Highlights of the NAASO 2005 Annual Scientific Meeting

Poster and Oral Presentations

Poster and oral presentations were scattered throughout the week and organized to support the various track themes. Poster sessions provided the opportunity to visit with new and experienced investigators and discuss emerging issues of importance.

Several oral and poster presentations focused on obesity drug development, including compounds, such as exenatide, APD356 (a selective 5-HT_2c agonist), and pramlintide.

Exenatide was recently approved for the treatment for type 2 diabetes. However, its weight-loss characteristics are also compelling. It represents a new class of drugs termed incretin mimetics because they are similar to the human glucagon-like peptide (GLP)-1 produced in the L cells in the small intestine. GLP-1 normally has a very short half-life of approximately 2 minutes because it is degraded by the enzyme dipeptidyl peptidase (DPP)-IV. However, exenatide is resistant to DPP-IV degradation and has a half-life of approximately 2.4 hours. Exenatide was derived from a GLP-1-like peptide found in the saliva of the Gila monster, which is found in the southwestern United States. This peptide improves blood glucose by restoring first-phase insulin response, improving glucose-dependent insulin secretion, and suppressing inappropriate glucagon secretion as well as increasing satiety. Obviously, a drug that lowers blood glucose and promotes weight loss is a useful tool to treat people with diabetes. The long-term, 82-week exenatide weight-loss data were presented at this conference.^[30] The data included 393 subjects who completed the 30-week placebo-controlled trials that studied patients treated with a combination of metformin, sulfonylurea, or both in combination with placebo, 5 mcg of exenatide twice daily, or 10 mcg exenatide twice daily. After the 30-week trial period, subjects entered this extension trial and all were placed on exenatide 10 mcg twice daily. The subjects who were originally in the placebo group and converted to 10 mcg twice daily had 3.9 + 0.4 kg weight loss. The group that was originally treated with exenatide 5 mcg twice daily and converted to 10 mcg twice daily had 4.7 ± 0.5 kg weight loss. The group that was originally in the exenatide 10-mcg twice-daily group and continued 10 mcg twice daily had 4.5 + 0.5 kg weight loss. An interesting fact pointed out by the investigators is that subjects with the highest BMIs had the greatest weight loss.

Another new class of drugs under development for the treatment of obesity are the 5-HT_2c modulators. Data were presented on APD356, a selective 5-HT_2c agonist.^[31] This compound is a highly selective activator of 5-HT_2c receptors in the hypothalamus and has been shown to reduce food intake in small studies. This study involved 352 subjects with a BMI between 30 and 45.^[31] Subjects received 1 mg, 5 mg, or 15 mg of APD356 daily. The subjects were treated for 28 days. The subjects who received 15 mg daily had a significant weight loss of 1.3 kg (P = .0002) vs the placebo group that lost 0.3 kg in this short study period. Subjects receiving the 1-mg and 5-mg doses did not have a statistically significant weight loss. The authors note that these data have confirmed the need for larger, long-term trials.

Pramlintide is an interesting compound that is being investigated in the treatment of obesity. This drug is an analog of the hormone amylin, which is a naturally occurring neuroendocrine hormone synthesized from pancreatic beta cells that contribute to glucose control during the postprandial period. It is currently approved for people with type 1 and 2 diabetes who are not adequately controlled with insulin. In people with type 1 diabetes, the dosing range is 15-60 mcg before major meals, and in people with type 2 diabetes the dosing range is 60-120 mcg before major meals. Data were presented by Fujioka and colleagues^[32] in regard to the characteristics of patients who lost more than 5% of their body weight with pramlintide treatment. In this weight-loss trial, a higher dose was used than indicated for the treatment of diabetes. Subjects titrated the dose to a goal dose of 240 mcg 3 times a day over 4 weeks and then maintained this dose for 12 weeks. Subjects had a baseline BMI of 37.8 ± 5.6 kg/m². At study week 16, the pramlintide-treated subjects had a weight loss of 3.7% ± 0.4%, which was highly significant (P < .0001). It was also notable that 31% of pramlintide-treated subjects achieved 5% weight loss compared with 2% of placebo-treated subjects (P < .0001). One of the possible side effects of pramlintide is mild nausea, especially in the first 3 weeks. Therefore, an important research question is whether nausea was a factor in the increased efficacy seen with the > 5% weight-loss responders. Therefore, data for the subjects who had greater than 5% weight loss were examined, and the investigators reported that there was no significant difference between the 2 groups. Thus, nausea was not a factor for the more successful subset of subjects who lost > 5% of body weight.

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