European Primary Care Cardiovascular Society

Lower risk of ischemic events with triglyceride-lowering agent in hypertriglyceridemic patients on statins

AHA 2018 – Chicago, IL, USA

News - Nov. 13, 2018

The Primary Results of the REDUCE-IT Trial

Presented at the AHA congress 2018 by: Deepak L. Bhatt (Boston, MA, USA)

Introduction and methods

High triglyceride (TG) levels seem a risk factor, but is unclear whether they represent a causal risk factor, because low-dose omega-3 interventions to lower TGs have not shown a significant CV benefit. The Japanese JELIS study, which has not received a lot of attention, did suggest CV risk reduction with eicosapentaenoic acid (EPA) in Japanese hypercholesterolemic patients, both in a primary and secondary prevention cohort. Critic to the JELIS study included that Japanese people have a higher degree of fish consumption in general, and that there was no placebo control.

The REDUCE-IT trial thus set out to test some of these observations. 6179 patients (43% of those screened) aged at least 45 years old with established CVD (secondary prevention cohort) or ≥50 years old with diabetes with ≥1 additional risk factor for CVD (primary prevention cohort) were randomized to either icosapent ethyl (2 mg twice daily), a highly purified EPA ethyl ester, or placebo. Fasting TG levels were ≥150 mg/dL and <500 mg/dL. LDL-c should be >40 mg/dL and ≤100 mg/dL, and patients should be on stable statin therapy (±ezetimibe) for at least 4 weeks. Median follow-up was 4.8 years.

Main results

Conclusion

Compared with placebo, icosapent ethyl 4 grams/day significantly reduced important CV events by 25%, including death due to CV causes (20%), heart attack (31%) and stroke (28%). The rate of adverse events was low, but a small but significant increase in atrial fibrillation or flutter was seen and a non-statistically significant increase in serious bleeding. Consistent efficacy was seen across multiple subgroups.

Discussion

The discussant Carl Orringer noted that hypertriglycerideamia is an independent marker of increased CVD risk, and TGs may increase remnant cholesterol to the arterial wall, which contributes to a pro-inflammatory milieu. Studies of statins combined with extended-release niacin and fibrates have shown no ASCVD risk reduction benefit. A reduced incidence of non-fatal CVD events was reported with low-intensity statin + EPA vs. low-intensity statin monotherapy in a Japanese primary and secondary prevention RCT.

The highly significant reductions observed now, in the presence of relatively modest effects on lipids, suggest that icosapent ethyl may act another aspects. Possible mechanisms of benefit include lipid or lipoprotein reduction, anti-thrombotic effects, anti-inflammatory effects, membrane stabilization or plaque stabilization. It should be noted that 90% of patients were white, thus the benefit in other ethnicities remains unclear.

Orringer concluded that there are now three proven therapies with favorable risk/benefit-ratio’s on top of statins: ezetimibe, PCSK9 inhibitors and icosapent ethyl.

- Our reporting is based on the information provided at the AHA Scientific Sessions -

This study was published simultaneously in NEJM View our video about this study

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