The risk of cardiovascular complications with current obesity drugs

References

• Hales CM, Carroll MD, Fryar CD, et al. Prevalence of obesity and severe obesity among adults: United States, 2017–2018. NCHS Data Brief, no 360. Hyattsville, MD: National Center for Health Statistics, 2020.
   Google Scholar
• Khan SS, Ning H, Wilkins JT, et al. Association of body mass index with lifetime risk of cardiovascular disease and compression of morbidity. JAMA Cardiol. 2018;3:280–287.
   PubMed Web of Science ®Google Scholar
• Shihab HM, Meoni LA, Chu AY, et al. Body mass index and risk of incident hypertension over the life course: the Johns Hopkins Precursors Study. Circulation. 2012;126:2983–2989.
   PubMed Web of Science ®Google Scholar
• Guh DP, Zhang W, Bansback N, et al. The incidence of co-morbidities related to obesity and overweight: A systematic review and meta-analysis. BMC Public Health. 2009;9:88.
   PubMed Web of Science ®Google Scholar
• Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an endocrine Society clinical practice guideline [published correction appears in J Clin Endocrinol Metab. 2015 May;100(5):2135–6]. J Clin Endocrinol Metab. 2015;100(2):342–362.
   PubMed Web of Science ®Google Scholar
• Jensen MD, Ryan DH, Apovian CM, 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. J Am Coll Cardiol. 2014;63:2985–3023.
   PubMed Web of Science ®Google Scholar
• Khera R, Murad MH, Chandar AK, 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.
   PubMed Web of Science ®Google Scholar
• Heymsfield SB, Wadden TA. Mechanisms, pathophysiology, and management of obesity. N Engl J Med. 2017;376:254–266.
   PubMed Web of Science ®Google Scholar
• Onakpoya IJ, Heneghan CJ, Aronson JK. Post-marketing withdrawal of anti-obesity medicinal products because of adverse drug reactions: a systematic review. BMC Med. 2016;14:191.
   PubMed Web of Science ®Google Scholar
• Fishman AP. Aminorex to fen/phen: an epidemic foretold. Circulation. 1999;99:156–161.
   PubMed Web of Science ®Google Scholar
• Arterburn DE, Crane PK, Veenstra DL. The efficacy and safety of sibutramine for weight loss: a systematic review. Arch Intern Med. 2004;164:994–1003.
   PubMed Web of Science ®Google Scholar
• Florentin M, Liberopoulos E, Elisaf M. Sibutramine‐associated adverse effects: a practical guide for its safe use. Obes Rev. 2008;9:378–387.
   PubMed Web of Science ®Google Scholar
• Products CfPM. Opinion following an article 31 referral: sibutramine. London, UK: European Agency for the Evaluation of Medicinal Products, 2002.
   Google Scholar
• James WPT, Caterson ID, Coutinho W, et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med. 2010;363:905–917.
   PubMed Web of Science ®Google Scholar
• U.S. Food & Drug Administration. Guidance for industry: developing products for weight management. Washington, DC: Food Drug Adm; 2007.
   Google Scholar
• Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363:245–256.
   PubMed Web of Science ®Google Scholar
• Fidler MC, Sanchez M, Raether B, 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.
   PubMed Web of Science ®Google Scholar
• O’Neil PM, Smith SR, Weissman NJ, 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.
   PubMed Web of Science ®Google Scholar
• Bohula EA, Wiviott SD, McGuire DK, et al. Cardiovascular safety of lorcaserin in overweight or obese patients. N Engl J Med. 2018;379:1107–1117.
   PubMed Web of Science ®Google Scholar
• Henness S, Perry CM. Orlistat: a review of its use in the management of obesity. Drugs. 2006;66:1625–1656.
   PubMed Web of Science ®Google Scholar
• Xenical (orlistat) capsules for oral use. [cited 2020 Apr 1]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020766s029lbl.pdf
   Google Scholar
• Khera R, Pandey A, Chandar AK, et al. Effects of weight-loss medications on cardiometabolic risk profiles: a systematic review and network meta-analysis. Gastroenterology. 2018;154(1309–19):e7.
   Google Scholar
• Torgerson JS, Hauptman J, Boldrin MN, et al. 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.
