Obesity Therapy. Endocrine Update 2012 March 10 th, Asem H Ali, MBBS Assistant professor clinical Division of Endocrinology

Transcription

1 Obesity Therapy Endocrine Update 2012 March 10 th, 2012 Asem H Ali, MBBS Assistant professor clinical Division of Endocrinology

2 Outline Significance of obesity Definitions Epidemiology Associations Etiology Management Lifestyle interventions Medications Surgical intervention 2

3 Outline Significance of obesity Definitions Epidemiology Associations Etiology Management Lifestyle interventions Medications Surgical intervention 3

4 Definitions of Overweight and Obesity BMI Calculated as weight (kg) height (m 2 ) Correlates well in adults with body fat Category BMI Health Risk Underweight < 18.5 Increased Normal* Normal Overweight ?Increased Obesity Class I High Class II Very High Class III 40.0 Extremely High NIH Natl Heart, Lung, and Blood Inst. Obes Res. 1998;6(suppl 2):51S. Willett WC et al. N Engl J Med. 1999;341:427.

5 Relationship Between BMI and Percent Body Fat in Men and Women Body Fat (%) Women Men Body Mass Index (kg/m 2 ) Adapted from: Gallagher et al. Am J Clin Nutr 2000;72:694.

6 More than 65% of US Adults Are Overweight, More than 30% are Obese Prevalence of adult obesity and overweight (US) over time (ages yrs) Prevalence (%) / NHANES I, II, III & Obesity Overweight Ogden C, et al. JAMA 2006;295: Hedley AA, et al. JAMA 2004;291:

7 Age-adjusted Percentage of U.S. Adults Who Were Obese No Data <14.0% % % % >26.0%

8 Medical Complications of Obesity Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome Pancreatitis Stroke Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis Gall bladder disease Cancer breast, uterus, cervix, prostate, kidney colon, esophagus, pancreas, liver Skin Gout Idiopathic intracranial hypertension Cataracts Coronary heart disease Diabetes Dyslipidemia Hypertension Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome Osteoarthritis Phlebitis venous stasis

9 J-Shaped Relationship Between BMI and Cardiovascular Disease Mortality Men Women Calle et al. N Engl J Med. 1999;341: Relative Risk of Death Lean Overweight Obese < Body Mass Index

10 Relative Risk Relative Risk Relationship Between BMI and Comorbidities Is Positive, Even in the Normal Range Type 2 diabetes Cholelithiasis Hypertension Coronary heart disease 6 Women 6 Men < < Body Mass Index (kg/m 2 ) Body Mass Index (kg/m 2 ) Willett WC, et al. N Engl J Med. 1999;341:

11 Outline Significance of obesity Definitions Epidemiology Associations Etiology Management Lifestyle interventions Medications Surgical intervention 11

12 Obesity Is Caused by Long-Term Positive Energy Balance Fat stores Energy intake Energy expenditure

13 BIOLOGICAL FUNCTION OF ADIPOCYTE Kahn BB, Flier JS. J Clin Invest 2000;106:

14 Substrates in regulation of appetite Harrold et al, Neuropharmacology Jan 30. [Epub ahead of print]

15 MW Schwartz, et al., Nature, 2000

16 16

17 Genetics of obesity MC4R mutation most common form (~3%) Leptin deficiency PC 1 / POMC GNAS PWS BDNF BBS 17

18 Baseline Time Spent Sitting vs. Standing/Walking in Lean vs. Obese Levine et al, Science, 2005, 307 Ravussin, Science, 2005, 307

19 Influence of Social Networks Based on Framingham study: participants had been asked to name their friends to facilitate follow-up in the study. Results adjusted for education and income level, prior obesity status Person developing Obesity Risk to subject over same time interval Caveats Friend 171% Only if mutual friendship of same gender Neighbor None Sibling 40% Only among same gender Spouse 37% N Engl J Med. 2007;357(4):370-9

20 Outline Significance of obesity Definitions Epidemiology Associations Etiology Management Lifestyle interventions Medications Surgical intervention 20

21 Strategies for Weight Loss Dietary Therapy Individually planned diet Deficit of 500 to 1,000 kcal/day BMIs in the range of need a decrease of kcal/day to lose ½ to 1 lb/week BMIs > 35 require deficits of up to 500 to 1,000 kcal/day to lose 1 to2 lbs/week Involvement of dietitian improves weight loss in primary care settings

22 Strategies for Weight Loss Dietary Therapy Low fat diet, Low carbohydrate diet, No difference, High Protein diet, commercial diets no difference at one year (5-10%) Experience reveals that lost weight usually will be regained unless a weight maintenance program consisting of dietary therapy, physical activity, and behavior therapy is continued indefinitely.

