OBJECTIVE - Weight loss improves glycemic control, lipid profiles, and blood pressure in patients with type 2 diabetes. However, successful long-term weight loss is difficult for these patients, particularly those treated with insulin. The aim of this study was to assess the effect of orlistat, a gastrointestinal lipase inhibitor, on weight loss, glycemic control, and cardiovascular risk factors in overweight or obese insulin-treated type 2 diabetic patients. RESEARCH DESIGN AND METHODS - This study was a 1-year multicenter, randomized, double-blind, placebo-controlled trial of orlistat (120 mg three times a day) or placebo combined with a reduced-calorie diet in overweight or obese adults (BMI 28-40 kg/m2) with type 2 diabetes treated with insulin alone or combined with oral agents, but with suboptimal metabolic control (HbA1c 7.5-12.0%). Outcome measurements included changes in body weight, glycemic control, blood pressure, and serum lipids. RESULTS - After 1 year, the orlistat group lost significantly more weight (-3.89 ± 0.3% of baseline body weight, means ± SE) than the placebo group (-1.27 ± 0.3%, P < 0.001). Orlistat treatment, compared with placebo, produced greater decreases in HbA1c (-0.62 ± 0.08 vs. -0.27 ± 0.08%, P = 0.002), fasting serum glucose (-1.63 ± 0.3 vs. -1.08 ± 0.3 mmol/l, P = 0.02), and the required doses of insulin and other diabetic medications. Orlistat also produced greater improvements than placebo in serum total cholesterol (P = 0.0002) and LDL cholesterol concentrations (P = 0.001) and LDL/HDL ratio (P = 0.01). CONCLUSIONS - Orlistat therapy produces clinically significant weight loss, with improvements in glycemic control and cardiovascular disease risk factors, in overweight or obese patients with type 2 diabetes who have suboptimal metabolic control with insulin therapy.