- Email: [email protected]
Effect of rimonabant on weight reduction and cardiovascular risk
Correspondence
Adjusted* Unadjusted
Mediterranean diet (n=90)
Control diet (n=90)
Difference
40 (44·4%) 30 (33·3%)
78 (86·6%) 73 (81·1%)
42·2% 47·8%
3
*For changes in bodyweight.
4 Table: Prevalence of metabolic syndrome after a 2-year lifestyle programme in 180 individuals with the disorder at baseline
rimonabant groups. Despite such modest weight change in the placebo group, there was a 21·3% reduction (significance not specified) in the prevalence of metabolic syndrome. Better results might have been achieved by improving the quality of the diet, as emphasised by current dietetic recommendations for the general population at risk.3 For example, overweight individuals with metabolic syndrome who followed a 2-year lifestyle programme focusing mainly on Mediterranean-style diet had a modest weight reduction (2·8 kg), which was associated with a 48% reduction in the prevalence of metabolic syndrome (table).4 This last figure is at least twice that achieved in the placebo group of Van Gaal and colleagues’ study and not much different from the 53·6% reduction seen in the 20 mg rimonabant group. The multidisciplinary programme of lifestyle changes adopted in our study was associated with limited dropouts (5–10%) at 2 years. The quality of diet may provide further benefit in terms of cardiovascular risk, especially for patients who lose less weight than expected. We declare that we have no conflict of interest.
Katherine Esposito, *Dario Giugliano [email protected] Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples, Italy 1
2
368
Van Gaal LF, Rissanen AM, Scheen AJ, et al. Effects of 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: 1389–97. Dansinger ML, Gleason JA, Griffith JI, Selker HP, Schaefer EJ. Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction. JAMA 2005; 293: 43–53.
Eyre H, Khan R, Robertson RM. Preventing cancer, cardiovascular disease, and diabetes: a common agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association. Diabetes Care 2004; 27: 1812–24. Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome. JAMA 2004; 292: 1440–46.
The study reported by Luc Van Gaal and colleagues1 indicates that the new antiobesity drug, rimonabant, has some advantages over existing compounds. However, despite being associated with a weight loss of 4·8 kg more than placebo over 1 year, rimonabant did not reduce blood pressure, total cholesterol, or LDL-cholesterol. Normally a weight loss of this size would be expected to reduce total cholesterol by 0·12 mmol/L, LDL-cholesterol by about 0·1 mmol/L,2 and blood pressure by 4 mm Hg.3 Van Gaal and colleagues do not report changes in the total cholesterol concentration among completers (their table 3), or effects on heart rate; nor do they comment on the lack of expected improvements in these cardiovascular risk factors. Instead they focus on the improvement in HDL-cholesterol, which is better than would be expected from the weight loss. The changes in risk-factor profiles achieved by rimonabant mimic those seen with sympathomimetic weight loss compounds such as sibutramine4 and ephedrine or caffeine: no or little reduction in LDL-cholesterol, blood pressure, or heart rate, and a greater increase in HDL-cholesterol than expected from the weight loss. Rimonabant acts on both the adrenal gland and the sympathetic nerves, and one wonders whether the net result is a local sympathetic activation that counteracts the beneficial effects of weight loss on LDL-cholesterol, blood pressure, and perhaps on heart rate. It would be interesting to know whether rimonabant has weight-lossindependent effects on risk factors, both positive and negative. This possibility can be examined by plotting the changes in risk factors against the
weight loss separately for the rimonabant and placebo groups. If the two regression lines show a significant parallel shift, the effects seen will be independent of weight loss. Van Gaal and colleagues have previously shown this point with the weight loss compound orlistat–ie, that for any category of weight loss during the double-blind treatment period, change in LDL-cholesterol was more pronounced among orlistat-treated patients than placebo recipients,5 indicating that orlistat had a direct cholesterol-lowering effect that was independent of weight reduction. It would be interesting to see such plots derived from the rimonabant trial. I am a member of the Danish Accomplia Advisory Board for Aventis-Sanofi.
Arne Astrup [email protected] Department of Human Nutrition, LMC, Royal Veterinary and Agricultural University, Rolighedsvej 30, DK-1958 Frederiksberg, Denmark 1
2
3
4
5
Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rössner S, for the RIO-Europe Study Group. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIOEurope study. Lancet 2005; 365: 1389–97. Poobalan A, Aucott L, Smith WC, et al. Effects of weight loss in overweight/obese individuals and long-term lipid outcomes—a systematic review. Obes Rev 2004; 5: 43–50. Neter JE, Stam BE, Kok FJ, Grobbee DE, Geleijnse JM. Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension 2003; 42: 878–84. James WPT, Astrup A, James WPT, et al. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. Lancet 2000; 356: 2119–25. Muls E, Kolanowski J, Scheen A, Van Gaal L, for the ObelHyx Study Group. The effects of orlistat on weight and on serum lipids in obese patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled, multicentre study. Int J Obes Relat Metab Disord 2001; 25: 1713–21.
