Anti-Obesity Drugs: Long-Term Efficacy and Safety: An Updated Review

Young Jin Tak, Sang Yeoup Lee, Young Jin Tak, Sang Yeoup Lee

Abstract

As a chronic and relapsing disease, obesity negatively impacts the health of men to a greater extent than that of women, with a higher risk of cardiovascular disease. Since lifestyle modifications alone are often challenging and limited for the maintenance of weight reduction, pharmacotherapy should be considered in a timely manner for obese men or overweight patients with weight-related comorbidities. Recent advances in anti-obesity drugs have enabled the potential of achieving clinically significant weight loss. Increasing evidence has shown that behavior-based interventions with one of these medications can result in greater weight loss than that elicited by usual care conditions. Data from most recent meta-analyses showed that the overall placebo-subtracted weight reduction (%) with the use of anti-obesity drugs for at least 12 months ranges from 2.9% to 6.8%; phentermine/topiramate (-6.8%) liraglutide (-5.4%), naltrexone/bupropion (-4.0%), lorcaserin (-3.1%), and orlistat (-2.9%). However, they have a high cost and may cause adverse outcomes depending on the individual. Very recently, on February 13, 2020, the US Food and Drug Administration requested withdrawal of lorcaserin from the market because a safety clinical trial showed an increased occurrence of cancer. Therefore the decision to initiate drug therapy in obese individuals should be made after the benefits and risks are considered. Thereafter, treatment should be tailored to specific patient subpopulations depending on their chronic conditions, comorbidities, and preferences. Herein, we provide an overview of the latest developments in weight loss medications, which may serve as one of the strategies for long-term obesity control.

Keywords: Liraglutide; Lorcaserin; Naltrexone/bupropion; Obesity; Orlistat; Phentermine/topiramate.

Conflict of interest statement

The authors have nothing to disclose.

Copyright © 2021 Korean Society for Sexual Medicine and Andrology.

