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

Background: Randomized trials of therapies that primarily lowered triglycerides have not consistently shown reductions in cardiovascular events.

Methods: 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 low-density lipoprotein cholesterol (LDL-C): fibrates, niacin, and marine-derived omega-3 fatty acids. Key inclusion criteria were a randomized controlled trial that reported 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.

Results: 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 major cardiovascular events. Starting with non-high-density lipoprotein cholesterol, a surrogate for very-low-density lipoproteins and low-density lipoproteins, the RR per 1-mmol/L reduction in non-high-density lipoprotein cholesterol was 0.79 (95% CI, 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 low-density lipoproteins and very-low-density lipoproteins, respectively), the RR was 0.80 (95% CI, 0.76-0.85; P<0.0001) per 1-mmol/L (0.79 per 40 mg/dL) reduction in LDL-C and 0.84 (95% CI, 0.75-0.94; P=0.0026) per 1-mmol/L (0.92 per 40 mg/dL) reduction in triglycerides. REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) was a significant outlier and strongly influential trial in the meta-regression. When removed, the RRs became 0.79 (95% CI, 0.76-0.83; P<0.0001) per 1-mmol/L (0.78 per 40 mg/dL) reduction in LDL-C and 0.91 (95% CI, 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 g/d eicosapentaenoic acid administered was associated with a 7% relative risk reduction in major vascular events (RR, 0.93 [95% CI, 0.91-0.95]; P<0.0001), whereas there was no significant association between the dose of docosahexaenoic acid and the relative risk reduction in major vascular events (RR 0.96 [95% CI, 0.89-1.03]).

Conclusions: In randomized controlled trials, triglyceride lowering is associated with a lower risk of major vascular events, even after adjustment for LDL-C lowering, although the effect is less than that for LDL-C and attenuated when REDUCE-IT is excluded. Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high-dose eicosapentaenoic acid, appear to exceed their lipid-lowering effects.

Keywords: fatty acids, omega-3; fibrates; lipids; lipoproteins, LDL; lipoproteins, VLDL; niacin; triglycerides.

Figure 1:

Regression of non-HDL-C reduction and RR for major vascular events in 37 trials of statins, fibrates, niacin, and omega-3 fatty acids. 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). (non-HDL-C = non-high-density lipoprotein; O3FA = Omega 3 Fatty Acid; RR = Risk Ratio).

Figure 2:

Effect of 1 mmol/L difference in (A) achieved TG on RR for major vascular events [all trials (solid regression line): RR 0.84 (0.75-0.94), P=0.0026 (0.92 per 40 mg/dl); without REDUCE-IT (dashed regression line): RR 0.91 (0.81-1.006, P=0.06) (0.96 per 40 mg/dl) at mean weighted LDL-C (0.5586 mmol/L) and (B) achieved LDL-C on RR for major vascular events [all trials (solid regression line): RR 0.80 (0.76-0.85), P<0.0001 (0.79 per 40 mg/dl); without REDUCE-IT (dashed regression line): RR 0.79 (0.76-0.83, P<0.0001) (0.78 per 40 mg/dl) at mean weighted achieved TG (0.2918 mmol/L). (LDL-C = low-density lipoprotein; TG = triglyceride; O3FA = Omega 3 Fatty Acid; RR = Risk Ratio)

Figure 3:

Regression of EPA dose (Panel A) and DHA dose (Panel B) and RR for major vascular events in trials of omega-3 fatty acids. The RR (95%CI) per 1 gram/day of EPA was 0.93 (0.91-0.95), p<0.0001), and for DHA was 0.96 (0.89-1.03), p=0.27. (EPA = eicosapentaenoic acid; DHA = docosahexaenoic acid; RR = Risk Ratio)