Association Between Triglyceride Lowering and Reduction of Cardiovascular Risk Across Multiple Lipid-Lowering Therapeutic Classes : A Systematic Review and Meta-Regression Analysis of Randomized Controlled Trials

Abstract

Randomized trials of therapies that primarily lowered triglycerides have not consistently shown reductions in cardiovascular events. We performed a systematic review and trial-level meta-regression analysis of 3 classes of lipid-lowering therapies that reduce triglycerides to a greater extent than they do LDL-C: fibrates, niacin, and marine-derived omega-3 fatty acids. Key inclusion criteria were a randomized controlled trial that reported on major vascular events. We also incorporated data from a previous meta-regression of 25 statin trials. The main outcome measure was the risk ratio (RR) for major vascular events associated with absolute reductions in lipid parameters. A total of 197,270 participants from 24 trials of non-statin 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 major CV events. Starting with non-HDL-C, a surrogate for VLDL and LDL, the RR (95%CI) per 1 mmol/L reduction in non-HDL-C was 0.79 (0.76-0.82, P<0.0001) (0.78 per 40 mg/dl). In a multivariable meta-regression model that included terms for both LDL-C and triglyceride (surrogates for LDL and VLDL), the RR (95%CI) was 0.80 (0.76-0.85, P<0.0001) per 1 mmol/L (0.79 per 40 mg/dl) reduction in LDL-C and 0.84 (0.75-0.94, P=0.0026) per 1 mmol/L (0.92 per 40 mg/dl) reduction in triglycerides. REDUCE-IT was a significant outlier and strongly influential trial in the meta-regression. When removed, the RRs became 0.79 (0.76-0.83, P<0.0001) per 1 mmol/L (0.78 per 40 mg/dl) reduction in LDL-C and 0.91 (0.81-1.006, P=0.06) per 1 mmol/L (0.96 per 40 mg/dL) reduction in triglycerides. In regard to omega-3 dose, each 1 gram/day of EPA administered was associated with a 7% relative risk reduction in major vascular events (RR 0.93 [0.91-0.95], P<0.0001) whereas there was no significant reduction in major vascular events with DHA (RR 0.96 [0.89-1.03]). In randomized controlled trials, triglyceride lowering is associated with lower risk of major vascular events, even after adjusting for LDL-C lowering, although the effect is attenuated when REDUCE-IT is excluded. Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high-dose EPA, appear to exceed their lipid-lowering effects.