Estimated glucose disposal rate and lipoprotein(a) as complementary markers of cardiovascular risk in the UK Biobank

Estimated glucose disposal rate (eGDR) summarizes waist circumference, hypertension, and glycated hemoglobin, whereas lipoprotein(a) [Lp(a)] reflects a largely inherited atherogenic pathway. We investigated their joint associations with cardiovascular disease (CVD) and examined whether either marker improves prediction beyond established risk factors. We followed 286,025 UK Biobank participants without baseline CVD. Low eGDR was defined as ≤ 6.28 mg/kg/min and high Lp(a) as ≥ 125 nmol/L. Multivariable Cox models estimated individual and joint associations. Interaction was evaluated on relative hazard and competing-risk-adjusted 10-year absolute-risk scales, and prediction was assessed using fivefold cross-validation. During a median follow-up of 14.1 years, 34,921 participants developed CVD. The adjusted HRs were 1.37 (95% CI, 1.35–1.39) per 1-SD lower eGDR and 1.07 (95% CI, 1.06–1.08) per 1-SD higher log-Lp(a). Compared with high eGDR/low Lp(a), low eGDR/high Lp(a) was associated with an HR of 1.51 (95% CI, 1.43–1.59). Standardized 10-year cumulative incidence accounting for competing death was 7.15% and 10.45% in these groups, respectively; neither multiplicative interaction (P = 0.207) nor the 10-year absolute-risk interaction contrast (− 0.08% points; 95% CI, − 0.58 to 0.47) was significant. In a comprehensive risk-factor model, adding eGDR increased the C-index from 0.71048 to 0.71174, and further adding Lp(a) increased it to 0.71208, without clear additional decision-curve benefit. Lower eGDR and higher Lp(a) were independently associated with incident CVD, and their combination identified participants at greatest risk without evidence of statistical interaction. Their incremental predictive value beyond comprehensive conventional risk assessment was small. Lower eGDR and higher Lp(a) are associated with cardiovascular events, but their joint absolute-risk profile and incremental predictive value require careful distinction. How do eGDR and Lp(a) jointly relate to CVD risk, and does using both improve prediction beyond established risk factors? The two markers were minimally correlated and independently associated with incident CVD. Participants with low eGDR and high Lp(a) had the highest relative and 10-year absolute risk, without statistically significant interaction on either scale. Prediction improved only modestly beyond a comprehensive conventional risk-factor model, particularly after adding Lp(a) to a model already containing eGDR. The joint classification summarizes distinct cardiometabolic and lipoprotein-related risk characteristics, although additional clinical net benefit was not demonstrated.