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Obesity as a CNS Disorder: Targeting the Neuronal Circuitry of Weight Loss

Obesity as a CNS Disorder: Targeting the Neuronal Circuitry of Weight Loss. Robert F. Kushner, MD, MS  Professor of Medicine Feinberg School of Medicine Northwestern University Clinical Director Northwestern Comprehensive Center on Obesity Chicago, Illinois. Learning Objectives.

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Obesity as a CNS Disorder: Targeting the Neuronal Circuitry of Weight Loss

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  1. Obesity as a CNS Disorder:Targeting the Neuronal Circuitry of Weight Loss Robert F. Kushner, MD, MS  Professor of Medicine Feinberg School of Medicine Northwestern University Clinical Director Northwestern Comprehensive Center on Obesity Chicago, Illinois

  2. Learning Objectives Upon completion of this activity, you should be able to: • Differentiate the mechanisms of action of the new targeted pharmacotherapies for obesity in development from the current approaches to obesity management • Evaluate the efficacy, safety, and tolerability of emerging antiobesity therapies, and where they may fit into the current obesity algorithms

  3. What percentage of your patients are either overweight or obese? • < 25% • 25%-50% • 51%-75% • > 75% • I don’t see patients currently

  4. Systems Review: Cardiovascular, Respiratory, Neurologic, Endocrine, and Psychological • Respiratory • Dyspnea • Obstructive sleep apnea • Hypoventilation syndrome • Pickwickian syndrome • Asthma • Endocrine • Metabolic syndrome • Type 2 diabetes mellitus • Dyslipidemia • Polycystic ovary syndrome/androgenicity • Amenorrhea/infertility/menstrual disorders • Cardiovascular • Hypertension • Congestive heart failure • Cor pulmonale • Varicose veins • Pulmonary embolism • Coronary artery disease • Neurologic • Stroke • Idiopathic intracranial hypertension • Meralgia paresthetica • Psychological • Depression • Body image disturbance • Low self-esteem • Impaired quality of life

  5. Systems Review: Musculoskeletal, Integumentary, GI, and Genitourinary • Gastrointestinal • GERD • Nonalcoholic fatty liver disease • Cholelithiasis • Hernias • Colon cancer • Genitourinary • Urinary stress incontinence • Obesity-related glomerulopathy • Kidney stones • Hypogonadism • Breast and uterine cancer • Pregnancy complications • Musculoskeletal • Hyperuricemia and gout • Immobility • Osteoarthritis (knees/hips) • Low back pain • Carpal tunnel syndrome • Integumentary • Striae distensae (stretch marks) • Stasis pigmentation of legs • Cellulitis • Acanthosis nigricans/skin tags • Intertrigo, carbuncles

  6. 93.2 54.0 40.3 42.1 27.6 21.3 15.8 8.1 5.0 4.3 11.6 2.9 2.2 6.7 1.5 1.0 1.0 1.0 4.4 Relationship Between BMI and Risk for Type 2 Diabetes Mellitus 100 Men Women 75 Age-Adjusted Relative Risk 50 25 0 23-23.9 < 22 < 23 24-24.9 25-26.9 27-28.9 29-30.9 31-32.9 33-34.9 35+ Body Mass Index (BMI; kg/m2) Chan J, et al. Diabetes Care. 1994;17:961-969. Colditz G, et al. Ann Intern Med. 1995;122:481-486.

  7. Association of Waist-to-Hip RatioWithin BMI Categories With MI Results expressed by waist-to-height ratio quintiles and BMI categories Yusuf S, et al. Lancet. 2005;366:1640-1649.

  8. > 35.0 < 18.5 18.5-20.4 23.5-24.9 25.0-26.4 26.5-27.9 28.0-29.9 30.0-31.9 32.0-34.9 20.5-21.9 22.0-23.4 Relative Risk for Death From Cardiovascular Disease, Cancer, and All Other Causes Cardiovascular disease Cancer All other causes Women Men 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 Relative Risk for Death Relative Risk for Death < 18.5 18.5-20.4 > 40.0 26.5-27.9 28.0-29.9 20.5-21.9 22.0-23.4 23.5-24.9 25.0-26.4 30.0-31.9 32.0-34.9 35.0-39.9 Body Mass Index Body Mass Index The reference category consisted of participants with BMIs of 23.5-24.9 kg/m2. Calle EE, et al. N Engl J Med. 1999;341:1097-1105.

  9. BMI and All-Cause Mortality Hazard ratio (HR) per 5 kg/m2 higher BMI. HR less than 1 if BMI is inversely associated with risk . All analyses exclude the first 5 years of follow-up and adjust for study and age at risk (in 5-year groups). The overall and age-specific analyses also adjust for sex, and the all-participant analyses also adjust for baseline smoking status. Prospective Studies Collaboration. Lancet. 2009;373:1083-1096.

