Long-term effectiveness and safety of metreleptin in the treatment of patients with partial lipodystrophy

Abstract

Purpose: To evaluate the effects of metreleptin in patients with partial lipodystrophy (PL).Methods: Patients aged ≥6 months with PL, circulating leptin <12.0 ng/mL, and diabetes mellitus, insulin resistance, or hypertriglyceridemia received metreleptin doses (once or twice daily) titrated to a mean of 0.124 mg/kg/day. Changes from baseline to month 12 in glycated hemoglobin (HbA1c) and fasting serum triglycerides (TGs; coprimary endpoints), fasting plasma glucose (FPG), and liver volume were evaluated. Additional assessments included the proportions of patients achieving target decreases in HbA1c or fasting TGs at month 12, long-term treatment effects, and treatment-emergent adverse events (TEAEs).Results: Significant (p<0.05) reductions in HbA1c (−0.6%), fasting TGs (−20.8%), FPG (−1.2 mmol/L), and liver volume (−13.4%) were observed in the overall PL population at month 12. In a subgroup of patients with baseline HbA1c ≥6.5% or TGs ≥5.65 mmol/L, significant (p<0.05) reductions were seen in HbA1c (−0.9%), fasting TGs (−37.4%), FPG (−1.9 mmol/L), and liver volume (−12.4%). In this subgroup, 67.9% of patients had a ≥1% decrease in HbA1c or ≥30%

Metreleptin in lipodystrophy: a profile of its use

“…Similar to patients with generalized LD, these benefits were more notable in the partial LD patients with higher baseline HbA 1C or triglyceride levels (Table 2) [8,29]. Consistent with these findings, some partial LD metreleptin recipients achieved a metabolic response, including 51.4% of the overall population and 67.9% of the patient subgroup with baseline HbA 1C ≥ 6.5% or triglyceride ≥ 5.65 mmol/L [29].…”

“…Metreleptin therapy for 12 months was associated with significant reductions in liver volume in the integrated Table 2 Efficacy of metreleptin after 12 months of treatment in patients with lipodystrophy in an integrated analysis of a pilot study and its long-term extension Weighted average daily metreleptin dose in first 12 months differed between the generalized lipodystrophy (2.6 or 5.3 mg in males and females weighing > 40 kg; 2.0 or 2.3 mg in males and females weighing ≤ 40 kg) and partial lipodystrophy (7.0 mg in males and females weighing > 40 kg) groups BL baseline, HbA 1C glycosylated haemoglobin, pt(s) patients(s) *p < 0.05, **p ≤ 0.005, ***p ≤ 0.001 vs BL a At BL, the median fasting leptin levels was 1 ng/mL [8] b Pts evaluated for HbA 1C ; number of pts evaluated for fasting TG was generally similar c p value obtained from an additional source [39] d The mean fasting leptin level at BL was 6-7 ng/mL [8] Pt analysis [− 13.4% in overall population (n = 9); − 12.4% in subgroup with baseline HbA 1C ≥ 6.5% or triglyceride ≥ 5.65 mmol/L (n = 8)], although liver enzyme levels were not significantly altered [29]. Notably, in an analysis of data from two clinical trials in patients with partial LD and NAFLD, 9 of the 18 patients who completed 12 months' treatment with metreleptin achieved a clinical hepatic response (i.e.…”

“…None of the 19 patients receiving insulin at baseline were able to discontinue it once receiving metreleptin, although 1 of 28 patients receiving oral glucose-lowering medications at baseline, and 1 of 34 patients receiving lipid-lowering medications at baseline, discontinued these therapies once receiving metreleptin [29].…”

“…Metreleptin improved glycaemic control and hypertriglyceridaemia in patients aged ≥ 6 months (overall median age 34 years) with partial LD in the integrated analysis of the pilot/extension study, significantly reducing levels of HbA 1C and triglycerides over 12 months of treatment (co-primary endpoints) in the overall patient population and each of the patient subgroups assessed (Table 2) [8,29]. Similar to patients with generalized LD, these benefits were more notable in the partial LD patients with higher baseline HbA 1C or triglyceride levels (Table 2) [8,29]. Consistent with these findings, some partial LD metreleptin recipients achieved a metabolic response, including 51.4% of the overall population and 67.9% of the patient subgroup with baseline HbA 1C ≥ 6.5% or triglyceride ≥ 5.65 mmol/L [29].…”

Acquired generalized lipodystrophy under immune checkpoint inhibition

“…Other classes of immunosuppressive agents were not used in our patient because of the lack of supportive data on acquired generalized lipodystrophy. Treatment with metreleptin, a recombinant analogue of human leptin approved for the management of metabolic complications associated with lipodystrophy, was discussed but was not available at the time of patient care. As lipodystrophy is still ongoing 12 months after pembrolizumab discontinuation, we may wonder whether its use would have been a better option.…”