Enhanced Weight Loss With Pramlintide/Metreleptin: An Integrated Neurohormonal Approach to Obesity Pharmacotherapy

被引:245
作者
Ravussin, Eric [2 ]
Smith, Steven R. [2 ]
Mitchell, Julie A. [1 ]
Shringarpure, Reshma [1 ]
Shan, Kevin [1 ]
Maier, Holly [1 ]
Koda, Joy E. [1 ]
Weyer, Christian [1 ]
机构
[1] Amylin Pharmaceut Inc, San Diego, CA USA
[2] Pennington Biomed Res Ctr, Baton Rouge, LA USA
关键词
CONGENITAL LEPTIN DEFICIENCY; DIET-INDUCED OBESITY; FOOD-INTAKE; GENERALIZED LIPODYSTROPHY; PRAMLINTIDE TREATMENT; REPLACEMENT THERAPY; RECOMBINANT LEPTIN; ENERGY-EXPENDITURE; SKELETAL-MUSCLE; DOSE-ESCALATION;
D O I
10.1038/oby.2009.184
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 mu g b.i.d. for 2 weeks, 360 mu g 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 mu g b.i.d.), or pramlintide/metreleptin (360 mu g/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.
引用
收藏
页码:1736 / 1743
页数:8
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