Cardiovascular Benefits of Cholesterol-Lowering Vary by Method

Statins plus cholesteryl ester transfer protein inhibitors may have the greatest cardiovascular benefits.

The results of a clinical trial presented at the European Society of Cardiology suggest that the overall benefit of lowering low-density lipoprotein (LDL) cholesterol may be contingent on how it is lowered.

“Our study suggests that the causal effect of LDL on the risk of cardiovascular disease (CVD) is determined by the circulating concentration of LDL particles, measured by apolipoprotein-B (apoB), rather than by the total cholesterol carried by those particles, as measured by LDL cholesterol,” said lead investigator Brian A Ference, MD.

Due to this hypothesis, some methods of lowering cholesterol may provide more protection against heart disease than others.

“The clinical benefit of LDL cholesterol lowering therapies may depend on the corresponding reduction in apoB particles, which in turn depend on how LDL cholesterol is lowered,” Dr Ference said.

In a previous clinical trial, researchers found that the cholesteryl ester transfer protein (CETP) inhibitor evacetrapib lowered LDL by 39% but did not reduce the risk of cardiovascular events. These findings called into question the relationship between LDL cholesterol and CVD risk, as well as the benefits of cholesterol-lowering methods, according to the study.

In the new study, the authors examined whether CETP inhibitors had similar effects on CVD risk compared with other methods to determine how the method of lowering cholesterol impacted the benefits.

Included in the study were 358,205 patients from 77 other studies. The authors randomized patients into 4 treatment groups by inherited gene variants that mimic the effect of common cholesterol-lowering drugs: CETP inhibition (mimicking CETP inhibitors), HMG-CoA reduction inhibition (mimicking statins), both treatments, or neither treatments.

The primary outcome was major cardiovascular events, such as death, non-fatal myocardial infarction, coronary revascularization, or non-fatal stroke. In total, patients experienced 76,061 cardiovascular events.

The authors discovered that genes that mimic CETP inhibitors were linked to elevated high-density lipoprotein (HDL) cholesterol, lower LDL cholesterol, lower apoB, which led to an overall lower risk of CVD, according to the study.

The authors reported the gene variants that mimic CETP inhibitors also lowered the risk of cardiovascular events similarly to variants that mimic the effect of statins, ezetimibe and PCSK9 inhibitors.

The combination of CTEP inhibitor and statin-mimicking genes was linked to similar decreases in LDL cholesterol; however, the change in apoB was weakened. Cardiovascular events were proportional to the change in apoB, but less than expected per unit change in LDL cholesterol, which suggests that the effects may determined by reduction in apoB, not LDL cholesterol, according to the study.

“These results may help to explain the failure of some CETP inhibitors to reduce the risk of cardiovascular events despite robustly lowering LDL cholesterol,” Dr Ference said.

These findings suggest the methods that lower apoB may be a better way to reduce CVD and cardiovascular events linked to high cholesterol, according to the study.

“Because the clinical benefit is determined by the reduction in apoB, rather than LDL cholesterol, combination therapy with a CETP inhibitor and a statin reduces the risk of cardiovascular events proportional to the attenuated reduction in apoB,” Dr Ference said. “This may be significantly less than expected for the observed change in LDL cholesterol depending on the degree of discordance between the reductions in apoB and LDL cholesterol.”