The following are key points to remember from this review of the association between triglyceride lowering and reduction of cardiovascular (CV) risk across multiple lipid-lowering therapeutic classes:

1. The association between triglycerides and CV risk is well established from epidemiological studies, genome-wide analyses, and Mendelian randomization studies. The authors conducted a systematic review and meta-regression analysis (allows the effects of multiple factors and groups to be investigated simultaneously) of lipid-lowering therapy to assess the impact of triglyceride lowering on CV risk.
2. Triglycerides are a biomarker of CV risk but are not considered a risk factor because drugs with a significant effect on triglycerides have not shown a consistent reduction in major adverse CV events (MACE). Whether because the effect on low-density lipoprotein cholesterol (LDL-C) masked the impact on triglycerides for which the studies were not powered, or the target should be triglyceride-rich very LDL (VLDL) particles is not clear. And possibly, the omega-3 fatty acids may reduce MACE via a nonlipid mechanism. The authors examined the association between the magnitude of non–high-density lipoprotein cholesterol (non–HDL-C) (a surrogate for VLDL and LDL), LDL-C, and triglyceride lowering and the reduction in major vascular events across trials of fibrates, niacin, and marine omega-3 fatty acids, as well as statins as an established reference.
3. A total of 197,270 participants from 24 trials of nonstatin therapy with 25,218 major vascular events and 177,088 participants from 25 trials of statin therapy with 20,962 major vascular events were included, for a total of 374,358 patients and 46,180 MACE. The risk ratio (RR) (95% confidence interval) per 1 mmol/L reduction in non–HDL-C was 0.79 (0.76-0.82) (0.78 per 40 mg/dl).
4. In a multivariable meta-regression model that included terms for both LDL-C and triglyceride (surrogates for LDL and VLDL), the RR was 0.80 (0.76-0.85) per 1 mmol/L (0.79 per 40 mg/dl) reduction in LDL-C and 0.84 (0.75-0.94) per 1 mmol/L (0.92 per 40 mg/dl) reduction in triglycerides. The REDUCE-IT trial (synthetic EPA) was a significant outlier and strongly influential trial in the meta-regression. Regarding omega-3 dose, each 1 g/day of EPA administered was associated with a 7% relative risk reduction in major vascular events (RR, 0.93 [0.91-0.95]), whereas there was no significant reduction in MACE with DHA.
5. Summary of new findings:
   • A reduction in non–HDL-C, a measure of atherogenic LDL and VLDL particles, is strongly associated with lower risk of major vascular events regardless of the lipid-lowering drug class.
   • Triglyceride lowering is associated with a lower risk of CV events, but to a lower extent per absolute risk reduction per amount of reduction with LDL-C (20% vs. 8% in mg/dl).
   • Nearly all nonstatin trials did not achieve sufficient non–HDL-C lowering to detect differences in MACE.
   • The benefits of marine-derived omega-3 fatty acids, particularly high-dose EPA, appear to exceed their lipid-lowering effects.
6. Clinical implications:
   • Fibrates could be considered in patients needing further non–HDL-C lowering, as they should offer clinical benefit proportional to the degree of non–HDL-C lowering. However, one must be mindful of side effects and drug interactions, particularly with statins.
   • If a disproportionate relationship between lipid lowering and CV risk reduction is validated in ongoing high-dose omega-3 fatty acid trials, it will support the hypothesis that they confer unique benefits beyond lipid lowering.

Keywords: Biomarkers, Cholesterol, LDL, Drug Interactions, Dyslipidemias, Fatty Acids, Omega-3, Fatty Acids, Fibric Acids, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertriglyceridemia, Hypolipidemic Agents, Lipoproteins, Lipoproteins, VLDL, Niacin, Primary Prevention, Risk Factors, Triglycerides

< Back to Listings