References

    1. World Health Organization. Obesity and overweight. Fact sheet [Internet] Geneva: World Health Organization; c2018. [cited 2020 Jan 12]. Available from:
    1. Chen Y, Peng Q, Yang Y, Zheng S, Wang Y, Lu W. The prevalence and increasing trends of overweight, general obesity, and abdominal obesity among Chinese adults: a repeated cross-sectional study. BMC Public Health. 2019;19:1293.
    1. Park YW, Choi KB, Kim SK, Lee DG, Lee JH. Obesity in Korean men: results from the fourth through sixth Korean National Health and Nutrition Examination Surveys (2007~2014) World J Mens Health. 2016;34:129–136.
    1. Palmer BF, Clegg DJ. The sexual dimorphism of obesity. Mol Cell Endocrinol. 2015;402:113–119.
    1. Hwang JH, Ryu DH, Park SW. Interaction effect between weight perception and comorbidities on weight control behavior in overweight and obese adults: Is there a sex difference? J Korean Med Sci. 2015;30:1017–1024.
    1. White UA, Tchoukalova YD. Sex dimorphism and depot differences in adipose tissue function. Biochim Biophys Acta. 2014;1842:377–392.
    1. Fui MN, Dupuis P, Grossmann M. Lowered testosterone in male obesity: mechanisms, morbidity and management. Asian J Androl. 2014;16:223–231.
    1. Masterson JM, Soodana-Prakash N, Patel AS, Kargi AY, Ramasamy R. Elevated body mass index is associated with secondary hypogonadism among men presenting to a tertiary academic medical center. World J Mens Health. 2019;37:93–98.
    1. Moon KH, Park SY, Kim YW. Obesity and erectile dysfunction: from bench to clinical implication. World J Mens Health. 2019;37:138–147.
    1. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults--the evidence report. National Institutes of Health. Obes Res. 1998;6 Suppl 2:51S–209S.
    1. Lee SY, Park HS, Kim DJ, Han JH, Kim SM, Cho GJ, et al. Appropriate waist circumference cutoff points for central obesity in Korean adults. Diabetes Res Clin Pract. 2007;75:72–80.
    1. Curioni CC, Lourenço PM. Long-term weight loss after diet and exercise: a systematic review. Int J Obes (Lond) 2005;29:1168–1174.
    1. Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129:S102–S138.
    1. Garvey WT, Mechanick JI, Brett EM, Garber AJ, Hurley DL, Jastreboff AM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract. 2016;22 Suppl 3:1–203.
    1. Bhat SP, Sharma A. Current drug targets in obesity pharmacotherapy - a review. Curr Drug Targets. 2017;18:983–993.
    1. Coulter AA, Rebello CJ, Greenway FL. Centrally acting agents for obesity: past, present, and future. Drugs. 2018;78:1113–1132.
    1. Daneschvar HL, Aronson MD, Smetana GW. FDA-approved anti-obesity drugs in the United States. Am J Med. 2016;129:879.e1–879.e6.
    1. Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, et al. Pharmacological management of obesity: an endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:342–362.
    1. Xenical (orlistat) patient information [Internet] South San Francisco (CA): Genentech USA, Inc.; c2016. [cited 2020 Jan 1]. Available from: .
    1. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA. 2014;311:74–86.
    1. Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27:155–161.
    1. Garcia SB, Barros LT, Turatti A, Martinello F, Modiano P, Ribeiro-Silva A, et al. The anti-obesity agent Orlistat is associated to increase in colonic preneoplastic markers in rats treated with a chemical carcinogen. Cancer Lett. 2006;240:221–224.
    1. Hong JL, Meier CR, Sandler RS, Jick SS, Stürmer T. Risk of colorectal cancer after initiation of orlistat: matched cohort study. BMJ. 2013;347:f5039.
    1. The US Food and Drug Administration. 2-13-2020 FDA drug safety communication [Internet] Silver Spring (MD): The US Food and Drug Administration; c2020. [cited 2020 Feb 16]. Available from: .
    1. The US Food and Drug Administration. 01-14-2020 FDA drug safety communication [Internet] Silver Spring (MD): U.S. Food and Drug Administration; c2020. [cited 2020 Jan 16]. Available from: .
    1. Bohula EA, Scirica BM, Inzucchi SE, McGuire DK, Keech AC, Smith SR, et al. Effect of lorcaserin on prevention and remission of type 2 diabetes in overweight and obese patients (CAMELLIA-TIMI 61): a randomised, placebo-controlled trial. Lancet. 2018;392:2269–2279.
    1. Patel DK, Stanford FC. Safety and tolerability of new-generation anti-obesity medications: a narrative review. Postgrad Med. 2018;130:173–182.
    1. Gustafson A, King C, Rey JA. Lorcaserin (Belviq): a selective serotonin 5-HT2C agonist in the treatment of obesity. P T. 2013;38:525–534.
    1. Roth BL, Willins DL, Kristiansen K, Kroeze WK. 5-Hydroxytryptamine2-family receptors (5-hydroxytryptamine2A, 5-hydroxytryptamine2B, 5-hydroxytryptamine2C): where structure meets function. Pharmacol Ther. 1998;79:231–257.
    1. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, et al. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000;102:2836–2841.
    1. Meltzer HY, Roth BL. Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype-targeted drugs. J Clin Invest. 2013;123:4986–4991.
