U-shaped association between LDL-c levels and all cause mortality in the general population
Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study
Introduction and methods
It has been clearly demonstrated that treatment with lipid lowering agents reduces the risk of atherosclerotic CV events [1-4]. This insight has led to a general perception that high levels of LDL-c are associated with a high risk of all cause mortality, while low levels are not. However, studies have shown conflicting results on the association between LDL-c and all cause mortality [5-11]. Most of these studies were conducted in historical population-based cohorts and in individuals aged over 65 years. This study determined the association between LDL-c levels and the risk of all cause mortality and cause specific mortality in a contemporary general population cohort.
The study included 108,243 individuals from the Copenhagen General Population study. Invited individuals were randomly selected from the national Danish Civil Registration System, reflecting the Danish general population. Participants were aged 20-100 years at baseline. All participants completed a questionnaire, underwent a physical examination, and gave (non-fasting) blood samples. Main outcome was all cause mortality. Secondary outcomes were cause specific mortality (CV, cancer, and other mortality). Median follow-up was 9.4 years. 11,376 people died during follow-up.
Main results
- A U-shaped association was found between levels of LDL-c and risk of all cause mortality in the overall population; low and high levels were associated with increased risk of all cause mortality. This association was also seen in individuals not receiving lipid lowering treatment. For those receiving lipid lowering treatment, the 95%CI included the HR of 1.0 for any level of LDL-c.
- The level of LDL-c associated with the lowest risk of all cause mortality was 3.6 mmol/L (140 mg/dL) in the overall population and in those not receiving lipid lowering therapy, and 2.3 mmol/L (89 mg/dL) in individuals receiving lipid lowering treatment.
- Compared with individuals with LDL-c levels of 3.4-3.9 mmol/L (132-154 mg/dL; 61st-80th centiles), the multivariable adjusted HR for all cause mortality in the overall population was 1.25 (95%CI 1.15-1.36) for individuals with LDL-c levels of <1.8 mmol/L (<70 mg/dL; 1st-5th centiles) and 1.15 (95%CI 1.05-1.27) for those with LDL-c levels >4.8 mmol/L (>189 mg/dL; 96th-100th centiles).
- A U-shaped association was also seen between levels of LDL-c and risk of cancer mortality and other mortality in the overall population. No association was observed for CV mortality overall.
- Any increase in LDL-c was associated with an increased risk of MI in the overall population and in participants not receiving lipid lowering therapy. In individuals receiving lipid lowering treatment, the 95%CI included a HR of 1.0 at any concentration of LDL-c.
Conclusion
This study showed a U-shaped association between levels of LDL-c and risk of all cause mortality in the general Danish population; low and high levels of LDL-c were associated with increased risk of all cause mortality. A LDL-c level of 3.6 mmol/L (140 mg/dL) was associated with the lowest mortality risk. A U-shaped association was also observed for cancer mortality and other mortality. A positive association was found between LDL-c levels and MI risk; any increase of LDL-c was associated with increased risk of MI.
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