Southern States Chapter of the American Association of Clinical Endocrinologists 2013 Annual Meeting Obesity Treatment Update Caroline M. Apovian, MD, FACN, FACP Director, Center for Nutrition and Weight Management Boston Medical Center Professor of Medicine and Pediatrics Boston University School of Medicine March 2, 2013 1 Objectives Discuss the rationale for using weight loss medications alone and or in combination with surgery Discuss the risks and benefits and describe the best candidates for newly prescribed weight loss medications Describe the physiological basis and lifestyle habits for weight regain 2 1
Rationale for Obesity Treatment 3 What is Obesity? BMI Classifications Disease Risk * BMI (kg/m 2 ) Obesity Class Men <40 in Women <35 in Men >40 in Women >35 in Underweight < 18.5 - - Normal 18.5 24.9 - - Overweight 25.0 29.9 Increased High Obesity 30.0 34.9 I High Very High Obesity 35.0 39.9 II Very High Very High Extreme Obesity 40.0 + III Extremely High Extremely High * Disease risk for type 2 diabetes, hypertension, and CVD Relative to normal weight and waist circumference + Increased waist circumference also can be a marker for increased risk, even in persons of normal weight www.nhlbi.nih.gov/health/public/heart/obesity/lose_wt/bmi_dis.htm 4 2
Contribution of Obesity to Chronic Disease Type 2 Diabetes Endometrial Cancer Gallbladder Disease Osteoarthritis Hypertension CHD Breast Cancer Colon Cancer 34% 30% 24% 17% 17% 11% 11% 61% 0% 20% 40% 60% 80% Obesity defined as BMI >29 kg/m 2 Adapted from: Wolf AM, et al. Obes Res 1998;6:97-106. 5 U.S. Obesity Prevalence, 2009-2010 78 Million Adults ~12.5 million Children and Adolescents Overweight or Obese CDC/NCHS, National Health and Nutrition Examination Survey, 2009-2010 http://www.cdc.gov/nchs/data/databriefs/db82.htm 6 3
50% of American MEN will be obese by 2030 Wang YC, et al. Lancet. 2011 Aug 27;378(9793):815-25. 7 45-52% of American WOMEN will be obese by 2030 Wang YC, et al. Lancet. 2011 Aug 27;378(9793):815-25. 8 4
Weight Classification BMI: <18.5 18.5-24.9 25.0-29.9 30.0-34.9 35-39.9 >40 Underweight Normal Overweight Obesity I Obesity II Obesity III Body Mass Index (BMI) Measure of weight in relation to height Formula: Weight (lb) x 703 Height (in) 2 www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/ 9 Overweight and Obesity Associated with Increased All-cause Mortality: MEN Berrington de Gonzalez et al. NEJM. 2010;363: 2211-9. 10 5
Overweight and Obesity Associated with Increased All-cause Mortality: WOMEN Berrington de Gonzalez et al. NEJM. 2010;363: 2211-9. 11 Obesity Treatment Guidelines 12 6
How is Adult Diabetes Treated? New Dogma Treat the Obesity For select patients; most effective treatment Can add 3-8% placebosubtracted weight loss Foundation of all weight management approaches Diet Surgery Diabetes Medication Metformin, Januvia, Byetta Weight Loss Medication Orlistat, Phentermine, others Pharmacotherapy Physical Activity Lifestyle Modification Improves insulin sensitivity and may cause weight loss or at least are weight neutral Slide Source: www.obesityonline.org 13 Guide for Selecting Obesity Treatment BMI (kg/m 2 ): 25-26.9 27-29.9 30-34.9 35-39.9 >40 Diet, Exercise, Behavior Tx + + + + + Pharmacotherapy + With co- + + + Surgery morbidities + With comorbidities + The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. October 2000, NIH Pub. No.00-4084 14 7
Aim for Modest (5-10%) Weight Loss Increases life expectancy 1 Improves glycemic control 2 Lowers blood pressure 3 Improves serum lipid profile 4 May decrease cancer risk 5 Encourage 5-10% weight loss 6 Rate: 1-2 lbs/week Improves lower back pain, reflux, lower extremity arthralgias, sleep apnea 6 Can decrease drugs for obesity-related conditions 6 1. Lean et al. DiabetMed. 1989;7:228-233. 2. Wing et al. Arch Intern Med. 1987;147:1749-1753. 3. Schotte et al. Arch Intern Med. 1990;150:1701-1704. 4. Dattilo et al. Am J Clin Nutr. 1992;56:320-328. 5. Bianchini F et al. Obesity Reviews 2002;3:5-8 6. NHLBI Guidelines, June 1998 15 Obesity Treatment: What Works? 8
