- Email: [email protected]
Discussion Following Dr. Jensen’s Presentation
Jensen
CB1 Receptor Blockade in Glucose and Lipid Management
SUMMARY 10
2
9
The results of the RIO-NA, RIO-Europe, RIO-Lipids, and RIO-Diabetes11 studies were highly consistent in terms of both efficacy and tolerability/safety outcomes. Treatment with rimonabant 20 mg/day resulted in marked and significant improvements compared with placebo in body weight and waist circumference, as well as HDL cholesterol, triglycerides, HbA1c, insulin resistance, metabolic syndrome, and other cardiometabolic risk factors. Moreover, the cardiometabolic benefits achieved with rimonabant treatment were sustained for up to 2 years. Importantly, the magnitude of these benefits was greater than what would be expected from weight reduction alone, suggesting direct effects of the drug on cardiometabolic parameters. Thus, rimonabant therapy as an adjunct to lifestyle modifications may significantly improve multiple cardiometabolic risk factors in overweight and obese patients in clinical practice. The potential of rimonabant to modulate multiple cardiometabolic risk factors may streamline therapy for overweight and obese patients by reducing the amount of polypharmacy currently required to treat each risk factor individually.
References 1. Kunos G. Understanding metabolic homeostasis and imbalance: what is the role of the endocannabinoid system? Am J Med. 2007;120(suppl 8B):S18 –S24. 2. 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 RIO-Europe study. Lancet. 2005;365:1389 –1397. 3. Di Marzo V, Goparaju SK, Wang L, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake [letter]. Nature. 2001;410:822– 825. 4. Cota D, Marsicano G, Tschop M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest. 2003;112:423– 431.
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5. Ravinet Trillou C, Arnone M, Delgorge C, et al. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol. 2003;284:R345–R353. 6. Jbilo O, Ravinet-Trillou C, Arnone M, et al. The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance. FASEB J. 2005;19: 1567–1569. 7. Bensaid M, Gary-Bobo M, Esclangon A, et al. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol. 2003;63:908 –914. 8. Liu YL, Connoley IP, Wilson CA, Stock MJ. Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep ob/Lep ob mice. Int J Obes (Lond). 2005;29:183–187. 9. Després JP, Golay A, Sjöström L, for the Rimonabant in ObesityLipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353:2121–2134. 10. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J, for the RIO-North America Study Group. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America, a randomized controlled trial. JAMA. 2006;295:761–775. 11. Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF, for the RIO-Diabetes Study Group. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomized controlled study. Lancet. 2006;368:1660 –1672. 12. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486 –2497. 13. Osei-Hyiaman D, DePetrillo M, Pacher P, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115:1298 – 1305. 14. Pi-Sunyer X, Després J-P, Scheen A, Van Gaal L. Improvement of metabolic parameters with rimonabant beyond the effect attributable to weight loss alone: pooled one-year data from the RIO (Rimonabant In Obesity and Related Metabolic Disorder) program. J Am Coll Cardiol. 2006;47(suppl 1):362A. Abstract 849 –3.
Discussion Following Dr. Jensen’s Presentation Question: Referring to the linear regression analysis in the Rimonabant in Obesity (RIO) studies, would it have been more appropriate to use the change in waist circumference, as opposed to weight, to determine weight loss–independent effects? Michael D. Jensen, MD (Rochester, Minnesota): If rimonabant* induced a greater reduction in waist circumference relative to the amount of weight loss, and was accompanied by a corresponding improvement in metabolic abnormalities, that would indicate that rimonabant had a *
Recently, an FDA Advisory Committee recommended a delay in the approval of rimonabant because of safety issues that need to be addressed in future studies.
preferential effect on the reduction in waist circumference. This would suggest that the beneficial effects were related to improved body fat distribution coincident with weight loss. Question: In clinical trials, was rimonabant effective in nonobese, slightly overweight, patients with the metabolic syndrome? Dr. Jensen: There were not enough patients in that particular subgroup to enable us to analyze and address that question. Question: Cannabinoids (CBs) exert an antianxiety effect. Therefore, what is the effect of CB1 blockade on anxiety? Is rimonabant contraindicated in patients with a preexisting anxiety disorder? George Kunos, MD, PhD (Bethesda, Maryland): No. However, careful screening is indicated, especially in pa-
S32
The American Journal of Medicine, Vol 120 (9A), September 2007
tients who may have a predisposition or an underlying serious anxiety disorder, particularly if inadequately treated. In terms of depressive disorders, some animal assays have shown that rimonabant increases depressive symptoms, whereas others have shown it decreases them. Therefore, it is advisable not to exceed the recommended dose, as it may increase the likelihood of central nervous system
side effects without enhancing therapeutic effects. It should be noted that, as per protocol, patients with a psychiatric history or who were taking antidepressant medication were excluded from the RIO studies; therefore there is little information on the safety of rimonabant in patients with depression or who are taking antidepressants.
