Donna K. Arnett, PhD, MSPH

The REDUCE-IT trial showed that a very high dose of icosapent ethyl was highly effective in reducing triglycerides and in reducing the primary outcome. These patients had LDL well-controlled on a statin and the majority of them already had a CV event. They were all hypertriglyceridemic. This was a special population, and amongst it, this very high-dose eicosapentaenoic acid product was effective. What that says is this is a good therapeutic option if you have high triglyceride levels and other high-risk factors.

We need to compare a combined fish oil product (eicosapentaenoic acid and docosahexaenoic acid) vs. the product from this study to see if we get equivalent results or whether the effect is limited to the eicosapentaenoic acid.

Kevin M. Pantalone, DO, ECNU, FACE

The REDUCE-IT CV outcome trial found icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, administered twice daily was associated with a 25% relative risk reduction on the composite endpoint of CV death, nonfatal MI, nonfatal stroke, coronary revascularization or unstable angina in patients with established CVD or diabetes with other risk factors, vs. placebo therapy (HR = 0.75; 95% CI, 0.68-0.83). Baseline LDL and triglyceride levels were 41 to 100 mg/dL and 135 to 499 mg/dL, respectively.  

An elevated triglyceride level has long been considered to be a marker of residual CV risk despite statin therapy, but the effect of triglyceride lowering on CV risk in various patient populations has long been debated. REDUCE-IT provides strong support for the use of icosapent ethyl to lower CV risk in this patient population. After a median follow-up of 4.9 years, among patients with elevated triglyceride levels despite the use of statins, risk reduction was observed with icosapent ethyl therapy. The change in triglyceride levels during the duration of trial was modest (median reduction from baseline was 19.7% greater with icosapent ethyl vs. placebo [44.5 mg/dL]), whereas the median change in LDL cholesterol level increased slightly from baseline in both groups 3.1%, (2 mg/dL) in the icosapent ethyl group and 10.2% (7 mg/dL) in the placebo group. The greater rise in LDL observed in the placebo arm is thought to be related to mineral oil use reducing statin absorption. This theory would be supported by the rise in C-reactive protein observed in the placebo arm. This issue may have contributed to differences in outcomes between the groups. While it is hard to explain the magnitude of the observed risk reduction with icosapent ethyl being related to this issue in the placebo arm, it must be taken into consideration when drawing conclusions about the study.

The results of this study do not necessarily mean lowering triglyceride levels in this population of patients reduces CV risk, rather, one can only conclude that the observed CV risk reduction is related to the icosapent ethyl therapy, perhaps, as the authors suggest, via anti-inflammatory, anti-oxidative, plaque-stabilizing and membrane-stabilizing properties.  Clinicians must avoid concluding that similar reductions in triglyceride levels afforded by other triglyceride-lowering therapies may also confer CV benefit. The icosapent ethyl therapy may be mitigating residual risk unrelated to triglyceride lowering.

As clinicians, we need to ensure that the focus on CV risk reduction occurs across the spectrum of management. Clinicians from the various specialties need to collaborate and coordinate so that our high-risk CV patients readily receive type 2 diabetes and CV-related therapies that have been reported to reduce CV risk.

Pradeep Natarajan, MD, MMSc

I found REDUCE-IT very compelling. The trial was done very well. It is increasingly recognized that triglyceride-rich lipoproteins influence recurrent risk for CVD and future CV events.

Does REDUCE-IT prove lowering triglycerides reduces CV risk? Probably not cleanly. Icosapent ethyl lowers triglycerides but seems to do several other things. It’s almost a polypill of sorts. It reduces triglyceride-rich lipoproteins, has an antithrombotic/antiplatelet effect, has a membrane-stabilizing effect and potentially has other effects as well. Regardless of the mechanism, the apparent relative reduction of 25% over 5 years is very similar to what has been observed in prior statin trials. Also, the association with reduced CVD mortality is compelling.

A key concern is that the placebo is not an inert placebo. Individuals assigned mineral oil may have had absorption of other lipid-lowering medicines interfered with. There was a slightly higher LDL level among those individuals. I don’t think the difference in LDL explains the full apparent treatment effect. The difference in LDL was between 5 and 10 mg/dL. In statin trials, a difference of 40 mg/dL led to a similar relative risk reduction. So, one can’t say the results are fully explained by an increase in LDL from the placebo, but it probably affects our understanding of the true treatment effect, which is probably lower than 25%. This concern came up previously in the ANCHOR study of icosapent ethyl, which used the same placebo which had the same effect on LDL. This came up at the FDA hearing. When the REDUCE-IT results ultimately go to the FDA, this will be brought up again, though because the treatment effect was so large, I don’t think the FDA will attribute it all to the effects from the placebo.

It’s not clear if stratifying patients by triglyceride levels is the best way to identify who is the best candidate for icosapent ethyl, given that it seems to have other effects. In the JELIS study, what correlated better with treatment effect was change in eicosapentaenoic acid level.

While there are still many questions to be answered, the findings are compelling and provide a new tool in our armamentarium to treat patients with residual hypertriglyceridemia and atherosclerotic CVD.