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Thursday, April 3, 2008

Rimonabant for CAD - it's Not Just About the Heart

The heart is an important organ. Heart disease kills millions every year. Abdominal obesity is an important risk factor for heart disease. Medical treatments for obesity should help reduce cardiovascular risk.

Not surprisingly, several large studies are examining the effect of anti-obesity drugs, both old (e.g. sibutramine) and new (e.g. rimonabant), on cardiovascular morbidity and mortality.

This week, one such study reported on its results. STRADIVARIUS, a double-blind randomized controlled trial with over 800 patients conducted at 112 centres in North America, Europe and Australia was designed to determine whether treatment with 20 mg of the CB-1 antagonist rimonabant (an anti-obesity drug now available in many countries but not in Canada or the US) would reduce progression of coronary artery disease (CAD) in patients with abdominal obesity and the metabolic syndrome. Progression of CAD was measured by intravascular ultrasound (IVUS) before and after 12 to 18 months of treatment.

On average, patients on rimonabant lost 4.5 Kg and as many cms off their waistlines. HDL cholesterol, triglycerides and HbA1c levels (in patients with diabetes) improved as expected. Although the primary endpoint (change in percent atheroma volume) was not different between rimonabant and placebo, other measures of atherosclerosis appeared to change favourably. Rimonabant was well tolerated although (as expected) there were more psychiatric and gastrointestinal side effects and discontinuations in the rimonabant group.

So why, with the significant reduction in weight and risk factors were the results not more positive? The authors speculate that this may have been because patients were already receiving effective treatment for CAD (e.g. 80% of patients were on statins). Therefore showing incremental benefits of adding rimonabant would have been difficult.

The real question to ask, however, is whether or not influencing heart disease is indeed the best and most important use of an anti-obesity drug. We already have a multitude of effective medications to reduce the progression of heart disease. When used according to current guidelines, these agents can indeed markedly reduce the risk of cardiovascular disease (obviously, this risk will never be zero, no matter how good the treatment).

So is reduction in heart disease really the great "unmet need" when it comes to obesity treatment? As a bariatrician, I would say NO!

Yes, while preventing heart disease (or its progression) is perhaps one benefit of treating obesity, I can think of many other benefits that are relevant to patients battling obesity-related comorbidities for which we currently have no effective medical treatments.

My short list would include sleep apnea, osteoarthritis, hepatic steatosis, polycystic ovary syndrome, infertility, pseudo tumor cerebri and many more. Sure, these conditions may not sound as dramatic as heart disease and may be less likely to kill you, but for the people who have these problems, these conditions are very real, distressing and affecting their quality of life. If obesity treatments can help alleviate these conditions, perhaps even just limit exacerbation by helping curb further weight gain, a lot would be won.

Remember, obesity is a chronic disease with virtually 100% rezidivism. It significantly affects many aspects of mental, physical and socioeconomic health. Effective treatments for obesity are required irrespective of whether or not they also help reduce heart disease.

Unfortunately, pharma companies, regulators and payors appear obsessed with the cardiometabolic consequences of obesity and fail to see the urgent need for treating obesity-related comorbidities beyond heart disease.

So, while the results of STRADIVARIUS are nice, I'd be far more interested in whether or not rimonabant reduces obesity-related comorbidities for which we have no alternative treatments - at least that's where I'd put my research money if I had any say in the matter.

Edmonton, Alberta

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