Reflections on the REDUCE-IT™ Study

Among the highlights of this year’s American Heart Association meeting in Chicago was the REDUCE-IT Study, masterfully presented by my colleague, Dr. Deepak Bhatt and simultaneously published in the New England Journal of Medicine. The study examined the use of a highly concentrated and purified form of EPA, icosapent ethyl, in more than 8,000 men and women with high triglycerides and either cardiovascular disease or high-risk patients with diabetes.

We’ve known for many years that having high levels of LDL (the bad cholesterol) promotes heart disease and effective therapies such as statins, reduce rates of heart attacks and strokes.   And while high triglycerides also increase the likelihood of adverse heart-related outcomes, garnering support to conduct a large clinical trial aimed at studying men and women with elevated triglyceride levels was lacking. Elevated triglycerides are common in the U.S. and other westernized societies; approximately ~1 in 3 adults have triglyceride levels above 150 and ~1 in 5 have levels above 200 mg/dL.

After several large pharma companies passed on supporting such a study in men and women with heart disease and high triglycerides, the small Irish biopharma company, Amarin stepped up to the plate… the end result is the REDUCE-IT study.

Men and women assigned to the active treatment arm received 4 grams of icosapent ethyl daily. EPA is found in oily fish, such as sardines, salmon, herring and mackerel, but if you believe you can consume that amount in 1 serving of these fish, think again. With a single 3.5 ounce (100 gram) serving of salmon, the amount of EPA approximates ~0.7 grams.   In other words, you would need to consume ~20 ounces (570 grams) of salmon each day to get the amount obtained with 4 grams icosapent ethyl!

To quote some of my colleagues, the results of REDUCE-IT were “unprecedented”, “game changer”, “sea change”, et cetera, because of the magnitude in the reductions of heart attacks, strokes and cardiovascular death compared to other contemporary lipid trials. In part, this reflects the fact that clinical trials that study patients with heart disease must utilize standard-of-care therapies. This would include statins, where cardiovascular risk is reduced by 25-35%. Consequently, it has been very difficult to show additional benefit on the background of statin therapy. Not surprisingly, early studies failed and it wasn’t until the past decade when more effective therapies (ezetimibe, PCSK9i) were able to show significant lowering of events in the range of 6-15%. Now contrast that with REDUCE-IT, where a more robust 25% decrease in heart attacks and strokes was observed as well as a 20% reduction in cardiovascular death. Importantly, REDUCE-IT is the first lipid-based study to show improvement in cardiovascular death on the background of statin therapy.

BOTTOM LINE: We finally have a safe and effective therapy to treat men and women with heart disease, diabetes and high triglycerides.

Michael Miller, MD is Professor of Cardiovascular Medicine at the University of Maryland School of Medicine in Baltimore, Maryland USA.  He served on the Steering Committee for the REDUCE IT trial.