Association of LDL-Cholesterol with Mortality

Researchers here report on a study of LDL-cholesterol and mortality risk in older people. As they note, data on this topic is conflicted once one moves beyond the matter of cardiovascular disease. Over a lifetime, higher LDL-cholesterol makes it easier to reach the tipping point at which cholesterol deposited in blood vessel walls produces enough cellular dysfunction to form a fatty streak and then an atherosclerotic plaque. For other forms of mortality, I would suspect that the unhealthy lifestyle or ongoing chronic disease required to have either an abnormally low or abnormally high LDL-cholesterol level in blood samples is the cause of increased mortality, rather than anything to do with cholesterol metabolism per se.

Low density lipoprotein cholesterol (LDL-C) is a well established causal risk factor for the development of atherosclerosis and cardiovascular disease. High levels of LDL-C consistently predict a risk of future atherosclerotic cardiovascular events in a variety of populations throughout the world. Also, many randomised controlled trials of treatment with lipid lowering agents have clearly shown that lowering LDL-C levels reduces the risk of atherosclerotic cardiovascular events in the future.

Because lowering levels of LDL-C reduces cardiovascular disease outcomes, the general perception is that high levels of LDL-C are associated with an increased risk of mortality but low levels are not. Studies on the association between LDL-C levels and the risk of all cause mortality, however, have provided conflicting results, with some studies showing a counterintuitive inverse association (lower mortality with increasing levels of LDL-C) and some showing no association. Most of these studies were conducted in individuals aged 65 and older, and in historical population based cohorts.

In this study, we determined the association between levels of LDL-C and the risk of all cause and cause specific mortality. Among 108,243 individuals aged 20-100, 11,376 (10.5%) died during the study, at a median age of 81. The association between levels of LDL-C and the risk of all cause mortality was U shaped, with low and high levels associated with an increased risk of all cause mortality. Compared with individuals with concentrations of LDL-C of 3.4-3.9 mmol/L (132-154 mg/dL), the multivariable adjusted hazard ratio for all cause mortality was 1.25 for individuals with LDL-C concentrations of less than 1.8 mmol/L (under 70 mg/dL) and 1.15 for LDL-C concentrations of more than 4.8 mmol/L (over 189 mg/dL).

The concentration 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 individuals not receiving lipid lowering treatment, compared with 2.3 mmol/L (89 mg/dL) in individuals receiving lipid lowering treatment. Similar results were seen in men and women, across age groups, and for cancer and other mortality, but not for cardiovascular mortality. Any increase in LDL-C levels was associated with an increased risk of myocardial infarction.