PACE-CME

A good day. It's my pleasure to present the effectiveness of icosapent ethyl on first and total cardiovascular events in the metabolic syndrome. This is the REDUCE-IT Met Syndrome study, and these are my disclosures.

The reason to do this analysis which was pre-specified is because metabolic syndrome is associated with a high risk of cardiovascular events, about twofold greater than those patients without a metabolic syndrome and irrespective of statin therapy. Metabolic syndrome is quite prevalent. More than one of three adult Americans have it, and one in four worldwide have the metabolic syndrome. It's a cluster of at least three of the following risk factors and they include elevated waist circumference, elevated blood pressure, elevated fasting glucose, triglycerides of at least 150 and a low HDL.

This study evaluated the pre-specified patient subgroup with metabolic syndrome that were characterized by at least three of these metabolic syndrome components but without having diabetes at baseline.

The baseline characteristics of patients with metabolic syndrome but without diabetes at baseline is shown on this slide. Essentially, there were no differences at baseline between the groups either assigned to icosapent ethyl or IPE versus placebo. Median age was about 62, about 80% male in the groups and 20% female. Then, if you look down on the other parameters, there were really no significant differences. There was a trend to a little bit of low HDL but other than that, there were no differences at baseline.

Similarly, baseline medications of patients with metabolic syndrome and the absence of diabetes at baseline is shown here. As would be expected from a group with metabolic syndrome, a high percentage were on anti-hypertensive medications as well as, of course, as part of REDUCE-IT, patients needed to be on a statin, so not surprisingly high percentages on these meds but no differences between the groups at baseline.

Now, this slide shows you the total, that's first plus subsequent events and the time to the initial composite endpoint in patients with Met Syndrome who had at least three of these risk factors but, again, without diabetes at baseline. Icosapent ethyl is seen in blue and placebo in the red. As you see at the bottom part of the slide, there was a pretty significant reduction in initial endpoints compared to placebo and then in total events, there was also a pretty hefty reduction in events of about 41%.

Total, that's first plus secondary and time to the key secondary composite endpoint, cardiovascular death, myocardial infarction and stroke is again shown here and there was a 20% reduction in those assigned to icosapent ethyl for the secondary endpoint.

All of these in primary and secondary endpoints were highly statistically significant as was the total number of endpoints.

This slide shows the primary and key secondary composite endpoints as well as new-onset diabetes by baseline metabolic syndrome in patients who did not have diabetes at baseline. As you could see here, those patients that had the metabolic syndrome certainly gained benefit to a much greater extent than those that did not have baseline metabolic syndrome, although there were no differences between the groups with respect to the P interaction. There was no evidence that icosapent ethyl led to an increase in new-onset diabetes compared to placebo.

This shows you diabetes status at baseline population. What we're looking at here are those patients that had metabolic syndrome with or without diabetes at baseline and there were no differences, again, between the groups here. More patients in the REDUCE-IT trial had diabetes, so all of the primary prevention patients in the study had diabetes and those that had metabolic syndrome without diabetes represent a secondary prevention population. There were 2866 patients in the group that comprised metabolic syndrome.

This shows the efficacy endpoints by the metabolic syndrome risk factors and here, again, virtually, all the risk factors with the exception of those that did not have hypertension and those that did not have a low HDL trended towards significance, but those with, of course, the risk factors did have benefit with the use of icosapent ethyl.

Finally, primary and secondary endpoints in patients who had metabolic syndrome by cardiovascular risk category and comparing, again, secondary versus primary prevention. Again, these are all the metabolic syndrome patients, so many of them had diabetes but no significant differences between the groups in as much as that there was a trend in secondary prevention, but the number of patients in primary prevention were also lower compared to secondary prevention. However, the interactive P-value was negative or was not significant.

Now, treatment-emergent atrial fibrillation and atrial flutter,something that we know is increased in patients receiving omega-3 fatty acids were, again, increased here although the P-value was at 0.06.

Here are some of the bleeding adverse events or hemorrhagic stroke. There was increased bleeding in those assigned to IPE, but there was no significant differences in hemorrhagic stroke.

Overall, in patients with metabolic syndrome and without diabetes at baseline hospitalization, there was an increase in positively adjudicated atrial fibril or flutter. It was higher. P-value was 0.06. Treatment-emergent adverse events showed that there was a trend towards increased bleeding with IPE, but there were no significant differences for either bleeding adverse events or hemorrhagic stroke endpoints, and there were no differences in new-onset diabetes with respect to IPE treatment.

Now, limitations of the study. REDUCE-IT was designed and powered for the primary endpoint, not powered for subgroup analysis. Some of these analyses were exploratory in nature such as cardiac arrest and sudden cardiac death, and a variation in subjective measures such as waist circumference, of course, may have affected some of the classification of that component of the definition of metabolic syndrome.

In conclusion, in statin-treated patients with a history of metabolic syndrome but without diabetes at baseline, icosapent ethyl significantly reduced the risk of first and total cardiovascular events compared with placebo. IPE reduces CVD risk in patients with metabolic syndrome, despite lacking robust effects on any of the metabolic syndrome parameters. The large relative and absolute reductions observed support icosapent ethyl as a potential therapeutic consideration for our patients who have metabolic syndrome and are at increased cardiovascular risk.

I wanted to thank our investigators, coordinators, and most importantly, all the patients that participated in the REDUCE-IT trial. This paper is now published in the European Heart Journal Open online. Thank you very much.