   PubMed Web of Science ®Google Scholar
• Heymsfield SB, Segal KR, Hauptman J, et al. Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults. Arch Intern Med. 2000;160:1321–1326.
   PubMed Web of Science ®Google Scholar
• Zhi J, Mulligan TE, Hauptman JB. Long‐term systemic exposure of orlistat, a lipase inhibitor, and its metabolites in obese patients. J Clin Pharmacol. 1999;39:41–46.
   PubMed Web of Science ®Google Scholar
• Zhi J, Melia AT, Eggers H, et al. Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers. J Clin Pharmacol. 1995;35:1103–1108.
   PubMed Web of Science ®Google Scholar
• Hussain SS, Bloom SR. The pharmacological treatment and management of obesity. Postgrad Med. 2011;123:34–44.
   PubMed Web of Science ®Google Scholar
• Singh J, Kumar R. Phentermine-topiramate: first combination drug for obesity. Int J Appl Basic Med Res. 2015;5:157–158.
   PubMedGoogle Scholar
• Qsymia (phentermine and topiramate extended-release). [cited 2020 May 1]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022580s000lbl.pdf.
   Google Scholar
• Aronne LJ, Wadden TA, Peterson C, et al. Evaluation of phentermine and topiramate versus phentermine/topiramate extended‐release in obese adults. Obesity (Silver Spring). 2013;21:2163–2171.
   PubMed Web of Science ®Google Scholar
• Allison DB, Gadde KM, Garvey WT, et al. Controlled‐release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20:330–342.
   PubMed Web of Science ®Google Scholar
• Gadde KM, Allison DB, Ryan DH, 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.
   PubMed Web of Science ®Google Scholar
• Garvey WT, Ryan DH, Look M, 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.
   PubMed Web of Science ®Google Scholar
• Jordan J, Astrup A, Engeli S, et al. Cardiovascular effects of phentermine and topiramate: a new drug combination for the treatment of obesity. J Hypertens. 2014;32:1178–1188.
   PubMed Web of Science ®Google Scholar
• A Qsymia™ CardiovascuLAr morbIdity and Mortality (AQCLAIM) Study in Subjects with Documented Cardiovascular Disease. EU Clinical Trials Register; 2013 [cited 2020 Jul 20]. Available from: https://www.clinicaltrialsregister.eu/ctr-search/search?query=AQCLAIM
   Google Scholar
• Ritchey ME, Harding A, Hunter S, et al. Cardiovascular safety during and after use of phentermine and topiramate. J Clin Endocrinol Metab. 2019;104:513–522.
   PubMed Web of Science ®Google Scholar
• Krystal JH, Cramer JA, Krol WF, et al. Veterans Affairs Naltrexone Cooperative Study 425 Group. Naltrexone in the treatment of alcohol dependence. N Engl J Med. 2001;345(24):1734–1739.
   PubMed Web of Science ®Google Scholar
• Foley KF, DeSanty KP, Kast RE. Bupropion: pharmacology and therapeutic applications. Expert Rev Neurother. 2006;6:1249–1265.
   PubMed Web of Science ®Google Scholar
• Contrave (naltrexone HCl and bupropion HCl) extended-release tablets. [cited 2020 May 1]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/200063s000lbl.pdf.
   Google Scholar
• Greenway FL, Whitehouse MJ, Guttadauria M, et al. Rational design of a combination medication for the treatment of obesity. Obesity (Silver Spring). 2009;17:30–39.
   PubMed Web of Science ®Google Scholar
• Greenway FL, Fujioka K, Plodkowski RA, 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.
   PubMed Web of Science ®Google Scholar
• Apovian CM, Aronne L, Rubino D, 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.
   PubMed Web of Science ®Google Scholar
• Wadden TA, Foreyt JP, Foster GD, 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.
   PubMed Web of Science ®Google Scholar
• Hollander P, Gupta AK, Plodkowski R, 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.
   PubMed Web of Science ®Google Scholar
• Wood S Feb. 1, 2011, FDA declines approval for contrave diet drug; asks for CVD outcomes studies. Retrieved from Heart Wire. 2012.
