Insulin resistance, vitamin D status, and cardiovascular risk in a general population cohort

Insulin resistance and vitamin D deficiency have each been implicated in cardiovascular disease development, yet their joint effects on major adverse cardiovascular events (MACE) remain unclear. We aimed to investigate the independent and combined associations of the triglyceride-glucose (TyG) index and serum 25-hydroxyvitamin D [25(OH)D] levels with the risk of MACE.

This retrospective analysis was conducted using data from the UK Biobank, a large prospective cohort comprising 335,206 participants who were free of cardiovascular disease at baseline. The TyG index and serum 25(OH)D concentrations were assessed at enrollment. MACE was defined as a composite of ischemic heart disease, stroke, sudden cardiac arrest, and cardiovascular mortality. Multivariable Cox proportional hazards models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Additive and multiplicative interactions were evaluated using the relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI). Population-attributable cases and excess incidence rates were also estimated.

During a median follow-up of 13.77 years, 33,532 incident MACE events occurred. After multivariable adjustment, both a higher TyG index and lower serum 25(OH)D levels were independently associated with an increased risk of MACE. Participants with concomitant high TyG (≥9.4) and vitamin D deficiency (<50 nmol/L) exhibited the highest risk (HR 1.26, 95% CI: 1.18-1.35). A significant additive interaction was observed (RERI 0.074, 95% CI 0.017-0.131; AP 0.059, 95% CI 0.014-0.104; SI 1.39, 95% CI 1.01-1.78). This joint exposure accounted for 4,369 attributable MACE cases and an excess incidence rate of 35.4 per 10,000 person-years.

Both an elevated TyG index and vitamin D deficiency are independently associated with an increased risk of MACE. Moreover, a significant statistical interaction between these factors further exacerbates cardiovascular risk in the general population. These findings identify the concomitance of insulin resistance and vitamin D deficiency as a high-risk phenotype, warranting further research to elucidate its clinical relevance.