  10. Effect of BMI on Lifespan Prospective Studies Collaboration. Lancet. 2009;373:1083-1096.

  11. All Healthcare Professionals Play a Role • Screening for Obesity in Adults. The US Preventive Services Task Force recommends that clinicians screen all adult patients for obesity and offer intensive counseling and behavioral interventions to promote sustained weight loss for obese adults (Grade B recommendation) U.S. Preventive Services Task Force. Ann Intern Med. 2003;139:930-932.

  12. All Healthcare Professionals Play a Role • Periodically monitor for change in weight by noting weight trajectory over time • Provide dietary, physical activity, and lifestyle counseling to “at-risk” patients, and consider pharmacologic and surgical treatment when indicated U.S. Preventive Services Task Force. Ann Intern Med. 2003;139:930-932.

  13. I understand the role of the central nervous system in weight regulation. • Strongly agree • Agree • Disagree • Strongly disagree • Neither agree nor disagree

  14. Mechanisms of Food Intake Family & Social Influences • Cognitive Factors: • Conscious rational control • Beliefs about the food • Advertising • Sensory Factors: • Taste • Smell • Texture • Sight • Effects of: • Variety • Sensory-specific satiety • Palatability • Food concentration • Ready availability • Brain Mechanisms: • Modulate sensory factors by satiety signals to produce reward value and appetite Eating • Satiety/Hunger Signals: • Fat cell hormones • Gut hormones • Gastric distention Adapted from: Rolls ET. Obes Rev. 2007;8(suppl1):67-72.

  15. Model Summarizing Different Levels of Control Over Appetite Regulation Woods SC, et al. J Clin Endocrinol Metab. 2008;93(suppl1):S37-S50.

  16. Gut Peptides That Regulate Appetite Murphy KG, Bloom SR. Nature. 2006;444:854-859.

  17. Gut Peptides That Regulate Appetite Murphy KG, Bloom SR. Nature. 2006;444:854-859.

  18. The Importance of the Hypothalamus in Appetite Regulation • Injury or lesions in the hypothalamus may result in a pattern of weight gain that is characterized as abrupt in onset and rapidly accelerating = hypothalamic obesity • Causes include: • Craniopharyngioma • Head trauma • Sarcoidosis • Aneurysm • Meningioma • Metastasis • Surgery • Radiation

  19. A Case of Hypothalamic Obesity

  20. Neuroregulation of Energy Balance 5-HT2c receptors

  21. Obesity Treatment Pyramid Surgery BMI Pharmacotherapy Lifestyle Modification Diet Physical Activity

  22. How confident are you that your understanding of emerging pharmacotherapies for treatment of obesity is up-to-date? • Very confident • Somewhat confident • Not very confident

  23. Emerging Antiobesity Drugs and Drug Combinations • Lorcaserin, a selective 5-HT2C receptor agonist • Naltrexone + bupropion • Phentermine and topiramate

  24. Lorcaserin Lorcaserin: selective 5-HT2C receptor agonist designed to promote weight loss • 5-HT2C receptor activation of proopiomelanocortin (POMC) neurons results in α-MSH activation of melanocortin-4 receptors • Serotonin receptor as a pharmacologic target for weight loss was validated by fenfluramine • Fenfluramine in combination with phentermine (Fen-Phen) was highly efficacious for weight loss • Safety concerns led to withdrawal: Fenfluramine activation of 5-HT2B receptor was linked to cardiac valvular disease Heisler LK, et al. Science. 2002;297:609-611.

  25. Behavioral Modification and Lorcaserin for Obesity and Overweight Management (BLOOM) N = 344 N = 140 N = 308 Lorcaserin (Lorc) vs placebo (PBO): P < .0001 at all timepoints Lorc/Lorc vs Lorc/PBO: P < .0001 at all year 2 timepoints Smith SR, et al. ADA 2009. Late-Breaking Abstract 96.

  26. Echocardiographic Monitoring and Endpoints • Echoes were performed every 6 months • Heart valve insufficiency (or regurgitation) is rated as follows: • Aortic: absent; trace; mild; moderate; severe • Mitral: absent; trace; mild; moderate; severe • Tricuspid: absent; trace; mild; moderate; severe • Pulmonic: absent; present • The US Food and Drug Administration (FDA) defines significant valvular disease as MILD or greater aortic regurgitation, or MODERATE or greater mitral regurgitation • Main endpoint: proportion of patients who develop “FDA valvulopathy” • Secondary endpoints: shift analyses of individual heart valve regurgitant scores CDC. MMWR Morb Mortal Wkly Rep. 1997;46:1061-1066.

  27. Lorcaserin Did Not Increase the Rate of FDA Valvulopathy N = number of evaluable echo pairs; n = number (%) with FDA valvulopathy aVs placebo with Fisher’s exact test Smith SR, et al. ADA 2009. Late-Breaking Abstract 96.

