22April2019

Good cholesterol may not be what keeps the heart healthy

By themselves, higher levels of HDL don’t explain lower cardiovascular risk

Some shine may have worn off “good” cholesterol’s halo. A new genetics study shows that merely raising levels of high-density lipoprotein — also known as HDL or good cholesterol — does not help protect against heart attacks.

The finding appears to contrast sharply with population studies showing that people with high levels of HDL have a lower than average risk of heart attack. But the results, published online May 17 in the Lancet, may mean that blood levels of good cholesterol serve as indicators of some other biological process that protects the heart, and that HDL itself is not directly involved in heart health.

Doctors often use measurements of two types of cholesterol in the blood as a tool for identifying patients facing a higher risk of heart attack. Data collected from large studies show a consistent pattern: People with high levels of low-density lipoprotein, called LDL or bad cholesterol, stand a greater than average chance of having a heart attack. Those epidemiological data have been backed up by drug studies showing that lowering LDL levels also lowers heart attack risk.

But the case for HDL has been less clear. “As a predictor, HDL is perfect. It’s unequivocal,” says Benjamin Voight, a geneticist at the University of Pennsylvania in Philadelphia and a lead author of the new study. Yet drugs that raise HDL levels haven’t performed well in clinical trials. On May 7, the drug company Roche announced that a trial of its HDL-boosting drug dalcetrapib had been stopped because the drug was not effective.

Losing weight, stopping smoking and increasing exercise — all actions that boost HDL levels — also improve other heart disease risk factors. That has made it difficult to tease out just how protective HDL is on its own. To find out, Voight and his colleagues compiled blood test results and genetic data gathered in earlier studies from more than 116,000 people, including more than 20,000 who had suffered from heart attacks. About 2.6 percent of those studied carry a gene mutation that raises HDL cholesterol levels about 7 milligrams per deciliter over levels of people who don’t carry the mutation. That increase in HDL was expected to decrease the mutation-carriers’ heart attack risk by 13 percent.

“But surprise, we didn’t find that,” says study coauthor Sekar Kathiresan, a cardiologist and geneticist at the Broad Institute of MIT and Harvard in Cambridge, Mass. People genetically endowed to make higher levels of HDL didn’t have a lower risk of heart attack.

To make sure the result wasn’t a fluke, the researchers compiled a genetic score for 53,813 people based on the number of 14 other HDL-boosting genetic variants the person carries. Even people with the highest genetic score, and thus the highest HDL levels, weren’t protected from heart attack. To make sure the technique works properly, the researchers also compiled an LDL genetic score and got the expected answer: higher LDL levels were associated with higher heart attack risk.

“Maybe HDL is not what we should be worried about as such,” says Ruth Loos, a genetic epidemiologist at Mt. Sinai School of Medicine in New York City. Although the finding doesn’t seem to mesh with epidemiological studies, she says, “to me the results are really credible and very convincing.”

While the genetic results indicate that HDL by itself doesn’t affect heart attack risk, “I’m still hopeful. I don’t think the entire thing is hogwash,” Kathiresan says. He still believes that HDL is a marker for an interesting biological process going on behind the numbers. He and Voight hope to tease out the genetic components of that hidden process in future studies.

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