Obesity Epidemic (Approaches to its Treatment) Ricardo Correa, M.D., Es.D., F.A.C.P., F.A.C.R., C.M.Q. Assistant Professor of Medicine University of Arizona College of Medicine-Phoenix and The Warren Alpert Medical School of Brown University Endocrinology, Diabetes and Metabolism Fellowship Program Director Editor Cureus, Dynamed, Int Arch Med Outreach Unit Director, Endotext and Thyroid Manager Board Member NBME and USMLE Composite Committee Member
Disclosure Disclosures: I have no conflicts of interest to report.
Objectives 1. List multiple proposed factors driving the obesity epidemic 2. Describe the pros and cons of the different types of FDAapproved medications for obesity 3. Briefly Discuss the role of inflammation in obesity-associated diseases, such as T2DM and cardiovascular disease
Case A 40F with a BMI of 37.3 kg/m2 comes into your office asking for one of the new medications to help her lose weight. You: a) Start lorcaserin (Belviq) b) Start bupropion/naltrexone (Contrave) c) Start phentermine/topiramate (Qsymia) d) Tell her to try diet and exercise and return in 3 months.
Obesity Definitions BMI (Body Mass Index) Calculated as weight (kg)/height 2 (m 2 ) Underweight: BMI < 18.5 Normal weight: BMI 18.5 25 Overweight: BMI 25 30 Obese: BMI 30 Morbid Obesity BMI 35 + obesity-related health condition or BMI 40
Obesity Definitions BMI (Body Mass Index) Calculated as weight (kg)/height 2 (m 2 ) Underweight: BMI < 18.5 Normal weight: BMI 18.5 25 Overweight: BMI 25 30 Obese: BMI 30 Morbid Obesity BMI 35 + obesity-related health condition or BMI 40
Obesity Epidemic
Obesity Epidemic O B E S I T Y
Obesity Trends* Among U.S. Adults BRFSS, 1990 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14%
Obesity Trends* Among U.S. Adults BRFSS, 2000 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20%
Obesity Trends* Among U.S. Adults BRFSS, 2010 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data 15% 19% 20% 24% 25% 29% 30%
Worldwide Epidemic World Obesity Federation 2014.
Adipose tissue as an endocrine gland Leptin is the first fat hormone identified
Why is this happening? Genetics Illnesses Medications Environment
Why is this happening? Genetics Illnesses Medications Environment
Genetics of Obesity Family Studies comparing identical twins raised together vs raised separately ~66% of BMI explained by genetics ~33% of BMI explained by other factors 1. Stunkard et al. N Engl J Med 1990; 322:1483-1487. 2. Drake et al. Reproduction 2010; 140: 387 398. 3. Shen et al. PLoS Genet. 2007 Oct; 3(10):2023-36.
Genetics of Obesity Monogenic (~5% of morbid obesity) MC4R (1-2.5%) Leptin (LEP) or its receptor (LEPR) POMC Pro-hormone convertase-1 Polygenetic 50+ possible genes identified Epigenetics 1. Walley et al. Hum Mol Genet 2006; 15 (suppl 2): R124-R130. 2. Farooqi et al. Endocrine Reviews 27(7):710 718.
Genetics of Obesity Monogenic (~5% of morbid obesity) MC4R (1-2.5%) Leptin (LEP) or its receptor (LEPR) POMC Pro-hormone convertase-1 FTO Polygenetic 50+ possible genes identified Epigenetics 1. Walley et al. Hum Mol Genet 2006; 15 (suppl 2): R124-R130. 2. Farooqi et al. Endocrine Reviews 27(7):710 718. 3. Choquet et al. Curr Genomics. 2011 May;12(3):169-79.
Genetics of Obesity Monogenic (~5% of morbid obesity) MC4R (1-2.5%) Leptin (LEP) or its receptor (LEPR) POMC Pro-hormone convertase-1 FTO Polygenetic 50+ possible genes identified Epigenetics Maternal obesity causing imprinting in utero? 1. Walley et al. Hum Mol Genet 2006; 15 (suppl 2): R124-R130. 2. Farooqi et al. Endocrine Reviews 27(7):710 718. 3. Choquet et al. Curr Genomics. 2011 May;12(3):169-79.
