The clinical benefit of lowering low-density lipoprotein cholesterol (LDL-C) appears to be determined by how LDL-C is lowered and the corresponding absolute reduction in apoB-containing lipoprotein particles, according to results from the REVEAL trial presented by Brian A. Ference, MD, Mphil, Dsc, FACC, in a Hot Line session on August 28 at ESC Congress 2017 in Barcelona and simultaneously published in the Journal of the American Medical Association.

The investigators sought to evaluate the association between changes in LDL-C and other lipoproteins with the risk of cardiovascular events due to CETP gene variants alone and combined with HMGCR gene variants.

The study consisted of three Mendelian randomization studies evaluating: 1) the association between lipid changes due to a genetic score consisting of CETP gene variants and the risk of cardiovascular disease, 2) the association between lipid changes due to combined exposure to the CETP and HMGCR genetic scores and risk of cardiovascular events, and 3) the association between a score consisting of genetic variants associated with discordant changes in LDL-C and apoB with the risk of coronary heart disease (CHD).

The primary outcome for the individual participant data analyses was major vascular events, a composite of the first occurrence of myocardial infarction (MI), coronary revascularization, stroke or coronary death. The primary outcome for analyses using summary level data was CHD.

The study participants (n = 102,837) experienced 13,821 first major vascular events. Participants with CTEP scores equal to or above the median compared with scores below the median had lower mean CTEP activity resulting in 4.62 mg/dl higher mean high-density lipoprotein cholesterol (HDL-C), 2.15 mg/dl lower mean LDL-C, 1.39 mg/dl lower mean apoB and a lower risk of major vascular events (odds ratio [OR], 0.964; 95 percent confidence interval [CI], 0.955-0.983; p < 0.001). Increasing quartiles of CETP score were associated with a step-wise increase in mean HDL-C, step-wise decreases in mean LDL-C and apoB, and a step-wise decrease in the risk of major vascular events.

The CETP score was associated with a similar risk of major vascular events per 10 mg/dl lower LDL-C (and per 10 mg/dl lower apoB) compared with the HMGCR, NPC1L1 and PCSK9 genetic scores.

External replication analyses of 62,249 patients with CHD and 127,299 controls showed that CTEP was associated with a lower risk of CHD (OR, 0.968; 95 percent CI, 0.956-0.981; p < 0.001).

Based on the discordant results in participants with combined exposure to genes encoding CETP inhibitor and statin targets, the authors concluded that the clinical benefit of LDL-C lowering may depend on how LDL-C is lowered and the corresponding absolute reduction in apoB-containing lipoprotein particles. 

In an accompanying editorial comment, Allan D. Sniderman, MD, and Eric D. Peterson, MD, MPH, FACC, note that “clinicians could consider the utility of apoB levels as the primary target of lipid lowering rather than LDL-C levels. From the standpoint of the clinician, these data provide additional support to an already large body of evidence indicating that apoB is a superior marker of CVD risk than LDL-C.”

Keywords: ESC Congress, ESC2017, Cholesterol, LDL, Cholesterol, HDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, American Medical Association, Apolipoproteins B, Hydroxymethylglutaryl-CoA Reductases, NAD-Dependent, Coronary Disease, Myocardial Infarction, Cardiovascular Diseases, Stroke

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