We diagnosed multiple sclerosis in a patient who was treated with rimonabant 5 mg per day in the context of Luc Van Gaal and colleagues’ RIO-Europe clinical trial.1,2 Although we cannot exclude a chance association, we feel that current insights into the physiological role of the cannabinoid system might explain why rimonabant could www.thelancet.com Vol 366 July 30, 2005
Adjusted* Unadjusted
Mediterranean diet (n=90)
Control diet (n=90)
Difference
40 (44·4%) 30 (33·3%)
78 (86·6%) 73 (81·1%)
42·2% 47·8%
3
*For changes in bodyweight.
4 Table: Prevalence of metabolic syndrome after a 2-year lifestyle programme in 180 individuals with the disorder at baseline
rimonabant groups. Despite such modest weight change in the placebo group, there was a 21·3% reduction (significance not specified) in the prevalence of metabolic syndrome. Better results might have been achieved by improving the quality of the diet, as emphasised by current dietetic recommendations for the general population at risk.3 For example, overweight individuals with metabolic syndrome who followed a 2-year lifestyle programme focusing mainly on Mediterranean-style diet had a modest weight reduction (2·8 kg), which was associated with a 48% reduction in the prevalence of metabolic syndrome (table).4 This last figure is at least twice that achieved in the placebo group of Van Gaal and colleagues’ study and not much different from the 53·6% reduction seen in the 20 mg rimonabant group. The multidisciplinary programme of lifestyle changes adopted in our study was associated with limited dropouts (5–10%) at 2 years. The quality of diet may provide further benefit in terms of cardiovascular risk, especially for patients who lose less weight than expected. We declare that we have no conflict of interest.
Katherine Esposito, *Dario Giugliano [email protected] Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples, Italy 1
2
368
Van Gaal LF, Rissanen AM, Scheen AJ, et al. Effects of 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: 1389–97. Dansinger ML, Gleason JA, Griffith JI, Selker HP, Schaefer EJ. Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction. JAMA 2005; 293: 43–53.
Eyre H, Khan R, Robertson RM. Preventing cancer, cardiovascular disease, and diabetes: a common agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association. Diabetes Care 2004; 27: 1812–24. Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome. JAMA 2004; 292: 1440–46.
The study reported by Luc Van Gaal and colleagues1 indicates that the new antiobesity drug, rimonabant, has some advantages over existing compounds. However, despite being associated with a weight loss of 4·8 kg more than placebo over 1 year, rimonabant did not reduce blood pressure, total cholesterol, or LDL-cholesterol. Normally a weight loss of this size would be expected to reduce total cholesterol by 0·12 mmol/L, LDL-cholesterol by about 0·1 mmol/L,2 and blood pressure by 4 mm Hg.3 Van Gaal and colleagues do not report changes in the total cholesterol concentration among completers (their table 3), or effects on heart rate; nor do they comment on the lack of expected improvements in these cardiovascular risk factors. Instead they focus on the improvement in HDL-cholesterol, which is better than would be expected from the weight loss. The changes in risk-factor profiles achieved by rimonabant mimic those seen with sympathomimetic weight loss compounds such as sibutramine4 and ephedrine or caffeine: no or little reduction in LDL-cholesterol, blood pressure, or heart rate, and a greater increase in HDL-cholesterol than expected from the weight loss. Rimonabant acts on both the adrenal gland and the sympathetic nerves, and one wonders whether the net result is a local sympathetic activation that counteracts the beneficial effects of weight loss on LDL-cholesterol, blood pressure, and perhaps on heart rate. It would be interesting to know whether rimonabant has weight-lossindependent effects on risk factors, both positive and negative. This possibility can be examined by plotting the changes in risk factors against the
weight loss separately for the rimonabant and placebo groups. If the two regression lines show a significant parallel shift, the effects seen will be independent of weight loss. Van Gaal and colleagues have previously shown this point with the weight loss compound orlistat–ie, that for any category of weight loss during the double-blind treatment period, change in LDL-cholesterol was more pronounced among orlistat-treated patients than placebo recipients,5 indicating that orlistat had a direct cholesterol-lowering effect that was independent of weight reduction. It would be interesting to see such plots derived from the rimonabant trial. I am a member of the Danish Accomplia Advisory Board for Aventis-Sanofi.
Arne Astrup [email protected] Department of Human Nutrition, LMC, Royal Veterinary and Agricultural University, Rolighedsvej 30, DK-1958 Frederiksberg, Denmark 1
2
3
4
5
Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rössner S, for the RIO-Europe Study Group. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIOEurope study. Lancet 2005; 365: 1389–97. Poobalan A, Aucott L, Smith WC, et al. Effects of weight loss in overweight/obese individuals and long-term lipid outcomes—a systematic review. Obes Rev 2004; 5: 43–50. Neter JE, Stam BE, Kok FJ, Grobbee DE, Geleijnse JM. Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension 2003; 42: 878–84. James WPT, Astrup A, James WPT, et al. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. Lancet 2000; 356: 2119–25. Muls E, Kolanowski J, Scheen A, Van Gaal L, for the ObelHyx Study Group. The effects of orlistat on weight and on serum lipids in obese patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled, multicentre study. Int J Obes Relat Metab Disord 2001; 25: 1713–21.
We diagnosed multiple sclerosis in a patient who was treated with rimonabant 5 mg per day in the context of Luc Van Gaal and colleagues’ RIO-Europe clinical trial.1,2 Although we cannot exclude a chance association, we feel that current insights into the physiological role of the cannabinoid system might explain why rimonabant could www.thelancet.com Vol 366 July 30, 2005