NEW YORK (Reuters Health) – In the absence of significantly reduced low-density lipoprotein (LDL) cholesterol, increasing high-density lipoprotein (HDL) cholesterol levels with a cholesteryl ester transfer protein (CETP) may not lower cardiovascular disease risk, researchers say.
“Increased HDL cholesterol has been associated with lower risk of cardiovascular disease in large-scale observational epidemiology studies,” Dr. Iona Millwood of the University of Oxford, UK, told Reuters Health.
“Blocking the activity of CETP, a key protein involved in the metabolism of HDL, raises HDL (and has) other potential favorable effects on lipids,” she said by email, “and CETP inhibition has been investigated as a treatment strategy for cardiovascular disease in several large-scale clinical trials.”
To assess the potential risks and benefits of lifelong lower CETP activity, Dr. Millwood said that she and her colleagues “studied genetic variants in the CETP gene, including an East Asian-specific functional variant, in 150,000 Chinese adults from the China Kadoorie Biobank (CKB).”
“These variants lowered CETP activity, resulting in substantially higher HDL levels, but unlike in some studies in Western populations, the variants did not lower LDL,” she explained.“This approach is called Mendelian randomization and can be considered ‘nature’s randomized trial, as genetic variants are randomly allocated so should not be affected by confounding or reverse causation.”
“Studying the effects of genetic variants in drug targets such as CETP is a cost-effective way to help predict the possible benefits and harms of new drug treatments before conducting clinical trials,” she added. “In a large-scale prospective study like CKB, as well as predicting drug efficacy, potential adverse effects can be identified, and opportunities for drug repurposing.”
As reported in JAMA Cardiology, online November 15, a total of 151,217 people (mean age, 52; 58% women) were included in the study. Their mean cholesterol levels were 91 mg/dL for LDL and 48 mg/dL for HDL.
CETP variants were strongly associated with higher HDL concentrations (e.g., 6.1 mg/dL per rs2303790-G allele) but not with lower LDL levels.
Within HDL particles, CETP variants were associated with increased cholesterol esters and lower triglycerides; by contrast, within very low-density lipoprotein particles, cholesterol esters were reduced and triglycerides increased.
When scaled to 10-mg/dL higher levels of HDL, the CETP genetic score was not significantly associated with occlusive cardiovascular disease, major coronary events, myocardial infarction, ischemic stroke, intracerebral hemorrhage, or other vascular diseases or carotid plaque.
The rs2303790 variant also was not associated with any vascular diseases or plaque.
There were no associations with nonvascular diseases other than an increased risk for eye diseases with the rs2303790 variant (OR, 1.43).
“CETP variants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for CVD,” the authors conclude.
Dr. Millwood said, “These results complement findings from the recent REVEAL trial of the CETP inhibitor anacetrapib (http://bit.ly/2yIJgHg), where the 10% lower risk of coronary heart disease was suggested to be due to lowering LDL cholesterol, rather than raising HDL cholesterol.”
“Although raising HDL cholesterol levels by CETP inhibition does not appear to be protective for cardiovascular disease, it is possible that intervening in HDL metabolism through other mechanisms might be beneficial,” she suggested.
“The advantages of studying a Chinese population are that some genetic variants are only found in certain populations and not others,” Dr. Millwood noted. “However, the results help us to understand the role of different types of cholesterol in disease more generally.”
Dr. Usman Baber of the Icahn School of Medicine at Mount Sinai in New York City, told Reuters Health, “These findings, utilizing an innovative approach that leverages genetic data to examine associations, substantiates earlier studies showing no benefit to such inhibition in non-Chinese populations.”
Like Dr. Millwood, Dr. Baber noted that the positive benefits in the REVEAL trial were primarily attributed to reductions in non-HDL (factors), rather than increases in HDL cholesterol.
“It appears that modulating other parameters related to HDL biology, such as efflux capacity, may be more relevant to influence cardiac risk,” Dr. Baber concluded.
The study was funded in part by a research grant to the University of Oxford from MSD (Merck and Co.), which manufactures the CETP inhibitor anacetrapib. One author is an MSD employee.
SOURCE: http://bit.ly/2ySuKJn
JAMA Cardiol 2017.
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