Systematic review of genotype-stratified treatment for monogenic insulin resistance.

OBJECTIVE

To assess the effects of pharmacologic and/or surgical interventions in monogenic insulin resistance (IR), stratified by genetic aetiology.

DESIGN

Systematic review.

DATA SOURCES

PubMed, MEDLINE and Embase, from 1 January 1987 to 23 June 2021.

REVIEW METHODS

Studies reporting individual-level effects of pharmacologic and/or surgical interventions in monogenic IR were eligible. Individual subject data were extracted and duplicate data removed. Outcomes were analyzed for each affected gene and intervention, and in aggregate for partial, generalised and all lipodystrophy.

RESULTS

10 non-randomised experimental studies, 8 case series, and 21 single case reports met inclusion criteria, all rated as having moderate or serious risk of bias. Metreleptin was associated with lower triglycerides and hemoglobin A1c in aggregated lipodystrophy (n=111), in partial lipodystrophy (n=71) and generalised lipodystrophy (n=41)), and in , , or subgroups (n=72,13,21 and 21 respectively). Body Mass Index (BMI) was lower after treatment in partial and generalised lipodystrophy overall, and in , but not or subgroups. Thiazolidinedione use was associated with improved hemoglobin A1c and triglycerides in aggregated lipodystrophy (n=13), improved hemoglobin A1c only in the subgroup (n=5), and improved triglycerides only in the subgroup (n=7). In -related IR, use of rhIGF-1, alone or with IGFBP3, was associated with improved hemoglobin A1c (n=15). The small size or absence of all other genotype-treatment combinations precluded firm conclusions.

CONCLUSIONS

The evidence guiding genotype-specific treatment of monogenic IR is of low to very low quality. Metreleptin and Thiazolidinediones appear to have beneficial metabolic effects in lipodystrophy, and rhIGF-1 appears to lower hemoglobin A1c in INSR-related IR. For other interventions there is insufficient evidence to assess efficacy and risks either in aggregated lipodystrophy or in genetic subgroups. There is a pressing need to improve the evidence base for management of monogenic IR.