Non-high-density lipoprotein cholesterol and residual cardiorenal risk in statin-treated patients with type 2 diabetes mellitus

Background Despite achieving low-density lipoprotein cholesterol (LDL-C) targets with statin therapy, patients with type 2 diabetes mellitus (T2DM) retain a high residual risk for cardiovascular and renal complications. Non-HDL cholesterol (non-HDL-C) captures the atherogenic burden of all apolipoprotein B-containing particles, including triglyceride-rich remnants that characterize diabetic dyslipidemia. Whether non-HDL-C stratifies residual cardiorenal risk in contemporary statin-treated patients achieving LDL-C control and T2DM remains uncertain. Purpose To determine whether non-HDL-C independently predicts the risk of major adverse cardiovascular events (MACE) and composite renal outcomes in statin-treated patients with controlled LDL-C levels and newly diagnosed T2DM. Methods Using a previously validated territory-wide registry, newly diagnosed T2DM patients between 2000 and 2022 were enrolled. Eligible patients had baseline lipid profiles within one year before T2DM diagnosis, achieved LDL-C ≤2.6 mmol/L for primary prevention during ≥90 consecutive days of statin therapy, and no prior cardiovascular disease. Primary outcomes were MACE (cardiovascular mortality, myocardial infarction, stroke, or heart failure hospitalisation), and composite renal outcomes (≥50% decline in estimated glomerular filtration rate [eGFR], end-stage renal failure, or kidney mortality). Results Among 79,008 eligible patients (mean age 64.9±8.4 years, 42.9% male), 4275 (5.4%) patients developed MACE, 5362 (6.8%) composite renal outcomes, and 2845 (3.6%) patients died at mean follow-up of 4.9±0.5 years. After multivariable adjustment, each 1-mmol/L increase in non-HDL-C conferred a 21% increased MACE risk (HR 1.21, 95% CI 1.12–1.30) and 34% increased renal risk (1.34, 95%CI 1.26–1.42). When analyzed by quartiles of non-HDL-C (Q1: median 2.2 mmol/L as reference), increasing hazard ratios for Q2, Q3, and Q4 were observed, with 1.06 (0.97–1.16), 1.14 (1.03–1.26), and 1.19 (1.07–1.33), respectively for MACE, and 1.15 (1.06–1.25), 1.29 (1.18–1.41), and 1.42 (1.29–1.56), respectively for composite renal outcomes. Among subgroup of 22,850 patients achieving intensive LDL-C control (< 1.8 mmol/L), non-HDL-C retained significant predictive value for MACE (HR per 1-mmol/L: 1.23 [1.08–1.40]) and composite renal outcomes (HR per 1-mmol/L: 1.25 [1.13–1.38]). No significant association was observed between non-HDL-C and all-cause mortality (HR 1.01; 95% CI 0.91-1.12). Restricted cubic spline analysis revealed linear risk relationships without threshold effects. Conclusion In statin-treated patients with controlled LDL-C and newly diagnosed T2DM, non-HDL-C is a robust, independent predictor of both cardiovascular events and progressive renal deterioration. These findings suggest that non-HDL-C is an essential, easily accessible clinical marker that should serve as a secondary therapeutic target to mitigate the residual cardiorenal burden in the diabetic population.