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, 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 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 (PLD; n=71) and generalised lipodystrophy (GLD (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 PLD and GLD overall, and in LMNA or BSCL2, but not PPARG or AGPAT2 subgroups. TZD 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=XX). In INSR-related IR, use of rhIGF-1, alone or with IGFBP3, was associated with improved HbA1c (n=15). The small size or absence of all other genotype x treatment combinations precluded firm conclusions. Conclusions: The evidence guiding genotype-specific treatment of monogenic IR is of low to very low quality. Metreleptin and TZDs appear to have beneficial metabolic effects in lipodystrophy, and rhIGF-1 appears to lower HbA1c in INSR-related IR. For other interventions there is insufficient evidence to assess efficacy and risks either in aggregated lipodystrophy or in genetic subgroups of IR. There is a pressing need to improve the evidence base for management of monogenic IR. ### Competing Interest Statement 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. ### Funding Statement R.K.S. is supported by the Wellcome Trust (grant WT 210752). R.J.B and S.A. are supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases. K.A.P. is funded by Wellcome Trust (219606/Z/19/Z). The ADA/EASD Precision Diabetes Medicine Initiative, within which this work was conducted, has received the following support: The Covidence license was funded by Lund University (Sweden) for which technical support was provided by Maria Bjorklund and Krister Aronsson (Faculty of Medicine Library, Lund University, Sweden). Administrative support was provided by Lund University (Malmo, Sweden), University of Chicago (IL, USA), and the American Diabetes Association (Washington D.C., USA). The Novo Nordisk Foundation (Hellerup, Denmark) provided grant support for in-person writing group meetings (PI: L Phillipson, University of Chicago, IL). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Not applicable