Dieting: Which is Best? Two recent studies Compared popular diets: Atkins, Zone, Weight Watchers, Ornish, Mediterranean, low-fat Same results Adherence is more important than the diet itself Dansinger ML, et al. JAMA. 2005 Jan 5;293(1):43-53. Sacks FM, Bray GA, Carey VJ, et al.nejm. 2009; 360:859-873. 17 Diet and Physical Activity For Best Results Weight Loss/Gain (kg) 0-2 - 4-6 - 8-10 - 12-14 - 16-1 2 3 4 5 6 7 8 9 10 11 12 30 Nonexerci se Exercise Treatment (wk) Follow-up (mo) Balanced caloric deficit diet Protein-sparing modified fast Adapted from Pavlou KN, et al. Am J Clin Nutr. 1989;49(5 Suppl):1115-1123. 18 9
CDC Recommendations for Physical Activity Adults 18 to 64 Years of Age Crucial Moderate Vigorous Strength Intensity Intensity Training 150 mins/week OR 30 mins/day for 5 days 75 mins/week OR 15 mins/day for 5 days 2 or more days/week Work all major muscles Make gradual, incremental changes Ultimate goal is 420 minutes/week of moderate intensity activity www.cdc.gov/physicalactivity/everyone/guidelines/adults.html 19 Diets and Long-term Weight Loss Preponderance of published literature and scientific research have found that diet and exercise is unsuccessful in 80-85% of patients at one year Kraschnewski, JL et al. Long-term weight loss maintenance in the United States. International Journal of Obesity 2010; 1-11 Sacks FM, et al, Comparison of Weight-Loss Diets with Different Composition of Fat, Protein, and Carbohydrates. NEJM 2009; 360:859-73. 20 10
Bariatric Surgery: currently best solution for obesity 21 Outcomes: Obesity Surgery Weight Loss Diabetes Mortality Meta-analysis 147 Studies Meta-analysis 621 Studies 2005 1 1990-2006 2 7-Year Follow-up 7925 Surgery Patients 1984-2002 3 Surgery is more effective than non-surgical treatment for weight loss in patients with a BMI of 40 kg/m 2 or greater 78.1% Complete resolution of diabetes (Band surgery) 86.6% Diabetes - improved or resolved 92% Decrease in cause-specific mortality from diabetes Outcomes depend on race and genes 1. MaggardMA, et al. Ann IntMed.2005 Vol142 (7);547-559. 2. Buchwald H, et al. Am J Med. 2009 Mar;122(3):248-256.e5. 3. Adams TD, et al. N EnglJ Med.2007;357(8):753-761. 68.2 % initial complete diabetes remission 5 years post-op 1995-2008; n= 4,434 Published online: November 18, 2012 4 22 11
How Gut Hormones May Contribute to Regression of Diabetes After Roux-en-Y Surgery KashyapSR. Cleveland Clinic Journal of Medicine 2010;77:468-476. 2010 by Cleveland Clinic Bariatric Surgery Trends Expands need for peri-op care expertise 135,985 Cases 124,838 Cases Nguyen NT, et al. J Am Coll Surg. 2011;213(2):261-6. 24 12
200+ medications to treat hypertension 10 classes of medications and 100 medication choices to treat diabetes Few choices for obesity 25 Anti-obesity Drugs and their Pathways Complex System needs expert understanding Endogenous Signaling of Appetite-regulating Hormones, Neuropeptides, and Neurotransmitters, and The Drugs That Target These Pathways 26 Valentino MA, Lin JE, Waldman SA. Clin Pharm & Therapeutics(2010) 87 6, 652 662. doi:10.1038/clpt.2010.57 13
Anti-obesity Medications Rationale and Criteria Non-drug interventions should be attempted for at least 6 months before considering pharmacotherapy 1 For patients with BMI > 30 For patients with BMI > 27 or above with concomitant risk factors or diseases (hypertension, dyslipidemia, CHD, type 2 diabetes, sleep apnea) 1 1. NIH Clinical Guidelines Evidence Report, Sept 1998. 27 The Problem Effectiveness of current three prescription diet drugs: Sibutramine (Meridia) 3-4% ave. weight loss in 6 mos 1 year of use (withdrawn from market Oct 2010) Phentermine 4-5% ave. weight loss in 3 months (longest it is approved for) Orlistat (Xenical) 3-4% ave. in 1 year www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm2 18821.pdf 28 14
Expected Weight Loss with Currently Approved and Investigational Drugs Qnexa Contrave Lorqess Powell AG, Apovian CM, Aronne LJ. Clin Pharmacol Ther. 2011 Jul;90(1):40-51 29 CONQUER Trial: Weight Loss Over Time Phentermine/Topiramate Placebo -2.4%, 6 lbs Mean % Weight Loss Mid-dose -10.5%, 24 lbs 7.5 mg phentermine/ 46 mg topiramate Full-dose -13.2%, 30 lbs 15 mg phentermine/92 mg topiramate Weeks Patients Placebo Mid Full Completers (% of randomized) 564 57% 344 634 69% 1 64% 1 1. Statistically greater number of patients completing study on Qnexa vs. placebo, p<0.0001 * Data from patients that completed 56 weeks on treatment 30 15
