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氯卡色林用于超重或肥胖患者的心血管安全性
Cardiovascular Safety of Lorcaserin in Overweight or Obese Patients


Erin A. Bohula ... 心脑血管疾病 • 2018.09.20

摘要


背景

氯卡色林(lorcaserin)是一种调节食欲的选择性5-羟色胺2C受体激动剂,已经证明对超重或肥胖患者的体重管理有效。氯卡色林的心血管安全性和疗效尚不明确。

 

方法

我们将患动脉粥样硬化性心血管疾病或有多种心血管危险因素的12,000例超重或肥胖患者随机分组,接受氯卡色林(每日2次,每次10 mg)或安慰剂治疗。在中期分析时对主要安全性结局主要心血管事件(由心血管死亡、心肌梗死或卒中组成的复合结局)进行了评估,以排除非劣效性界值1.4。如果符合非劣效性,则在试验结束时对主要心血管疗效结局(由主要心血管事件、心力衰竭、因不稳定型心绞痛住院治疗或冠状动脉血运重建[扩展主要心血管事件]组成的复合结局)进行评估,以确定优效性。

 

结果

1年时,氯卡色林组5,135例患者中的1,986例(38.7%)和安慰剂组5,083例患者中的883例(17.4%)体重减轻≥5%(比值比,3.01;95%置信区间[CI],2.74~3.30;P<0.001)。氯卡色林组患者的心脏危险因素(包括血压、心率、血糖控制和血脂)值比安慰剂组患者略好。在3.3年的中位随访期间,在氯卡色林组和安慰剂组中,主要安全性结局的发生率分别为每年2.0%和每年2.1%(风险比,0.99;95% CI,0.85~1.14;非劣效性P<0.001);扩展主要心血管事件的发生率分别为每年4.1%和每年4.2%(风险比,0.97;95% CI,0.87~1.07;P=0.55)。特别关注的不良事件不常见,除了氯卡色林组出现严重低血糖的患者数量较多(13 vs. 4,P=0.04)之外,两组的发生率通常相似。

 

结论

在超重或肥胖患者组成的高危人群中,与安慰剂相比,氯卡色林有助于持续的体重减轻,且未增加主要心血管事件发生率(由卫材资助;CAMELLIA-TIMI 61在ClinicalTrials.gov注册号为NCT02019264)。





作者信息

Erin A. Bohula, M.D., D.Phil., Stephen D. Wiviott, M.D., Darren K. McGuire, M.D., M.H.Sc., Silvio E. Inzucchi, M.D., Julia Kuder, M.S., KyungAh Im, Ph.D., Christina L. Fanola, M.D., Arman Qamar, M.D., Conville Brown, M.D., Andrzej Budaj, M.D., Armando Garcia-Castillo, M.D., Milan Gupta, M.D., Lawrence A. Leiter, M.D., Neil J. Weissman, M.D., Harvey D. White, D.Sc., Tushar Patel, Ph.D., Bruce Francis, M.D., Wenfeng Miao, M.D., Carlos Perdomo, Ph.D., Shobha Dhadda, Ph.D., Marc P. Bonaca, M.D., M.P.H., Christian T. Ruff, M.D., M.P.H., Anthony C. Keech, M.D., Steven R. Smith, M.D., Marc S. Sabatine, M.D., M.P.H., and Benjamin M. Scirica, M.D., M.P.H. for the CAMELLIA–TIMI 61 Steering Committee and Investigators*
From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston (E.A.B., S.D.W., J.K., K.I., A.Q., M.P.B., C.T.R., M.S.S., B.M.S.); the Cardiovascular Division, University of Texas Southwestern Medical Center, Dallas (D.K.M.); the Section of Endocrinology, Yale School of Medicine, New Haven, CT (S.E.I.); the Department of Medicine, University of Minnesota, Minneapolis (C.L.F.); the Partners Clinical Research Centre, Nassau, Bahamas (C.B.); the Department of Cardiology, Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland (A.B.); Cardiolink Clinical Trials, Monterrey, Mexico (A.G.-C.); McMaster University, Brampton, ON (M.G.), and the Division of Endocrinology and Metabolism, St. Michael’s Hospital, University of Toronto, Toronto (L.A.L.) — both in Canada; MedStar Health Research Institute, Hyattsville, MD (N.J.W.); the Cardiology Department, Auckland City Hospital, Auckland, New Zealand (H.D.W.); Eisai, Woodcliff Lake, NJ (T.P., B.F., W.M., C.P., S.D.); National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (A.C.K.); and the Translational Research Institute for Metabolism and Diabetes, Florida Hospital and the Sanford–Burnham Institute, Winter Park (S.R.S.). Address reprint requests to Dr. Bohula at the TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 60 Fenwood Rd., Suite 7022, Boston, MA 02115, or at ebohula11@bwh.harvard.edu. *A complete list of the CAMELLIA–TIMI 61 steering committee members and investigators is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Obesity and overweight fact sheet. Geneva: World Health Organization, 2016 (http://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight).