   Google Scholar
• Nissen SE, Wolski KE, Prcela L, et al. Effect of naltrexone-bupropion on major adverse cardiovascular events in overweight and obese patients with cardiovascular risk factors: a randomized clinical trial. JAMA. 2016;315:990–1004.
   PubMed Web of Science ®Google Scholar
• Form 8K [filed by Orexigen Therapeutics Inc]. 2016 [cited 2015 Mar 3]. Available from: https://www.sec.gov/Archives/edgar/data/1382911/000119312515074251/d882841d8k.htm
   Google Scholar
• Naltrexone/Bupropion Cardiovascular Outcomes Study. [cited 2020 May 1]. Available from: https://clinicaltrials.gov/ct2/show/NCT02638129?term=contrave+cardiovascular&rank=1.
   Google Scholar
• Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87:1409–1439.
   PubMed Web of Science ®Google Scholar
• Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27:740–756.
   PubMed Web of Science ®Google Scholar
• Knudsen LB, Nielsen PF, Huusfeldt PO, et al. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem. 2000;43:1664–1669.
   PubMed Web of Science ®Google Scholar
• Saxenda (liraglutide [rDNA origin] injection. [cited 2020 May 1]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206321Orig1s000lbl.pdf.
   Google Scholar
• Astrup A, Rössner S, Van Gaal L, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374:1606–1616.
   PubMed Web of Science ®Google Scholar
• Astrup A, Carraro R, Finer N, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond). 2012;36:843–854.
   PubMed Web of Science ®Google Scholar
• Wadden TA, Hollander P, Klein S, 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. 2013;37:1443–1451.
   PubMed Web of Science ®Google Scholar
• Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373:11–22.
   PubMed Web of Science ®Google Scholar
• Davies MJ, Bergenstal R, Bode B, 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.
   PubMed Web of Science ®Google Scholar
• Blackman A, Foster G, Zammit G, et al. Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE Sleep Apnea randomized clinical trial. Int J Obes (Lond). 2016;40:1310–1319.
   PubMed Web of Science ®Google Scholar
• Robinson LE, Holt TA, Rees K, et al. Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis. BMJ Open. 2013;3:e001986.
   PubMed Web of Science ®Google Scholar
• Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–322.
   PubMed Web of Science ®Google Scholar
• Davies MJ, Aronne LJ, Caterson ID, et al. Liraglutide and cardiovascular outcomes in adults with overweight or obesity: a post hoc analysis from SCALE randomized controlled trials. Diabetes Obes Metab. 2018;20:734–739.
   PubMed Web of Science ®Google Scholar
• Kushner RF, Calanna S, Davies M, et al. Semaglutide 2.4 mg for the treatment of obesity: key elements of the STEP trials 1 to 5. Obesity (Silver Spring). 2020;28:1050–1061.
   PubMed Web of Science ®Google Scholar
• Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–1844.
   PubMed Web of Science ®Google Scholar
• Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381:841–851.
   PubMed Web of Science ®Google Scholar
• O’Neil PM, Birkenfeld AL, McGowan B, 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.
   PubMed Web of Science ®Google Scholar
• Ryan DH, Lingvay I, Colhoun HM, et al. SELECT (Semaglutide effects on cardiovascular outcomes in people with overweight or obesity) rationale and design. Am Heart J. 2020. In press.
   PubMed Web of Science ®Google Scholar
• A study of tirzepatide (LY3298176) in participants with obesity or overweight (SURMOUNT-1). Clinicaltrials.gov, 2019 [cited 2020 Jul 20]. Available from: https://clinicaltrials.gov/ct2/show/NCT04184622
   Google Scholar
• A study of tirzepatide (LY3298176) compared with dulaglutide on major cardiovascular events in participants with type 2 diabetes (SURPASS-CVOT). Clinicaltrails.gov. 2020 [cited 2020 Jul 20]. Available from: https://clinicaltrials.gov/ct2/show/NCT04255433
   Google Scholar
• Pilitsi E, Farr OM, Polyzos SA, et al. Pharmacotherapy of obesity: available medications and drugs under investigation. Metabolism. 2019;92:170–192.
   PubMed Web of Science ®Google Scholar
• Davidson MH, Hauptman J, DiGirolamo M, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA. 1999;281:235–242.
