Multicenter, placebo-controlled trial of lorcaserin for weight management.

BACKGROUND Lorcaserin is a selective serotonin 2C receptor agonist that could be useful in reducing body weight. METHODS In this double-blind clinical trial, we randomly assigned 3182 obese or overweight adults (mean body-mass index [the weight in kilograms divided by the square of the height in meters] of 36.2) to receive lorcaserin at a dose of 10 mg, or placebo, twice daily for 52 weeks. All patients also underwent diet and exercise counseling. At week 52, patients in the placebo group continued to receive placebo but patients in the lorcaserin group were randomly reassigned to receive either placebo or lorcaserin. Primary outcomes were weight loss at 1 year and maintenance of weight loss at 2 years. Serial echocardiography was used to identify patients in whom valvulopathy (as defined by the Food and Drug Administration) developed. RESULTS At 1 year, 55.4% of patients (883 of 1595) receiving lorcaserin and 45.1% of patients (716 of 1587) receiving placebo remained in the trial; 1553 patients continued into year 2. At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo group had lost 5% or more of their body weight (P<0.001), corresponding to an average loss of 5.8+/-0.2 kg with lorcaserin and 2.2+/-0.1 kg with placebo during year 1 (P<0.001). Among the patients who received lorcaserin during year 1 and who had lost 5% or more of their baseline weight at 1 year, the loss was maintained in more patients who continued to receive lorcaserin during year 2 (67.9%) than in patients who received placebo during year 2 (50.3%, P<0.001). Among 2472 patients evaluated at 1 year and 1127 evaluated at 2 years, the rate of cardiac valvulopathy was not increased with the use of lorcaserin. Among the most frequent adverse events reported with lorcaserin were headache, dizziness, and nausea. The rates of serious adverse events in the two groups were similar. CONCLUSIONS In conjunction with behavioral modification, lorcaserin was associated with significant weight loss and improved maintenance of weight loss, as compared with placebo. (Funded by Arena Pharmaceuticals; ClinicalTrials.gov number, NCT00395135.)

[1]  A. Bianco,et al.  Crossing the hurdles of thyroid hormone receptor-α activation. , 2011, Endocrinology.

[2]  C. Rock,et al.  Weight Loss With Naltrexone SR/Bupropion SR Combination Therapy as an Adjunct to Behavior Modification: The COR‐BMOD Trial , 2011, Obesity.

[3]  G. Kennett,et al.  New approaches to the pharmacological treatment of obesity: Can they break through the efficacy barrier? , 2010, Pharmacology Biochemistry and Behavior.

[4]  S. Bartlett,et al.  The Neurokinin 1 Receptor Antagonist, Ezlopitant, Reduces Appetitive Responding for Sucrose and Ethanol , 2010, PloS one.

[5]  F. Greenway,et al.  Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial , 2010, The Lancet.

[6]  A. Astrup,et al.  The effect of the triple monoamine reuptake inhibitor tesofensine on energy metabolism and appetite in overweight and moderately obese men , 2010, International Journal of Obesity.

[7]  A. Astrup,et al.  Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study , 2009, The Lancet.

[8]  A. Bianco,et al.  A TRbeta-selective agonist confers resistance to diet-induced obesity. , 2009, The Journal of endocrinology.

[9]  J. Chan,et al.  It Takes Two to Tango , 2009, Journal of Investigative Medicine.

[10]  E. Ravussin,et al.  Enhanced Weight Loss With Pramlintide/Metreleptin: An Integrated Neurohormonal Approach to Obesity Pharmacotherapy , 2009, Obesity.

[11]  T. Wadden,et al.  Attrition from randomized controlled trials of pharmacological weight loss agents: a systematic review and analysis , 2009, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[12]  C. Anderson,et al.  Lorcaserin (APD356), a Selective 5‐HT2C Agonist, Reduces Body Weight in Obese Men and Women , 2009, Obesity.

[13]  A. Astrup,et al.  Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial , 2008, The Lancet.

[14]  Kevin W. Williams,et al.  5-HT2CRs Expressed by Pro-Opiomelanocortin Neurons Regulate Energy Homeostasis , 2008, Neuron.

[15]  Brian M. Smith,et al.  Lorcaserin, a Novel Selective Human 5-Hydroxytryptamine2C Agonist: in Vitro and in Vivo Pharmacological Characterization , 2008, Journal of Pharmacology and Experimental Therapeutics.

[16]  S. O’Rahilly,et al.  Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors. , 2008, Endocrinology.

[17]  Brian M. Smith,et al.  Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity. , 2008, Journal of medicinal chemistry.

[18]  K. Laugero,et al.  Pharmacological actions of the peptide hormone amylin in the long-term regulation of food intake, food preference, and body weight. , 2007, American journal of physiology. Regulatory, integrative and comparative physiology.

[19]  W. Poewe,et al.  Fibrotic heart-valve reactions to dopamine-agonist treatment in Parkinson's disease , 2007, The Lancet Neurology.

[20]  K. Gadde,et al.  Combination therapy of zonisamide and bupropion for weight reduction in obese women: a preliminary, randomized, open-label study. , 2007, The Journal of clinical psychiatry.

[21]  G. Bray,et al.  Pharmacological Treatment of the Overweight Patient , 2007, Pharmacological Reviews.

[22]  P. O'Suilleabhain,et al.  Cardiac valve regurgitation with pergolide compared with nonergot agonists in Parkinson disease. , 2007, Archives of neurology.

