Cholesterol and lipid metabolism used to simple. There was good (HDL) cholesterol and bad (LDL) cholesterol. Eat a diet low in cholesterol and fat and your blood vessels will be as open as a new straw. On the basis of very little solid scientific information a litany of assumptions was issued by both the medical and lay press. As is virtually always so, when cooler eyes were cast on the association of lipid metabolism and cardiovascular disease the relationship proved more complex than the initial sets of breezy assumptions.

A paper in the May 18, 2017 issue of the New England Journal of Medicine presents additional data that go against the grain of our thinking about lipid metabolism and CVD. Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease by Lincoff and a posse of collaborators sought to examine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. This drug inhibits cholesteryl ester transfer protein and thus substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity.

“In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, [they] enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina.”

The figure below shows that the desired changes in both HDL and LDL cholesterol were achieved. According to conventional thinking these changes should have had beneficial effects on the treated patients compared to those who received a placebo.

The graph below compares the occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina in the time‑to‑event analysis between the drug and placebo groups. As is obvious there is no difference. The cumulative incidence (inset) is the percentage of patients in each trial group who had at least one primary composite end‑point event over the course of the trial. Again there is no difference.

The discussion section of the paper tries to explain these unexpected findings –  without much success. The unanswered question is why was there no beneficial effect in high risk patients from changing their lipid levels in what should have been salutary directions?  Lincoff and co-workers end their paper with this: “Treatment with evacetrapib was associated with an increase in the HDL cholesterol level and a reduction in the LDL cholesterol level that were both significant and substantial, but evacetrapib treatment did not have a beneficial effect on cardiovascular outcomes.”

As is typical in medicine, we often know less about the pathophysiology of a disease then we initially thought. This study is another example of why medicine consists of making important decisions on the basis of inadequate information.