Rethinking the Risk of Low HDL

Despite plenty of evidence that people with low levels of “good”cholesterol are more prone to heart attacks, a large new study suggests that the lacking lipid is not to blame.

The analysis of data on nearly 70,000 people in Denmark affirmed the link between low levels of high-density lipoprotein (HDL), the so-called “good” cholesterol, and raised heart attack risk in the general population. But in people with a gene mutation that lowers HDL, heart attack risk was not found to be higher at all.

“Association itself doesn’t mean causality,” said lead author Dr. Ruth Frikke-Schmidt, a consultant in the Department of Clinical Biochemistry at Rigshospitalet in Copenhagen.

The results, published in the Journal of Clinical Endocrinology and Metabolism, indicate that just having low HDL is not what raises the likelihood of a heart attack.

“People with low ‘good’ cholesterol also have a whole bunch of other factors that relate to heart disease,” said Dr. Christopher Cannon, professor of medicine at Harvard Medical School and editor of the American College of Cardiology’s website.

It’s difficult to study and isolate “good” cholesterol, added Cannon, who was not involved in the new study. People with low HDL often suffer from obesity, high blood pressure and diabetes and sometimes have higher levels of LDL, or “bad” cholesterol, he said.

To try to isolate the effects of HDL itself, Frikke-Schmidt and her colleagues focused on people with a well-known variant of a gene called LCAT, which lowers HDL levels and occurs in about four percent of the population.

The variant gene is used as a stand-in for low HDL, she noted, but people with the variant don’t necessarily have the other risk factors that usually affect HDL levels in the larger population.

In the new study, a 13 percent decrease in HDL relative to average levels in the population was linked to an 18 percent increase in heart attack risk — if the low HDL was not explained by a gene variant. For people with the variant gene, the same HDL reduction was not linked to any increased risk of heart attack.

The findings fit in with Frikke-Schmidt’s earlier research showing that two other genetic variants that lower “good” cholesterol levels are not associated with an increased risk of heart disease.

According to both Frikke-Schmidt and Cannon, the debate is particularly important, because there are currently drugs in trials that would raise “good” cholesterol.

If low HDL is not a cause of heart attacks, raising HDL may not be protective, they point out.

Ruling out low levels of “good” cholesterol, Frikke-Schmidt said the most likely cause of the increased risk is so-called remnant lipoproteins, which are like “bad” cholesterol and carry fats through the blood.

Until the real mechanisms are sorted out, Cannon said it’s still important for people to try and raise their “good” cholesterol by exercising and losing weight.

“Beyond that there are so many question marks,” he said. “We’re kind of in a wait and see mode.”

SOURCE: The Journal of Clinical Endocrinology and Metabolism, online November 16, 2011.

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