Clinical effects of long-term metreleptin treatment in patients with lipodystrophy

Abstract

Objective: To evaluate the long-term clinical effect of treatment with metreleptin (an analogue of human leptin) on glycemic and lipid abnormalities and markers of hepatic steatosis in patients with inherited or acquired lipodystrophy.

Methods: Fifty-five patients (36 with generalized lipodystrophy and 19 with partial lipodystrophy) with at least 1 of 3 metabolic abnormalities (diabetes mellitus, fasting triglyceride level ≥200 mg/dL, and insulin resistance) and low leptin levels received subcutaneous injections of metreleptin once or twice daily in an ongoing clinical trial at the National Institutes of Health.

Results: At baseline, hemoglobin A1c-8.5% ± 2.1% (mean ± standard deviation [SD])-and triglycerides-479 ± 80 mg/dL (geometric mean ± standard error [SE])-were substantially elevated. Robust and sustained reductions in both variables were evident for the observed patient population during a 3-year metreleptin treatment period (-2.1% ± 0.5% [mean ± SE] and -35.4% ± 13.7% [mean ± SE], respectively). Mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated at baseline (100 ± 120 U/L and 71 ± 77 U/L [mean ± SD], respectively) and decreased by -45 ± 19 U/L and -33 ± 14 U/L (mean ± SE), respectively, during the 3-year metreleptin treatment period. Improvements in hemoglobin A1c, triglycerides, ALT, and AST were more pronounced in the subsets of patients having elevated levels at baseline. The most notable adverse events observed in this patient population were likely attributable to underlying metabolic abnormalities or comorbidities.

Conclusion: Metreleptin treatment substantially reduced glycemic variables, triglycerides, and liver enzymes (ALT and AST) and demonstrated durability of response throughout a 3-year treatment period. These results support metreleptin as a potential treatment for certain metabolic disorders (for example, diabetes mellitus and hypertriglyceridemia) associated with lipodystrophy.

Trial registration: ClinicalTrials.gov NCT00025883.

Figures

Fig. 1

Effect of metreleptin treatment on hemoglobin A1c (A1C) during a 3-year treatment period. A, Effect of metreleptin on A1C over time (observed population). A decline in A1C was observed 4 months after the initiation of metreleptin treatment, and A1C continued to decrease during the 3-year treatment period. B, In patients with elevated baseline A1C, metreleptin treatment substantially lowered A1C throughout the treatment period, achieving a mean A1C of 6.3% ± 0.3% at the end of the 3-year treatment period. The dashed line in both figures denotes a common treatment goal for glucose control (A1C 7%). SE = standard error.

Fig. 2

Effect of metreleptin treatment on triglycerides during a 3-year treatment period. A, Metreleptin treatment substantially improved geometric mean triglyceride concentrations during the 3-year treatment period in the observed population, achieving a geometric mean ± standard error (SE) concentration of 164 ± 26 mg/dL. B, In patients with elevated triglyceride levels at baseline (n = 41), metreleptin treatment substantially lowered triglyceride concentrations throughout the treatment period, achieving a geometric mean ± SE concentration of 197 ± 35 mg/dL at the end of the 3-year treatment period. The dashed line in both figures denotes a common criterion for hypertriglyceridemia of 200 mg/dL.

Fig. 3

Effect of metreleptin treatment on alanine aminotransferase (ALT) during a 3-year treatment period. A, A rapid decline in ALT concentrations was observed after 4 months of metreleptin treatment, after which the ALT concentrations were sustained during the 3-year study period. B, In patients with elevated ALT concentrations at baseline, an initial reduction at 4 months of metreleptin treatment was observed, and patients achieved further reductions after 3 years of treatment. The dashed line in both figures denotes the upper limit of normal for ALT of 41 U/L in this assay. SE = standard error.

Fig. 4

Effect of metreleptin treatment on aspartate aminotransferase (AST) during a 3-year treatment period. A, A robust decline in AST concentration was observed after 4 months of treatment. The reduction was sustained throughout 3 years. B, In patients with elevated AST concentrations at baseline, an initial reduction at 4 months of metreleptin treatment was observed, and patients achieved further reductions after 3 years of treatment. The dashed line in both figures denotes the upper limit of normal for AST of 34 U/L in this assay. SE = standard error.