  28. Lorcaserin: Adverse Events Reported by 5% or More in Any Group in Year 1 Smith SR, et al. ADA 2009. Late-Breaking Abstract 96. 28

  29. Naltrexone and Bupropion Rationally Designed Around MOA to Initiate and Sustain Weight Loss MC4R Neuron • Obesity: complex, multiple pathways to defend body weight • Preclinical/clinical evidence for drug synergy • Naltrexone/bupropion synergistic increase in POMC activity • Synergistic decrease in food intake and body weight Weight loss α-MSH Bupropion Naltrexone β-endorphin POMC MC4R = melanocortin-4 receptor; MOA = mechanism of action; MSH = melanocyte-stimulating hormone; POMC = proopiomelanocortin Greenway FL, et al. Obesity. 2009;17:30-39.

  30. COR-I, II: Body Weight, Percentage of Change From Baseline Placebo (N=511) COR-II COR-I Observed ITT-LOCF Observed# ITT-LOCF NB16 (N=471) NB32 (N=702) NB32 (N=471) Completers: Placebo (N = 267): -1.4% NB32 (N = 434): -8.2%* Completers: Placebo (N = 290): -1.8% , NB16 (N = 284): -6.7%* NB32 (N = 296): -8.1%* Placebo (N=456) NB = naltrexone/bupropion. #COR-II: NB observed data are NB32/NB48 pooled (N = 825); no differences were observed for patients rerandomized to NB32 vs NB48. LS mean ± SE; *P < .001 vs placebo at all timepoints. COR-II: week 56 ITT-LOCF data from patients rerandomized to NB32 are double weighted to account for the prespecified exclusion of patients rerandomized to NB48. ITT-LOCF: patients with a baseline and ≥ 1 postbaseline weight measurement while on study drug. Press release. October 27, 2009. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irol-newsArticle&ID=1346886&highlight Accessed April 29, 2010.

  31. COR-I, II: Categoric Weight Loss at Week 56, ITT-LOCF COR-I ITT-LOCF COR-II ITT-LOCF NB32 (N=702) NB32 (N=471) patients patients Placebo (N=456) Placebo (N=511) Data are for the ITT-LOCF population. *P < .001 vs placebo . COR-II: week 56 data from patients rerandomized to NB32 are double weighted to account for the prespecified exclusion of patients rerandomized to NB48. ITT-LOCF: patients with a baseline and ≥ 1 postbaseline weight measurement while on study drug. Press release. October 27, 2009. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1346886&highlight Accessed April 29, 2010.

  32. COR-I: Improvements in Control of Eating, ITT-LOCF COR-I How difficult has it been to control your eating? NB32 (N = 471) How difficult has it been to resist any food cravings? How often have you eaten in response to food cravings? More Less Placebo (N = 511) Change from baseline to week 56 endpoint for eating/craving-related items showing differences (P < .05) at weeks 8, 16, 28, and 56 in both COR-I and COR-II; responses reflect experiences during the 7 days prior to answering the questionnaire; ITT-LOCF: patients with a baseline and ≥ 1 postbaseline weight measurement while on study drug. Data are LS mean ± SE; *P < .05 vs placebo; the COEQ consists of 21 questions with responses given using a 100-mm visual analogue scale. COR-II: week 56 data from patients rerandomized to NB32 are double weighted to account for the prespecified exclusion of patients rerandomized to NB48. Press release. October 27, 2009. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1346886&highlight Accessed April 29, 2010.

  33. COR-II: Improvements in Control of Eating, ITT-LOCF COR-II How difficult has it been to control your eating? NB32 (N = 702) How difficult has it been to resist any food cravings? How often have you had food cravings? More Less Placebo (N = 456) Change from baseline to week 56 endpoint for eating/craving-related items showing differences (P < .05) at weeks 8, 16, 28, and 56 in both COR-I and COR-II; responses reflect experiences during the 7 days prior to answering the questionnaire; ITT-LOCF: patients with a baseline and ≥ 1 postbaseline weight measurement while on study drug. Data are LS mean ± SE; *P < .05 vs placebo; the COEQ consists of 21 questions with responses given using a 100-mm visual analogue scale. COR-II: week 56 data from patients rerandomized to NB32 are double weighted to account for the prespecified exclusion of patients rerandomized to NB48. Press release. October 27, 2009. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1346886&highlight Accessed April 29, 2010.

  34. COR-I, II: Most Common Treatment-Emergent Adverse Events (TEAE) TEAEs > 5% in any NB group and 2x the incidence in the respective placebo group. Top 5 TEAEs leading to discontinuation in NB groups. Data are for the safety analysis set: patients taking ≥ 1 tablet of study drug and with ≥ 1 investigator contact/assessment at any time after the start of study treatment. *P < .05 vs placebo Press release. October 27, 2009. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1346886&highlight Accessed April 29, 2010.

