Layered Effects of LDL ‐C Burden and Variability on Cardiovascular Events and Mortality in Type 2 Diabetes: A Nationwide Cohort Study

AIMS: To assess whether threshold-based low-density lipoprotein cholesterol (LDL-C) burden and visit-to-visit variability jointly stratify cardiovascular and mortality risk in adults with Type 2 diabetes (T2DM). MATERIALS AND METHODS: We studied 258 183 Korean adults with T2DM who underwent National Health Insurance Service health screening in 2015-2016. LDL-C burden was defined as the number of measurements ≥ 130 mg/dL across four examinations (0-4), and variability was assessed using average successive variability (Q4 vs. Q1-Q3). Outcomes through 2022 were incident cardiovascular disease (CVD), myocardial infarction (MI), ischemic stroke, cardiovascular mortality, and all-cause mortality. Adjusted hazard ratios (HRs) were estimated using Cox models. RESULTS: During a median 7.14 years, composite CVD occurred in 10 886 participants. Incidence was 6.22 versus 6.62 per 1000 person-years in participants with 0 versus 4 LDL-C elevation episodes; adjusted HRs increased from 1.10 (95% CI 1.04-1.15) to 1.49 (1.39-1.60). The association was stronger for MI (HR 1.66, 1.52-1.82) than for stroke (HR 1.32, 1.20-1.46). High variability modestly increased CVD risk overall (HR 1.09, 1.05-1.14), but in the four-episode group, Q4 had a higher event rate than Q1-Q3 (7.49 vs. 6.47 per 1000 person-years). Cardiovascular mortality risk was elevated only at the highest burden (HR 1.48, 95% CI 1.21-1.81) and increased further with concurrent Q4 variability (HR 2.48, 95% CI 1.53-4.00). All-cause mortality was inversely associated overall, but this pattern was modified by high variability, particularly in younger adults or longer-duration diabetes subgroups. CONCLUSIONS: In T2DM, LDL-C burden and variability jointly identified patients at greater risk, especially for MI and cardiovascular mortality.