Comprehensive Weight Control Center 2013 AHA/ACC/TOS Guideline for the Louis J. Aronne, MD, FACP, FTOS, DABOM Jonathan A. Waitman, MD Sanford I. Weill Professor of Metabolic Research Assistant Professor of Medicine Management of Medical Director, Comprehensive Weight Control Internal Medicine, Clinical Nutrition, Medicine Center Overweight and

Alpana P. Shukla, MD, MRCP (UK) Rekha B. Kumar, MD, MS Leon I. Igel, MD Obesity in Adults: Assistant Professor of Research Assistant Professor of Medicine Assistant Professor of Clinical A Report of the American College Medicine Medicine Endocrinologist Endocrinologist Endocrinologist of Cardiology/ American Heart Association Task Force on Practice Guidelines and The Obesity Society Katherine H. Saunders, MD Joy Pape, MSN RN FNP-C Wanda Truong, MS CDE WOCN CFCN FAADE Instructor in Medicine Clinical Research Coordinator Internal Medicine, Obesity Clinical Nurse Practitioner Medicine July 1, 2014 Rachel A. Lustgarten, MS, RD, Janet L. Feinstein, MS, RD, Anthony J. Casper, BS CDN CDN Senior Research Aide Clinical Dietitian Clinical Dietitian In my opinion,

Devika Umashanker, MD Jeselin Andono, MS Samir Touhamy, MS this is the “standard of care”. Clinical Fellow in Obesity Graduate Student (IHN) Graduate Student (IHN) Medicine

1165 York Avenue, New York, NY weillcornell.org/weight J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):2985-3023.

PHARMACOLOGICAL MANAGEMENT of OBESITY: An Endocrine Society Clinical Practice Guideline

January 15, 2015

Obesity Medicine: The Newest Specialty in Medicine

Apovian CM, Aronne LJ, Bessesen D et al. J Clin Endocrinol Metab. 2015;100:342-362. 7

Number of Certificates Issued in Various Medical Specialties Many Most people believe that

400 obesity is a disorder of willpower.

350 Obesity Medicine Infectious Disease However, 300 Endocrinology

250

200 Rheumatology Many prominent medical societies

150 Geriatric Medicine agree that current scientific evidence

100 supports the view that obesity is a

50 disease. Certificates issued per year (#) X Certificates issued in 2011 0 2011 2012 2013 2014 What is the disease?

10 11 The Fat Cell is a Multiendocrine Organ: Medical Complications of Obesity: now 70+ ! Obesity Produces Too Much of Some / Less of Others, Almost every organ system is affected by obesity and may benefit from weight loss Leading to Disease Hypertension Hypertension Idiopathic Stroke Coronary  Lipoprotein intracranial Dyslipidemia heart disease Type 2 DM Lipase hypertension Cataracts  Lactate Cancer  Angiotensinogen Pulmonary disease Nonalcoholic fatty • Breast, uterus, cervix Inflammation • Asthma liver disease • Colon, esophagus Dyslipidemia • Obstructive sleep • Steatosis Diabetes • Pancreas  IL - 6 apnea • Steatohepatitis • Kidney  Fat • Hypoventilation • Cirrhosis Arthritis  Leptin  FFA  Insulin • Prostate Stores syndrome Severe pancreatitis  TNF-  Type 2 DM Osteoarthritis Gall bladder disease Skin Resistin Reproductive  Adipsin Thrombosis abnormalities (Complement D) • Abnormal menses Estrogen Phlebitis  Plasminogen • Infertility • Venous Activator Inhibitor 1 • Polycystic ovarian ASCVD stasis Adiponectin (PAI-1) syndrome DM=diabetes mellitus; FFA=free fatty acid; PAI-1=plasminogen activator inhibitor-1; TNF=tumor necrosis 1. Bays HE. Am J Cardiol. 2012;110:4B‐12B. 2. Bays HE. Expert Rev Cardiovasc Ther. Gout factor alpha; IL-6=interleukin 6. 2008;6:343‐368. 3. Bays HE. J Am Coll Cardiol. 2011;57:2461‐2473. Slide: LJ Aronne after Dr. G Bray

Why Is 5%-10% Weight Loss the Goal of Interactions among hormonal and neural pathways Treatment? Major Health Benefits ! that regulate food intake and body-fat mass Modest weight loss (5%-10%) can: • Prevent T2DM1 • Improve glycemic control in T2DM • Reduce need for antidiabetic agents • Reduce blood pressure • Reduce triglycerides • Increase HDL-C • Reduce CRP Why? Dramatic change in • Improve symptoms of sleep apnea adipocyte hormones with small weigh loss? • Improve markers of NAFLD

