Chapter 25 – Historical Drug Therapies in Obesity

Laxatives were the first known weight-reducing drugs, used in the 2nd century AD. Inspite of the side effects of hypokalemia and metabolic alkalosis two millennium on, they are still used notably by patients with anorexia nervosa and bulimia. Although thyroid gland extract and then thyroid hormones have been used for weight loss for two centuries, they are known to lead to lean body mass loss, osteoporosis, cardiac muscle hypertrophy, and increased mortality. Unfortunately, despite being unlicensed for obesity, they are still used by some. Thyroid hormone mimetics were developed aiming at addressing these side effects of thyroid hormones; however, the weight loss achieved during clinical trials was disappointing. Central-acting drugs including dinitrophenol, amphetamines, their analogues, phentermine, phenylpropanolamine, diethylpropion, aminorex, rainbow pills, fenfluramine, fenfluramine-related drugs, and sibutramine were associated with central nervous stimulation, addiction, pulmonary artery hypertension, or increased cardiovascular events. They were all withdrawn except for phentermine, which is currently used for only short periods in some countries. The latest drug cannabinoid agonist rimonabant has also been withdrawn because of increased depression and suicide rates. It appears that a critical factor of essentially all drugs described here and used for treating obesity in the past is one of life-threatening side effects. The chronicity of obesity with associated comorbidities in itself poses difficulties in developing safe therapies.