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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 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 What percentage of your patients are either overweight or obese? < 25% 25%-50% 51%-75% > 75% I don’t see patients currently Systems Review: Cardiovascular, Respiratory, Neurologic, Endocrine, and Psychological • Cardiovascular Hypertension Congestive heart failure Cor pulmonale Varicose veins Pulmonary embolism Coronary artery disease • Neurologic Respiratory Endocrine Stroke Idiopathic intracranial hypertension Meralgia paresthetica Depression Body image disturbance Low self-esteem Impaired quality of life Psychological Dyspnea Obstructive sleep apnea Hypoventilation syndrome Pickwickian syndrome Asthma Metabolic syndrome Type 2 diabetes mellitus Dyslipidemia Polycystic ovary syndrome/androgenicity Amenorrhea/infertility/menstrual disorders Systems Review: Musculoskeletal, Integumentary, GI, and Genitourinary • 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 • 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 Age-Adjusted Relative Risk Relationship Between BMI and Risk for Type 2 Diabetes Mellitus 93.2 100 Men Women 75 54.0 40.3 50 42.1 27.6 25 1.0 2.9 1.0 4.3 1.0 5.0 1.5 23-23.9 24-24.9 8.1 2.2 21.3 15.8 6.7 11.6 4.4 0 < 22 < 23 25-26.9 27-28.9 29-30.9 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. 31-32.9 33-34.9 35+ Association of Waist-to-Hip Ratio Within BMI Categories With MI Results expressed by waist-to-height ratio quintiles and BMI categories Yusuf S, et al. Lancet. 2005;366:1640-1649. Relative Risk for Death From Cardiovascular Disease, Cancer, and All Other Causes Cardiovascular disease Cancer All other causes Women 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 Men 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 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. 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. Effect of BMI on Lifespan Prospective Studies Collaboration. Lancet. 2009;373:1083-1096. 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. 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. I understand the role of the central nervous system in weight regulation. Strongly agree Agree Disagree Strongly disagree Neither agree nor disagree Mechanisms of Food Intake Family & Social Influences Sensory Factors: •Taste •Smell •Texture •Sight Effects of: •Variety •Sensory-specific satiety •Palatability •Food concentration •Ready availability Cognitive Factors: •Conscious rational control •Beliefs about the food •Advertising Brain Mechanisms: •Modulate sensory factors by satiety signals to produce reward value and appetite Satiety/Hunger Signals: •Fat cell hormones •Gut hormones •Gastric distention Adapted from: Rolls ET. Obes Rev. 2007;8(suppl1):67-72. Eating Model Summarizing Different Levels of Control Over Appetite Regulation Woods SC, et al. J Clin Endocrinol Metab. 2008;93(suppl1):S37-S50. Gut Peptides That Regulate Appetite Murphy KG, Bloom SR. Nature. 2006;444:854-859. Gut Peptides That Regulate Appetite Murphy KG, Bloom SR. Nature. 2006;444:854-859. 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 A Case of Hypothalamic Obesity Neuroregulation of Energy Balance 5-HT2c receptors Obesity Treatment Pyramid Surgery BMI Pharmacotherapy Lifestyle Modification Diet Physical Activity 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 Emerging Antiobesity Drugs and Drug Combinations •Lorcaserin, a selective 5-HT2C receptor agonist •Naltrexone + bupropion •Phentermine and topiramate 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. Behavioral Modification and Lorcaserin for Obesity and Overweight Management (BLOOM) Study Week 0 Weight change (kg) 8 16 24 -2 32 40 48 64 72 80 88 96 104 ITT/LOCF -4 Per Protocol ITT/LOCF -6 -8 -10 N = 344 N = 140 N = 308 PBO/PBO Lorc/PBO Lorc/Lorc 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. 