Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy.

Abstract

The neurohormonal control of body weight involves a complex interplay between long-term adiposity signals (e.g., leptin), and short-term satiation signals (e.g., amylin). In diet-induced obese (DIO) rodents, amylin/leptin combination treatment led to marked, synergistic, fat-specific weight loss. To evaluate the weight-lowering effect of combined amylin/leptin agonism (with pramlintide/metreleptin) in human obesity, a 24-week, randomized, double-blind, active-drug-controlled, proof-of-concept study was conducted in obese or overweight subjects (N = 177; 63% female; 39 +/- 8 years; BMI 32.0 +/- 2.1 kg/m(2); 93.3 +/- 13.2 kg; mean +/- s.d.). After a 4-week lead-in period with pramlintide (180 microg b.i.d. for 2 weeks, 360 microg b.i.d. thereafter) and diet (40% calorie deficit), subjects achieving 2-8% weight loss were randomized 1:2:2 to 20 weeks of treatment with metreleptin (5 mg b.i.d.), pramlintide (360 microg b.i.d.), or pramlintide/metreleptin (360 microg/5 mg b.i.d.). Combination treatment with pramlintide/metreleptin led to significantly greater weight loss from enrollment to week 20 (-12.7 +/- 0.9%; least squares mean +/- s.e.) than treatment with pramlintide (-8.4 +/- 0.9%; P < 0.001) or metreleptin (-8.2 +/- 1.3%; P < 0.01) alone (evaluable, N = 93). The greater reduction in body weight was significant as early as week 4, and weight loss continued throughout the study, without evidence of a plateau. The most common adverse events with pramlintide/metreleptin were injection site events and nausea, which were mostly mild to moderate and decreased over time. These results support further development of pramlintide/metreleptin as a novel, integrated neurohormonal approach to obesity pharmacotherapy.

• Authors: Eric Ravussin, Steven R Smith, Julie A Mitchell, Reshma Shringarpure, Kevin Shan, Holly Maier, Joy E Koda, Christian Weyer
• Journal: Obesity (Silver Spring, Md.) (Obesity (Silver Spring)) Vol. 17 Issue 9 Pg. 1736-43 (Sep 2009) ISSN: 1930-7381 [Print] United States
• PMID: 19521351 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Amyloid
• Anti-Obesity Agents
• Drug Combinations
• Islet Amyloid Polypeptide
• LEPR protein, human
• Leptin
• Receptors, Islet Amyloid Polypeptide
• Receptors, Leptin
• Receptors, Peptide
• pramlintide
• metreleptin

Topics

• Adiposity (drug effects)
• Adult
• Amyloid (adverse effects, pharmacokinetics, therapeutic use)
• Anti-Obesity Agents (adverse effects, pharmacokinetics, therapeutic use)
• Body Mass Index
• Combined Modality Therapy
• Double-Blind Method
• Drug Combinations
• Energy Intake
• Feeding Behavior (drug effects)
• Female
• Humans
• Islet Amyloid Polypeptide
• Leptin (adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Male
• Middle Aged
• Obesity (drug therapy)
• Overweight (diet therapy, drug therapy, metabolism)
• Receptors, Islet Amyloid Polypeptide
• Receptors, Leptin (agonists, metabolism)
• Receptors, Peptide (agonists, metabolism)
• Satiation (drug effects)
• Signal Transduction (drug effects)
• Time Factors
• Treatment Outcome
• United States
• Weight Loss (drug effects)