Why is this happening? Genetics Illnesses Medications Environment
Illnesses Hypothyroidism Cushing s Syndrome Uncontrolled cortisol production Growth hormone deficiency Depression Eating Disorders 1. The American Heritage Dictionary of the English Language, 5th edition. 2013. 2. Biller B. In Atlas of Clinical Endocrinology: Neuroendocrinology and Pituitary Disease. 2000
Medications Psychiatric/Neurological Antidepressants SSRI: Paroxetine (Paxil) TCA: Amitriptyline (Elavil) Nortriptyline (Aventyl) Mirtazipine (Remeron) Antipsychotics Clozapine (Clozaril) Olanzapine (Zyprexa) Risperidone (Risperdal) Anticonvulsants Valproic Acid (>10% BW in ~50% pts) Gabapentin (>10% BW in ~25% pts) 1. Apiovan et al. JCEM 2015; 100: 1-21.
Medications Diabetic Insulin Insulin secretagogues Sulfonylureas (eg. Glipizide) Glitinides (eg. Prandin, Starlix) Other Steroids β-blockers Oral contraceptives 1. Apiovan et al. JCEM 2015; 100: 1-21.
Why is this happening? Genetics Illnesses Medications Environment
Environmental/Other Factors Diet Larger plate size More energy dense foods More dining out Decreased Sleep Environment Central Heating/Air conditioning Decreased access to walk/bike paths Decreased access to fresh fruits/vegetables Endocrine Disrupters (e.g. DDT, BPA) Microorganism & microbiome Older Maternal Reproductive Age McAllister et al. Crit Rev Food Sci Nutr. 2009 Nov; 49(10): 868 913.
What s the Big Deal? Morbidity Hypertension Cardiovascular Disease Type 2 Diabetes Obstructive Sleep Apnea NAFLD/NASH/Cirrhosis Osteoarthritis Cancer Other
What s the Big Deal? Mortality Overweight (BMI 25-30): 1.28 (95% CI, 0.89-1.84) Obesity, Grade 1 (30-35): 1.67 (95% CI, 1.15-2.40) Obesity, Grade 2&3 (35+): 2.15 (95% CI, 1.47-3.14) Cost $190 billion in annual medical spending in 2012 21% of US annual medical spending Increased worker absenteeism Lower worker productivity 1. Stokes A. Population Health Metrics 2014, 12:6. 2. Cawley et al. J Health Econ. 2012; 31:219-30.
Treatment Strategies
Treatment Strategies Lifestyle Modification Medications Surgeries ** Research on the horizon **
Treatment Strategies Lifestyle Modification Medications Surgeries ** Research on the horizon **
Lifestyle Modification
Lifestyle Modification Behavior/Education Frequent interactions (1-2/mo) Nutritionist Food diary or other self-monitoring of food intake Diet Females: 1200-1500 kcal/day Males: 1500-1800 kcal/day Exercise 150 minutes per week = 30 min/day, 5 days per week (long term) 200-300 minutes/wk = 40-60 min/day, 5 days per week Jensen et al. Circulation. 2013;00:000 000.
Lifestyle Modification Look AHEAD Study At 8 year follow up: 4.7% weight loss 40% of individuals had 10% weight loss Diabetes Prevention Program 1. Look AHEAD. N Engl J Med 2013; 369:145-154. 2. DPP Group. Lancet 2009; 374(9702): 1677 1686.
Treatment Strategies Lifestyle Modification Medications Surgeries ** Research on the horizon **
Treatment Strategies Lifestyle Modification Medications Long term (lifelong) Short term Off-label Surgeries ** Research on the horizon **
Pharmacotherapy Indications BMI 30 (obese) BMI 27 + comorbidity Reasoning Weight loss may improve ability for increased exercise Reduce appetite/increase satiety May reinforce positive, weight-loss behaviors ** Use as an adjunct to Lifestyle Therapy! **
Timeline Dose titration/adverse Side Effects Start 1 month 2 months 3 months 5% wt loss q3mo Continue < 5% wt loss Change Therapy!
