Lowering LDL-C Alone Does Not Reduce CV Risk

The clinical cardiovascular benefit of lowering low-density lipoprotein cholesterol (LDL-C) levels depends on the corresponding reduction of apolipoprotein B (apoB) levels, according to the results of a recent study presented at the European Society of Cardiology Congress.

Cholesteryl ester transfer protein (CETP) inhibitors are commonly used to lower LDL-C levels. However, their use often does not reduce the incidence of cardiovascular events, indicating that the clinical benefit of lowering LDL-C levels may depend on how they are lowered.
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For their primary analysis, the researchers evaluated 102,837 participants enrolled in 14 studies across North America and the United Kingdom between 1948 and 2012. They assessed how changes in LDL-C levels are associated with the risk of cardiovascular events related to variants of the CETP gene alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene.

Additionally, to determine associations with cardiovascular events, the researchers externally validated their results against 189,539 participants with 62,240 cases of coronary heart disease (CHD) enrolled in 48 studies between 2011 and 2015.

Results of the primary analysis indicated that the CETP score alone was associated with higher levels of high-density lipoprotein cholesterol (HDL-C), lower levels of LDL-C, lower apoB, and a lower risk of major vascular events. This association was similar to the association between the HMGCR score and the risk of major cardiovascular events per unit change in LDL-C levels and apoB.

The CETP score in combination with the HMGCR score was associated with the same reduction in LDL-C levels. However, these combined scores were contrastingly associated with an attenuated reduction in apoB levels and a corresponding attenuated nonsignificant risk of major cardiovascular events.

In the external validation analyses, the researchers found that a genetic score composed of variants with naturally occurring discordance between levels of LDL-C and apoB was associated with a similar risk of CHD per unit change in apoB level.

“Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C,” the researchers concluded. “The clinical benefit of lowering LDL-C levels may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles.”

—Christina Vogt

Reference:

Ference BA, Kastelein JJP, Ginsberg HN, et al. Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk [Published online August 28, 2017]. JAMA. doi:10.1001/jama.2017.11467.