According to observational studies, increasing the level of high-density lipoprotein (HDL) or good cholesterol reduces the risk of heart attack. But is the association really true?

But a study published today (May 17) in The Lancet suggests that a high HDL cholesterol level need not necessarily lower the risk of suffering from a heart attack.

If HDL is indeed a true plasma biomarker of an underlying pathological process (heart attack), then an increase in this biomarker should result in reduced risk of heart attack.

To test this, the researchers used a particular randomisation (mendelian randomisation) to check if people carrying a well known inherited gene variant (LIPG 396Ser) that is known to inherently increase the HDL level actually were at reduced risk of heart attack.

The proof

They found that people who had the variant had a higher HDL level but that did not result in reduced risk.

This came out by analysing 21,000 people who had suffered a heart attack and 95,000 controls (those who had not suffered an attack) from 20 studies.

Moreover, they constructed a genetic risk score for the 14 common single nucleotide polymorphisms (SNPs) that are commonly associated with HDL cholesterol and tested this score in nearly 12,500 people with a history of heart attack and over 41,000 controls.

The score did not show any high HDL level-low risk association, either.

Simultaneously, they put the 13 common SNPs that are “exclusively” associated with LDL cholesterol (bad cholesterol) through the same test and found that low LDL level did lower the risk.

“These results challenge several established views about plasma HDL cholesterol,” they write. “First, these data question the concept that raising plasma HDL cholesterol should uniformly translate into reductions in risk of myocardial infarction.”

Their conclusion, which is particularly linked to the gene variant (LIPG 396Ser), is that increasing the HDL level will not result in a positive clinical outcome.

Other ways of increasing the HDL levels have been tried earlier but have not achieved the desired result.

For instance, the authors cite the instance of increasing the HDL level by resorting to hormone replacement therapy in randomised controlled trials. Though the HDL level did increase, it did not produce a concomitant reduction in heart attack risk.

The same randomisation used in this study was used even earlier and the outcome was the same — high HDL level did not mean low risk of heart attack.

Hence the authors assert that “interventions (lifestyle or pharmacological) that raise plasma HDL cholesterol cannot be assumed ipso facto to lead to a corresponding benefit with respect to risk of myocardial infarction.”

However, the gene variant the authors used is rare in the population. Hence it may not serve as a strong indicator.

But as the Comment piece accompanying the Lancet article mentions, the study was robust and “any negative association [as seen in this study] can be regarded as definite.”

Clinical limitation

But the second salvo by the authors of the study is critical for clinical settings. They warn that using the plasma biomarker (HDL level) as a “surrogate measure for risk of heart attack” has some limitations.

However, more studies and re-evaluations are needed before the high HDL level-low risk of heart attack assumption is dismissed altogether.

In short, the search for the true biomarkers for coronary heart disease has begun in full earnest.