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/m2; 93.3 ± 13.2 kg; mean ± s.d.). After a 4‐week lead‐in period with pramlintide (180 µg b.i.d. for 2 weeks, 360 µg 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 µg b.i.d.), or pramlintide/metreleptin (360 µg/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.

Amylin-induced downregulation of hippocampal neurogenesis is attenuated by leptin in a STAT3/AMPK/ERK-dependent manner in mice

“…The physiological effects of amylin receptor agonism include decreased food intake [4] and reduction of postprandial glucagon release in a glucose-dependent manner [5]. Moreover, it has been proposed that a combination of amylin and leptin may be more effective than leptin or amylin alone for treatment of obesity in both animals [2] and humans [5]. Adiponectin, the most abundant adipokine in circulation, is synthesised and secreted by adipose tissue [6].…”

“…Amylin is a 37-amino-acid peptide hormone that is co-secreted with insulin from pancreatic beta cells [4]. The physiological effects of amylin receptor agonism include decreased food intake [4] and reduction of postprandial glucagon release in a glucose-dependent manner [5]. Moreover, it has been proposed that a combination of amylin and leptin may be more effective than leptin or amylin alone for treatment of obesity in both animals [2] and humans [5].…”

The effect of leptin, caffeine/ephedrine, and their combination upon visceral fat mass and weight loss

“…There has also been interest in combining leptin with other therapeutic drugs to induce weight loss. Amylin and Takeda were pursuing the combination of pramlintide and metreleptin as an anti-obesity therapy, and the combination showed promising results in early clinical trials (17). However, in 2011, phase II clinical trials were halted and the program was discontinued after patients reportedly developed antibodies to metreleptin.…”

Medical Therapy for Obesity

“…45 The combination of leptin with pramlintide, however, produced additive weight loss in a 6-month clinical trial that may offer promise for the future. 46 Clinical trials have shown weight-loss results with leptin alone to be disappointing, but a 6-month trial combining leptin with pramlintide produced an additive weight loss that may offer promise for the future.…”