Pharmacodynamics/Clinical Studies

Observational epidemiologic studies have established a relationship between obesity and the risks for cardiovascular disease, non-insulin dependent diabetes mellitus, certain forms of cancer, gallstones, certain respiratory disorders, and an increase in overall mortality. These studies suggest that weight loss, if maintained, may produce health benefits for some patients with chronic obesity who may also be at risk for other diseases.

The long-term effects of reductil on the morbidity and mortality associated with obesity have not been established. Sibutramine's effect on weight loss was examined in double-blind, placebo-controlled obesity trials with study durations of 8 weeks to 18 months and doses ranging from 1 to 30mg once daily. A total of 8052 patients were included in these studies; 5335 patients being treated with reductil and 2717 patients with placebo. The patients involved in these studies either had uncomplicated obesity with Body Mass Index (BMI) ranging from 27 to 40 kg/m2 or were obese with comorbid condition(s) and BMI  27kg/m2.  

Weight was significantly reduced in a dose-related manner in sibutramine-treated patients compared to placebo over the dose range of 5mg to 30mg once daily. In two 12-month studies (one of these studies only involved obese patients who had lost at least 6 kg on a 4-week very low calorie diet), maximal weight loss was achieved by 6 months and statistically significant weight loss was maintained over 12 months. The amount of weight loss achieved with reductil was consistent across studies.

Significant dose-related reductions in waist circumference, an indicator of intra-abdominal fat, have also been observed over 6 and 12 months treatment with reductil in placebo-controlled clinical trials. These data were consistent with more objective measurements of abdominal visceral adiposity such as computed tomography (CT) scans; CT scans on obese patients in a 2-year study provide evidence of a significant decrease in abdominal visceral fat of 24% and in subcutaneous fat of 17% after Reductil 10 mg, compared to baseline. These changes were associated with significant reductions from baseline in mean weight, waist circumference and fasting blood glucose, insulin, C-peptide and triglycerides.

Double-blind, placebo-controlled obesity trials with study durations of 12 weeks to 18 months have provided evidence that the weight loss resulting from treatment with reductil was associated with improvements in patients' glycaemic control, serum lipid profiles (similar to those seen with non-pharmacological mediated weight loss), and serum uric acid. Treatment with reductil (5 to 20mg once daily) is associated with mean increases in blood pressure of 1 to 3mmHg and with mean increases in pulse rate of 4 to 5 beats per minute relative to placebo. These findings, which were not associated with any clinically significant outcomes, are similar in normotensives and in patients with hypertension controlled with medication. With the latter patients, control of blood pressure was not adversely affected. Those patients who lose significant amounts of weight on reductil tend to have smaller increases in blood pressure and pulse rate.

Studies in healthy volunteers indicate that reductil does not affect the sympathoadrenal system, the hypothalamic-pituitary-end organ axes and other endocrine parameters including testosterone and postprandial cholecystokinin.