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. Lorcaserin Did Not Increase the Rate of FDA Valvulopathy Treatment Lorcaserin 10 mg BID Placebo N n (%) Week 52 1278 1194 34 (2.66%) 28 (2.35%) P .70a Week 104 Lorcaserin/lorcaserin Lorcaserin/placebo Placebo/placebo 500 258 627 13 (2.6%) 5 (1.9%) 17 (2.7%) .99a 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. Lorcaserin: Adverse Events Reported by 5% or More in Any Group in Year 1 N (%) Lorcaserin (N = 1593) Placebo (N = 1584) Headache 287 (18.0) 175 (11.0) Dizziness 130 (8.2) 60 (3.8) Nausea 119 (7.5) 85 (5.4) Constipation 106 (6.7) 64 (4.0) Fatigue 95 (6.0) 48 (3.0) Dry mouth 83 (5.2) 37 (2.3) Smith SR, et al. ADA 2009. Late-Breaking Abstract 96. 28 Naltrexone and Bupropion Rationally Designed Around MOA to Initiate and Sustain Weight Loss Obesity: complex, multiple pathways to defend body weight Preclinical/clinical evidence for drug synergy Weight loss α-MSH Naltrexone/bupropion synergistic Bupropion increase in POMC activity Synergistic decrease in food intake and body weight MC4R = melanocortin-4 receptor; MOA = mechanism of action; MSH = melanocyte-stimulating hormone; POMC = proopiomelanocortin Greenway FL, et al. Obesity. 2009;17:30-39. Naltrexone β-endorphin COR-I, II: Body Weight, Percentage of Change From Baseline COR-I Observed Change from baseline (%) 0 ITT-LOCF -2 -1.9% -4 -1.3% -5.0%* -6 Placebo (N=456) NB32 (N=471) NB16 (N=471) -6.8%* -6.1%* -8 COR-II NB32 (N=702) Observed# 0 Change from baseline (%) Placebo (N=511) ITT-LOCF -1.4% -1.2% -2 -4 -6 -6.4%* -8 -8.1%* -8.2%* -10 0 8 16 24 32 40 48 56 56 Week Completers: Placebo (N = 290): -1.8% , NB16 (N = 284): -6.7%* NB32 (N = 296): -8.1%* -10 0 8 16 24 32 40 48 56 56 Week Completers: Placebo (N = 267): -1.4% NB32 (N = 434): -8.2%* 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. COR-I, II: Categoric Weight Loss at Week 56, ITT-LOCF 80 Placebo (N=511) COR-I 56.3% ITT-LOCF 60 Percentage of patients subjects Percentage of patients subjects ITT-LOCF * 48.0% 40 * 24.6% 20 16.4% * 60 * 50.5% 40 * 28.3% 20 17.1% 5.7% 2.0% 5% * 13.5% 11.9% 7.4% 0 NB32 (N=702) Placebo (N=456) 80 COR-II * NB32 (N=471) 10% 15% 0 5% 10% 2.4% 15% 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. COR-I: Improvements in Control of Eating, ITT-LOCF COR-I Placebo (N = 511) NB32 (N = 471) How difficult has it been to control your eating? How difficult has it been to resist any food cravings? How often have you eaten in response to food cravings? Less More 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. COR-II: Improvements in Control of Eating, ITT-LOCF COR-II Placebo (N = 456) NB32 (N = 702) How difficult has it been to control your eating? How difficult has it been to resist any food cravings? How often have you had food cravings? Less More 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. COR-I, II: Most Common Treatment-Emergent Adverse Events (TEAE) Placebo NB16 COR-I COR-II N=569 N=569 NB32 N=573 Nausea 5.3% 27.2%* 29.8%* 6.9% 29.2%* Headache 9.3% 16.0%* 13.8%* 8.7% 17.5%* Constipation 5.6% 15.8%* 15.7%* 7.1% 19.1%* Dizziness 2.6% 7.7%* 9.4%* 3.7% 6.9%* Vomiting 2.5% 6.3%* 9.8%* 2.0% 8.5%* Dry mouth 1.9% 7.4%* 7.5%* 2.6% 9.1%* 9.8% 21.4%* 19.5%* 13.8% 24.3%* Nausea 0.4% 4.6%* 6.3%* 0.2% 6.0%* Dizziness 0.5% 2.3%* 1.2% 0.2% 1.0% Headache 0.7% 1.6% 0.9% 0.8% 2.6%* Vomiting 0.2% 0.7% 0.9% 0% 0.8% Insomnia 0.2% 0.7% 0.7% 1.0% 0.8% Patients discontinuing due to a TEAE Placebo N=492 NB32/48 N=992 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. COR-I, II: Incidence of Nausea by Week and Intensity Placebo N = 1061 100 NB N = 2134 100 titration period 15 Mild Moderate Severe 10 5 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Incidence of nausea (%) Incidence of nausea (%) titration period 15 Mild Moderate Severe 10 5 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Nausea events are shown during week of onset only. If a patient had multiple-event onsets during the same week, Week 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. Potential Activities of Topiramate