Lorcaserin for the treatment of obesity? A closer look at its side effects

Correspondence to Dr James J DiNicolantonio; [email protected] Obesity is developing into a pandemic in countries like the USA, the UK and India. The WHO projects that by 2015, about 700 million adults will be clinically obese. Obesity is a major public health problem, beyond the disability directly related to excessive adiposity, and it also increases the risk of several chronic diseases such as hypertension, sleep apnoea, diabetes, coronary artery disease and cancer. Clearly, obesity is a serious threat, imposing a vast economic burden on the healthcare system. Obesity is the second most common preventable cause of death, second only to tobacco use. Evidence suggests that weight reduction substantially lowers the risk of related comorbidities and fosters their therapeutic management. 8 Although bariatric surgery has emerged as the most clinically effective strategy for decreasing body weight for people with morbid obesity (body mass index (BMI) ≥40) or for those who cannot be managed otherwise, it is a very invasive procedure with significant risks. 11 At this juncture, behavioural therapy, lifestyle modification and pharmacotherapy remain the mainstays of treatment. The most appealing solution for the public in general would be a ‘weight loss pill’. Several drugs have been tested since the 1960s, such as thyroid hormone, dinitrophenol, various forms of amphetamines, aminorex, fenfluramine, phenylpropanolamine, rimonabant, orlistat and sibutramine. All but phentermine, phendimetrazine and orlistat have been banned because of serious side effects. Aminorex was introduced in 1965 in Switzerland and was found to cause pulmonary hypertension. Lorcaserin (ADP356; Trade name: Belviq marketed by Arena Pharmaceuticals) and topiramate/phentermine (Qsymia) are the most recent additions to the armamentarium of antiobesity medications. Lorcaserin is a novel drug acting selectively as a 5-HT2C receptor agonist in the hypothalamus with a functional selectivity of 15 times higher affinity for 5-HT2C than for 5-HT2A receptors and 100 times higher selectivity for 5-HT2C than for the 5-HT2B receptors. 13–15 It has achieved a clinically meaningful weight loss as per Food and Drug Administration’s (FDA’s) guidance criteria (2007), that is, a mean efficacy criterion (a medicationassociated (ie, greater than placebo) weight reduction of 5%) and a categorical efficacy criterion (a significantly greater proportion (at least 35%) of those individuals receiving the medication compared with placebo controls maintaining a 5% weight loss from their initial weight). Lorcaserin is indicated as an adjunct to a reduced-calorie diet and increased physical activity for the chronic weight management in adults with an initial BMI of 30 kg/m or greater (obese) or 27 kg/m or greater (overweight) in the presence of at least one weight-related comorbid condition (ie, hypertension, dyslipidemia, type 2 diabetes). With one-third of the adults living in the USA considered to be overweight and more than a third obese, a potentially huge market exists for lorcaserin. Thus, it is important to understand lorcaserin’s side effect profile and its risk-to-benefit ratio. Despite the fact that the lorcaserin package insert states that it does not cause a significant increase in FDA-defined valvulopathy, defined as mitral regurgitation greater than mild or aortic regurgitation greater than trace (pooled relative risk (RR) of the phase 3 echocardiographic data: 1.16; 95% CI 0.81 to 1.67), a look at the FDA Medical Review states that lorcaserin causes a significant increase in moderate or greater mitral regurgitation at week 52 (RR 1.95; 95% CI 1.05 to 3.59, p value not stated) and (RR 1.88; 95% CI 1.02 to 3.47, p=0.04) based on our forest plot) (figure 1). These data were based on a meta-analysis of three randomised controlled trials testing lorcaserin 10 mg twice daily versus placebo. Moreover, the upper bound of the 95% CI (1.67) exceeded the 1.5 upper