23 Shai et al, N Engl J Med Jul 17;359(3):

24 Strategies for Weight Loss Physical Activity Lean and Obese (no change in appetite and little change in Leptin) do not appear to have same hormonal response to exercise* Important, although will not lead to substantially greater weight loss over 6 months (2.9kg in 8months) Most weight loss occurs because of caloric intake Sustained physical activity - prevention of weight regain Benefit in reducing CVD and DM risks beyond that produced by weight reduction alone. *Endocrine Society 2008

25 Outline Significance of obesity Definitions Epidemiology Associations Etiology Management Lifestyle interventions Medications Surgical intervention 25

26 Drugs Approved by FDA for Treating Obesity Generic Name Trade Names DEA Schedule Approved Use Year Approved Diethylpropion Tenulate IV Short-term 1973 Phentermine Phendimetrazine Adipex, lonamin Bontril, Prelu-2 IV Short-term 1973 III Short-term 1961 Benzphetamine Didrex III Short-term 1960 Sibutramine Meridia IV Long-term 1997 Orlistat Xenical None Long-term 1999

27 Drug Trade name Mode of action Company USA Orlistat Phentermine Xenical / Alli (OTC) Ionamin, Duromi ne European Union Lipase inhibitor Roche Marketed Marketed Noradrenaline (NA) + dopamine (DA) releasing agent Generic Marketed Methamphetamine Desoxyn DA + NA releasing agent Generic Marketed Phendimetrazine Diethylpropion Tepanil, Bontril Sympathomimetic Generic Marketed Tenuate, Apisate Sympathomimetic Generic Marketed Benzphetamine Didrex Sympathomimetic Generic Marketed Sibutramine Reductil, Meridia Noradrenaline (NA) + 5â HT reuptake inhibitor Abbott Withdrawn in 2010 Rimonabant Accomplia Cannabinoid CB1 antagonist Sanofi-Aventis Not approved Bupropion/naltrexone Contrave DA reuptake inhibitor/opioid antagonist Orexigen/Taked a Topiramate/ phentermine Qnexa Unknown/NA + DA releasing agent Vivus Lorcaserin (APD356) Lorqess 5-HT2C agonist Arena/Eisai Withdrawn in 2001 Withdrawn in 2000 Withdrawn in 2000 Withdrawn in 2000 Withdrawn in 2000 Withdrawn in 2010 Withdrawn in 2008 Non- Approva ble Phase 3 Preregistrati on Preregistrati on Preregistrati on Phase 3 Zonisamide + bupropion Empatic Unknown/DA reuptake inhibitor Orexigen Phase 2 Phase 2 Heal, D.J., et al., Neuropharmacology (2012), doi: /j.neuropharm

28 Effects of leptin in a child with leptin deficiency Farooqi et al J Clin Invest; 106: ,

29 Little efficacy of leptin monotherapy in obese humans who are not leptin deficient

30 Weight loss effect of combined amylin and leptin agonism in DIO rats and overweight/obese humans Roth J. D. et.al. PNAS 2008;105:

31 Lorcaserin Body weight change from baseline to wk 52. Fidler M C et al. JCEM 2011;96: by Endocrine Society

32 Phentermine + topiramate (Qnexa) Gadde et al, Lancet Apr 16;377(9774):

33 Naltrexone + bupropion (Contrave) Greenway et al, Lancet Aug 21;376(9741):

34 Drug Trade name Mode of action Company Clinical development phase Obinepitide (TM30338) _ NPY Y2/Y4 agonist 7-TM Phase 2 TM30339 _ Y4 agonist 7-TM Phase 2 Velneperit (S2367) _ Y5 antagonist Shinogi Phase 2 Tesofensine (NS2330) _ Triple monoamine reuptake inhibitor Neurosearch Phase 2 PRX00933 _ 5-HT2C agonist Proximagen Phase 2 MK-0493 _ MC4 agonist Merck Phase 2 Symlin + metreleptin _ Amylin agonist + leptin agonist Amylin/Takeda Phase 2 Betahistine Histalaen H1 agonist/h3 antagonist Obecure Phase 2 ALB _ MCH1 antagonist Albany Phase 1 Synthetic peptide YY (PYY) 3-36 _ Y2 agonist Amylin Phase 1 S _ Y5 antagonist Shinogi Phase 1 GSK _ μ-opioid inverse agonist GSK Phase 1 ZYO1 _ CB1 antagonist Zydus Phase 1 MK5046 _ Not revealed Merk Phase 1 OAP189 _ Not revealed Pfizer Phase 1 PF _ Not revealed Pfizer Phase 1 TKS1225 _ Not revealed Pfizer Phase 1 HPP404 _ Not revealed TransTech Phase 1 P _ Not revealed Piramal/Lilly Phase 1 Heal, D.J., et al., What is the prognosis for new centrally-acting anti-obesity drugs?, Neuropharmacology (2012), doi: /j.neuropharm

