Association of Low‐Density Lipoprotein Cholesterol Levels with More than 20‐Year Risk of Cardiovascular and All‐Cause Mortality in the General Population

BACKGROUND: Current cholesterol guidelines have recommended very low low‐density lipoprotein cholesterol (LDL‐C) treatment targets for people at high risk of cardiovascular disease (CVD). However, recent observational studies indicated that very low LDL‐C levels may be associated with increased mortality and other adverse outcomes. The association between LDL‐C levels and long‐term risk of overall and cardiovascular mortality among the U.S. general population remains to be determined. METHODS AND RESULTS: This prospective cohort study included a nationally representative sample of 14 035 adults aged 18 years or older, who participated in the National Health and Nutrition Examination Survey III 1988–1994. LDL‐C levels were divided into 6 categories: <70, 70–99.9, 100–129.9, 130–159.9, 160–189.9 and ≥190 mg/dL. Deaths and underlying causes of deaths were ascertained by linkage to death records through December 31, 2015. Weighted Cox proportional hazards regression models were used to estimate the hazard ratios (HR) of mortality outcomes and its 95% CIs. During 304 025 person‐years of follow up (median follow‐up 23.2 years), 4458 deaths occurred including 1243 deaths from CVD. At baseline, mean age was 41.5 years and 51.9% were women. Very low and very high levels of LDL‐C were associated with increased mortality. After adjustment for age, sex, race and ethnicity, education, socioeconomic status, lifestyle factors, C‐reactive protein, body mass index, and other cardiovascular risk factors, individuals with LDL‐C<70 mg/dL, compared to those with LDL‐C 100–129.9 mg/dL, had HRs of 1.45 (95% CI, 1.10–1.93) for all‐cause mortality, 1.60 (95% CI, 1.01–2.54) for CVD mortality, and 4.04 (95% CI, 1.83–8.89) for stroke‐specific mortality, but no increased risk of coronary heart disease mortality. Compared with those with LDL‐C 100–129.9 mg/dL, individuals with LDL‐C≥190 mg/dL had HRs of 1.49 (95% CI, 1.09–2.02) for CVD mortality, and 1.63 (95% CI, 1.12–2.39) for coronary heart disease mortality, but no increased risk of stroke mortality. CONCLUSIONS: Both very low and very high LDL‐C levels were associated with increased risks of CVD mortality. Very low LDL‐C levels was also associated with the high risks of all‐cause and stroke mortality. Further investigation is needed to elucidate the optimal range of LDL‐C levels for CVD health in the general population.