CRP: C-reactive protein; DPP: Diabetes Prevention Program; HDL-C: high-density lipoprotein cholesterol; NAFLD: nonalcoholic fatty liver disease. AGRP: agouti-related peptide; α-MSH: α-melanocyte-stimulating hormone; GHSR: growth hormone secretagogue receptor; INSR: insulin receptor; LepR: leptin receptor; MC4R: melanocortin-4 receptor; NPY: neuropeptide Y; POMC: proopiomelanocortin; 1. Hamman RF et al. Diabetes Care. 2006;29:2102-2107. PYY: peptide YY; Y1R; neuropeptide Y1 receptor; Y2R: neuropeptide Y2 receptor. 2. http://www.lookaheadtrial.org/public/bibliography.pdf. Accessed September 17, 2014. 14 Apovian CM, Aronne LJ, Bessesen D et al. J Clin Endocrinol Metab. 2015;100:342-362. 15

Bad Habits Damage Hypothalamic Pathways if Hypothalamus is Damaged, Leptin Resistance is a Result

Hypothalamic Injury

AGRP: agouti-related peptide; α-MSH: α-melanocyte-stimulating hormone; GHSR: growth hormone secretagogue receptor; INSR: insulin receptor; LepR: leptin receptor; MC4R: melanocortin-4 receptor; NPY: neuropeptide Y; POMC: proopiomelanocortin; PYY: peptide YY; Y1R; neuropeptide Y1 receptor; Y2R: neuropeptide Y2 receptor. Thaler PT, et al. J Clin Invest. 2012 Jan 3;122(1):153-62. doi: 10.1172/JCI59660. Epub 2011 16 Apovian CM, Aronne LJ, Bessesen D et al. J Clin Endocrinol Metab. 2015;100:342-362. 17 Hypothetical “Feed-forward” Fattening food causes physical changes in weight regulating pathways ! Creates a Positive Feedback Mechanism to Drive Weight Up, Up, Up Why People Can’t Lose Weight: the Plateau Phenomenon DIRECT: Dietary Intervention Randomized Controlled Trial, two-year results

High Fat/High Carb Food n=272 completers

Increased Diet type and mean weight loss: Hypothalamic injury - endocannabinoids Low-fat: -3.3 kg CNS insulin and leptin and resistance to resistance leptin and insulin Mediterranean: -4.6 kg Low-carbohydrate: -5.5 kg

1. Increased food “Brain can’t tell how intake much fat is stored, how much food is Partial rebound and plateau 2. Weight gain eaten” Weight Loss Maintenance 6 months 18 months 1.Reduced sense of satiety © 2007 Louis J. Aronne, MD 2. Craving Wang J, Diabetes, 2001 DiMarzo V pers comm Ozcan L, et al, Cell Metabolism; 2009 19 Shai I, et al. N Engl J Med. 2008;359:229-241. 21

14% Weight Loss Produced Changes in OK, Great, Now What? 8 Hormones That Encourage Weight Regain Mean fasting and postprandial levels of some peripheral signals at baseline and 62 weeks

15% Weight Loss •What do I do for my patients Reduced: Increased: Leptin - 65% Ghrelin until we have better Peptide YY Pancreatic polypeptide Cholecystokinin Gastric inhibitory polypeptide treatments! Insulin Amylin Measures of appetite 10-week, lifestyle-based weight loss intervention in healthy overweight and obese adults (n=34) led to sustained elevations in appetite stimulating hormone(s) and decreases in appetite suppressing hormones NET RESULT OF THESE HORMONAL CHANGES is WEIGHT GAIN!

Sumithran P et al. N Engl J Med. 2011;365:1597-1604. 28

What’s the best diet for my patients? Primary Prevention of Cardiovascular Disease with a Mediterranean Diet • 7447 persons were enrolled (55-80 years); 57% were women. • Med Diet /Extra Virgin Olive oil – I L/week •No diet is “The Best” • Med Diet /Nuts – 1 oz/day • Control Diet - Low Fat • We favor low glycemic, Mediterranean diet – Appears to improve compliance – Reduces CV risk Event Rate

Years Among persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events. 30 Estruch R, et al, N Engl J Med. 2013 Apr 4;368(14):1279-90. 31 Eat Vegetables and Protein Before Carbs The Order in Which Food is Consumed Impacts Post-prandial Glycemia