35 Drug Mode of action Company Clinical development phase MCH1 antagonists MCH1 receptor antagonists Albany Research PT15 MC4 receptor agonist AstraZeneca Research PYY336 EMISPHERE Y2 agonist Emisphere Research GEMS-PYY Y2 agonist engene Research BMS Y1 antagonist BMS Research LY HT2C receptor agonist Eli Lilly Research 5-HT2C agonists 5-HT2C agonists Athersys Research AMR-SIX-1 5-HT6 antagonist Albany Research Not stated Ghrelin antagonist Elixir Research AEZS123 Ghrelin receptor antagonist AEterna Zentaris Research AMX808 with VRS859 AMX808 (glucagon receptor agonist) + VRS859 (exenatide) Amunix Inc/Versartis Research AC GLP-1 receptor agonist Amylin Research AOD9604 Growth hormone receptor Agonist Calcoza Research PSN602 _ NA + 5-HT reuptake inhibitor/5-ht1a agonist OSI Pharmaceuticals Discontinued Heal, D.J., et al., What is the prognosis for new centrally-acting anti-obesity drugs?, Neuropharmacology (2012), doi: /j.neuropharm

36 Meta-analysis of Weight-Loss Trials with Minimum 1 Year Follow-up Review of 80 studies, N=28,455, 18,199 completers (67%) Franz et al, J Am Diet Assoc 2007;107:

37 Outline Significance of obesity Definitions Epidemiology Associations Etiology Management Lifestyle interventions Medications Surgical intervention 37

38 Types of Surgery: Gastric Bypass Roux-en-Y gastric bypass is the most popular in the US Pouch can be created with staples or complete division Long-term weight loss of 50% of excess body weight >80% of diabetics revert to euglycemia Moving Roux limbs distally creates more rapid weight loss Malabsorption problems may be exacerbated

39 Types of Surgery: Gastroplasty Vertical banded gastroplasty now the preferred type of gastroplasty Less enlargement over time Produces weight loss, but usually less than gastric bypass

40 Types of Surgery: Gastric Banding Problems with original gastric band Pouch too large or small Adjustable gastric band developed in the 1980s Controls restriction by injection/withdrawal of saline May be performed laparoscopically

41 Laparoscopic Adjustable Gastric Banding Produces Greater Weight Loss than Comprehensive C Medical Therapy* in Patients with Class I Obesity (BMI kg/m 2 ) 0-5 Weight Loss, % Surgical Nonsurgical Baseline 6 mo 12 mo 18 mo 24 mo *(VLCD, behavioral modification, and pharmacotherapy) Obrien et al. Ann Intern Med. 2006;144:625-33

42 Mean % Weight Change over 15 Years Swedish Obesity Study Sjostrom: NEJM 2007;357:741-52

43 Prevention of Type 2 Diabetes at 8 Years After Bariatric Surgery Incidence of Type 2 Diabetes (% Patients) Control Bariatric surgery Follow-up After Surgery (y) 3.6 Control Surgery Initial BMI (kg/m 2 ) 41 ± 5 41 ± 4 Weight change at year 8: 1 ± 11% -16 ± 12% Sjostrom et al. Hypertension 2000;36:20.

44 Recommended Follow-up Labs for Bariatric Surgery Test Pre-Op 6 mo 12 mo 18 mo As indicated CBC X X X X X Iron Studies X X X X X Magnesium X X X X X LFTs & Lipids X X X X X HbA1C X X X X X Folate X X X X X Chem Panel X X X X X 25OH D X X X X X PTH-intact X X X X X Vitamin B12 X X X X X R. Kushner, Obesity Management 2005;1:203-6

45 Cases 45

46 Case 1 35 y.o. obese female, wt. 367 kg, BMI 49, with osteoarthritis that has impaired her movement significantly. She has no other complications of obesity, and failed several supervised programs She is only on analgesics 24 hour urine free cortisol, thyroid, lipid, and glucose within normal, leptin is normal for her weight

47 Which of the following would you recommend for her treatment? 1. Leptin therapy 2. Orlistat 3. Phetermine 4. Refer to supervised lifestyle modification 5. Refer to bariatric surgery 0% 0% 0% 0% 0%

48 Case 2 47 y.o. female with history of DM, HTN, and dyslipidemia is seen for management of obesity. She has failed lifestyle intervention previously On 3 anti-htn medication, metfromin, and gemfibrozil She has a strong family history of CAD On exam, BP 139/98, BMI is 32 kg/m2, and has carotid bruit

49 The next step in her management would be? 1. Phentermine 2. Orlistat 3. Orlistat plus phentermine 4. Referral for bariatric surgery 5. Referral to supervised weight loss program 0% 0% 0% 0% 0%

50 Thank you!