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Dyslipidemia—Clinical Data

ECSN Faculty

H. Bryan Brewer, Jr, MD
Director, Lipoprotein and Atherosclerosis Research
Cardiovascular Research Institute
Washington Hospital Center
Washington, DC

Henry N. Ginsberg, MD
Irving Professor of Medicine
College of Physicians and Surgeons of Columbia University
Director, Irving Center for Clinical Research
NewYork-Presbyterian Hospital
New York, New York

Samuel Klein, MD
Professor of Medicine
Washington University School of Medicine
Director, Washington University Center for Human Nutrition
Associate Program Director, General Clinical Research Center
Medical Director, Barnes-Jewish Hospital Nutrition Support Service
St. Louis, Missouri

Kenneth Mackie, MD
Professor of Psychology
Department of Psychological and Brain Sciences
Indiana University
Bloomington, Indiana

Overview to Dyslipidemia

Cardiovascular disease is the leading cause of mortality in the United States today.1 Approximately 75% of all deaths because of cardiovascular disease result from heart attack or stroke caused by atherosclerosis.1 One of the most prevalent modifiable risk factors for atherosclerosis is dyslipidemia, abnormalities in serum lipids.2 Dyslipidemia includes elevated total cholesterol, low-density lipoprotein cholesterol (LDL-C), lipoprotein (a), and triglycerides (TGs); low levels of high-density lipoprotein cholesterol (HDL-C); and small, dense LDL particles.2 These lipid abnormalities can be present individually or in combination.

Approximately 50% of the adults in the United States have elevated total cholesterol levels, at least 200 mg/dL.1 Because early recognition and treatment of lipid abnormalities reduces the risk for cardiovascular disease, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) recommends routine lipid analysis for all adults 20 years old or older.3 Obesity, particularly obesity with excess abdominal fat distribution, is associated with a lipoprotein profile that is characterized by increased TGs, low levels of HDL-C, and alterations in LDL-C composition and concentration, which accelerates atherogenesis.4-7

Studies conducted in animal models suggest that obesity leads to chronic stimulation of the endocannabinoid system (ECS) and persistent activation of cannabinoid type 1 (CB1) receptors.8,9 In addition to being present in several areas of the brain, CB1 receptors are also present in peripheral organs and tissues, including those involved in energy balance (adipose tissue), glucose homeostasis (pancreas and skeletal tissue), and lipogenesis (liver and adipose tissue).9-12 Notably, CB1-receptor activation has been shown to enhance de novo lipogenesis in hepatocytes.8,13



Clinical Data

Results from two recently completed clinical trials evaluating rimonabant, the first CB1-receptor blocker to enter clinical development, suggest that CB1-receptor blockade may be useful for managing the atherogenic dyslipidemia commonly associated with obesity and insulin resistance. Both trials were randomized, double-blind, placebo-controlled, multicenter trials designed to evaluate the efficacy of once-daily rimonabant in reducing body weight and improving cardiovascular risk factors for patients who were overweight or obese.14

The Rimonabant In Obesity (RIO)-Europe trial enrolled a total of 1507 men and women ages 18 years or older with treated or untreated dyslipidemia, hypertension, or both, a body-mass index (BMI) of at least 30 kg/m2 for men or BMI greater than 27 kg/m2 for women.14 Subjects were randomly assigned to receive placebo, rimonabant 5 mg/day, or rimonabant 20 mg/day, and restricted to a mildly hypocaloric diet. At 1-year follow-up, significantly greater weight loss was shown in subjects in the rimonabant 5 mg/day (P = 0.002) and rimonabant 20 mg/day (P <0.001) groups compared with subjects in the placebo group. Rimonabant 20 mg/day also produced significantly greater improvements in waist circumference, HDL-C, TGs, insulin resistance, and cardiovascular and metabolic risk factors. Metabolic variables improved over the entire 1-year period, whereas weight loss peaked at approximately 9 months and then remained relatively stable through the end of the first year. Improvements in HDL-C and TGs could not be fully explained by weight loss alone because approximately half of the effect on HDL-C and TGs was independent of weight loss.

The RIO-Lipids trial also examined the effects of rimonabant on metabolic risk factors, including adiponectin levels.15 This trial enrolled 1036 men and women without diabetes who had a BMI in the range of 27 to 40 kg/m2 and untreated dyslipidemia. Subjects were randomly assigned to one of three treatment groups, either placebo, rimonabant 5 mg/day, or rimonabant 20 mg/day, and restricted to a 600-kcal/day deficit hypocaloric diet. Efficacy measures included mean weight loss from baseline to the end of 12 months of follow-up; HDL-C; TGs; glucose and insulin during an oral glucose-tolerance test; prevalence of the metabolic syndrome; waist circumference; and leptin and adiponectin levels. As compared with placebo, rimonabant 20 mg/day was associated with significant (P <0.001) weight loss, reduction in waist circumference, increase in HDL-C, and reduction in TGs. Levels of adiponectin increased roughly 60% in the rimonabant 20 mg group, and were positively correlated with increases in HDL-C levels.

