Metabolic Risk Factors, Drugs, and Obesity
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Després et al. (Nov. 17 issue)1 report that in the placebo-controlled Rimonabant in Obesity–Lipids (RIO-Lipids) study, rimonabant reduced weight by 5.4 kg in healthy overweight or obese patients with dyslipidemia. This study involved the randomized assignment of only those subjects who were at least 80 percent adherent to a regimen of diet and placebo during a one-month run-in period, yet 40 percent of the patients did not complete the 12-month trial. Small but statistically significant improvements in high-density lipoprotein cholesterol levels, triglyceride levels, and blood pressure were noted. On the basis of these and similar results from the four trials in the RIO program, involving more than 6600 subjects,2 rimonabant will probably be approved by the Food and Drug Administration for use in the United States in 2006.
Drugs that improve surrogate end points, such as weight or glycemic control, may not necessarily improve more clinically important outcomes such as cardiovascular morbidity or mortality.3 There is a potential global market for rimonabant of more than 1 billion persons,4 many of whom will not meet the narrow enrollment criteria of the RIO studies. Given this enormous market and the questionable safety record of previous antiobesity agents,5 would it not be prudent to demonstrate before its widespread use that rimonabant reduces cardiovascular events?
Raj Padwal, M.D.
Sumit Majumdar, M.D.
University of Alberta
Edmonton, AB T6G 2B7, Canada
rpadwal@ualberta.ca
References
Després J-P, Golay A, Sj?str?m L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005;353:2121-2134.
Boyd ST, Fremming BA. Rimonabant -- a selective CB1 antagonist. Ann Pharmacother 2005;39:684-690.
Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005;294:2581-2586.
Haslam DW, James WPT. Obesity. Lancet 2005;366:1197-1209.
Padwal R, Li SK, Lau DCW. Long-term pharmacotherapy for obesity and overweight. Cochrane Database Syst Rev 2003;4:CD004094-CD004094.
The authors reply: There is an epidemic of obesity, but not every obese patient is a candidate for pharmacotherapy.1 Patients with abdominal obesity often have cardiovascular and metabolic risk factors that increase the risk of type 2 diabetes and cardiovascular disease,2,3 thereby justifying pharmacotherapy. The RIO-Lipids trial involved high-risk, overweight or obese patients with untreated dyslipidemia due to their abdominal obesity. The trial first showed that, irrespective of the weight loss achieved after the run-in period (2 kg or >2 kg), rimonabant demonstrated efficacy in terms of weight loss and increased high-density lipoprotein cholesterol levels in both subgroups of patients. Second, rimonabant significantly improved a comprehensive set of cardiovascular and metabolic risk variables, including a substantial reduction in waist circumference. Glucose tolerance was improved in the RIO-Lipids and RIO-Europe4 studies, suggesting that rimonabant therapy may reduce the rate of conversion to type 2 diabetes, an issue to be tested soon in a large clinical trial. Efficacy and safety results of the RIO-Lipids trial appear promising, but the point made by Drs. Padwal and Majumdar is relevant. Losing weight through pharmacotherapy should not be the primary objective: whether the risk of major cardiovascular disease events is reduced with pharmacotherapy needs to be evaluated. This hypothesis is currently being tested in another large clinical trial.
Jean-Pierre Després, Ph.D.
Laval Hospital Research Center
Quebec, QC G1V 4G5, Canada
jean-pierre.despres@crhl.ulaval.ca
Alain Golay, M.D.
University Hospital Geneva
1205 Geneva, Switzerland
Lars Sj?str?m, M.D., Ph.D.
Sahlgrenska University Hospital
S-413 45 G?teborg, Sweden
References
Després JP, Lemieux I, Prud'homme D. Treatment of obesity: need to focus on high risk abdominally obese patients. BMJ 2001;322:716-720.
Yusuf S, Hawken S, Ounpuu S, et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 2005;366:1640-1649.
Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004;109:433-438.
Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005;365:1389-1397.
Drugs that improve surrogate end points, such as weight or glycemic control, may not necessarily improve more clinically important outcomes such as cardiovascular morbidity or mortality.3 There is a potential global market for rimonabant of more than 1 billion persons,4 many of whom will not meet the narrow enrollment criteria of the RIO studies. Given this enormous market and the questionable safety record of previous antiobesity agents,5 would it not be prudent to demonstrate before its widespread use that rimonabant reduces cardiovascular events?
Raj Padwal, M.D.
Sumit Majumdar, M.D.
University of Alberta
Edmonton, AB T6G 2B7, Canada
rpadwal@ualberta.ca
References
Després J-P, Golay A, Sj?str?m L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005;353:2121-2134.
Boyd ST, Fremming BA. Rimonabant -- a selective CB1 antagonist. Ann Pharmacother 2005;39:684-690.
Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005;294:2581-2586.
Haslam DW, James WPT. Obesity. Lancet 2005;366:1197-1209.
Padwal R, Li SK, Lau DCW. Long-term pharmacotherapy for obesity and overweight. Cochrane Database Syst Rev 2003;4:CD004094-CD004094.
The authors reply: There is an epidemic of obesity, but not every obese patient is a candidate for pharmacotherapy.1 Patients with abdominal obesity often have cardiovascular and metabolic risk factors that increase the risk of type 2 diabetes and cardiovascular disease,2,3 thereby justifying pharmacotherapy. The RIO-Lipids trial involved high-risk, overweight or obese patients with untreated dyslipidemia due to their abdominal obesity. The trial first showed that, irrespective of the weight loss achieved after the run-in period (2 kg or >2 kg), rimonabant demonstrated efficacy in terms of weight loss and increased high-density lipoprotein cholesterol levels in both subgroups of patients. Second, rimonabant significantly improved a comprehensive set of cardiovascular and metabolic risk variables, including a substantial reduction in waist circumference. Glucose tolerance was improved in the RIO-Lipids and RIO-Europe4 studies, suggesting that rimonabant therapy may reduce the rate of conversion to type 2 diabetes, an issue to be tested soon in a large clinical trial. Efficacy and safety results of the RIO-Lipids trial appear promising, but the point made by Drs. Padwal and Majumdar is relevant. Losing weight through pharmacotherapy should not be the primary objective: whether the risk of major cardiovascular disease events is reduced with pharmacotherapy needs to be evaluated. This hypothesis is currently being tested in another large clinical trial.
Jean-Pierre Després, Ph.D.
Laval Hospital Research Center
Quebec, QC G1V 4G5, Canada
jean-pierre.despres@crhl.ulaval.ca
Alain Golay, M.D.
University Hospital Geneva
1205 Geneva, Switzerland
Lars Sj?str?m, M.D., Ph.D.
Sahlgrenska University Hospital
S-413 45 G?teborg, Sweden
References
Després JP, Lemieux I, Prud'homme D. Treatment of obesity: need to focus on high risk abdominally obese patients. BMJ 2001;322:716-720.
Yusuf S, Hawken S, Ounpuu S, et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 2005;366:1640-1649.
Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004;109:433-438.
Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005;365:1389-1397.