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Cholesterol report

Raising so-called “good” cholesterol by blocking a key protein involved in its metabolism does not protect against heart disease or stroke, according to a large genetic study of Chinese adults published this week in JAMA Cardiology.

There are two types of cholesterol in the blood: LDL-C, so-called “bad” cholesterol, which is carried in low-density lipoproteins (LDL), and HDL-C, so-called “good” cholesterol which is found in high-density lipoproteins (HDL). Lowering  LDL-C (e.g. by statins) has been demonstrated to reduce the risk of heart diseases and stroke, but the causal role of HDL-C is less.

Cholesterol ester transfer protein (CETP) transfers cholesterol between different lipoproteins. Blocking this protein, which raises levels of HDL-C as well as causing other changes to blood lipids, is a potentially important approach for prevention and treatment of cardiovascular diseases. Genetic variants which alter the activity of CETP can mimic some of the effects of drugs which target this protein and can be used to help assess the potential benefits and harm of this cholesterol-modifying treatment.

Researchers in NDPH, Peking University and Chinese Academy of Medical Sciences explored the health effects of CETP genetic variants, including an East Asian specific functional variant, in 150,000 Chinese adults enrolled into the China Kadoorie Biobank. After ten years of follow-up, over 5,000 study participants had coronary heart disease and 19,000 had a stroke.

The researchers found that CETP genetic variants raised levels of HDL-C substantially, but did not lower LDL-C and did not lower the risk of cardiovascular diseases such as heart disease and stroke. There was also no effect on atherosclerotic plaques and thickness of the arteries, or on other conditions such as diabetes and kidney disease. However, the study found increased risk of eye diseases as a possible adverse effect of CETP inhibition, a finding supported by other genetic studies in East Asian and Western populations.

The study results complement findings from the recent REVEAL clinical trial of the CETP inhibitor anacetrapib, which found that beneficial effects of CETP inhibition for heart disease were more likely to be due to lowering “bad” cholesterol LDL-C than raising “good” HDL-C.

New treatments are discovered by exploring biological pathways that cause disease but can be modified by drugs. The journey from basic biology to large-scale randomised trials in humans is long and expensive: the estimated cost of getting a single product to market is over $2 billion. Using genetic data to predict the benefits and harms of new treatments can reduce costs and this approach is likely to become much more widely used to examine the causal nature of biological pathways involved in diseases before mounting large-scale clinical trials.

Study author Dr Iona Millwood said “Our research has helped clarify the role of different types of cholesterol, and suggests that raising levels of HDL-C by blocking CETP activity, without also lowering LDL-C, does not confer any major benefits for cardiovascular disease.”

Professor Zhengming Chen, study co-author said “This study demonstrates the value of large prospective biobank studies with genetic data linked to health records, carried out in diverse global populations, to predict the potential benefits or harms of new drug treatments.”