Bread first Vegs and chicken 15 min later

Vegs and chicken first Bread 15 min This finding and many others fit with our clinical experience. later A low glycemic diet reduces food intake in many people by reducing the urge to eat later in the day. A high glycemic breakfast may make some people hungrier. 32 Shukla AP, Iliescu RG, Thomas CE, Aronne LJ. Diabetes Care. 2015 Jul;38(7):e98-9. 33

Treatment Gap in Mid-BMI Range Current Treatments: Efficacy and Risks New drugs and devices can reduce weight and weight-related comorbidities Lower Risk Diets

VLCD Pharma Diet and Lifestyle Sleeve gastrectomy & Drugs Lower Efficacy Devices Higher Efficacy prior to 2012 • Gastric • Lap Band Bypass BPD Lap band Sleeve NOT TOO EFFECTIVE Treatment RISKY Roux- enough for en-Y for many many Bypass people Gap people BPD- 0% 5% 10% 15% 20% 25% 30% 35% DS Weight Loss Higher Risk

After Aronne L. FDA VI-0521 EMDAC 2010. 39 J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):2985-3023. 40

Before You Prescribe, Insert, or Cut: Presentation Medications Can Cause Weight Gain Case Study • 69-year-old M with: 2 • Psychotropic medications • Diabetes medications • Obesity (BMI 35.7 kg/m ) • DM2 (HA1c 6.2) – Tricyclic antidepressants – Insulin • HTN – Monoamine oxidase inhibitors – Sulfonylureas – Specific SSRIs – Thiazolidinediones • S/p lap band 10 years ago – Lithium • -adrenergic receptor – Regained all weight • Atypical antipsychotics blockers – Poor dietary compliance • Specific anticonvulsants • Steroid Hormones • Medications: • Highly active antiretroviral – Glucocorticoids – Pioglitazone 45 mg daily therapy – Progestational steroids – 500 mg daily • Antihistamines Patient AC – Lisinopril 40 mg daily Weight Regain – Fenofibrate 145 mg daily s/p Lap Band – Ezetimibe simvastatin10-10 mg daily

Apovian CM, Aronne LJ, Bessesen D et al. J Clin Endocrinol Metab. 2015;100:342-362. 43 44 Prescription Patient AC Case Study

• Low glycemic index diet • D/c’d Pioglitazone • Increased metformin – 500 mg BID – Titrated up to 1000 mg BID 12/2014 9/2015 • Added liraglutide 249 lbs 186 lbs – 0.6 mg daily Actos 45 mg Metformin 2000 mg Metformin 500 mg Victoza 1.8 mg Patient AC – Titrated up to 1.8 mg daily Weight Regain 63 lb wt loss s/p Lap Band over 9 months

45 46

Pharmacotherapy for Obesity: ENDO Society Guidelines1

Mean Weight Study Drug Mechanism of Action Lossa Duration Phentermine Norepinephrine-releasing agent 3.6 kg 2 to 24 weeks Diethylpropion Norepinephrine-releasing agents 3.0 kg 6 to 52 weeks Pancreatic and gastric lipase 2.9 to 3.4 kg, Orlistat 1 year inhibitor 2.9% to 3.4%

Lorcaserin 5HT2C receptor agonist 3.6 kg, 3.6% 1 year 6.6 kg GABA receptor modulation (recommended dose) Phentermine/ 1 year () plus norepinephrine- 6.6%; topiramate releasing agent (phentermine) 8.6 kg (high dose), 8.6% Reuptake inhibitor of dopamine and norepinephrine () 4.8% 1 year bupropion and opioid antagonist (naltrexone) Liraglutide GLP-1 agonist 5.8 kg 1 year

a Mean weight loss in excess of placebo as percentage of initial body weight or mean kg weight loss over placebo. GABA: gamma-aminobutyric acid; GLP-1: glucagon-like peptide-1.

Apovian CM, Aronne LJ, Bessesen D et al. J Clin Endocrinol Metab. 2015;100:342-362. 50

ENDO Society Guidelines: common side effects Key Point: Side Effects Guide Treatment Odds of Reducing Body Weight by % Categories at 1 Year With Adjunctive Medication Among Those Who Complete Treatment Drug Common Side Effects Combined with lifestyle modification Phentermine resin 100.00 5% weight loss 10% weight loss Avoid CV risk, HTN, DM Diethylpropion 85.1 75.00 74.5 73 Avoid , bowel disorders, , and kidney Orlistat 64.3 65.8 65 stones 50.00 49.1 Avoid valvular dz, headaches Patients, Patients, % 39 41 35.2 Phentermine/ 25.00 Avoid insomnia, kidney stones, CV? topiramate Naltrexone Avoid Headaches, pain sensitivity 0.00 bupropion PHEN/TPM PHEN/TPM LOR 10 BID BUP/NAL LIR 3.0 Liraglutide Avoid in Pancreatitis, thyroid Ca 7.5/46 15/92 32/360 PHEN: phentermine LOR: lorcaserinBUP: bupropion LIR: liraglutide TPM: topiramate NAL: naltrexone