Involved in Energy Balance Activity Significance to Body Weight Loss 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 corticotropinreleasing 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 Topiramate in Obesity: Percentage of Body Weight Change From Baseline to Week 24 Weeks 0 2 4 6 8 10 12 14 16 18 20 22 24 0 Weight Change (%) -2 Placebo (n=48) -4 64 mg/d TPM (n=57) -6 96 mg/d TPM (n=49) -8 192 mg/d TPM (n=50) 384 mg/d TPM (n=44) -10 P < .05 from week 4 TPM = topiramate Bray G, et al. Obes Res. 2003;11:722-733. Proprietary Investigational Treatment for Obesity • Once-daily, oral, controlled-release formulation of lowdose phentermine and topiramate • Specifically designed to affect normal eating patterns over 24 hours -- simultaneously addressing appetite, satiety, and cravings 23 46 92 Maximum Approved Doses Topiramate 0 50 100 150 200 250 300 350 400 mg Phentermine 0 3.75 Low 5 7.5 Mid 10 15 20 25 Full Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=407933 Accessed April 27, 2010. 30 mg (free base) EQUIP: Weight Loss Over Time (Completer Population) Mean % Weight Loss Placebo -2.5%, 6 lb Low (23T, 3.75P) -7.0%, 18 lb Full (92T, 15P) -14.7%, 37 lb Data from patients who completed 56 weeks on treatment Weeks Patients Placebo Low Full Completers (% of randomized) 241 (47%) 138 (57%)* 301 (59%)* *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. CONQUER: Weight Loss Over Time (Completer Population) Mean % Weight Loss Placebo -2.4%, 6 lb Mid (46T, 7.5P) -10.5%, 24 lb Full (92T, 15P) -13.2%, 30 lb Data from patients who completed 56 weeks on treatment Weeks Patients Placebo Completers (% of randomized) *Statistically 564 (57%) Mid 344 (69%)* Full 634 (64%)* 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. EQUIP: Significant Categoric Weight Loss With Phentermine and Topiramate (Low and Full Dose) Completers Weight Loss 15% **P < .0001 vs placebo *P = .026 vs placebo 10% 5% 0 10 20 30 40 50 % of Patients Placebo Qnexa LowLow 60 70 80 % 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%** 90 Qnexa FullFull Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010. CONQUER: Significant Categoric Weight Loss With Phentermine and Topiramate (Mid and Full % of Patients with: Dose) Completers **P < .0001 vs placebo Weight Loss 15% • ≥ 15% wt loss Placebo 4% Mid 26%** Full 39%** • ≥ 10% wt loss Placebo 10% Mid 49%** Full 64%** 10% 5% 0 10 20 30 40 50 60 70 80 • ≥ 5% wt loss Placebo 26% Mid 75%** 90 Full 85%** % of Patients Placebo Placebo Qnexa Mid Low FullFull Qnexa Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010. EQUIP & CONQUER: TEAEs > 5% EQUIP (N = 1264) % of Patients (N = 3749) CONQUER (N = 2485) Placebo Low Full Placebo Mid Full Dry mouth 3.7 6.7 17.0 2.4 13.5 20.8 Tingling 1.9 4.2 18.8 2.0 13.7 20.5 Constipation 6.8 7.9 14.1 5.9 15.1 17.4 Altered taste 1.0 1.3 8.4 1.1 7.4 10.4 Insomnia 4.9 5.0 7.8 4.7 5.8 10.3 Dizziness 4.1 2.9 5.7 3.1 7.2 10.0 Nausea 4.7 5.8 7.2 4.2 3.6 6.8 Blurred vision 3.1 6.3 4.5 3.6 4.0 6.0 Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010. EQUIP & CONQUER: Discontinuation Rate Due to AEs in All Doses Studied Number of patients Discontinuation due to AEs Blurred vision Headache Insomnia Depression Tingling Irritability Anxiety Dizziness Placebo Low Mid Full 1508 9% 241 12% 498 12% 1507 18% 0.5% 0.7% 0.4% 0.2% 0.0% 0.1% 0.3% 0.2% 2.1% 1.7% 0.0% 0.0% 0.4% 0.8% 0.0% 0.4% 0.8% 0.2% 0.4% 0.8% 1.0% 0.8% 0.2% 1.2% 0.7% 0.9% 1.7% 1.4% 1.2% 1.2% 1.1% 0.8% 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. A Guide to Selecting Obesity Treatment BMI Category (kg/m2) Treatment Diet, physical activity, and behavior therapy 25-26.9 27-29.9 30-34.9 35-39.9 40 With comorbidity + - + - + - + - With comorbidity + - + - + - With comorbidity + - Pharmacotherapy Surgery NIH, et al. NIH. 2000;00-4804:1-84. 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 Thank you for participating in this activity. To proceed to the online CME test, click on the Earn CME Credit link on this page.