CONQUER Trial: Significant Weight Loss Phentermine/Topiramate Completers 15% 10% 4% 10% 26% 39% 49% 64% Placebo P/T Mid P/T Full 7.5 mg phentermine/ 46 mg topiramate 15 mg phentermine/92 mg topiramate 5% 26% 75% 85% 0 10 20 30 40 50 60 70 80 90 % of Patients P <.0001 vs placebo for both doses Gadde M, et al. Lancet. 2011;377:1341-1352; FDA VI-0521 (QNEXA ) Briefing Document, Table 6. 31 Side Effects Phentermine/Topiramate FDA saw increases in heart rate among patients taking the drug, but the clinical significance was not conclusive Other side effects included: Increased anxiety Sleep disturbances Dry mouth Tingling Constipation Altered taste Depression Infections in the sinus and respiratory tracts http://ir.vivus.com/releasedetail.cfm?releaseid=407933 32 16
Lorcaserin Phase 3 Trials n=3,182 2 years tx Dosage 10 mg QD 1 n=4,008 1 year tx Dosage 10 mg QD 2 n=604 obese/ overweight with type 2 DM 1 year+ tx Dosage 10 mg BID or 10 mg QD 3 1. Smith SR, et al. N Engl J Med 2010;363:245-56. 2. Fidler MC, et al. J Clin Endocrinol Metab, October 2011, 96(10):3067 3077. 3. O Neil PM, et al. Obesity (16 March 2012) doi:10.1038/oby.2012.66 Arena Pharmaceuticals 33 Side Effects Lorcaserin The most frequent adverse events were headache, nausea, dizziness, fatigue and dry mouth Headache the only adverse event increased over placebo by > 5% Arena Pharmaceuticals 34 17
Mean Weight Loss Naltrexone SR/Bupropion SR COR-I Phase 3 56 Weeks Completer Population Greenway FL, et al. Lancet 2010 Aug 21; 376:595. DOI:10.1016/S0140-6736(10)60888-4. 35 Percent Change in Body Weight Naltrexone/Bupropion COR/BMOD Trial BMI 36.5 ± 4.2 kg/m 2 Change in Body Weight (%) 0-5 -10-15 * * * * * NB32 + BMOD *P <.001, for NB32 + BMOD vs placebo + BMOD COR/BMOD = Contrave Obesity Research/Behavioral Modification ITT = intent to treat NB32 = naltrexone 32 mg/bupropion 360 Wadden TA, et al. Obesity. 2011;19:110-120. * Modified-ITT-LOCF * Placebo + BMOD * * * * n = 482-5.1% 0 8 16 24 32 40 48 56 Week * n = 193 * * -9.3% Completers -7.3% n = 106 * -11.5% n = 301 56 36 18
Side Effects Naltrexone/Bupropion Most frequent events: Nausea N=171 (29.8%) naltrexone 32 mg plus bupropion N=155 (27.2%) naltrexone 16 mg plus bupropion N=30 (5.3%) placebo Headache, constipation, dizziness, vomiting, and dry mouth were also more frequent in the naltrexone plus bupropion groups vs. placebo Transient increase of ~15 mm Hg in mean systolic and diastolic blood pressure was followed by a reduction of around 1 mm Hg below baseline in the naltrexone plus bupropion groups Combination treatment was not associated with increased depression or suicides vs. placebo Greenway FL, et al. Lancet. 2010 Aug 21;376(9741):595-605.PMID: 20673995. 37 Weight Regain 19
Interactions Among Hormonal and Neural Pathways That Regulate Food Intake and Body- Fat Mass SOLID LINE = Hormonal stimulatory effects DASHED LINE = Hormonal inhibitory effects 39 The Plateau Phenomenon Why can t people lose weight? ShaiI, et al. N Engl J Med. 2008;359:229-241. 40 20
Obstacle to Successful Weight Loss THE PROBLEM Regain of weight lost through diet and exercise Body weight is controlled by complex interactions between hormones and neurons in the hypothalamus, influencing appetite and food intake and, in most obese people, conspiring to prevent permanent weight loss Obese individuals are biologically defending their elevated body weight / set-point POSSIBLE EXPLANATION Structural change in the hypothalamus Results of a high-fat diet in the brains of mice and rats bred to become obese revealed evidence of very early and lasting injury to neurocircuits that control energy balance in specific part of the hypothalamus Similar damage in the same area of the brain in obese humans NEXT Prove cause and effect between hypothalamic neuron injury and defense of elevated body weight Schwartz M, et al. J Clin Invest. 2012;122(1):153 162. doi:10.1172/jci59660. 41 Hypothetical Feed-forward Positive Feedback Mechanism to Drive Weight Up High Fat/High Carb Food Increased endocannabinoids and resistance to leptin and insulin CNS insulin and leptin resistance 1. Increased food intake 2. Weight gain Brain can t tell how much fat is stored 2007 Louis J. Aronne, MD Wang J, Diabetes, 2001; DiMarzo V pers comm OzcanL et al Cell Metabolism; 2009 1.Reduced sense of satiety 2. Craving 42 21