  35. COR-I, II: Incidence of Nausea by Week and Intensity Placebo N = 1061 NB N = 2134 titration period titration period Nausea events are shown during week of onset only. If a patient had multiple-event onsets during the same week, only the most severe event is shown. Safety analysis set: patients taking ≥ 1 tablet of study drug and with ≥ 1 investigator contact/assessment at any time after the start of study treatment. Placebo data are combined for COR-I and COR-II. All NB data are combined for COR-I and COR-II (NB16, NB32, NB48). Press release. October 27, 2009. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1346886&highlight Accessed April 29, 2010.

  36. Potential Activities of Topiramate Involved in Energy Balance Significance to Body Weight Loss Activity • Inhibits activity of glutamate at AMPA/kainate receptors • Inhibits activation of L-type voltage-dependent Ca++ channels • Inhibits carbonic anhydrase (CA-II, CA-IV) • Modulates lipoprotein lipase activity • Stimulates thermogenesis and energy expenditure (some models) • Downregulation of corticotropin-releasing hormone, glucocorticoids (GC), and GC receptors (depends on model) • Other preliminary data Reduces body weight (?) Reduces body weight (?) Reduces body weight (?) Reduces fat deposition and triglycerides Reduces body weight Reduces body weight, other effects on energy metabolism Effects on energy metabolism

  37. Topiramate in Obesity: Percentage of Body Weight Change From Baseline to Week 24 Weeks Placebo (n=48) 64 mg/d TPM (n=57) 96 mg/d TPM (n=49) Weight Change (%) 192 mg/d TPM (n=50) 384 mg/d TPM (n=44) P < .05 from week 4 TPM = topiramateBray G, et al. Obes Res. 2003;11:722-733.

  38. Proprietary Investigational Treatment for Obesity Once-daily, oral, controlled-release formulation of low-dose phentermine and topiramate Specifically designed to affect normal eating patterns over 24 hours -- simultaneously addressing appetite, satiety, and cravings Maximum Approved Doses 23 46 92 Topiramate 0 50 100 150 200 250 300 350 400 mg Phentermine 20 7.5 15 25 3.75 0 5 10 30 mg (free base) Low Mid Full Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=407933 Accessed April 27, 2010.

  39. EQUIP: Weight Loss Over Time (Completer Population) Placebo -2.5%, 6 lb Full(92T, 15P) -14.7%, 37 lb Low (23T, 3.75P) -7.0%, 18 lb Mean % Weight Loss Data from patients who completed 56 weeks on treatment Weeks *Statistically greater number of patients completing study on combination drug vs placebo, P < .0001 Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010.

  40. CONQUER: Weight Loss Over Time (Completer Population) Placebo -2.4%, 6 lb Full(92T, 15P) -13.2%, 30 lb Mean % Weight Loss Mid (46T, 7.5P) -10.5%, 24 lb Data from patients who completed 56 weeks on treatment Weeks *Statistically greater number of patients completing study on combination drug vs placebo, P < .0001 Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010.

  41. EQUIP: Significant Categoric Weight Loss With Phentermine and Topiramate (Low and Full Dose) % of Patients with: • ≥ 15% wt loss Placebo 5% Low 11%* Full 43%** • ≥ 10% wt loss Placebo 12% Low 27%** Full 60%** • ≥ 5% wt loss Placebo 26% Low 59%** Full 84%** Completers **P < .0001 vs placebo *P = .026 vs placebo Weight Loss Full Low Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010.

  42. CONQUER: Significant Categoric Weight Loss With Phentermine and Topiramate (Mid and Full Dose) % of Patients with: ≥ 15% wt loss Placebo 4% Mid 26%** Full 39%** ≥ 10% wt loss Placebo 10% Mid 49%** Full 64%** ≥ 5% wt loss Placebo 26% Mid 75%** Full 85%** Completers **P < .0001 vs placebo Weight Loss Full Placebo Low Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010.

  43. EQUIP & CONQUER: TEAEs > 5% Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010.

  44. EQUIP & CONQUER: Discontinuation RateDue to AEs in All Doses Studied Includes adverse events (AEs) by dose for EQUIP & CONQUER, which lead to discontinuation in > 1% of patients Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010.

  45. A Guide to Selecting Obesity Treatment NIH, et al. NIH. 2000;00-4804:1-84.

  46. Summary • Appetite control and energy expenditure are regulated by peripheral and central signaling mechanisms • Newer antiobesity agents target these processes • Due to the complexity of the hypothalamic circuitry, combined drug therapy is likely to be more effective than monotherapy for weight control • Antiobesity medications are anticipated to have a more significant role in the treatment of patients with obesity

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