Orlistat 120 mg improves glycaemic control in type 2 diabetic patients with or without concurrent weight loss

Background: Both obesity and type 2 diabetes are associated with increased morbidity and mortality. Published data suggest that orlistat 120 mg, a lipase inhibitor used to treat obesity, may improve glycaemic parameters through weight loss-independent effects. Aim: To investigate the effect of orlistat 120 mg on weight loss, and assess whether changes in glycaemic parameters [fasting plasma glucose (FPG) and haemoglobin A(1c) (HbA(1c))] are independent of weight loss. Methods: This retrospective analysis of pooled data from seven multicentre, double-blind, placebo-controlled studies involved overweight or obese patients with type 2 diabetes (aged 18-70 years). Patients were required to have a body mass index of 27-43 kg/m(2), HbA(1c) of 6.5 to < 13%, and stable weight for >= 3 months. Subjects received orlistat 120 mg tid or placebo for 6 or 12 months. Results: A total of 2550 overweight or obese patients with type 2 diabetes were enrolled and randomized to treatment with orlistat 120 mg tid (n = 1279) or placebo (n = 1271). For the whole population, patients treated with orlistat 120 mg had significantly greater mean decreases in FPG compared with placebo-treated patients (-1.39 mmol/l vs. -0.47 mmol/l; p < 0.0001). In addition, orlistat 120 mg provided significantly larger mean decreases in HbA(1c) compared with placebo (-0.74% vs. -0.31%; p < 0.0001). For patients with minimal weight loss (-1% of baseline body weight), orlistat 120 mg still provided a significantly greater decrease in the least squares mean value for both FPG (-0.83 mmol/l vs. +/- 0.02 mmol/l; p = 0.0052) and HbA(1c) -0.29% vs. +/- 0.14%; p = 0.0008). This suggested that the improvement of glycaemic control with orlistat 120 mg was independent of weight loss. Using linear regression analysis, improvement in glycaemic control (FPG and HbA(1c)) with orlistat 120 mg was less strongly correlated with weight loss than for placebo. Conclusion: Orlistat 120 mg appears to improve glycaemic control more than would be predicted by weight loss alone in overweight or obese patients with type 2 diabetes. Postulated mechanisms underlying this effect include an improvement of insulin sensitivity, a slower and incomplete digestion of dietary fat, reduction of postprandial plasma non-esterified fatty acids, decreased visceral adipose tissue, and stimulation of glucagon-like peptide-1 secretion in the lower small intestine.