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A Randomized, Controlled, Dose-Escalation Trial

Steven B. Heymsfield, MD; Andrew S. Greenberg, MD; Ken Fujioka, MD; Russell M. Dixon, MD; Robert Kushner, MD; Thomas Hunt, MD; John A. Lubina, PhD; Janet Patane, MPH; Barbara Self, MPH; Pam Hunt, PhD; Mark McCamish, PhD, MD

JAMA. 1999;282:1568-1575.

Context  The protein hormone leptin is important to the homeostatic regulation of body weight. Treatment with exogenous leptin may affect weight loss.

Objective  To determine the relationship between increasing doses of exogenous leptin administration and weight loss in both lean and obese adults.

Design  A randomized, double-blind, placebo-controlled, multicenter, escalating dose cohort trial conducted from April 1997 to October 1998.

Setting  Four university nutrition and obesity clinics and 2 contract clinical research clinics.

Participants  Fifty-four lean (body mass index, 20.0-27.5 kg/m²; mean [SD] body weight, 72.0 [9.7] kg) and 73 obese (body mass index, 27.6-36.0 kg/m²; mean [SD] body weight, 89.8 [11.4] kg) predominantly white (80%) men (n = 67) and women (n = 60) with mean (SD) age of 39 (10.3) years.

Interventions  Recombinant methionyl human leptin self-administered by daily morning subcutaneous injection (0 [placebo], 0.01, 0.03, 0.10, or 0.30 mg/kg). In part A, lean and obese subjects were treated for 4 weeks; in part B, obese subjects were treated for an additional 20 weeks. Lean subjects consumed a eucaloric diet to maintain body weight at the current value, and obese subjects were prescribed a diet that reduced their daily energy intake by 2100 kJ/d (500-kcal/d) from the amount needed to maintain a stable weight.

Main Outcome Measures  Body weight, body fat, and incidence of adverse events.

Results  Weight loss from baseline increased with increasing dose of leptin among all subjects at 4 weeks (P = .02) and among obese subjects at 24 weeks (P = .01) of treatment. Mean (SD) weight changes at 4 weeks ranged from -0.4 (2.0) kg for placebo (n = 36) to -1.9 kg (1.6) kg for the 0.1 mg/kg dose (n = 29). Mean (SD) weight changes at 24 weeks ranged from -0.7 (5.4) kg for the 0.01 mg/kg dose (n = 6) to –7.1 (8.5) kg for the 0.30 mg/kg dose (n = 8). Fat mass declined from baseline as dose increased among all subjects at 4 weeks (P = .002) and among obese subjects at 24 weeks of treatment (P = .004); more than 95% of weight loss was fat loss in the 2 highest dose cohorts at 24 weeks. Baseline serum leptin concentrations were not related to weight loss at week 4 (P = .88) or at week 24 (P = .76). No clinically significant adverse effects were observed on major organ systems. Mild-to-moderate reactions at the injection site were the most commonly reported adverse effects.

Conclusions  A dose-response relationship with weight and fat loss was observed with subcutaneous recombinant leptin injections in both lean and obese subjects. Based on this study, administration of exogenous leptin appears to induce weight loss in some obese subjects with elevated endogenous serum leptin concentrations. Additional research into the potential role for leptin and related hormones in the treatment of human obesity is warranted.

Author Affiliations: Weight Control Unit, St Luke's-Roosevelt Hospital, New York, NY (Dr Heymsfield); Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, New England Medical Center, Boston, Mass (Dr Greenberg); Scripps Clinic, San Diego, Calif (Dr Fujioka); Covance Inc and University of Wisconsin, Madison (Dr Dixon); Northwestern University, Chicago, Ill (Dr Kushner); and PPD Pharmaco Inc, Austin, Tex (Dr T. Hunt); and Departments of Biostatistics (Dr Lubina), Clinical Affairs (Ms Patane), International Clinical Safety (Ms Self), Product Development (Dr P. Hunt), and Clinical Research (Dr McCamish), Amgen Inc, Thousand Oaks, Calif.

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