Investigators report that a genetic variant that substantially raises HDL-cholesterol levels did not alter the risk of MI, whereas genetic polymorphisms related to plasma LDL-cholesterol were consistently associated with an increased risk of MI.
"These results challenge several established views about plasma HDL cholesterol," write Dr Benjamin Voight (University of Pennsylvania, Philadelphia) and colleagues in a report published online May 16, 2012 in the Lancet. "First, these data question the concept that raising plasma HDL cholesterol should uniformly translate into reduction in risk of myocardial infarction. . . . Second, these findings emphasize the potential limitation of plasma HDL cholesterol as a surrogate measure for risk of myocardial infarction in intervention trials."
In an editorial accompanying the study , Drs Seamus Harrison, Michael Holmes, and Steve Humphries (University College London, UK) echo the conclusions of the researchers, stating that "genetically raised HDL-cholesterol concentrations do not seem to reduce risk of coronary heart disease--an observation that calls into question whether raising HDL cholesterol therapeutically would translate into the expected clinical benefit."
The genetic data emerge after a couple of high-profile failures with drugs, as well as extended-release niacin, which showed no benefit in terms of hard clinical events despite substantial increases in HDL-cholesterol levels.
Earlier this month, Roche stopped the phase 3 dal-OUTCOMES trial of the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib after interim analysis of the study showed the HDL-cholesterol–boosting drug did not reduce cardiovascular adverse events. The AIM-HIGH study, with niacin given on top of statin therapy, showed the vitamin significantly increased HDL-cholesterol levels but failed to reduce the composite end point of coronary heart disease death, nonfatal MI, ischemic stroke, or hospitalization for acute coronary syndrome or symptom-driven coronary or cerebral revascularization. And of course, torcetrapib, another CETP inhibitor, was stopped in late 2006 when investigators discovered the drug increased the risk of death and cardiovascular events.
HDL and MI: It's a Complicated Relationship
Senior investigator Dr Sekar Kathiresan (Massachusetts General Hospital, Boston) explained that the genetic study overcomes two limitations of observational epidemiological studies in that it eliminates the possibility of reverse causation and confounding variables. A Mendelian randomization, he said, is often referred to as "nature's randomized trial."
"When we went into this study, the background is that low HDL cholesterol is associated with an increased risk of heart attack, and that's been known for 30 or 40 years," he told heartwire . "What is not known is whether that association is a causal relationship or an indirect one."
In the present study, the researchers performed two Mendelian analyses. With the first, they tested the association with a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn 396Ser) in 95 407 healthy controls and 20 913 patients who had an MI.
Carriers of the LIPG Asn 396Ser allele, which occurred in 2.6% of the study cohort, had HDL-cholesterol levels approximately 5.5 mg/dL (0.14 mmol/L) higher than those without the allele but similar levels of other lipids. Despite the increase in HDL cholesterol, carriers of the LIPG Asn 396Ser allele did not have a significantly decreased risk of MI (odds ratio 0.99; 95% CI 0.88–1.11). Similarly, in an analysis of six prospective cohort studies alone, which included 46 535 controls and 4228 MI patients, as well as a separate analysis of case-control studies, there was no significant association between the LIPG Asn 396Ser allele and the risk of MI.
On the basis of the association between the LIPG Asn 396Ser allele and HDL cholesterol, the 5.5-mg/dL increase in HDL should have translated into a 13% decreased risk of MI. "The people who are carriers of the HDL-boosting variant should have had a reduced risk of heart attack, but to our surprise, there was no association between the gene variant and heart-attack risk," said Kathiresan. He noted that while the boost in HDL-cholesterol levels might appear small, it is the same boost that patients receive when treated with niacin.
The researchers also constructed a genetic score by combining common SNPs that had statistical evidence at genomewide levels of significance for plasma LDL- and HDL-cholesterol levels. The genetic score for LDL and HDL cholesterol included 13 and 14 SNPs, respectively. In the Mendelian randomized analysis, each standard-deviation (SD) increase in LDL cholesterol due to the genetic score significantly increased the risk of MI (OR 2.13; 95% CI 1.69–2.69). In contrast, each 1-SD increase in HDL cholesterol due to the genetic score did not decrease the risk of MI.
"So we have these two lines of evidence, one from the single variant and another from a group of 14 variants, that lead to the same conclusion--that people who are genetically predisposed to having higher HDL-cholesterol levels are not protected from heart-attack risk, as would be expected."
Low HDL Levels Still a Red Flag
To heartwire , Kathiresan stressed that the genetic data do not question the value of using low HDL-cholesterol levels as a marker of patient risk for MI. Clinicians should continue to check HDL-cholesterol levels, and if the HDL level is low, then they can tell the patient that they are at an increased risk for MI. The open question, however, had been whether clinicians should use drugs such as niacin or fibrates to address the low HDL levels. Their data suggest that patients should not be treated with therapies designed for the sole intention of raising HDL cholesterol.
The number of risk factors that track with HDL-cholesterol levels is extensive, added Kathiresan, and include obesity, physical inactivity, smoking, small LDL-cholesterol particles, coagulation factors, diabetes, prediabetes, and so on. The association between HDL cholesterol and the risk of cardiovascular events in the epidemiological data might be driven by these other risk factors that are truly causal, he said.
Trials with drugs that raise HDL cholesterol remain ongoing. More data on the use of niacin will come from the 24 000-patient HPS2-THRIVE study, while other CETP inhibitors, evacetrapib (Lilly, Indianapolis, Indiana) and anacetrapib (Merck, Whitehouse Station, NJ), are still in development.
Kathiresan said that dalcetrapib was likely the best "pure test of the HDL hypothesis," as it was a weak CETP inhibitor and only raised HDL levels without affecting LDL-cholesterol or triglyceride levels as the other drugs in the class do. Lacking the off-target effects of torcetrapib and significantly raising HDL-cholesterol levels 30%, it failed to show any benefit. "That's pretty amazing," he said. "To me, those data are entirely consistent with our genetic data."