Low, high LDL-C levels tied to increased all-cause mortality risk

Individuals with high or low levels of low-density lipoprotein cholesterol (LDL-C) are at higher risk of all-cause mortality, reveals a study in Denmark. On the other hand, those with an LDL-C concentration of 3.6 mmol/L (140 mg/dL) live the longest.

“Low and high levels of LDL-C were associated with an increased risk of all-cause mortality in individuals in the general population,” the researchers said. “Similar results were seen for cancer and other mortality, whereas no association was found for cardiovascular mortality overall.”

This prospective cohort study randomly selected 108,243 individuals aged 20–100 years from the national Danish Civil Registration System, with a median follow-up of 9.4 years. Baseline LDL-C levels associated with a mortality risk were assessed on a continuous scale (restricted cubic splines) and by a priori defined centile categories with Cox proportional hazards regression models.

Of the participants, 11,376 (10.5 percent; median age, 81 years) died during the study. A U-shaped association between LDL-C concentrations and all-cause mortality risk was observed, with low and high levels both increasing such risk. [BMJ 2020;371:m426]

The multivariable-adjusted hazard ratio for all-cause mortality was 1.25 (95 percent confidence interval [CI], 1.15–1.36) for individuals with LDL-C concentrations of <1.8 mmol/L (<70 mg/dL; 1st–5th centiles) and 1.15 (95 percent CI, 1.05–1.27) for LDL-C concentrations of >4.8 mmol/L (>189 mg/dL; 96th–100th centiles) compared to those with LDL-C levels of 3.4–3.9 mmol/L (132–154 mg/dL; 61st–80th centiles).

LDL-C concentration of 3.6 mmol/L (140 mg/dL) in the overall population and in individuals not receiving lipid-lowering treatment correlated with the lowest all-cause mortality risk as compared with 2.3 mmol/L (89 mg/dL) in those receiving lipid-lowering treatment. Results were similar in men and women, across age groups, and for cancer and other mortality, but not for cardiovascular mortality.

Any increase in LDL-C levels also correlated with an increased risk of myocardial infarction.

“The association between low levels of LDL-C and an increased risk of all-cause mortality could be explained by reverse causation,” the researchers said. “Debilitation and illness have been hypothesized to cause a decrease in levels of cholesterol and, in this study, comorbidities were more frequent in individuals with the lowest levels of LDL-C.” [Circulation 1992;86:1046-1060; Exp Aging Res 1998;24:169-179]

Previous studies that investigated the relation between LDL-C levels and all-cause mortality risk found no association or an inverse association. [J Am Geriatr Soc 2005;53:219-226; Age Ageing 2008;37:207-213; Arch Intern Med 1993;153:1065-1073; JAMA 1998;279:585-592]

“Our study showed that the inverse association can be explained by the increased risk of all-cause mortality associated with low levels of LDL-C rather than representing an actual decreased risk at high levels of LDL-C,” the researchers noted.

“Together, these results indicate the importance of assessing the absolute risk of atherosclerotic cardiovascular disease in deciding when to use lipid lowering treatment, rather than starting treatment based solely on a moderate increase in levels of LDL-C,” they added. [Atherosclerosis 2017;257:9-15; Circulation 2019;139:e1082-1143]