Studies Spotlight Role Of Triglycerides, Put HDL In The Background

Two new studies provide more evidence tilting the balance in favor of triglycerides rather than HDL playing a causative role in cardiovascular disease. But it is still too early to know whether the findings of any of the studies will point to useful new methods to prevent and treat disease.

In the first study, published in Circulation: Cardiovascular Quality and Outcomes, researchers in Israel analyzed 22 year followup data from more than 15,000 patients who had been screened for the Bezafibrate Infarction Prevention (BIP) trial. They found a significant and independent association between triglyceride levels and mortality. At 22 years the survival rate for people with triglyceride levels over 500 mg/dL was significantly lower when compared to people with triglyceride levels below 100 mg/dL (25% versus 41%).

In an accompanying editorial, Karol Watson and Philipp Wiesner write that the study “adds to our scientific knowledge about the potential role of elevated triglycerides in cardiovascular risk, especially given the large numbers of individuals studied and the long follow-up.” But, they point out, BIP was performed in the era before widespread use of statins. It is unclear whether the findings would be the same in a contemporary population. However, it is known that there is significant residual risk in people taking statins who still have elevated triglycerides, but outcomes trials with drugs that lower triglycerides have not demonstrated benefit.

“The results of these outcome trials fail to support the hypothesis that a triglyceride-lowering drug reduces the risk for cardiovascular events among statin-treated patients—or at least the drugs that were studied in those trials,” write the editorialists. “We must always remember that simply because something may or may not be a cardiovascular risk factor, altering it pharmacologically does not always mean that we will lower risk,” they conclude.

In the second new study, published in Science, researchers identified a rare genetic variation in an HDL receptor gene that leads to increased levels of HDL in the blood. Although they have elevated HDL levels, people with this gene apparently have an increased risk for heart disease. The finding runs counter to expectations raised by several generations of epidemiology studies which consistently found that HDL cholesterol is inversely correlated with heart disease–  though studies with drugs that raise HDL cholesterol have not been successful.

This is “another nail in coffin for the simple notion that anything that raises HDL must be good for you,” said Sekar Kathiresan (Broad Institute), a co-author of the study. But Kathiresan, who has led previous genetic studies that found a causal role for triglycerides, admits that the new study does not rule out “an alternative HDL hypothesis emerging now that what really matters is HDL functionality.” However, he cautions that “this is a new hypothesis that requires evidence.”

The Science study examined the effect of a variant of scavenger receptor BI (SR-BI) gene, the first identified HDL receptor. The rare variant, found primarily in an Ashkenazi Jewish population, prevents cells from extracting HDL cholesterol, thereby leaving more circulating HDL cholesterol in the blood.

Monty Krieger (MIT), who discovered SR-BI twenty years ago, agrees with Kathiresan that the study “appears to be another case where the most simple model of the HDL hypothesis (HDL-C itself is atheroprotective) does not hold.” Krieger also agrees that there are a number of mechanisms which might explain the atheroprotective effect of SR-BI because this receptor, in addition to controlling circulating HDL in the blood, has been shown to have other functions.

Regarding triglycerides, Kathiresan also emphasizes the distinction between plasma triglycerides and points out that the latest genetic studies suggest that plasma triglycerides may be less important than triglyceride-rich lipoproteins (TRLs). Recent genetic studies performed by Kathiresan and others, including one published just last week,  have identified TRL-regulating genes that appear to have a direct causal role in heart disease.

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