ADA 2011: Pharmacologic Options for Weight Management in Diabetic Patients

Researchers are investigating a variety of targets and pathways in the search for an effective weight-loss drug.

Researchers are investigating a variety of targets and pathways in the search for an effective weight-loss drug.

During his presentation, titled “Novel Mechanisms of Action for Weight Management Therapies on the Horizon,” part of the “Challenges and Expectations for Obesity Pharmacotherapy” symposium at the ADA 71st Annual Scientific Sessions in San Diego, George A. Bray, MD, Boyd Professor at the Pennington Biomedical Research Center of Louisiana State University in Baton Rouge, Louisiana, and Professor of Medicine at the Louisiana State University Medical Center in New Orleans, noted that drug developers have quite a challenge in developing anti-obesity medications. He said that although there are a number of drugs approved for other indications that happen to affect weight, the current pharmacological options available for treating obesity are limited. He also described several potentially viable targets for future drug development.

Bray outlined three main reasons why anti-obesity drugs are ineffective: recidivism, drug toxicity, and failed or overlapping mechanisms. With regard to recidivism, he cited studies showing patients who initially lose weight, but then either plateau or gain weight back. “It’s a real challenge to keep patients in clinical trials to see the weight loss they really want,” he explained. Drug toxicity is another challenge, and if one reviews what has happened over the last century, a number of drugs were withdrawn or simply not used because of toxicity. It is often impossible to predict side effects. The third reason Bray provided was failed or overlapping mechanisms. An example was fluoxetine, where patients lost weight then gained it back. “There was something about the serotonergic mechanism that doesn’t remain potent over time,” he said. The lack of efficacy due to mechanisms was also seen in melanocortin-4 receptor agonist (MK-0493) and ciliary neurotrophic factor. In the latter, weight loss was actually eliminated by antibodies to ciliary neurotrophic factor.

Rather than focusing on sensing nutrients in central sites, as has been a main focus of drug development, Bray believes that drugs focusing on the peripheral systems may be more effective. Only one peripheral-acting drug, orlistat, has so far been approved for treatment of obesity. Studies have shown significant decreases in body weight over two years compared to placebo, and this is fairly well-maintained.

Bray spent much of the remainder of his talk discussing drugs not developed to treat obesity but that have been tested for their effects on weight. Metformin, approved for use in type 2 diabetes, demonstrated reduced weight in patients receiving it compared to placebo. Understandably, weight loss was related to adherence, so if patients were adherent, they maintained the loss for up to 10 years. Leptin is a peptide that works best if a patient is deficient in leptin. “If patients are not deficient, then results are discouraging; the heavier the patient, the higher the leptin he/she has, but the response to leptin is greatest at lower weights,” said Bray. Amylin is a pancreatic hormone that may enhance sensitivity to leptin. When given a combination of amylin and leptin treatments, such as pramlintide and phentermine, patients experience considerably greater weight loss compared with pramlintide alone. Similar results were observed when pramlintide was combined with metreleptin—either drug alone did not differ, but the combination resulted in greater weight loss. Glucagon-like peptide 1, exenatide, liraglutide, and polypeptide YY also showed greater weight loss compared to placebo.

Other potential peripheral targets are brown fat and white adipose tissue, though Bray favors the latter for targeting treatment. Visceral fat can be modulated through weight loss, hormones, smoking cessation, the sympathetic nervous system, and thiazolidinediones.

So there are clearly options when it comes to treating obesity, both in terms of pharmacological and non-pharmacological methods. “Predicting the future is hazardous,” cautioned Bray, but he said that he was confident that progress will be made.