FRI117 Major Adverse Cardiovascular Events In Severe Insulin Resistance Syndromes: Lipodystrophy Compared To Pathogenic Variants Of The Insulin Receptor
Authors: Lightbourne Marissa , Brown Rebecca J 
Published: October 2023

Abstract
Disclosure: M. Lightbourne: None. R.J. Brown: None.
Patients with insulin resistance (IR) associated with obesity and/or type 2 diabetes have increased atherosclerotic cardiovascular disease (ASCVD) risk. Rare, syndromic forms of severe IR (SIR) exist, in which ASCVD risk is not established. SIR can be classified into post-receptor IR, where insulin signaling is increased in some signaling pathways, and decreased in others (i.e. lipodystrophy) or receptor IR, where all insulin signaling is blocked at the insulin receptor (i.e. insulin receptor pathogenic variants, INSR). These differences in insulin signaling associate with differences in ASCVD risk factors, i.e. dyslipidemia and uric acid (high in lipodystrophy, low in INSR), but the incidence of ASCVD in these population is unknown. We hypothesized that patients with post-receptor IR due to lipodystrophy would have more major adverse cardiovascular events (MACE) vs those with receptor IR due to INSR. This is a retrospective chart review of patients with lipodystrophy and INSR aged ≥18 years. Our primary outcome was incidence of MACE (composite of cardiovascular death, non-fatal myocardial infarction, ischemic stroke and hospitalization for unstable angina, heart failure or revascularization). Patients with INSR (n=24) were younger than those with lipodystrophy (n=241) (32 ± 12 vs 40 ± 15 years, p=0.02) at first MACE or last follow-up. 62% of patients with INSR were female vs 82% with lipodystrophy (p=0.02); 50% with INSR were white vs 75% with lipodystrophy (p=0.0098). Of patients with lipodystrophy, 153 had partial, 79 had generalized, and 9 had progeroid forms of lipodystrophy. Nine patients with INSR had homozygous or compound heterozygous variants and 15 had heterozygous variants. MACE occurred in 33 patients with lipodystrophy (5 generalized, 24 partial, 4 progeroid; age 42.6 ± 12.7 years) and in 0 patients with INSR with a Hazard Ratio of 2.9 (95% CI 0.6-14.5, P=0.2). In patients with lipodystrophy, 9 patients had cardiovascular deaths (mean age 32.4 ± 15.4 years, 3 with progeroid syndromes); 11 had non-fatal myocardial infarcts with 2 patients having recurrent events; 8 were hospitalized for strokes or transient ischemic attacks; 12 were hospitalized for coronary revascularization with 7 patients having recurrent events; 5 were hospitalized due to heart failure. In addition to MACE, 4 patients with lipodystrophy had peripheral revascularization or amputation vs 0 with INSR. MACE events did not occur in patients with INSR and were highly prevalent at a young age in patients with lipodystrophy, suggesting higher risk of MACE in lipodystrophy. There was no statistical difference for MACE events between the 2 groups; however, statistical power was limited by the small sample size and young age of patients INSR. These data suggest that contributions from both increased and decreased insulin signal transduction in patients with post-receptor IR may lead to increased ASCVD risk.
Presentation: Friday, June 16, 2023