Results from the RIO-Europe and RIO-Lipids trials demonstrate that selective CB1 receptor blockade with rimonabant significantly reduces bodyweight and waist circumference as well as improves the profile of several metabolic risk factors in patients who are overweight or obese and have an atherogenic lipoprotein profile.14,15 These results suggest that CB1 receptor blockade may be beneficial as an approach to treating obesity and its associated cardiovascular risk factors. Further studies are needed to determine the possible metabolic effects of rimonabant in adipose tissue as well as to confirm the weight loss-dependent and weight-loss-independent effects of rimonabant on serum lipid profiles.

Safety

The overall withdrawal rate in the RIO studies was high,14-17 but was not different from the overall withdrawal rate observed in other obesity studies.18 A pooled meta-analysis showed that, compared with placebo, subjects treated with rimonabant 20 mg/day reported a greater rate of discontinuation due to adverse events in the 12 months of active treatment (P <0.00001).19 Adverse events leading to discontinuation were not different for the rimonabant 20 mg and placebo groups during the second year of treatment in the RIO-North America and RIO-Europe 2-year studies.14,16 Adverse events leading to study discontinuation over 1 year of treatment that were reported more commonly in subjects treated with rimonabant 20 mg included depressive disorders, nausea, anxiety, and dizziness. Reported depressive disorders were usually mild or moderate in severity. Subjects treated with rimonabant 20 mg/day reported significantly more serious adverse effects (P = 0.03),19 most commonly depression and anxiety. All subjects who reported depressive disorders recovered either after corrective treatment or discontinuation of rimonabant and did not exhibit any differentiating characteristics compared with cases reported in the control groups. However, it is important to note that individuals with a history of significant depression or other psychiatric disorders, or who had prior use of antidepressant medications, were excluded from all of the RIO studies.

Data from preclinical and human postmortem studies are equivocal with regard to the effect of CB1 receptor blockade and emotional responses to stress (reviewed in Gadde and Allison).20 Additional studies are needed to determine the potential effects of rimonabant treatment on psychiatric events in different patient populations.

References

  1. Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics-2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113:e85-151.
  2. Ballantyne C, O’Keefe J, Gotto A. Dyslipidemia Essentials. Royal Oak, Mich, Physicians’ Press, 2005.
  3. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. 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). Circulation. 2002;106:3143-3421.
  4. Zamboni M, Armellini F, Cominacini L, et al. Obesity and regional body-fat distribution in men: separate and joint relationships to glucose tolerance and plasma lipoproteins. Am J Clin Nutr. 1994;60:682-687.
  5. Cnop M, Havel PJ, Utzschneider KM, et al. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia. 2003;46:459-469.
  6. Park KG, Park KS, Kim MJ, et al. Relationship between serum adiponectin and leptin concentrations and body fat distribution. Diabetes Res Clin Pract. 2004;63:135-142.
  7. St-Pierre J, Miller-Felix I, Paradis ME, et al. Visceral obesity attenuates the effect of the hepatic lipase -514C>T polymorphism on plasma HDL-cholesterol levels in French-Canadian men. Mol Genet Metab. 2003;78:31-36.
  8. 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.
  9. Pagotto U, Vicennati V, Pasquali R. The endocannabinoid system and the treatment of obesity. Ann Med. 2005;37:270-275.
  10. 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.
  11. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89:2548-2556.
  12. Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nat Neurosci. 2005;8:585-589.
  13. Cota D, Woods S. The role of the endocannabinoid system in the regulation of energy homeostasis. Curr Opin Endocrinol Diabetes. 2005;12:338-351.
  14. 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.
  15. Després JP, Golay A, Sjöström L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353:2121-2134.
  16. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. 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.
  17. Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet. 2006;368:1660-1672.
  18. Douketis JD, Macie C, Thabane L, Williamson DF. Systematic review of long-term weight loss studies in obese adults: clinical significance and applicability to clinical practice. Int J Obes (Lond). 2005;29:1153-1167.
  19. Curioni C, André C. Rimonabant for overweight or obesity. Cochrane Database Syst Rev. 2006:CD006162.
  20. Gadde KM, Allison DB. Cannabinoid-1 receptor antagonist, rimonabant, for management of obesity and related risks. Circulation. 2006;114:974-984.
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