For all the panic about a spiralling global epidemic of obesity, weight loss drugs are getting a tough ride in the medical literature.

Just as concerns about psychiatric side-effects associated with Sanofi-Aventis’ Acomplia (rimonabant) were resurfacing in The Lancet, another leading UK journal, the BMJ, weighed in with a meta-analysis by researchers from Canada and Brazil that found three anti-obesity therapies recommended for long-term use – rimonabant, orlistat (Xenical, Roche) and sibutramine (Meridia/Reductil, Abbott Laboratories) reduced weight by less than 5kg or 5% of total body weight.

The researchers led by Raj Padwell, assistant professor in the Department of Medicine at the University of Alberta in Edmonton, Canada, reviewed the evidence from 30 double-blind, randomised, placebo-controlled trials in which adults took anti-obesity drugs for a year or longer. The mean weight of the trial participants was 100kg, with a mean body mass index of 35-36.

The meta-analysis showed that, compared with placebo, orlistat reduced weight by a mean of 2.9kg (95% confidence interval 2.5kg to 3.2kg), sibutramine by 4.2kg (3.6kg to 4.7kg) and rimonabant by 4.7kg (4.1kg to 5.3kg). Patients receiving active drug treatment were, however, significantly more likely to achieve 5% and 10% weight loss thresholds.

The ancillary benefits of the weight-loss drugs were mixed. Orlistat reduced the incidence of diabetes and improved concentrations of total cholesterol and low density lipoprotein (LDL) cholesterol, as well as blood pressure and glycaemic control, in patients with diabetes. But it also resulted in higher rates of gastrointestinal side effects and slightly lowered concentrations of high density lipoprotein.

Sibutramine raised concentrations of high density lipoprotein (HDL) cholesterol and reduced those of triglycerides while pushing up blood pressure and pulse rates. Rimonabant improved concentrations of HDL cholesterol and triglycerides, blood pressure, and glycaemic control in patients with diabetes but also increased the risk of mood disorders. More generally, there were high drop-out levels in all of the trials, with 30-40% of patients on average failing to complete the studies.

Don’t go OTC
In an accompanying editorial, Gareth Williams, professor of medicine and dean of the Faculty of Medicine at Bristol University in the UK, expressed reservations about GlaxoSmithKline’s (GSK) approval application to the European Medicines Agency to market orlistat over the counter across Europe as Alli (its OTC brand name in the US).

It was unlikely many OTC users would see significant health benefits from orlistat, Professor Williams contended, especially as anti-obesity drugs inevitably performed best in clinical trials where participants were relatively motivated and supported by dedicated staff reinforcing lifestyle advice. Moreover, the weight loss observed with orlistat in clinical studies was modest – typically 2-5kg after one year, reducing to 2.7kg after four years. Then there were the unpleasant side-effects (faecal incontinence) associated with the drug.

“Possibly, few users will even finish their first pack of Alli, let alone buy a second, and the drug may cause only a small and transient downward blip in the otherwise inexorable climb in weight and cardiometabolic risk,” he warned. Making orlistat available OTC could also cause “insidious collateral damage” by distracting from the radical lifestyle changes needed to fight obesity.

The problem could only be eased by “public health campaigns that somehow persuade people to eat less and exercise more”, Professor Williams argued. “Selling anti-obesity drugs over the counter will perpetuate the myth that obesity can be fixed simply by popping a pill,” he wrote, adding: “The only real beneficiary will be GSK.”