Lifelong Therapies Orlistat (Alli, Xenical) Lorcaserin (Belviq) Phentermine/Topiramate (Qsymia) Bupropion/Naltrexone (Contrave) Liraglutide (Saxenda)
Weight Loss 16 14 12 10 8 6 4 2 0 Weight Loss (over placebo) 45 40 35 30 25 20 15 10 5 0 % Reaching Target Goals Weight (lbs) % Wt Loss > 5% Weight Loss > 10% Weight Loss
Bang for the Buck? 1000 900 800 700 600 500 400 300 200 100 0 Cost (USD/mo) Out of Pocket
Pharmacology Mechanism of Action Implementation Pros and Cons Contraindications and Cautions
Phentermine/Topiramate (Qsymia) Phentermine sympathomimetic (norepinephrine) Decreases appetite through central pathways Topiramate mood stabilizer (GABA receptor modulator) Appetite Suppression Satiety enhancement
Phentermine/Topiramate (Qsymia) Implementation: Start 3.75/23mg 2 Weeks 7.5/46mg 3 months 3% wt loss 15 lb (6.6%) Weight Loss < 3% wt loss High Dose 11.25/69mg 2 Weeks 15/92mg 19 lb (8.6%) Weight Loss
Phentermine/Topiramate (Qsymia) Pros Most effective Once daily Cons Rapid discontinuation can cause seizures Can increase HR up to 20bpm Insomnia (if taken at night) Cognitive Impairment Paresethesias, dizziness, dysgeusia, constipation, dry mouth
Phentermine/Topiramate (Qsymia) Avoid In: Pregnancy Uncontrolled HTN Recent MAOI use Glaucoma Hyperthyroidism Alcoholics Caution In: Depression CVD Hepatic/Renal Impairment Non K-sparing diuretics
Liraglutide (Saxenda) Liraglutide glucagon-like peptide 1 (GLP-1) agonist Decreases appetite through central pathways Increases satiety Delayed gastric emptying
Liraglutide (Saxenda) Implementation: Week Daily Dose 1 0.6mg 2 1.2mg 3 1.8mg 4 2.4mg 5 and beyond 3.0mg
Liraglutide (Saxenda) Implementation:
Liraglutide (Saxenda) Pros Once daily Can be used to lower A1c in T2DM Cons GI symptoms (68%) Pancreatitis (0.3% vs 0.1%) Gallbladder (1.5% vs 0.5%) Hypoglycemia in T2DM pts Usually mild, and concomitantly on a sulfonylurea Increased HR by 4 to 9 bpm
Liraglutide (Saxenda) Avoid In: Pregnancy or Nursing Medullary Thyroid CA Personal or FHx MEN2 Chronic Pancreatitis Caution In: Hepatic or Renal Impairment Depression Gastroparesis
Bupropion/Naltrexone (Contrave) Bupropion Norepinephrine Dopamine Reuptake Inhibitor (NDRI) Decreases appetite Increases energy expenditure through centrally mediated pathways Naltrexone opiate antagonist Decreases reward
Bupropion/Naltrexone (Contrave) Implementation: Week AM Dose PM Dose 1 2 3 4 = 8mg/90mg
Bupropion/Naltrexone (Contrave) Pros Antidepressant Smoking Cessation Aid Cons Avoid high fat meals (incr absorption) GI symptoms Headache, dizziness, insomnia Antidepressants have shown increased suicidality in adolescents/young adults (<24yo) No incr seen specifically in Contrave clinical trials
Bupropion/Naltrexone (Contrave) Avoid In: Pregnancy or Nursing Uncontrolled HTN Recent MAOI use Seizure History Abrupt discontinuation of alcohol or benzos Anorexia or Bulimia Chronic opiod use Caution In: Depression CAD Hepatic/Renal Impairment
Lorcaserin (Belviq) Lorcaserin serotonin (5HT 2C ) receptor agonist Promotes satiety through central pathways Implementation: One tab bid One tab daily almost as effective 3.0% vs 1.9% weight loss 22.2% vs 15.2% lost 5%
Lorcaserin (Belviq) Pros Easy to take Safe in CVD Cons Reduced BP and HR Least effective Valvulopathy (2.4% vs 2.0% at 1 year) Mild GI symptoms Headache, dizziness, fatigue
