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REDUCE-IT results suggest rethinking what’s elevated triglyceride

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More chipping away at statin residual risk

Potential "game-changing" trials appear infrequently, but needless to say, they make a huge impact when they are validated. The atherosclerotic cardiovascular disease (ASCVD)/diabetes community fortunately has benefited from several lipid-lowering outcomes in recent years. Clinical trials with the PCSK9 and SGLT2 inhibitors already have had substantial impact on how we approach the patient with ASCVD, and now REDUCE-IT promises to move the needle substantially in both primary and secondary ASCVD prevention and in how we view triglyceride elevations.

After achieving LDL levels of 40-100 mg/dL with statin therapy, the 8,000-patient, 4.8-year trial demonstrated a robust 25% reduction in both primary and secondary outcomes in patients treated with 4 g/day of icosapent ethyl. Patients without previous cardiovascular disease (CVD) events with diabetes and one additional CVD risk factor (primary prevention cohort) achieved the same benefit. The "total event" as opposed to the first event analysis demonstrated a 30% overall risk reduction in patients having subsequent events.

The most stunning finding in REDUCE-IT was clearly that the benefit was not directly related to the baseline triglyceride level even though icosapent ethyl is a triglyceride-lowering agent. The subgroups with baseline triglycerides 150 mg/dL or less and those with 151-200 mg/dL had a comparable CVD benefit. The "total event" analysis, however, did demonstrate a more robust relative risk reduction in patients with baseline triglycerides of 251 mg/dL or higher.

Based on the REDUCE-IT findings, pure icosapent ethyl can be added to ezetimibe and PCSK9 inhibitors as agents that amplify the statin benefit and robustly reduce the elusive statin residual risk. The role of triglycerides in CVD remains unclear, although subgroup analysis from several fibrate studies suggest a CVD benefit from treating hypertriglyceridemia in patients with triglycerides of greater than 200 mg/dL. REDUCE-IT points to a largely independent action of icosapent ethyl. Laboratory studies suggest icosapent ethyl has potent plaque-stabilizing properties. The lowering of triglycerides may well play an additive but not primary role.

Just as was the case with LDL, as studies like this evolve our understanding of "normal" triglyceride levels will also evolve. Triglycerides may eventually join LDL with strong evidence that "lower is better." Stay tuned.

Paul Jellinger, MD, MACE, is a member of the editorial advisory board for Clinical Endocrinology News. He is professor of clinical medicine on the voluntary faculty at the University of Miami Miller School of Medicine and a practicing endocrinologist at The Center for Diabetes & Endocrine Care in Hollywood, Fla. He is past president of the American Association of Clinical Endocrinologists and the American College of Endocrinology.

This comment was added 6/10/2019.



– The success of icosapent ethyl in cutting triglyceride levels and reducing cardiovascular disease events in at-risk patients in the REDUCE-IT trial may make clinicians rethink the threshold for an unhealthy triglyceride level that merits intervention.

Dr. Deepak L. Bhatt, professor of medicine, Harvard Medical School, Boston Mitchel L. Zoler/MDedge News

Dr. Deepak L. Bhatt

Study results are also showing that the patients enrolled in REDUCE-IT are common, with apparently millions of Americans who could potentially receive the icosapent ethyl–processed fish oil used in the study if the Food and Drug Administration were to approve new labeling for the drug that the manufacturer filed for in late March 2019. Icosapent ethyl (Vascepa) already has U.S. marketing approval for reducing triglyceride (TG) levels in patients with baseline values of 500 mg/dL or greater, while the REDUCE-IT trial enrolled patients with established cardiovascular disease or diabetes plus at least one more risk factor with a TG level of 150-499 mg/dL. REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) enrolled only patients already on statin treatment and with a LDL cholesterol level of 41-100 mg/dL.