2. Hales CM, Fryar CD, Carroll MD, Freedman DS, Ogden CL. Trends in obesity and severe obesity prevalence in US youth and adults by sex and age, 2007-2008 to 2015-2016. JAMA 2018;319:1723-1725.

3. The GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 2017;377:13-27.

4. Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA 2013;309:71-82.

5. Bray GA, Heisel WE, Afshin A, et al. The science of obesity management: an Endocrine Society scientific statement. Endocr Rev 2018;39:79-132.

6. 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. Circulation 2014;129:Suppl 2:S102-S138.

7. Garvey WT, Garber AJ, Mechanick JI, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the 2014 advanced framework for a new diagnosis of obesity as a chronic disease. Endocr Pract 2014;20:977-989.

8. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine–phentermine. N Engl J Med 1997;337:581-588.

9. 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.

10. Topol EJ, Bousser MG, Fox KA, et al. Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet 2010;376:517-523.

11. Brashier DB, Sharma AK, Dahiya N, Singh SK, Khadka A. Lorcaserin: a novel antiobesity drug. J Pharmacol Pharmacother 2014;5:175-178.

12. 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.

13. 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.

14. 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.

15. Bohula EA, Scirica BM, Fanola C, et al. Design and rationale for the Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61 (CAMELLIA-TIMI 61) trial. Am Heart J 2018;202:39-48.

16. Leblanc ES, O’Connor E, Whitlock EP, Patnode CD, Kapka T. Effectiveness of primary care-relevant treatments for obesity in adults: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 2011;155:434-447.

17. Hiatt WR, Thomas A, Goldfine AB. What cost weight loss? Circulation 2012;125:1171-1177.

18. 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.

19. Vorsanger MH, Subramanyam P, Weintraub HS, et al. Cardiovascular effects of the new weight loss agents. J Am Coll Cardiol 2016;68:849-859.

20. Jordan J, Astrup A, Engeli S, Narkiewicz K, Day WW, Finer N. Cardiovascular effects of phentermine and topiramate: a new drug combination for the treatment of obesity. J Hypertens 2014;32:1178-1188.

21. Sjöström L, Narbro K, Sjöström CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007;357:741-752.

22. Guidance for industry: developing products for weight management. Rockville, MD: Food and Drug Administration, 2007 (https://www.fda.gov/downloads/Drugs/Guidances/ucm071612.pdf).

23. 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.

24. Sjöström L, Peltonen M, Jacobson P, et al. Bariatric surgery and long-term cardiovascular events. JAMA 2012;307:56-65.

25. Sundström J, Bruze G, Ottosson J, Marcus C, Näslund I, Neovius M. Weight loss and heart failure: a nationwide study of gastric bypass surgery versus intensive lifestyle treatment. Circulation 2017;135:1577-1585.

26. Zhou X, Yu J, Li L, et al. Effects of bariatric surgery on mortality, cardiovascular events, and cancer outcomes in obese patients: systematic review and meta-analysis. Obes Surg 2016;26:2590-2601.

27. The Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145-154.

28. Meltzer HY, Roth BL. Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype-targeted drugs. J Clin Invest 2013;123:4986-4991.

29. Thomsen WJ, Grottick AJ, Menzaghi F, et al. Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. J Pharmacol Exp Ther 2008;325:577-587.

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