Metreleptin improves blood glucose in patients with insulin receptor mutations

Abstract

Context: Rabson-Mendenhall syndrome (RMS) is caused by mutations of the insulin receptor and results in extreme insulin resistance and dysglycemia. Hyperglycemia in RMS is very difficult to treat, and patients are at risk for early morbidity and mortality from complications of diabetes.

Objective: Our objective was to study 1-year effects of recombinant human methionyl leptin (metreleptin) in 5 patients with RMS and 10-year effects in 2 of these patients.

Design and setting: We conducted an open-label nonrandomized study at the National Institutes of Health.

Patients: Patients were adolescents with RMS and poorly controlled diabetes.

Intervention: Two patients were treated with escalating doses (0.02 up to 0.22 mg/kg/d) of metreleptin for 10 years, including 3 cycles of metreleptin withdrawal and reinitiation. In all 5 patients, 1-year effects of metreleptin (0.22 mg/kg/d) were studied.

Outcome measures: Hemoglobin A1c (HbA1c) and body mass index (BMI) z-scores were evaluated every 6 months.

Results: HbA1c decreased from 11.4% ± 1.1% at baseline to 9.3% ± 1.9% after 6 months and 9.7% ± 1.6% after 12 months of metreleptin (P = .007). In patients treated for 10 years, HbA1c declined with each cycle of metreleptin and rose with each withdrawal. BMI z-scores declined from -1.4 ± 1.8 at baseline, to -2.6 ± 1.6 after 12 months of metreleptin (P = .0006). Changes in BMI z-score correlated with changes in HbA1c (P < .0001).

Conclusions: Metreleptin treatment for 12 months was associated with a 1.7% reduction in HbA1c; part of this improvement was likely mediated via decreased BMI. Metreleptin is a promising treatment option for RMS, but additional therapies are needed to achieve HbA1c targets.

Trial registration: ClinicalTrials.gov NCT00085982.

Figure 1.

Metreleptin doses (gray shaded area), HbA1c (blue triangles), and insulin dose (red inverted triangles) in 2 siblings with RMS treated with metreleptin for 10 years. Metreleptin was initiated at doses of 0.02 to 0.03 mg/kg/d, and gradually titrated up over 6 months to 0.06–0.09 mg/kg/d. After the 10-month pilot study ended, metreleptin was withdrawn for 10 months and subsequently restarted at doses of 0.06 to 0.09 mg/kg/d for 18 months. After a second withdrawal period of 1 to 3 months, these patients restarted metreleptin, and the doses were gradually increased over 2.5 years to a maximum of 0.22 to 0.24 mg/kg/d. After 5 years of continuous metreleptin treatment, a third withdrawal of 2.5 months was performed, followed by reinitiation of metreleptin at the previous doses and another 2 years of follow-up to date. Periods of metreleptin initiation or dose increase were generally associated with reductions in HbA1c, whereas HbA1c rose during periods of metreleptin withdrawal (black arrows).

Figure 2.

A, Effects of 1 year of high-dose metreleptin in 5 patients with RMS. HbA1c decreased from 11.4% to 9.7% (P = .007). B, OGTTs showed a significant decline in glucose AUC (black circles with solid line, P = .01) and no change in insulin (black squares with dashed line) or C-peptide (open triangles with dotted line) AUC. C and D, BMI z-scores (C) decreased from −1.4 to −2.5 (P = .0006), and percent body fat (D) declined from 20.5% to 16.1% (P = .14).