Lorcaserin (Belviq) Avoid In: Pregnancy or Nursing Caution In: Use of other serotonin or anti-dopamine meds Valvulopathy Hx of priapism
Orlistat (Xenical) Pancreatic and gastric lipase inhibitor Blocks the absorption of fats Implementation: One tab before each meal
Orlistat (Xenical) Pros: Non-systemic Long safety profile Approved in adolescents Cons TID Oily spotting Fat soluble vitamin deficiencies Avoid: Must take a daily multivitamin Pregnancy, Malabsorption Syndromes, certain meds (eg. Warfarin, LT4)
Treatment Strategies Lifestyle Modification Medications Long term (lifelong) Short term Off-label Surgeries ** Research on the horizon **
Short-term Medications Phentermine 37.5mg daily Approved in 1960s by FDA 3 months 7.9 lb weight loss Side effects Headaches, palpitations, elevated HR and BP, insomnia Diethylpropion 75mg daily Approved in 1960s by FDA 3 months 6.6 lb weight loss Side effects Same as above
Treatment Strategies Lifestyle Modification Medications Long term (lifelong) Short term Off-label Surgeries ** Research on the horizon **
Off-label Weight Loss Meds ADHD Methylphenidate Antidepressants Bupropion Antiseizure meds Topiramate Zonisamide Diabetes meds Metformin GLP-1 agonists (exanetide) SGLT2 inhibitors
Treatment Strategies Lifestyle Modification Medications Long term (lifelong) Short term Off-label Surgeries ** Research on the horizon **
Different Approach to Management Weight loss is very difficult Other strategies to block or delay the consequences of obesity What s the connection between obesity and disease?
Inflammation
Inflammation The source of inflammation in chronic obesity involves multiple organs but the Adipose Tissue (AT) is the most important one. AT: adipocytes, fibroblast, vascular tissue, adipose tissue macrophages (ATM) Non-obese Macrophages <10% of the AT Less volumen of adipocytes High secretion of adiponectin and omega-3= macrophages M2 Macrophages M2: anti-inflammatory properties, secrete IL-10 and FNTβ----increase insulin-sensitivity in muscle and fatty tissue Obese Adipocytes in large volumen and quantity Increase FA and ceramides Stimulate macrophages M1 Macrophages M1: pro-inflammatory, secrete FNTα, IL-1β, IL- 6, IL-18, ROS. Increase recruitment of more macrophages
Inflammation BMI is correlated with hscrp Elevated inflammation (CRP or IL-6) increases risk for development of T2DM and CVD Weight loss results in decreased Inflammation Insulin Resistance Cardiovascular Disease Visser. NEJM 1999. Le et al. Diabetes 2011. Bremer et al. JCEM 2011.
Inflammation Peripheral Tissues Pancreas Vasculature
Case A 40F with a BMI of 37.3 kg/m2 and no other past medical history comes into your office asking for one of the new medications to help her lose weight. You: a) Start lorcaserin (Belviq) 10mg twice daily b) Start bupropion/naltrexone (Contrave) c) Start phentermine/topiramate (Qsymia) d) Tell her to try diet and exercise and return in 3 months.
Case Things to consider: Planning any more children? On effective birth control? Completely Healthy Phentermine/Topiramate (Qsymia) Diabetic Liraglutide (Saxenda) Smoker Bupropion/Naltrexone (Contrave) Cardiovascular Disease Lorcaserin (Belviq)
Questions? ASAP
Thanks for your attention riccorrea20@hotmail.com