R3i Editorial

Omega-3 fatty acids have seen a resurgence of interest over the last couple of years. This has been largely driven by the landmark study REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), which demonstrated a 25% reduction in major adverse cardiovascular events (MACE), in individuals with elevated triglycerides (TG), with an even higher relative risk reduction when total MACE were considered.^1,2 There are, however, clouds on the horizon, with the early termination of STRENGTH (Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia) this year. The decision to stop the STRENGTH study was based on the recommendation of an independent Data Monitoring Committee as it was unlikely to demonstrate a benefit to patients. Although the only public information available to date is from the press release,³ it is useful to consider the background to the two studies which may help to inform on this conundrum.

Both REDUCE-IT and STRENGTH were conducted in patients at high to very high cardiovascular risk, either with a prior cardiovascular event or diabetes and other cardiovascular risk factors, with elevated TG levels and controlled low-density lipoprotein cholesterol (LDL-C). Lipid inclusion criteria were generally similar. In REDUCE-IT, patients were required to have fasting TG ≥150 mg/dL (subsequently amended to >200 mg/dL) and <500 mg/dL. In STRENGTH, inclusion criteria were TG ≥ 180 to <500 mg/dL and high-density lipoprotein cholesterol <42 mg/dL (men) or <47 mg/dL (women), against a background of controlled LDL-C levels (on statin ± ezetimibe).⁴

While the total omega-3 fatty acid dose was approximately similar, the components differed between the two trials. REDUCE-IT used a regimen of 4 g/day eicosapentaenoic acid (EPA) ethyl ester, whereas in STRENGTH, the investigational treatment was Epanova 4 g/day, a mixture of EPA and docosahexaenoic acid (DHA), as ethyl esters (each 1-g capsule containing 0.465 g EPA and 0.375 DHA). Thus, the actual EPA daily dose was lower (less than 50%) in STRENGTH than in REDUCE-IT. The choice of placebo in the two studies also differed. REDUCE-IT used mineral oil as a placebo, whereas in STRENGTH, the placebo was corn oil. This may have some relevance in explaining the different results of the studies, given debate regarding the effects of the mineral oil placebo in REDUCE-IT. Notably, the placebo group in this study showed a 32% increase from baseline in C-reactive protein and 11.5% increase in LDL-C, which would indicate that the placebo was not neutral and may have confounded the study findings. No information is currently available from STRENGTH.

Prior to REDUCE-IT, controversy had raged regarding the potential cardiovascular benefit of marine omega-3 fatty acids. In 2018, a meta-analysis of aggregated data from 10 studies concluded that ‘omega-3 fatty acids had no significant association with fatal or nonfatal coronary heart disease or any major vascular events’; however, this was based on a dose range of 0.226-1.8 g/day, substantially lower than in REDUCE-IT.^1,5 Last year, another meta-analysis of 13 studies (including REDUCE-IT) revisited this question.⁶ This analysis concluded that marine omega-3 fatty acids significantly reduce the risk of cardiovascular events (overall relative risk reduction 12%, p<0.001); the significance of this finding persisted even after exclusion of REDUCE-IT (overall relative risk reduction 8%, p=0.02). Moreover, the risk reductions appeared to be linearly related to the omega-3 fatty acid dose.

It is, however, important to bear in mind that this cardiovascular benefit may be attributed partly to effects beyond TG lowering. Two lines of evidence from REDUCE-IT support this. First, the magnitude of TG-lowering in REDUCE-IT (median decrease from baseline to 1 year 18.3%, 39.0 mg/dL) was less than that expected based on the cardiovascular benefit.1 Second, there was no evidence of a dose-response relationship for TG lowering and cardiovascular benefit.⁷ Potential contenders for these non-lipid effects might include anti-inflammatory, anti-arrhythmic and anti-thrombotic effects, based on current knowledge of the pharmacology of omega-3 fatty acids.⁸

In the absence of the results of STRENGTH, these explanations are speculative. Clinicians will be eagerly awaiting public presentation of the STRENGTH data to draw their own conclusions.

References
1. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22.
2. Bhatt DL, Steg PG, Miller M, et al. Effects of Icosapent Ethyl on total ischemic events: from REDUCE-IT. J Am Coll Cardiol 2019;73:2791-802.
3. Update on Phase III STRENGTH trial for Epanova in mixed dyslipidaemia. Press release 13 January 2020. https://www.astrazeneca.com/media-centre/press-releases/2020/update-on-phase-iii-strength-trial-for-epanova-in-mixed-dyslipidaemia-13012020.html
4. Nicholls SJ, Lincoff AM, Bash D, et al. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: Rationale and design of the STRENGTH trial. Clin Cardiol 2018;41:1281-8.
5. Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77 917 individuals. JAMA Cardiol 2018;3:225-34.
6. Hu Y, Hu FB, Manson JE. Marine omega-3 supplementation and cardiovascular disease: an updated meta-analysis of 13 randomized controlled trials involving 127 477 participants. J Am Heart Assoc 2019;8¹⁹:e013543.
7. Bhatt DL, Steg PG, Miller M, et al. Reduction in first and total ischemic events with icosapent ethyl across baseline triglyceride tertiles. J Am Coll Cardiol 2019;74:1159-61.
8. Boden WE, Bhatt DL, Toth PP, et al. Profound reductions in first and total cardiovascular events with icosapent ethyl in the REDUCE-IT trial: why these results usher in a new era in dyslipidaemia therapeutics. Eur Heart J 2019 ;doi: 10.1093/eurheartj/ehz778. [Epub ahead of print]