In the study appearing in the medical journal The Lancet, a team led by researchers from Massachusetts General Hospital and the Broad Institute examined the health of more than 100,000 people, some of them with genetic variations that elevated their levels of HDL, and found that those variations did not protect against heart attacks.
The results come shortly after a clinical trial of an HDL-raising drug being tested by the Swiss pharmaceutical giant Roche was halted, only the most recent high-profile problem to surface with a potential treatment aimed at lowering heart disease risk by boosting HDL.
“What this really suggests to us is we can’t simply assume just because something raises HDL cholesterol in the blood, that risk for heart attack will be lowered,” said Dr. Sekar Kathiresan, a cardiologist at Mass. General and associate member of the Broad Institute who led the work. “It’s very important, because if you ask the average person, the average doctor when they see someone with low HDL cholesterol, their impulse is to raise it with something.”
For several decades, the medical community has been drumming into patients the importance of knowing their cholesterol readings—many people can rattle off their levels of the “bad” LDL cholesterol and “good” HDL as easily as their Social Security number. Studies had found that higher levels of LDL were associated with increased risk for heart attacks, while the opposite was true for HDL. It’s also been clearly shown that statins, drugs that lower LDL cholesterol, decrease cardiovascular risk. But it has been unclear whether the association with HDL was analogous—whether raising HDL levels would be protective.
To test this notion in the new study, the scientists studied a gene variation that is present in about 2.6 percent of the population and raises HDL levels, with no effect on other cardiovascular risk factors. People with that gene should have a 13 percent decreased risk of heart attack, the researchers calculated. But when they compared them with people who did not have the gene, there was no difference in heart attack risk. In a second study, researchers examined a panel of 14 genetic variations that raised HDL levels and found inheriting those variations did not confer protection against heart attacks either.
For years, epidemiological studies have found that naturally high HDL levels are associated with heart disease protection, but it has not been clear whether those high levels are themselves protective. They could, for example, simply be a marker of a healthy lifestyle.
The researchers said HDL cholesterol, combined with other factors, remains a valuable way to assess a person’s risk for a heart attack. And outside scientists said the new study does not definitely show that raising HDL fails to protect against heart attacks. For example, there may be subtypes of HDL, some of which reduce and some of which promote cardiovascular risk.
In a study published online last month in the Journal of the American Heart Association, Dr. Frank Sacks, a professor of cardiovascular disease prevention at the Harvard School of Public Health, found that people with a certain type of HDL had an elevated risk of heart disease. Those with high levels of a protein, called apolipoprotein C-III, attached to their HDL molecules had about a 60 percent greater risk of developing heart disease over the next 10 to 14 years compared with people with low levels of this protein.
“There’s a growing concept that maybe not all HDL is good, that maybe some is bad even,” Sacks said.
If confirmed in future studies, the finding could pave the way for more sophisticated cholesterol testing to tease out the different kinds of HDL. Physicians could use such a distinction to better determine which patients should be treated more aggressively with cholesterol-lowering statins, Sacks added, to prevent heart disease.
“It’s not a test we can order right now,” said Sacks, “but that’s where I hope we’ll go.”
Already, hundreds of millions of dollars have been spent on the development and testing of drugs aimed at raising HDL, leading to high-profile failures.
Roche last week announced it terminated a late-stage trial of an HDL-raising drug called dalcetrapib after an independent committee found a lack of “clinically meaningful efficacy.” That followed the 2006 suspension of a trial of torcetrapib, a Pfizer drug, because there were more deaths among patients receiving the experimental drug combination than one of the drugs alone. That drug also raised blood pressure.
Other companies are still pursuing drugs aimed at raising HDL levels, including Merck and Eli Lilly and Co., said Steve Scala, a pharmaceutical industry analyst for Cowen and Co. Even if drugs still in development succeed, it may be difficult to tease out whether their success stems from raising HDL. For example, Merck’s drug anacetrapib also lowers LDL.
“We treat LDL very well, and yet people still die of heart attacks, which implies something else is going on,” Scala said. “We’re all searching for whatever that missing link is.”
Dr. Richard Karas, director of the preventive cardiology center at Tufts Medical Center, praised the Lancet study for its meticulous analysis, but said he would still recommend raising HDL levels to patients. In part, he said that’s because ways to raise HDL levels include behaviors with other benefits—maintaining a normal body weight, eating a healthy diet, and exercising. He also said in appropriate patients he suggests niacin, a B vitamin used to raise HDL.
Dr. Steven Nissen, chair of cardiovascular medicine at the Cleveland Clinic, said HDL has been “a very murky area of science.”
Nissen is involved in a clinical trial testing Merck’s drug, which is expected to be completed by December. “If this drug fails and Eli Lilly’s evacetrapib fails,” Nissen said, “it will be awfully difficult to advocate for HDL-raising.”Carolyn Y. Johnson can be reached at firstname.lastname@example.org. Follow her on Twitter @carolynyjohnson.