Pharmacotherapy for the management of
obesity is primarily aimed at
weight loss,
weight loss maintenance and risk reduction, and has included
thyroid hormone,
amphetamines,
phentermine,
amfepramone (
diethylpropion),
phenylpropanolamine,
mazindol, fenfluramines and, more recently,
sibutramine and
orlistat. These agents decrease appetite, reduce absorption of fat or increase energy expenditure. Primary endpoints used to evaluate
anti-obesity drugs most frequently include mean
weight loss, percentage
weight loss and proportion of patients losing >or=5% and >or=10% of initial bodyweight. Secondary endpoints may include reduction in body fat, risk factors for cardiovascular disease and the incidences of diseases such as
diabetes mellitus. Most
pharmacotherapies have demonstrated significantly greater
weight loss in patients on active treatment than those receiving placebo in short-term (<or=1 year) randomised controlled trials of pharmacological treatment in conjunction with a calorie-controlled diet or lifestyle intervention. The evidence of long-term efficacy is limited to
sibutramine (2 years) and
orlistat (4 years). These are the only drugs currently approved for the long-term management of
obesity in adults.
Sibutramine recipients randomised following 6 months' treatment to either
sibutramine or placebo demonstrated significantly better weight maintenance at 2 years than those taking placebo (p<0.001), with >or=10% loss of initial bodyweight in 46% of patients. For patients taking
orlistat,
weight loss was 2.2 kg greater than those on placebo at 4 years (p<0.001), with significantly more patients achieving >or=10% loss of initial bodyweight (26.2% and 15.6%, respectively; p<0.001). Other drugs that have been evaluated for
weight loss include
ephedrine, the
antidepressants fluoxetine and
bupropion, and the
antiepileptics topiramate and
zonisamide. Two clinical trials with
fluoxetine both reported no significant difference in
weight loss compared with placebo at 52 weeks. Clinical trials evaluating
ephedrine,
bupropion,
topiramate and
zonisamide have demonstrated significantly greater
weight loss than placebo but have been limited to 16-26 weeks' treatment. A major obstacle to the evaluation of the clinical trials is the potential bias resulting from low study completion rates. Completion rates varied from 52.8% of
phentermine recipients in a 9-month study, to 40% of
fenfluramine recipients in a 24-week comparative study with
phentermine and 18% of
amfepramone recipients in a 24-week study. One-year completion rates range from 51% to 73% for
sibutramine and from 66% to 85% for
orlistat. Other potential sources of bias include run-in periods and subsequent patient selection based on compliance or initial
weight loss. Several potential new
therapies targeting
weight loss and
obesity through the CNS pathways or peripheral adiposity signals are in early phase clinical trials. Over the next decade the
drug treatment of
obesity is likely to change significantly because of the availability of new
pharmacotherapies to regulate eating behaviours, nutrient partitioning and/or energy expenditure.