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[Preprint]. 2023 Apr 21:2023.04.17.23288671.
doi: 10.1101/2023.04.17.23288671.

Systematic review of genotype-stratified treatment for monogenic insulin resistance

Robert K Semple  1   2 , Kashyap A Patel  3   4 , Sungyoung Auh  5 ; ADA/EASD PMDI; Rebecca J Brown  6
Affiliations

Systematic review of genotype-stratified treatment for monogenic insulin resistance

Robert K Semple et al. medRxiv. .

Update in

Abstract

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 LMNA , PPARG , AGPAT2 or BSCL2 subgroups (n=72,13,21 and 21 respectively). Body Mass Index (BMI) was lower after treatment in partial and generalised lipodystrophy overall, and in LMNA or BSCL2 , but not PPARG or AGPAT2 subgroups. Thiazolidinedione use was associated with improved hemoglobin A1c and triglycerides in aggregated lipodystrophy (n=13), improved hemoglobin A1c only in the PPARG subgroup (n=5), and improved triglycerides only in the LMNA subgroup (n=7). In INSR -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.

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Conflict of interest statement

Authors’ declaration of personal interests

R.K.S. has received speaker fees from Eli Lilly, Novo Nordisk, and Amryt. R. J. B. has received research support from Amryt, Third Rock Ventures, Ionis, and Regeneron. K.A.P. and S.A. report no conflicts of interest.

Figures

Figure 1:
Figure 1:
Flow diagram of publications evaluated based on the search strategy.
Figure 2:
Figure 2:. Effects of metreleptin in monogenic forms of lipodystrophy
Least square mean change in (A) Hemoglobin A1c (A1c), (B) Log10 serum triglyceride concentration and (C) Body Mass Index (BMI) in patients with partial lipodystrophy, generalized lipodystrophy, all forms of lipodystrophy, and subgroups with PPARG, LMNA, BSCL2, and AGPAT2 mutations.
Figure 3:
Figure 3:. Effects of recombinant human Insulin-like Growth Factor-1 (rhIGF) alone or in combination with Insulin-like Growth Factor Binding Protein-3 (IGFBP3) in patients with INSR mutations
Least square mean change in hemoglobin A1c (A1c), in all patients with INSR mutations, and in subgroups with biallelic and monoallelic mutations.
Figure 4:
Figure 4:. Effects of thiazolidinediones in monogenic forms of lipodystrophy
Least square mean change in (A) Hemoglobin A1c (A1c), (B) Log10 serum triglyceride concentration and (C) Body Mass Index (BMI) in patients with partial lipodystrophy, generalized lipodystrophy, all forms of lipodystrophy, and subgroups with PPARG, and LMNA mutations.
See this image and copyright information in PMC

References

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