Is It Time to Stop Treating High Triglycerides?

Recent trial evidence has failed to show a cardiovascular benefit to treating high triglycerides. The publication of the PROMINENT trial, where pemafibrate successfully lowered high levels but was not associated with a lower risk for cardiovascular events, reinforced the point. Is it time to stop measuring and treating high triglycerides?

Christopher Labos, MD CM, MSc, March 29, 2023

There may be noncardiovascular reasons to treat hypertriglyceridemia. Pancreatitis is the most cited one, given that the risk for pancreatitis increases with increasing triglyceride levels, especially in patients with a prior episode.

There may also be practical reasons to lower trigs. Because most cholesterol panels use the Friedewald equation to calculate low-density lipoprotein cholesterol (LDL-C) rather than measuring it directly, very high triglyceride levels can invalidate the calculation and return error messages on lab reports.

But we now have alternatives to measuring LDL-C, including non–high-density lipoprotein cholesterol (HDL-C) and apolipoprotein B (apoB), that better predict risk and are usable even in the setting of nonfasting samples when triglycerides are elevated.

Independent Cardiovascular Risk Factor?

If we are going to measure and treat high triglycerides for cardiovascular reasons, the relevant question is, are high triglycerides an independent risk factor for cardiovascular disease?

Proponents have a broad swath of supportive literature to point at. Multiple studies have shown an association between triglyceride levels and cardiovascular risk. The evidence even extends beyond traditional epidemiologic analyses, to genetic studies that should be free from some of the problems seen in observational cohorts.

But it is difficult to be certain whether these associations are causal or merely confounding. An unhealthy diet will increase triglycerides, as will alcohol. Patients with diabetes or metabolic syndrome have high triglycerides. So do patients with nephrotic syndrome or hypothyroidism, or hypertensive patients taking thiazide diuretics. Adjusting for these baseline factors is possible but imperfect, and residual confounding is always an issue. An analysis of the Reykjavik and the EPIC-Norfolk studies found an association between triglyceride levels and cardiovascular risk. That risk was attenuated, but not eliminated, when adjusted for traditional risk factors such as age, smoking, blood pressure, diabetes, and cholesterol.

Randomized trials of triglyceride-lowering therapies would help resolve the question of whether hypertriglyceridemia contributes to coronary disease or simply identifies high-risk patients. Early trials seemed to support the idea of a causal link. The Helsinki Heart Study randomized patients to gemfibrozil or placebo and found a 34% relative risk reduction in coronary artery disease with the fibrate. But gemfibrozil didn’t only reduce triglycerides. It also increased HDL-C and lowered LDL-C relative to placebo, which may explain the observed benefit.