibutramine + brief therapy 12 Combined therapy Weight Loss (kg) 14 16 0 3 6 10 18 40 52 Weeks

Mean (±SE) weight loss in four groups, as determined by an Intention-to-Treat Analysis Wadden TA, et al. N Engl J Med 2005;353:2111-2120. The Look Ahead Study One-Year Weight Losses, ILI vs. DSE

!!5,145 men and women with type 2 DM !!Randomized to intensive lifestyle intervention vs. control condition !!Goals: !!> 7% weight loss !!> 175 minutes per week of PA !!Year 1 data, loss of initial weight – ILI vs. DSE !!ILI " 8.6 ± 6.9% !!DSE " 0.7 ± 4.8%

DM = diabetes mellitus; PA = physical activity; ILI = intensive lifestyle intervention; DSE = diabetes support and education Wadden TA, et al. Obesity (Silver Spring) 2009;17:713-722. The Look Ahead Study Factors Associated with Success

!!Greater self-reported physical activity strongest correlate of weight loss !!Treatment attendance !!Consumption of meal replacements !!Highly correlated measures !!Stepwise multiple regression !!Physical activity accounted for 16.1% of the variance !!Increase to 19.0% with addition of attendance !!19.6% with addition of MR MR = meal replacements Wadden TA, et al. Obesity (Silver Spring) 2009;17:713-722. Nonsurgical Weight Loss for Extreme Obesity in Primary Care Settings !!The Louisiana Obese Subjects Study (LOSS) !!Tested whether with a brief training PCPs could effectively implement weight loss for individuals with a BMI of 40 to 60 !!2-year trial, randomized, controlled, 7 PCPs !!N = 200 intensive medical intervention (IMI) !!N = 190 usual care condition (UCC)

Ryan DH, et al. Arch Intern Med 2010;170:146-154. Intensive Medical Intervention The LOSS Study

!!900 kcal liquid diet for 12 weeks or less !!Group behavioral counseling !!Structured diet !!Choice of pharmacotherapy !!Sibutramine !!Orlistat !!Diethylpropion hydrochloride

Ryan DH, et al. Arch Intern Med 2010;170:146-154. Weight Loss: IMI vs. UCC from Baseline Over 2 Years The LOSS Study

Baseline 1 Year (n = UCC/IMI Week 12 Week 26 Week 38 (n = UCC/IMI Week 78 2 Years = 90/2000) (n = IMI 152) (n = IMI 139) (n = IMI 117) = 95/119) (n = IMI 73) (n = UCC/IMI = 86/101)

Usual care condition BOCF (n = IMI 200)*

LOCF (n = IMI 200)*

Intensive medical intervention

Low-calorie liquid diet

IMI = intensive medical intervention; UCC = usual care condition; BOCF = baseline observation carried forward; LOCF = last observation carried forward; * p < .001 Ryan DH, et al. Arch Intern Med 2010;170:146-154. Is the Glass Half Full or Empty?

!!Retention rates !!IMI = 51% !!UCC = 46% !!For all those offered the intensive treatment !!31% achieved a loss of 5% or more !!21% achieved a loss of 10% or more !!If seen at 2 years !!61% achieved a 5% or more weight loss !!41% achieved a 10% or more weight loss Ryan DH, et al. Arch Intern Med 2010;170:146-154. How Do We Get Better Results? Emerging Treatment Strategies

!!New pharmacotherapy !!Targeting weight loss maintenance !!Technology to monitor and support behavioral change in our current environment The Future of Obesity Pharmacotherapy Following the Path of Diabetes Treatment?

!!Combinations* !!Bupropion and zonisamide !!Bupropion and naltrexone !!Lower dose topiramate and phentermine !!Amylin and leptin !!New compounds* !!5-HT2C agonists !!Lorcaserin hydrochloride

* Not FDA approved for the treatment of obesity Treatment of Obesity Bupropion Plus Naltrexone*

Intention to Treat Completers

Randomization included: BUP (300 mg) + NAL (50 mg), BUP (300 mg) + placebo (P), NAL (50 mg) + P or P + P for up to 24 weeks * Not FDA approved for the treatment of obesity Greenway FL, et al. Obesity (Silver Spring) 2009;17:30-39. Lorcaserin* 5-HT2C Agonist

* Not FDA approved for the treatment of obesity Smith S, et al. Obesity (Silver Spring) 2009;17:494-503. Successful Obesity Treatment Over Time

Acute Weight Loss Strategy

Chronic Weight Loss

Strategy

Weight Loss Weight Maintenance Strategy 1 Strategy 2

4-6 months Years/Forever? Technology to Monitor and Support Behavioral Change !!Technology may have gotten us here – can technology also solve the problem? !!Physical activity arm bands !!Internet-based remote scales !!Cell phone applications and programs that count calories, measure activity, and provide real time healthier choices !!Tailored text messaging and data collection !!Internet- and phone-based delivery of programs Clinical Connections

!!Current evidence-based treatment options include behavioral lifestyle modification, drugs, and surgery !!The most successful studies used a combination of strategies to produce weight loss in the range of 5-15% !!It is hoped emerging therapies can improve these outcomes Clinical Connections

!!Drug development trends include combination therapy that target appetite control !!Other emerging areas include new technology to support and deliver behavioral change www.cmeoutfitters.com