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

Obesity (Silver Spring). 2009 Sep;17(9):1736-43. doi: 10.1038/oby.2009.184. Epub 2009 Jun 11.

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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adiposity / drug effects
  • Adult
  • Amyloid / adverse effects
  • Amyloid / pharmacokinetics
  • Amyloid / therapeutic use*
  • Anti-Obesity Agents / adverse effects
  • Anti-Obesity Agents / pharmacokinetics
  • Anti-Obesity Agents / 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
  • Leptin / analogs & derivatives*
  • Leptin / pharmacokinetics
  • Leptin / therapeutic use
  • Male
  • Middle Aged
  • Obesity / drug therapy*
  • Overweight / diet therapy
  • Overweight / drug therapy*
  • Overweight / metabolism
  • Receptors, Islet Amyloid Polypeptide
  • Receptors, Leptin / agonists
  • Receptors, Leptin / metabolism
  • Receptors, Peptide / agonists
  • Receptors, Peptide / metabolism
  • Satiation / drug effects
  • Signal Transduction / drug effects
  • Time Factors
  • Treatment Outcome
  • United States
  • Weight Loss / drug effects*

Substances

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