    1. Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363:245–256.
    1. Fidler MC, Sanchez M, Raether B, Weissman NJ, Smith SR, Shanahan WR, et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011;96:3067–3077.
    1. Bohula EA, Wiviott SD, McGuire DK, Inzucchi SE, Kuder J, Im K, et al. Cardiovascular safety of lorcaserin in overweight or obese patients. N Engl J Med. 2018;379:1107–1117.
    1. O'Neil PM, Smith SR, Weissman NJ, Fidler MC, Sanchez M, Zhang J, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity (Silver Spring) 2012;20:1426–1436.
    1. Weissman NJ, Sanchez M, Koch GG, Smith SR, Shanahan WR, Anderson CM. Echocardiographic assessment of cardiac valvular regurgitation with lorcaserin from analysis of 3 phase 3 clinical trials. Circ Cardiovasc Imaging. 2013;6:560–567.
    1. Rothman RB, Baumann MH. Appetite suppressants, cardiac valve disease and combination pharmacotherapy. Am J Ther. 2009;16:354–364.
    1. Velazquez A, Apovian CM. Updates on obesity pharmacotherapy. Ann N Y Acad Sci. 2018;1411:106–119.
    1. Picard F, Deshaies Y, Lalonde J, Samson P, Richard D. Topiramate reduces energy and fat gains in lean (Fa/?) and obese (fa/fa) Zucker rats. Obes Res. 2000;8:656–663.
    1. Richard D, Picard F, Lemieux C, Lalonde J, Samson P, Deshaies Y. The effects of topiramate and sex hormones on energy balance of male and female rats. Int J Obes Relat Metab Disord. 2002;26:344–353.
    1. Allison DB, Gadde KM, Garvey WT, Peterson CA, Schwiers ML, Najarian T, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP) Obesity (Silver Spring) 2012;20:330–342.
    1. Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377:1341–1352.
    1. Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95:297–308.
    1. Greenway FL, Whitehouse MJ, Guttadauria M, Anderson JW, Atkinson RL, Fujioka K, et al. Rational design of a combination medication for the treatment of obesity. Obesity (Silver Spring) 2009;17:30–39.
    1. Greenway FL, Fujioka K, Plodkowski RA, Mudaliar S, Guttadauria M, Erickson J, 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. Lancet. 2010;376:595–605.
    1. Apovian CM, Aronne L, Rubino D, Still C, Wyatt H, Burns C, et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II) Obesity (Silver Spring) 2013;21:935–943.
    1. Wadden TA, Foreyt JP, Foster GD, Hill JO, Klein S, O'Neil PM, et al. Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial. Obesity (Silver Spring) 2011;19:110–120.
    1. Hollander P, Gupta AK, Plodkowski R, Greenway F, Bays H, Burns C, et al. Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. Diabetes Care. 2013;36:4022–4029.
    1. Fujioka K, Braverman-Panza J. Answers to clinical questions in the primary care management of people with obesity: pharmacologic management. J Fam Pract. 2016;65:S16–S23.
    1. Jeon WS, Park CY. Antiobesity pharmacotherapy for patients with type 2 diabetes: focus on long-term management. Endocrinol Metab (Seoul) 2014;29:410–417.
    1. Apovian CM, Istfan NW. Obesity: guidelines, best practices, new research. Endocrinol Metab Clin North Am. 2016;45:xvii–xviii.
    1. Upadhyay J, Polyzos SA, Perakakis N, Thakkar B, Paschou SA, Katsiki N, et al. Pharmacotherapy of type 2 diabetes: an update. Metabolism. 2018;78:13–42.
    1. van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. Int J Obes (Lond) 2014;38:784–793.
    1. Ten Kulve JS, Veltman DJ, van Bloemendaal L, Barkhof F, Drent ML, Diamant M, et al. Liraglutide reduces CNS activation in response to visual food cues only after short-term treatment in patients with type 2 diabetes. Diabetes Care. 2016;39:214–221.
    1. Farr OM, Tsoukas MA, Triantafyllou G, Dincer F, Filippaios A, Ko BJ, et al. Short-term administration of the GLP-1 analog liraglutide decreases circulating leptin and increases GIP levels and these changes are associated with alterations in CNS responses to food cues: a randomized, placebo-controlled, crossover study. Metabolism. 2016;65:945–953.
    1. Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ, et al. Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA. 2016;315:2424–2434.
    1. Lean ME, Carraro R, Finer N, Hartvig H, Lindegaard ML, Rössner S, et al. Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults. Int J Obes (Lond) 2014;38:689–697.
    1. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373:11–22.
    1. Farr OM, Sofopoulos M, Tsoukas MA, Dincer F, Thakkar B, Sahin-Efe A, et al. GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial. Diabetologia. 2016;59:954–965.
    1. Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA. 2015;314:687–699.
    1. Wadden TA, Hollander P, Klein S, Niswender K, Woo V, Hale PM, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond) 2013;37:1443–1451.
    1. Fujioka K, O'Neil PM, Davies M, Greenway F, C W, Claudius B, et al. Early weight loss with liraglutide 3.0 mg predicts 1-year weight loss and is associated with improvements in clinical markers. Obesity (Silver Spring) 2016;24:2278–2288.
