Managing Cardiometabolic Risk

Orlistat

Mechanism of action
Approved in 1998, orlistat inhibits the activity of gastric and pancreatic lipases to reduce the digestion and absorption of dietary fat by approximately 30% (19). The inhibitor is a derivative of a natural lipstatin produced by Streptomyces toxytricini. Typically, the drug is taken (120 mg) three times a day with meals. Half-strength orlistat is currently being assessed by the American Food and Drug Administration (FDA) for over-the-counter use in the USA. Because of low systemic absorption and first-pass hepatic metabolism, the bioavailability of orlistat is very low (<1%). The drug therefore acts entirely within the digestive tract and is mostly excreted unchanged in feces (20).

Efficacy
A few studies lasting two or more years have examined the efficacy of orlistat. Pooled two-year data from four of these studies showed dose-dependent weight loss with orlistat (optimal dose: 120 mg, three times a day) (5, 7). When combined with a rather stringent lifestyle modification program, an average cumulative maximal weight loss (–9.5%) was attained at 6-9 months, followed by a slow regain in all experimental groups, including placebo. Weight loss after two years was approximately 7% below baseline in the 120 mg orlistat group.

In a longer-term, four-year double-blind placebo-controlled randomized study of 3,305 Swedish obese patients, orlistat reduced weight by an average of 2.7 kg over placebo (21) (Figure 1). The greatest reduction in body weight occurred during the first year and was –11% below baseline in the orlistat-treated group vs. –6% below baseline in the placebo-treated group. There was some weight regain over the remaining three years, with orlistat-treated patients ending up at –6.9% below baseline compared to –4.1% for those receiving placebo.