Leptin for Weight Loss
Abstract & commentary
Source: Jacobsen FM, et al. Recombinant leptin for weight loss in obese and lean adults: A randomized, controlled, dose-escalation trial. JAMA 1999;282:1568-1575.
An association between peptide, the hormone leptin, and obesity has been established in recent years. Specifically, obese individuals are noted to have higher serum levels of leptin compared to lean individuals. Extrapolating from compelling animal studies, investigators hypothesized that leptin may play a compensatory role to reverse adiposity, and that exogenous administration of recombinant methionyl leptin would induce a homeostatic regulation of caloric intake and energy consumption, resulting in a dose-dependent weight loss in both lean and obese healthy adults.
The hypothesis was tested by monitoring body weight and composition changes among subjects randomly assigned to escalating dose groups of recombinant methionyl human leptin (rL) or matching placebo (pH-adjusted solution of sorbitol and sodium acetate). The study drug was given by subcutaneous bolus injections (0.01, 0.03, 0.10, or 0.30 mg/kg/d or placebo) to lean subjects whose body mass index (BMI) was 20.0-27.5 kg/m2 and to obese subjects whose BMI was 27.6-36.0 kg/m2. The first phase of the study (part A) involved both lean and obese patients and was continued for four weeks. Because the long-term safety of rL has not been established and lean subjects should not incur weight loss for long periods of time, only obese subjects continued into the second phase of the study, continuing treatment for another 20 weeks (part B). Subjects with drug-treated diabetes, hyperlipidemia, hypertension, and other medical illnesses commonly associated with obesity were excluded from the trial. The primary efficacy variable was body weight; other outcome variables included body composition (i.e., fat mass and lean mass), as measured by dual X-ray absorptiometry. Lean subjects were maintained on a diet that maintains current body weight and obese subjects were prescribed a diet that reduced their daily energy intake by 500 kcal/d. Three-day food intake diaries were used to monitor subject adherence to the diet. Obese subjects were encouraged to walk briskly for 20-30 minutes, 3-5 times per week. Blinded study drug (placebo and rL) was self-administered subcutaneously once daily before 11 a.m. In addition to multiple safety measures such as physical exams and electrocardiograms, subjects received an oral glucose tolerance test at baseline and at the end of parts A and B.
Of the 274 subjects screened for the study, 147 were ineligible and 127 were randomized. The mean body weight of the 54 lean subjects was 72.0 kg and was 89.8 kg for the 73 obese subjects. Sixty of the 70 obese subjects who completed part A continued into part B. Absolute weight changes across the doses for part A averaged between -0.4 and -1.9 kg, while weight changes in part B averaged between -0.7 and -7.1 kg, with the greatest average weight loss in the highest dose cohort. The study also reported statistically significant differences across dose, establishing a dose-response relationship of rL in obese patients. Most of the weight loss in the study was attributable to a loss of fat mass.
Injection site reactions (ISRs) such as erythema, pruritus, or inflammation were mild (86%) to moderate (14%) in severity and were the most common adverse events are reported. Although ISRs were generally well tolerated by most subjects, two patients withdrew from the trial as a result of ISRs. Additionally, a cohort of patients who received 0.3 mg/kg/d of rL in higher concentrations experienced intolerable ISRs, causing a halt enrollment. Those patients were excluded from analysis in this report. The next most common adverse event was headache, which occurred in 38% and 44% of the placebo- and rL-treated subjects, respectively. No other medically important adverse effects were reported.
Comment by Michael F. Barber, pharmD
There are numerous reports in the literature that document the health hazards associated with obesity as well as the benefit of weight reduction. While front-line management of obesity for most adults should consist of dietary modifications in addition to exercise, such regimens may fall short of expectations in many patients for a variety of reasons. In such patients, more aggressive interventions such as pharmacotherapy should be considered. However, the risks of pharmacotherapy and long-term safety data are often not well-defined, as demonstrated by the recent problems with the combined use of phentermine and fenfluramine. The current study provides provocative yet preliminary data. Weight loss was more pronounced after 24 weeks compared to four weeks, suggesting that this effect is not transient and quickly reversed. At this time, it would not appear that the rL should be broadly prescribed for weight loss since its role is not clearly defined. More data are needed to warrant its use, including long-term safety, use in patients with comorbid illnesses such as diabetes, and quantification of its beneficial effect on health. In addition, rL therapy is likely to be expensive and difficult for patients to administer, requiring daily subcutaneous injections, which can be painful and irritating. While rL therapy represents an exciting potential option in the management of obesity, its use at this time is still experimental.
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