    1. Monami M, Nreu B, Scatena A, Cresci B, Andreozzi F, Sesti G, et al. Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): data from randomized controlled trials. Diabetes Obes Metab. 2017;19:1233–1241.
    1. Bahtiyar G, Pujals-Kury J, Sacerdote A. Cardiovascular effects of different GLP-1 receptor agonists in patients with type 2 diabetes. Curr Diab Rep. 2018;18:92.
    1. Steinberg WM, Rosenstock J, Wadden TA, Donsmark M, Jensen CB, DeVries JH. Impact of liraglutide on amylase, lipase, and acute pancreatitis in participants with overweight/obesity and normoglycemia, prediabetes, or type 2 diabetes: secondary analyses of pooled data from the SCALE clinical development program. Diabetes Care. 2017;40:839–848.
    1. Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. 2013;62:2595–2604.
    1. Koehler JA, Baggio LL, Yusta B, Longuet C, Rowland KJ, Cao X, et al. GLP-1R agonists promote normal and neoplastic intestinal growth through mechanisms requiring Fgf7. Cell Metab. 2015;21:379–391.
    1. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141:150–156.
    1. Hegedüs L, Sherman SI, Tuttle RM, von Scholten BJ, Rasmussen S, Karsbøl JD, et al. No evidence of increase in calcitonin concentrations or development of C-cell malignancy in response to liraglutide for up to 5 years in the LEADER trial. Diabetes Care. 2018;41:620–622.
    1. Nauck MA, Jensen TJ, Rosenkilde C, Calanna S, Buse JB LEADER Publication Committee on behalf of the LEADER Trial Investigators. Neoplasms reported with liraglutide or placebo in people with type 2 diabetes: results from the LEADER randomized trial. Diabetes Care. 2018;41:1663–1671.
    1. O'Neil PM, Aroda VR, Astrup A, Kushner R, Lau DCW, Wadden TA, et al. Neuropsychiatric safety with liraglutide 3.0 mg for weight management: results from randomized controlled phase 2 and 3a trials. Diabetes Obes Metab. 2017;19:1529–1536.
    1. Wilding JP. Combination therapy for obesity. J Psychopharmacol. 2017;31:1503–1508.
    1. Lupsa BC, Inzucchi SE. Use of SGLT2 inhibitors in type 2 diabetes: weighing the risks and benefits. Diabetologia. 2018;61:2118–2125.
    1. Bays HE, Weinstein R, Law G, Canovatchel W. Canagliflozin: effects in overweight and obese subjects without diabetes mellitus. Obesity (Silver Spring) 2014;22:1042–1049.
    1. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499–508.
    1. Hollander P, Bays HE, Rosenstock J, Frustaci ME, Fung A, Vercruysse F, et al. Coadministration of canagliflozin and phentermine for weight management in overweight and obese individuals without diabetes: a randomized clinical trial. Diabetes Care. 2017;40:632–639.
    1. Frías JP, Guja C, Hardy E, Ahmed A, Dong F, Öhman P, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4:1004–1016.
    1. Thomas CE, Mauer EA, Shukla AP, Rathi S, Aronne LJ. Low adoption of weight loss medications: a comparison of prescribing patterns of antiobesity pharmacotherapies and SGLT2s. Obesity (Silver Spring) 2016;24:1955–1961.
    1. Xia Y, Kelton CM, Guo JJ, Bian B, Heaton PC. Treatment of obesity: pharmacotherapy trends in the United States from 1999 to 2010. Obesity (Silver Spring) 2015;23:1721–1728.
    1. Colbert JA, Jangi S. Training physicians to manage obesity--back to the drawing board. N Engl J Med. 2013;369:1389–1391.
    1. Handjieva-Darlenska T, Handjiev S, Larsen TM, van Baak MA, Jebb S, Papadaki A, et al. Initial weight loss on an 800-kcal diet as a predictor of weight loss success after 8 weeks: the Diogenes study. Eur J Clin Nutr. 2010;64:994–999.
    1. Rissanen A, Lean M, Rössner S, Segal KR, Sjöström L. Predictive value of early weight loss in obesity management with orlistat: an evidence-based assessment of prescribing guidelines. Int J Obes Relat Metab Disord. 2003;27:103–109.
    1. Fujioka K, Plodkowski R, O'Neil PM, Gilder K, Walsh B, Greenway FL. The relationship between early weight loss and weight loss at 1 year with naltrexone ER/bupropion ER combination therapy. Int J Obes (Lond) 2016;40:1369–1375.
    1. Singh AK, Singh R. Pharmacotherapy in obesity: a systematic review and meta-analysis of randomized controlled trials of anti-obesity drugs. Expert Rev Clin Pharmacol. 2020;13:53–64.
    1. Kuo HH, Wang KT, Lee YH, Lin PL, Liu ME, Lin CY, et al. Effects of lorcaserin on cardiometabolic risk factors in overweight and obese patients: a systematic review and meta-analysis. J Clin Pharm Ther. 2020;45:35–44.
    1. Singh AK, Singh R. Efficacy and safety of lorcaserin in obesity: a systematic review and meta-analysis of randomized controlled trials. Expert Rev Clin Pharmacol. 2020 doi: 10.1080/17512433.2020.1703109. [Epub]
    1. O'Neil PM, Birkenfeld AL, McGowan B, Mosenzon O, Pedersen SD, Wharton S, et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet. 2018;392:637–649.
    1. Dong Z, Xu L, Liu H, Lv Y, Zheng Q, Li L. Comparative efficacy of five long-term weight loss drugs: quantitative information for medication guidelines. Obes Rev. 2017;18:1377–1385.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren