1. Section overview: Cardiometabolic risk reduction

2. More details from this meta-analysis are presented in the next slides.
Currently approved pharmacologic options for long-term weight management
In the US, sibutramine and orlistat are the only 2 drugs approved by the FDA as adjuncts to a hypocaloric diet for weight reduction.
Orlistat acts via lipase inhibition, which prevents digestion and absorption of dietary fats. In a recent meta-analysis, the mean placebo-corrected weight loss was 6.4 lbs. The most frequent side effects were GI (fatty/oily stool, fecal urgency, and oily spotting, each occurring at frequency rates of 15%-30% in most studies).
Orlistat over-the-counter (OTC) is one-half of the dose requiring a doctor’s prescription.
Sibutramine acts via NE and serotonin reuptake inhibition, which suppresses appetite. It may also stimulate thermogenesis.(1) In a meta-analysis (conducted as part of a Cochrane collaboration systemic review) the drug was associated with a mean placebo-corrected weight loss of 9.3 lbs. In these trials, placebo-corrected increases in systolic BP (1.7 mm Hg, range mm Hg), diastolic BP (2.4 mm Hg, range mm Hg), and heart rate (4.5 beats per minute [bpm], range bpm) were reported.
More details from this meta-analysis are presented in the next slides.
1. Sarac F et al. Adv Ther. 2006;23:

3. Weight loss with orlistat: Meta-analysis
A total of 14 randomized, double-blind, placebo-controlled trials were included in the meta-analysis, representing 4948 and 4509 subjects in the orlistat and placebo groups, respectively.
All trials were at least 1 year in duration.

4. Orlistat: Change in cardiometabolic parameters
As expected, weight reduction with orlistat was associated with improvements in several cardiometabolic risk factors.

5. Weight loss with sibutramine: Meta-analysis
A total of 10 (7 weight-loss, 3 weight-maintenance) randomized, double-blind, placebo-controlled trials of sibutramine were included in the meta-analysis, representing 1362 and 986 subjects in the sibutramine and placebo groups, respectively.
All trials were at least 1 year in duration.

6. Sibutramine: Change in cardiometabolic parameters
Treatment with sibutramine improved adiposity measures and levels of TG and HDL-C.
Changes in glycemic control were inconsistently reported, and when reported were not significantly different from placebo.

7. New targets for weight loss and cardiometabolic risk reduction
A number of new approaches to pharmacologic weight loss are under investigation.(1,2)
The goal of this section is to review data on 2 drugs currently approved for glucose lowering in diabetes which also show promise for weight loss.
1. Aronne LJ, Thornton-Jones ZD. Clin Pharmacol Ther. 2007;81:
2. Neff LM, Aronne LJ. Curr Atheroscler Rep. 2007;9:

8. Exenatide: Effects on weight
DeFronzo et al conducted a triple-blind, placebo-controlled trial of exenatide in 336 patients with T2DM treated with metformin. Study subjects were randomized to placebo or exenatide 5 mcg or 10 mcg twice daily for 30 weeks.
The primary efficacy endpoint was glycemic control, as assessed by change in hemoglobin A1C (A1C). Change in weight was a secondary endpoint.
When added to a background of metformin, exenatide was associated with dose-dependent reductions in weight (2.9 lbs and 5.6 lbs, respectively, placebo corrected).

9. Pramlintide: Effects on weight
Aronne et al conducted a randomized, double-blind, placebo-controlled weight-loss trial of pramlintide in 204 obese subjects (BMI kg/m[2]).
The study design consisted of a 1-week placebo lead-in, a 4-week nonforced dose escalation phase (during which pramlintide was initiated at 60 mcg tid and increased every 3 days up to a maximum of 240 mcg tid), a 12-week maintenance phase (during which patients received either 120, 180, or 240 mcg tid, based on the dose achieved during the escalation phase), and finally an 8-week nontreatment follow-up.
At week 16, the placebo-corrected weight loss in the intention-to-treat (ITT) population was 6 lbs (using last observation carried forward [LOCF]).

10. Pramlintide plus recombinant leptin for weight loss: Pilot study
Leptin is an adipokine with receptors located in several regions of the brain and in peripheral tissues.(1) During periods of negative energy balance, levels of leptin rise and are associated with increased food intake.
However, obesity is associated with a state of leptin resistance and clinical weight-loss trials of leptin have proved disappointing.
Roth et al conducted a randomized, double-blind, parallel-group study of leptin plus pramlintide vs either treatment alone. During the lead-in phase, study subjects (N = 177, BMI kg/m[2]) were given pramlintide 360 mcg tid and instructed to follow a hypocaloric diet. They were then randomized to continue on pramlintide alone, be switched to recombinant leptin (metreleptin 5 mg bid), or their combination for 20 weeks.
At study end, weight loss in the ITT population (using LOCF) was 16 lbs (pramlintide), 16 lbs (metreleptin), and 22 lbs (combination, P < 0.05 vs each monotherapy).
The investigators speculate that pramlintide may, in some way, influence the hypothalamic response to leptin.
1. Seeley RJ, Woods SC. Nat Rev Neurosci. 2003;4:901-9.

11. New systems targeting cardiometabolic risk reduction: Summary
Clinical data are emerging for a number of promising new pharmacologic approaches to weight loss.
However, data are lacking on the effects of these agents on CV events.