Orlistat

Orlistat is an inhibitor of gastrointestinal lipases and, therefore, prevents the absorption of dietary fat. This agent reduces weight in obese adults and adolescents with or without comorbidities (including type 2 diabetes mellitus, hypercholesterolaemia, hypertension, metabolic syndrome) who received up to 4 years of therapy in conjunction with a hypocaloric diet. In obese patients, orlistat in combination with a hypocaloric diet improved metabolic risk factors and reduced the risk of developing type 2 diabetes. Furthermore, this agent was cost effective in patients with obesity, particularly those with type 2 diabetes. Orlistat is generally well tolerated, with gastrointestinal adverse events being most commonly reported. Orlistat, in addition to lifestyle and dietary intervention, is thus an attractive option for the treatment of patients with obesity, especially those with associated comorbidities or at risk of developing type 2 diabetes.

Orlistat potently and selectively inhibits gastric and pancreatic lipases, thereby preventing the hydrolysis of dietary fat. Consequently, the absorption of dietary fat is inhibited, with increased faecal fat excretion. This agent also decreases postprandial gastric acid secretion, gastric emptying and cholecystokinin release in response to a meal. Orlistat has a beneficial effect on several metabolic parameters, including plasma lipid levels, measurements of glycaemic control, blood pressure, plasma leptin and haemostatic factors. It is not associated with significant changes in fat-free mass or resting energy expenditure. Orlistat prevents weight loss-induced reductions in biliary composition.

Absorption of oral orlistat is minimal, with no evidence of accumulation after long-term administration. Orlistat is rapidly eliminated and excreted primarily in the faeces. With the exception of ciclosporin (cyclosporin), there are no clinically relevant drug interactions between orlistat and other commonly coadministered agents.

In obese patients treated with a mildly hypocaloric diet for the first year, bodyweight was reduced to a significantly greater extent with orlistat than placebo in large well designed trials (5–10% vs 2–7%).

In the XENDOS (XENical in the prevention of Diabetes in Obese Subjects) trial (all patients received lifestyle and dietary intervention), the between-group difference in weight reduction was still significant after 4 years of treatment (5% vs 3%; p < 0.001). In this trial, orlistat also reduced the risk of developing type 2 diabetes by 37.3% compared with placebo; the risk reduction in patients with impaired glucose tolerance was 45%.

In obese patients with type 2 diabetes, weight reduction was significantly greater with up to 1 year's treatment with orlistat (4–6%) than with placebo (1–4%).

In obese and overweight adolescents, 1 year of orlistat treatment was significantly more effective than placebo in reducing body mass index, waist circumference and fat mass.

Orlistat improved aspects of quality of life to a significantly greater extent than placebo in obese patients.

Weight reduction of ≥5% after 12 weeks of orlistat treatment, but not weight reduction ≥2.5kg during a 4-week placebo plus hypocaloric diet lead-in period, was predictive of subsequent weight loss during long-term orlistat therapy.

Orlistat was significantly more effective than placebo in improving metabolic risk factors in obese patients with one or several comorbidities (including type 2 diabetes, hypercholesterolaemia, hypertension or metabolic syndrome). Generally, orlistat, compared with placebo, significantly improved levels of total cholesterol, low-density lipoprotein-cholesterol, glycosylated haemoglobin, fasting and postprandial insulin, fasting and postprandial glucose and systolic and/or diastolic blood pressure in these patients.

Orlistat was considered cost effective in the management of obese patients with type 2 diabetes, according to two long-term cost-effectiveness analyses. Incremental costs per event-free life year gained were €3462–19 986 (depending on level of complication) or $US8327.

Orlistat was generally well tolerated in obese patients, with or without type 2 diabetes, in well controlled trials of up to 4 years' duration. The tolerability profile of orlistat in obese and overweight adolescents was similar to that in obese adults. Gastrointestinal adverse events were most commonly reported with orlistat therapy and were generally mild and transient. The incidence of mild-to-moderate hypoglycaemia was higher in obese patients with type 2 diabetes treated with orlistat than placebo; however, no patients required medical intervention. Decreases in plasma levels of fat-soluble vitamins occurred with orlistat therapy, although levels generally remained within the normal reference range.