SAT-583 - High Predicted Cardiovascular Event Risk in Patients with Lipodystrophy Versus Pathogenic Insulin Receptor Variants

Insulin resistance (IR) is associated with cardiovascular disease (CVD). Previously, we found that patients with youth-onset type 2 diabetes have IR and high predicted CVD risk based on the International Childhood Cardiovascular Cohort (i3C) combined-risk Z-score and hazard ratio (HR), which predict 35-year risk of adult CVD events. Syndromes of severe IR include lipodystrophy (LD) and insulin receptor gene (INSR). In LD, IR is pathway selective, meaning insulin signaling is increased in some signal transduction pathways and decreased in others, whereas in INSR, rare mutations of the INSR gene block all insulin signal transduction pathways. CVD risk in these patients is not well-established. We hypothesized that patients with LD would have increased CVD risk assessed by the i3C Z-score compared to those with INSR due to differences in insulin signal transduction.
We performed a retrospective chart review of patients with LD and INSR aged 4-40 years. CVD risk was evaluated using the i3C combined risk Z-score and estimated HR equations [1] which incorporate body mass index (BMI), systolic blood pressure (SBP), smoking history, fasting total cholesterol (TC) and fasting total triglyceride levels (TG).
Patients with LD (n=51) were older than INSR (n=34) (23.2±9.6 vs 15.0±8.8 years, mean±SD; p=0.0001). Among patients with LD, 49% had partial and 51% had generalized LD. Among patients with INSR, 52% had biallelic and 48% had monoallelic variants. Both groups were predominantly white females with elevated A1c (LD 8.2 [6.1,9.6], INSR 7.1 [5.7,9.6] %, median, [25th-75th percentile]; p= 0.6). Patients with LD had higher i3C z-scores compared to INSR (1.1 [0.58,2.15] vs -0.09 [-0.44,0.21]; p< 0.0001]. Patients with LD had higher i3C HR compared to INSR (3.04 [1.80,8.78] vs 0.91 [0.64,1.24]; p< 0.0001). Compared to INSR, patients with LD had higher TC (191 [138,242] vs 148 [130,185] mg/dL; p=0.004), higher TG (360 [203,1211] vs 69 [49,82] mg/dL; p< 0.0001), elevated SBP (128.3±14.34 vs 111.6±10.87 mmHg; p< 0.0001), and higher BMI (23 [20,28] vs 18 [15,23] kg/m2; p=0.0008).
Higher i3C z-score and HR in LD compared to INSR suggest increased CVD risk in persons with pathway selective IR. The increased risk is consistent with a more atherogenic lipid profile, higher SBP and higher BMI. These findings suggest that pathway selective IR imposes greater risk of adverse CVD events later in life. Further studies are needed to evaluate the utility of i3C risk assessment and CVD prevention paradigms for such patient populations.
1. Malandrino N, Davis FS, Glaros SB, et al. High predicted cardiac event risk in youth with obesity and type 2 diabetes: a pooled cohort analysis. Cardiovasc Diabetol. Oct 24 2025;24(1):405. doi:10.1186/s12933-025-02951-x.

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