Fasting insulin predicts cardiovascular mortality in pre-diabetes and remains elevated across type 2 diabetes: An NHANES 2007-2018 cohort analysis

Background. Cardiovascular disease accounts for most mortality in type 2 diabetes (T2D), yet treatment is anchored on glucose-derived metrics and fasting insulin is rarely measured. We tested whether fasting insulin carries cardiovascular-mortality information across the dysglycaemic spectrum and approaches non-diabetic levels with longer oral-therapy T2D duration. Methods and Findings. We analysed six NHANES cycles [2007-2018] linked to National Death Index follow-up through 2019. Baseline characteristics were described in participants with complete kidney-function data: normoglycaemic (n = 2,913), pre-diabetes (n = 3,993), and oral-therapy T2D (n = 1,381). Survey-weighted Cox models used the covariate-complete mortality sample (pre-diabetes n = 4,019; oral-therapy T2D n = 1,387) and adjusted for age, sex, race/ethnicity, BMI, smoking, physical activity, education, poverty:income ratio, and insulin assay generation. Per +1 natural-log-unit fasting insulin, all-cause hazard ratios (HRs) were 1.69 (95% CI 1.14-2.50; P = 0.008) in pre-diabetes and 0.71 (0.51-0.98; P = 0.039) in oral-therapy T2D; cardiovascular HRs were 3.09 (1.69-5.63; P < 0.001) and 0.50 (0.26-0.99; P = 0.046), respectively. Cancer mortality was not associated with fasting insulin. In oral-therapy T2D, geometric-mean fasting insulin remained 1.6- to 2.3-fold the normoglycaemic referent across duration bands. After BMI adjustment, fasting insulin declined during the first five years (-4.0%/year, P = 0.018) and was flat thereafter (-0.1%/year, P = 0.66). Conclusions. Fasting insulin predicted cardiovascular mortality in pre-diabetes. In oral-therapy T2D, the inverse association was most consistent with survivor effects and accumulated renal and vascular damage. Fasting insulin remained above normoglycaemic levels throughout treated T2D.