Safety of Drug Therapies Used for Weight Loss and Treatment of Obesity

Abstract

Some of the medications used for weight loss in the management of obesity have been associated with unacceptable morbidity and mortality. Safety concerns have led to the withdrawal of aminorex, followed by the fenfluramines in 1997, and phenylpropanolamine (norephedrine) in 2000. Aminorex was associated with an increased prevalence of primary pulmonary hypertension (PPH), fenfluramines with an increased prevalence of PPH and valvulopathy, and phenylpropanolamine with an increased risk of haemorrhagic stroke. Several studies have investigated the safety of the fenfluramines, yet the benefit-risk profile has not been conclusively quantified. This is due to several deficiencies in the published studies, including a lack of data on the baseline prevalences of comorbid conditions in obese subjects, and potential confounders and biases in the study designs. Although several studies and systematic reviews support an increased risk of PPH and valvulopathy in patients who have taken fenfluramines, without knowledge of the background prevalence it is not possible to determine if the exposure preceded the outcome. The population at higher risk of these adverse effects includes those taking higher doses or with a longer duration of exposure to fenfluramines and those with pre-existing cardiac disease or a genetic predisposition. Patients exposed to fenfluramines continue to be monitored, with some follow-up studies indicating no overall worsening in valvulopathy over time. There are limited efficacy and safety data for amfepramone (diethylpropion) and phentermine and their approval for the management of obesity is limited to short-term use. Orlistat and sibutramine are the only currently approved medications for long-term management of obesity. Although the benefit-risk profiles of sibutramine and orlistat appear positive, sibutramine continues to be monitored because of long-term safety concerns. The safety and efficacy of currently approved drug therapies have not been evaluated in children and elderly patient populations and there is limited information in adolescents, whilst the long-term safety of current and potential new drug therapies in adults will require several years of postmarketing surveillance to fully elucidate their adverse effect profiles.

Cardiovascular Risk-Benefit Profile of Sibutramine

“…[38,39] Several randomised clinical trials were performed in overweight/obese patients with T2DM demonstrating the potential of sibutramine to improve glucose control. [36,40] In general, sibutramine has been well tolerated, [41,42] with no induction of primary pulmonary hypertension [43] or adverse effects on cardiac valves [44,45] , in contrast to what was previously reported with fenfluramine and dexfenfluramine [25,26] . However, its action on the sympathetic nervous system has linked sibutramine to blood pressure (BP) and heart rate (HR) elevations [46,47] .…”

Rise and fall of anti-obesity drugs

“…As sibutramine is no longer available, orlistat is currently the only antiobesity drug to have been approved for longterm use [15] . The development of new antiobesity drugs is therefore urgently needed.…”

“…The combination of phen termine with fenfluramine or dexfenfluramine was not thought to be more effective than either drug alone, but lower doses of each drug could be used in combina tion, leading to fewer side effects [14] . However, both fen fluramine and dexfenfluramine were withdrawn from market by the USFDA in 1997 [15] . The decision was pro mpted by a preliminary report of 24 women receiving fenfluramine [13] .…”

“…Sibutramine was widely used after its approval by the USFDA in 1997 [7,15] . It is a serotonergic and adrenergic drug that inhibits the reuptake of serotonin and norepine phrine [16] .…”

Sibutramine-induced acute myocardial infarction in a young lady

“…Adverse effects in therapeutic doses include xerostomia, insomnia, anorexia, and constipation. Cardiovascular toxicities include tachycardia, palpitation, hypertension, and tachyarrhythmia (8). The mechanism of sibutramine-induced acute coronary syndrome is not established, but sibutramine may behave like amphetamine or amphetamine-like substance through reversible coronary narrowing or vasospasm.…”