Low-Density Lipoprotein Cholesterol, Cardiovascular Disease Risk, and Mortality in China is a study published in the JAMA Open Network. It is remarkable for the number of subjects studied – 3, 789, 025 participants!  They were categorized into low-risk, primary prevention, and secondary prevention cohorts based on their medical history and ASCVD (atherosclerotic cardiovascular disease) risk. The primary end point was all-cause mortality, and secondary end points included cause-specific mortality. 

The key findings of this investigation are shown on the figures below. Click on them to view a larger image. Primary prevention is a treatment intended to prevent a disease from happening for the first time. Secondary prevention is designed to avoid a recurrence of a disease.

The data are similar to what has been reported in previous studies. All cause mortality in the low-risk and primary prevention groups was higher at both very low and increased LDL levels. In the secondary prevention patients increased mortality was only seen at high levels of LDL. The explanation for the association of increased mortality with low LDL levels remains uncertain. This study controlled for underlying disease and still found the relationship between low HDL and increased mortality.

The authors suggest that frailty or sarcopenia (muscle loss), which was not examined in this study, could be the explanation for the relationship between bad outcomes and low LDL levels. Regardless of the cause, this relationship has been repeatedly observed in many studies.

While it’s nice to have more data of the kind presented in the paper, the authors go off the rails in their discussion: “Because CVD mortality is the leading cause of mortality in China, lipid-lowering treatments to reduce ASCVD events will greatly increase life expectancy.” The statement assumes, without a reference, that lipid lowering drugs reduce mortality in patients with coronary disease. The statement is based solely on the relationship between high HDL levels and increased mortality as there was no intervention arm to this study.

This relationship could have any one of three explanations. It could be a coincidence. But it’s found so often that chance seems unlikely. High lipid levels could cause plaque formation and hence vascular disease which might benefit from lipid lowering therapy. Finally, the association might be the reverse – ie, vascular disease might lead to increased lipid levels.

There is considerable doubt in the literature concerning lipid lowering and decreased and a favorable effect on cardiovascular disease. Consider this study in the NEJM. It showed that the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, but treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. The study was also discussed on this site shortly after it was published.

That the authors were allowed to make such a claim without a citation suggests that the review process for JAMA Online is not as rigorous as that of the print journal. The data from this Chinese are interesting and useful but cast a jaundiced eye on their conclusions. The full paper is below as a pdf.