CB1 Receptor Blockade in Glucose and Lipid Management
SUMMARY 10
2
9
The results of the RIO-NA, RIO-Europe, RIO-Lipids, and RIO-Diabetes11 studies were highly consistent in terms of both efficacy and tolerability/safety outcomes. Treatment with rimonabant 20 mg/day resulted in marked and significant improvements compared with placebo in body weight and waist circumference, as well as HDL cholesterol, triglycerides, HbA1c, insulin resistance, metabolic syndrome, and other cardiometabolic risk factors. Moreover, the cardiometabolic benefits achieved with rimonabant treatment were sustained for up to 2 years. Importantly, the magnitude of these benefits was greater than what would be expected from weight reduction alone, suggesting direct effects of the drug on cardiometabolic parameters. Thus, rimonabant therapy as an adjunct to lifestyle modifications may significantly improve multiple cardiometabolic risk factors in overweight and obese patients in clinical practice. The potential of rimonabant to modulate multiple cardiometabolic risk factors may streamline therapy for overweight and obese patients by reducing the amount of polypharmacy currently required to treat each risk factor individually.
References 1. Kunos G. Understanding metabolic homeostasis and imbalance: what is the role of the endocannabinoid system? Am J Med. 2007;120(suppl 8B):S18 –S24. 2. 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 RIO-Europe study. Lancet. 2005;365:1389 –1397. 3. Di Marzo V, Goparaju SK, Wang L, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake [letter]. Nature. 2001;410:822– 825. 4. Cota D, Marsicano G, Tschop M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest. 2003;112:423– 431.
S31
5. Ravinet Trillou C, Arnone M, Delgorge C, et al. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol. 2003;284:R345–R353. 6. Jbilo O, Ravinet-Trillou C, Arnone M, et al. The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance. FASEB J. 2005;19: 1567–1569. 7. Bensaid M, Gary-Bobo M, Esclangon A, et al. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol. 2003;63:908 –914. 8. Liu YL, Connoley IP, Wilson CA, Stock MJ. Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep ob/Lep ob mice. Int J Obes (Lond). 2005;29:183–187. 9. Després JP, Golay A, Sjöström L, for the Rimonabant in ObesityLipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353:2121–2134. 10. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J, for the RIO-North America Study Group. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America, a randomized controlled trial. JAMA. 2006;295:761–775. 11. Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF, for the RIO-Diabetes Study Group. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomized controlled study. Lancet. 2006;368:1660 –1672. 12. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486 –2497. 13. Osei-Hyiaman D, DePetrillo M, Pacher P, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115:1298 – 1305. 14. Pi-Sunyer X, Després J-P, Scheen A, Van Gaal L. Improvement of metabolic parameters with rimonabant beyond the effect attributable to weight loss alone: pooled one-year data from the RIO (Rimonabant In Obesity and Related Metabolic Disorder) program. J Am Coll Cardiol. 2006;47(suppl 1):362A. Abstract 849 –3.
Discussion Following Dr. Jensen’s Presentation Question: Referring to the linear regression analysis in the Rimonabant in Obesity (RIO) studies, would it have been more appropriate to use the change in waist circumference, as opposed to weight, to determine weight loss–independent effects? Michael D. Jensen, MD (Rochester, Minnesota): If rimonabant* induced a greater reduction in waist circumference relative to the amount of weight loss, and was accompanied by a corresponding improvement in metabolic abnormalities, that would indicate that rimonabant had a *
Recently, an FDA Advisory Committee recommended a delay in the approval of rimonabant because of safety issues that need to be addressed in future studies.
preferential effect on the reduction in waist circumference. This would suggest that the beneficial effects were related to improved body fat distribution coincident with weight loss. Question: In clinical trials, was rimonabant effective in nonobese, slightly overweight, patients with the metabolic syndrome? Dr. Jensen: There were not enough patients in that particular subgroup to enable us to analyze and address that question. Question: Cannabinoids (CBs) exert an antianxiety effect. Therefore, what is the effect of CB1 blockade on anxiety? Is rimonabant contraindicated in patients with a preexisting anxiety disorder? George Kunos, MD, PhD (Bethesda, Maryland): No. However, careful screening is indicated, especially in pa-
S32
The American Journal of Medicine, Vol 120 (9A), September 2007
tients who may have a predisposition or an underlying serious anxiety disorder, particularly if inadequately treated. In terms of depressive disorders, some animal assays have shown that rimonabant increases depressive symptoms, whereas others have shown it decreases them. Therefore, it is advisable not to exceed the recommended dose, as it may increase the likelihood of central nervous system
side effects without enhancing therapeutic effects. It should be noted that, as per protocol, patients with a psychiatric history or who were taking antidepressant medication were excluded from the RIO studies; therefore there is little information on the safety of rimonabant in patients with depression or who are taking antidepressants.