   PubMed Web of Science ®Google Scholar
• Wadden TA, Tsai AG, Tronieri JS. A protocol to deliver intensive behavioral therapy (IBT) for obesity in primary care settings: the MODEL‐IBT program. Obesity (Silver Spring). 2019;27:1562–1566.
   PubMed Web of Science ®Google Scholar
• Wadden TA, Walsh OA, Berkowitz RI, et al. Intensive behavioral therapy for obesity combined with liraglutide 3.0 mg: a randomized controlled trial. Obesity (Silver Spring). 2019;27:75–86.
   PubMed Web of Science ®Google Scholar
• Wadden TA, Berkowitz RI, Womble LG, et al. Randomized trial of lifestyle modification and pharmacotherapy for obesity. N Engl J Med. 2005;353:2111–2120.
   PubMed Web of Science ®Google Scholar
• Thomas CE, Mauer EA, Shukla AP, et al. Low adoption of weight loss medications: A comparison of prescribing patterns of antiobesity pharmacotherapies and SGLT 2s. Obesity (Silver Spring). 2016;24:1955–1961.
   PubMed Web of Science ®Google Scholar
• Xia Y, Kelton CM, Guo JJ, et al. Treatment of obesity: pharmacotherapy trends in the United States from 1999 to 2010. Obesity (Silver Spring). 2015;23:1721–1728.
   PubMedGoogle Scholar
• Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2020;43:487–493.
   PubMed Web of Science ®Google Scholar
• Cefalu WT, Kaul S, Gerstein HC, et al. Cardiovascular outcomes trials in type 2 diabetes: where do we go from here? Reflections from a diabetes care editors’ expert forum. Diabetes Care. 2018;41:14–31.
   PubMed Web of Science ®Google Scholar
• Krentz AJ, Rodriguez-Araujo G. Cardiovascular outcome trials of diabetes and obesity drugs: implications for conditional approval and early phase clinical development. Pharm Med. 2017;31:399–421.
   Web of Science ®Google Scholar
• Januzzi JL, Butler J, Jarolim P, et al. Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes. J Am Coll Cardiol. 2017;70:704–712.
   PubMed Web of Science ®Google Scholar
• Tardif JC, Heinonen T, Orloff D, et al. Vascular biomarkers and surrogates in cardiovascular disease. Circulation. 2006;113:2936–2942.
   PubMed Web of Science ®Google Scholar
• Rhainds D, Brodeur MR, Tardif JC. Lipids, apolipoproteins, and inflammatory biomarkers of cardiovascular risk: what have we learned? Clin Pharmacol Ther. 2018;104:244–256.
   PubMed Web of Science ®Google Scholar
• Baldassarre MPA, Andersen A, Consoli A, et al. Cardiovascular biomarkers in clinical studies of type 2 diabetes. Diabetes Obes Metab. 2018;20:1350–1360.
   PubMed Web of Science ®Google Scholar
• Chao AM, Wadden TA, Pearl RL, et al. A randomized controlled trial of lorcaserin and lifestyle counselling for weight loss maintenance: changes in emotion‐and stress‐related eating, food cravings and appetite. Clin Obes. 2018;8:383–390.
   PubMed Web of Science ®Google Scholar
• Chao AM, Wadden TA, Walsh OA, et al. Effects of liraglutide and behavioral weight loss on food cravings, eating behaviors, and eating disorder psychopathology. Obesity (Silver Spring). 2019;27:2005–2010.
   PubMed Web of Science ®Google Scholar
• October 24–25, 2018: meeting of the endocrinologic and metabolic drugs advisory committee meeting announcement. 2018 [cited 2020 Jul 20]. Available from: https://www.fda.gov/advisory-committees/advisory-committee-calendar/october-24-25-2018-meeting-endocrinologic-and-metabolic-drugs-advisory-committee-meeting
   Google Scholar
• Sharma A, Pagidipati NJ, Califf RM, et al. Impact of regulatory guidance on evaluating cardiovascular risk of new glucose-lowering therapies to treat type 2 diabetes mellitus: lessons learned and future directions. Circulation. 2020;141:843–862.
   PubMed Web of Science ®Google Scholar