In reality, the clinicians who enrolled the 8,139 participants at 473 worldwide sites included patients with a TG level as low as 81 mg/dL, and 10% of entered patients had levels below the minimum threshold in the trial’s written design of at least 150 mg/dL. Initial results reported with the primary endpoint finding suggested that the icosapent ethyl treatment benefit extended to these patients who entered with what are currently considered normal TG values, and additional analyses reported by the study’s lead investigator, Deepak L. Bhatt, MD, which used a larger endpoint dataset that included total cardiovascular events rather than just first events, further confirmed that patients with lower baseline TG levels had reductions in their cardiovascular disease events that matched what was seen in patients who entered with substantially higher TG levels.

In the analysis that included total events, the tertile of patients with a baseline TG of 81-190 mg/dL had a statistically significant 26% relative reduction in events during an average 3.5-year follow-up, compared with the tertile of patients with a baseline level of 251 mg/dL or higher, who had a 40% reduction in their events during follow-up, reported Dr. Bhatt, professor of medicine at Harvard Medical School, Boston.

“We had patients [in REDUCE-IT] with lower triglycerides than the inclusion criteria. This shows that the study results apply to a broader range of patients,” he said in a talk at the annual meeting of the American College of Cardiology. “The total-event analysis gives us an appreciation of the large burden of ischemic events that statin-treated patients still have with baseline triglyceride levels of about 100 mg/dL.” Further analysis of the REDUCE-IT data, as well as future studies of TG-lowering drugs like icosapent ethyl, “may help redefine normal TG levels” in a manner similar to what happened over a 2-decade span as serial studies of statins and other drugs that reduced levels of LDL cholesterol led to incremental reductions in goal lipid levels.

In addition to providing greater precision in defining the impact of icosapent ethyl on events in patients with lower baseline TG levels, the total-event analysis “provided a better sense of what is actually going on” with patients clinically as they experience multiple cardiovascular events during follow-up, as well as the impact of treatment on reducing health-related costs. Concurrently with Dr. Bhatt’s report of the total-event analysis at the meeting, some of the new findings he presented also appeared online (J Am Coll Cardiol. 2019 March 18. doi: 10.1016/j.jacc.2019.02.032).

Dr. William E. Boden, professor of medicine, Boston Univerrsity Mitchel L. Zoler/MDedge News

Dr. William E. Boden

Recent analyses have also begun to assess the scope of patients who could potentially receive icosapent ethyl based on the enrollment criteria of REDUCE-IT. One analysis of more than 1 million people in the U.S. Veterans Affairs Health System during 2010 identified 439,019 people on statin treatment and with an LDL cholesterol of 41-100 mg/dL, the cardiovascular disease history or risk pattern that matched the trial, and not on treatment that could reduce TG levels such as fish oil. Among these people, 30% had a TG level at or above 150 mg/dL that would have qualified them to enter REDUCE-IT, said William E. Boden, MD, professor of medicine at Boston University. Among the 132,203 patients in this group who were on statin treatment and at their target LDL cholesterol level, the 5-year rate of cardiovascular disease events was 8.5% in those with higher TG levels and 6.3% in those with levels below 150 mg/dL, a statistically significant 19% increased risk after adjustment for some potential confounders, Dr. Boden reported in a poster he presented at the meeting. This analysis hinted at the magnitude of patients who are candidates for icosapent ethyl treatment based on REDUCE-IT, and the 19% residual increased risk they displayed showed what this treatment could address.

Analysis of another database identified 16% of more than 24,000 patients with stable coronary artery disease in the CLARIFY registry who would qualify for icosapent ethyl treatment by matching the REDUCE-IT enrollment criteria (J Am Coll Cardiol. 2019 March;73[11];doi: 10.1016/j.jacc.2019.01.016).

REDUCE-IT was sponsored by Amarin, the company that markets icosapent ethyl (Vascepa). Dr. Bhatt is an adviser to Cardax, PhaseBio, and Regado Biosciences, he is on the board of TobeSoft, and he has received research funding from several companies. Dr. Boden reported no disclosures.

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