[23]  B. Roth.  Drugs and valvular heart disease. , 2007, The New England journal of medicine.

[24]  W. Haverkamp,et al.  Dopamine agonists and the risk of cardiac-valve regurgitation. , 2007, The New England journal of medicine.

[25]  A. Antonini,et al.  Valvular heart disease and the use of dopamine agonists for Parkinson's disease. , 2007, The New England journal of medicine.

[26]  T. Lutz.  Amylinergic control of food intake , 2006, Physiology and Behavior.

[27]  C. Dowrick,et al.  Factors associated with suicidal ideation in the general population: five-centre analysis from the ODIN study. , 2006, The British journal of psychiatry : the journal of mental science.

[28]  R. Horowski,et al.  Lisuride, a Dopamine Receptor Agonist With 5-HT2B Receptor Antagonist Properties: Absence of Cardiac Valvulopathy Adverse Drug Reaction Reports Supports the Concept of a Crucial Role for 5-HT2B Receptor Agonism in Cardiac Valvular Fibrosis , 2006, Clinical neuropharmacology.

[29]  F Xavier Pi-Sunyer,et al.  Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. , 2006, JAMA.

[30]  Dennis D. Kim,et al.  Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. , 2005, Diabetes care.

[31]  Robert V Farese,et al.  Atvb in Focus Novel Approaches to the Treatment of Dyslipidemia Inhibition of Triglyceride Synthesis as a Treatment Strategy for Obesity Lessons from Dgat1-deficient Mice Dgat Enzymes and Triglyceride Synthesis , 2022 .

[32]  T. Lutz.  Pancreatic amylin as a centrally acting satiating hormone. , 2005, Current drug targets.

[33]  C. Weyer,et al.  Effect of pramlintide on weight in overweight and obese insulin-treated type 2 diabetes patients. , 2004, Obesity research.

[34]  J. Cleary,et al.  Our journey with neuropeptide Y: effects on ingestive behaviors and energy expenditure , 2004, Peptides.

[35]  D. Lau,et al.  Long-term pharmacotherapy for overweight and obesity: a systematic review and meta-analysis of randomized controlled trials , 2003, International Journal of Obesity.

[36]  Mohammad A Ghatei,et al.  Inhibition of food intake in obese subjects by peptide YY3-36. , 2003, The New England journal of medicine.

[37]  T. Ryan,et al.  Effect of fenfluramine-derivative diet pills on cardiac valves: a meta-analysis of observational studies. , 2002, American heart journal.

[38]  Adesh K. Jain,et al.  Bupropion SR vs. placebo for weight loss in obese patients with depressive symptoms. , 2002, Obesity research.

[39]  M. Humbert,et al.  Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension , 2002, Nature Medicine.

[40]  M. Low,et al.  Activation of Central Melanocortin Pathways by Fenfluramine , 2002, Science.

[41]  R. Rothman,et al.  Therapeutic and adverse actions of serotonin transporter substrates. , 2002, Pharmacology & therapeutics.

[42]  N. Weissman,et al.  Testing the test: the reliability of echocardiography in the sequential assessment of valvular regurgitation. , 2002, American heart journal.

[43]  A. Stamford,et al.  Neuropeptide Y receptors as targets for anti-obesity drug development: perspective and current status. , 2002, European journal of pharmacology.

[44]  M. Flechtner-Mors,et al.  Lipoprotein responses to weight loss and weight maintenance in high-risk obese subjects , 2002, European Journal of Clinical Nutrition.

[45]  S. Fowler,et al.  Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. , 2002, The New England journal of medicine.

[46]  B. Roth,et al.  Evidence for Possible Involvement of 5-HT2B Receptors in the Cardiac Valvulopathy Associated With Fenfluramine and Other Serotonergic Medications , 2000, Circulation.

[47]  K. Karason,et al.  Relief of cardiorespiratory symptoms and increased physical activity after surgically induced weight loss: results from the Swedish Obese Subjects study. , 2000, Archives of internal medicine.

[48]  L. V. Van Gaal,et al.  Overweight, obesity, and blood pressure: the effects of modest weight reduction. , 2000, Obesity research.

[49]  Robert V Farese,et al.  Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat , 2000, Nature Genetics.

[50]  K. Oommen,et al.  Zonisamide: a new antiepileptic drug. , 1999, Clinical neuropharmacology.

[51]  Robert V Farese,et al.  Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[52]  N. Weissman,et al.  An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine, or placebo. Sustained-Release Dexfenfluramine Study Group. , 1998, The New England journal of medicine.

[53]  W. Edwards,et al.  Valvular heart disease associated with fenfluramine-phentermine. , 1997, The New England journal of medicine.

[54]  J. Shutter,et al.  Overexpression of Agrt leads to obesity in transgenic mice , 1997, Nature Genetics.

[55]  C. Strader,et al.  Diet-induced obese mice develop peripheral, but not central, resistance to leptin. , 1997, The Journal of clinical investigation.

[56]  S. Premakumari,et al.  Energy and protein requirements. , 1986, WHO chronicle.

[57]  N. Unwin,et al.  Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Detection, Evaluation, and Treatment of High Blood Cholesterol Education Program (NCEP) Expert Panel on Executive Summary of the Third Report of the National , 2009 .

[58]  B. Largent,et al.  Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. , 2000, Molecular pharmacology.