Long-term effects of metreleptin in Rabson-Mendenhall Syndrome on glycemia, growth, and kidney function.

CONTEXT Rabson-Mendenhall syndrome (RMS) is caused by biallelic pathogenic variants in the insulin receptor gene (INSR) leading to insulin-resistant diabetes, microvascular complications, and growth hormone resistance with short stature. Small, uncontrolled studies suggest that one year treatment with recombinant leptin (metreleptin) improves glycemia in RMS. OBJECTIVE Determine effects of long-term metreleptin in RMS on glycemia, anthropometrics, the growth hormone axis, and kidney function. DESIGN/PARTICIPANTS/INTERVENTION/SETTING Comparison of patients with RMS during non-randomized open-label treatment with metreleptin (≥0.15 mg/kg/day) versus no metreleptin over 90 months (5 subjects in both groups at different times, 4 only in metreleptin group, 2 only in control group). MAIN OUTCOME MEASURE(S) A1c; glucose; insulin; 24-hour urine glucose; standard deviation scores (SDS) for height, weight, BMI, and IGF-1; growth hormone (GH), estimated glomerular filtration rate. RESULTS Over time, metreleptin-treated subjects maintained 1.8 percentage point lower A1c vs controls (P=0.007), which remained significant after accounting for changes in insulin doses. Metreleptin-treated subjects had a reduction in BMI SDS, which predicted decreased A1c. GH increased after metreleptin treatment vs. control, with no difference in SDS between groups for IGF-1 or height. Reduced BMI predicted higher GH, while reduced A1c predicted higher IGF-1. CONCLUSIONS Metreleptin alters the natural history of rising A1c in RMS, leading to lower A1c throughout long-term follow-up. Improved glycemia with metreleptin is likely attributable to appetite suppression and lower BMI SDS. Lower BMI after metreleptin may also worsen growth hormone resistance in RMS, resulting in a null effect on IGF-1 and growth despite improved glycemia.