Endocrine Abstracts

The use of drugs for weight loss dates back to the first half of the 20th century. These older agents were mostly amfetamine-derived, centrally acting sympathomimetics, and although effective, their side-effect profile would not be acceptable today. A new generation of drugs, acting on brain serotoninergic pathways was developed in the 1960’s, including fenfluramine and later dexfenfluramine. In the 1990’s, a combination of fenfluramine with an older agent – phentermine, was promoted as an answer to the obesity epidemic on the basis of a single, poorly conducted, clinical trial. Fenfluramine and dexfenfluramine were withdrawn in 1997 after their use was linked with carcinoid-like valvular heart disease. Phentermine and diethylpropion remain available for clinical use, although the evidence supporting their efficacy and safety is poor by modern standards. This chequered history has overshadowed the acceptance by clinicians of newer drugs, although these now require much closer regulatory scrutiny before approval. The reality of treating obese patients, especially those with co-morbidities such as diabetes, is that weight loss is difficult to achieve even with diet and exercise supported by behavioural change, and that a high proportion of those who initially lose weight will regain it within one year. Pharmacotherapy increases the proportion of patients who will achieve a clinically meaningful weight loss target, and importantly, continued therapy often prevents weight regain. The newer drugs, orlistat, sibutramine and rimonabant have been evaluated in clinical trials of at least 2 years duration. A four year study with the intestinal lipase inhibitor, orlistat, showed improvement in several cardiovascular risk factors and a 46% reduction in development of diabetes in the subgroup of patients with impaired glucose tolerance; its use is however often limited by GI side-effects. Sibutramine is a serotonin and nor-adrenaline reuptake inhibitor; mean weight loss in clinical trials is 5.4 kg more than placebo, and it significantly reduces triglycerides and increases HDL cholesterol. Although blood pressure may rise in some patients, it is reassuring that it fell during the 6 week lead-in period of the Sibutramine Cardiovascular Outcomes Trial that will report in 2010. Rimonabant is the first cannabinoid receptor-1 blocker. Its efficacy is comparable to sibutramine, and it has favourable effects on lipids and blood glucose control. Concerns over psychiatric adverse events and a contraindication in depression may limit its clinical use, but the results of ongoing diabetes-prevention and cardiovascular outcome trials with rimonabant are awaited.