The Fat Trap Body continues to fight against weight loss long after dieting has stopped 2009, 50 obese men and women Men: 233 lbs/average, Women: 200 lbs/average Extreme low-calorie diet Optifast shakes + 2 cups of low-starch vegetables Total 500 to 550 calories a day for eight weeks At 10 weeks: 30 lb/average weight loss At Year One: 11 lb/average weight regain Reported feeling far more hungry and preoccupied with food than before they lost the weight Sumithran P, et al. N Engl J Med 2011; 365:1597-1604 October 27, 2011 43 Long-Term Persistence of Hormonal Adaptations to Weight Loss Changes in Weight from Baseline to Week 62 30 lb loss 11 lb gain 10 week weight-loss program ITT = intention to treat Sumithran P, et al. N Engl J Med 2011; 365:1597-1604 October 27, 2011 44 22
Fasting/Postprandial Hormone Levels Mean (+SE)Fasting and Postprandial Levels of Ghrelin, Peptide YY, Amylin, and CCK at Baseline, 10 weeks, 62 Weeks Sumithran P, et al. N Engl J Med 2011; 365:1597-1604 October 27, 2011 45 Short Sleep Duration Associated with Reduced Leptin, Elevated Ghrelin, and Increased BMI Increased BMI + Short Sleep Reduced Leptin + Short Sleep Elevated Ghrelin + Short Sleep Plos Medicine. December2004 Volume1 Issue3 e62 www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0010062 46 23
Summary Obesity epidemic expected to increase Surgery is the best solution for severe obesity Medications can enhance weight loss for select candidates despite adverse effects Weight regain may be related to structural changes in the brain Sleep deprivation contributes to overweight 47 Caroline M. Apovian, MD, FACN, FACP Professor of Medicine and Pediatrics Boston University School of Medicine Director, Center for Nutrition and Weight Management Boston Medical Center 88 East Newton Street Robinson Bldg. Suite 4400 Boston, MA 02118 tel: 617 638-8556 fax:617 638-8599 Caroline.Apovian@bmc.org Slide design and development by Susan Morreale, Belmont, MA 48 24
Medical Weight Management at BMC Nutrition and Weight Management Center (617) 638-7470 for Adults Longest-running program in Boston Treat ~450 patients/week Comprehensive programs: diet to surgery Modest weight loss to severe obesity Individual or group settings Current 12 week wait for appointment 49 Medical Weight Management at BMC Nutrition and Weight Management Center Additional Services Food Pantry Stocked with fresh fruits and vegetables in addition to canned foods Demo Kitchen Classes for patients with diseases (type II diabetes, cardiovascular disease, hypertension, obesity) Pediatric Program Family-focused, pediatric weight management Individual, group or community settings Nutrition, behavior, physical activity 50 25
Medical Weight Management at BMC Nutrition and Weight Management Center Operations Staff: 2 MDs, 4 RDs, psychologist, 4 admin, registration Facility expanded in 2002, 3150 sq ft Size-friendly equipment Wheelchair accessible State-of-the-art medical equipment and computer tracking system Free, weekly patient orientation led by RD Strongly encouraged to make their first appt at orientation 51 Medical Weight Management at BMC Nutrition and Weight Management Center Weight Loss Options 5 Diet Plans: Balanced Calorie Deficit Food and Liquid Formula Full Liquid Formula Medication and Balanced Calorie Deficit Protein-Sparing Modified Fast Weight Loss Medications Obesity Surgery 52 26
Weight Management Resources The Evidence Report, June 1998 www.nhlbi.nih.gov The Practical Guide, October 2000 www.nhlbi.nih.gov Assessment and Management of Adult Obesity: A Primer for Physicians www.ama-assn.org/ama/pub/category/10931.html 53 27