1. Apovian CM et al. J Clin Endocrinol Metab. 2015;100:342‐362. This tells you more about the drug than the mean weight loss 54 Key Point: If It Does Work, Don’t Bother! Metformin –10 year Follow‐Up Data Those Who Lost ≥ 4.5% Total Body Weight by Week 12 Lost 10.2% at 1 year CONCLUSIONS: “Metformin used for diabetes prevention is safe and well Lorcaserin tolerated. Weight loss is related to adherence to metformin and is durable for at least 10 years of treatment”

STOP -2.46%

-10.22%

MITT Lorcaserin BID Week 12 Completed Week 12 Completed Week 52 N = 3097 ≥4.5% wt loss 1369/3097 (44.2%) 1083/1369 (79.1%) <4.5% wt loss 1168/3097 (37.7%) 680/1168 (58.2%) Diabetes Prevention Program Research Group. Diabetes Care. 2012 Apr;35(4):731-7 55

FDA Approval January 14, 2015 Vagal Blocking Therapy

RC2 Neuroregulator Electrodes Year 2 Devices Year 1 EWL EWL 22% 24%

• Pacemaker-like device designed to control

and fullness by Body Weight Total % blocking the vagus Weight Body Excess % 7% 7.5% nerve to affect the perception of hunger and fullness

• Satiation by delaying food processing and n=28 gastric emptying At 2 years: 57% of subjects achieved 20% EWL (5% TWL) 43% of subjects achieved >25% EWL (7.5% TWL) 30% of subjects achieved >10% TWL Shirkora SA, et al. Obes Surg. 2015 Oct 15. [Epub ahead of print] 62

Procedure for Endocrine and Recently Approved: Aspire Assist Obesity Medicine ? • Removable device Swallowable Balloon Devices Name Procedure Time Weight Loss • 20 minute procedure is performed under conscious sedation – no Obalon Attached to 3 mos 50.2% Excess general anesthesia is required Balloon Pill lightweight Weight Loss • Removes ~30% of food from Obalon catheter; swallow 8.3% Total Body stomach before calories are with water; Weight Loss and 2.8 absorbed, causing weight loss deflates in point reduction in stomach and BMI in 3 months • Thin tube connects inside of passes (n=110) stomach directly to a discreet Skin-Port on outside of abdomen. The Elipse “Procedure-less” 3 mos 13% Excess Allurion Swallowed and Weight Loss Valve on port valve controls flow of 16 weeks mean weight reduction: stomach contents – 12.4 kg, 32.2% Excess Weight Loss Technologies excreted without at 6 weeks surgery, 3.0 kg total body • Aspiration process is performed endoscopy, or weight loss 6 weeks ~20 minutes after entire meal is anesthesia consumed and takes 5 to 10 minutes to complete, 3x/day http://www.obalon.com/hcp/en/ http://allurion.com/the-elipse-gastric-balloon/ http://aspirebariatrics.com/about-the-aspireassist/ 63 64 Devices in Trial: GELESIS100 Polymer Treatment Gap in Mid-BMI Range New drugs and devices can reduce weight and weight-related comorbidities More Drug • Superabsorbent hydrogel capsules taken orally prior to a options: meal More Drug Lorcaserin options Liraglutide • Contain small particles that expand ~100 times when (2015): • Lorcaserin Combination hydrated in the stomach and small intestine, triggering • Liraglutide Pharmacotherapy Phen/top several important satiety and glycemic control Nalt/bup mechanisms Diet and Lifestyle Less Invasive • Mean ± SD body weight percent change from baseline to & Drugs Procedures Sleeve gastrectomy prior to 2012 Vagal block therapy Gastric the end of 12 week treatment were -6.1 ± 5.1% (P=0.026) • Orlistat BPD with Gelesis100 2.25 g • Phentermine Endoscopic sleeve Lap Band Bypass NOT TOO EFFECTIVE Treatment RISKY enough for for many many people Gap people

0% 5% 10% 15% 20% 25% 30% 35% Weight Loss The gap is being filled www.gelesis.com/press-releases/06232014.php 65 After Aronne L. FDA VI-0521 EMDAC 2010. 72