Atherosclerotic cardiovascular disease (ASCVD) took center stage early on at Pri-Med Southwest 2022 in Houston when Christie M. Ballantyne, MD, FACP, FACC, and Peter P. Toth, MD, PhD, joined together to present a comprehensive talk on “Evaluating the Latest Evidence in ASCVD Risk Reduction.”
Dr. Ballantyne, of Baylor College of Medicine, Houston, is one of the nation’s foremost experts on lipids, atherosclerosis, and heart disease prevention. His research interest in the prevention of heart disease has led him to become an established investigator for the American Heart Association and to receive continuous funding from the NIH since 1988. Dr. Toth, Adjunct Associate Professor of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, is a Past President of the National Lipid Association and American Board of Clinical Lipidology and President of the American Society of Preventive Cardiology.
The clinically focused session addressed several important issues regarding the management of elevated triglycerides in patients at high CV risk. The first two topics discussed were the causal association between triglycerides (TG), TG-rich lipoproteins (TRL), TRL remnants, and significant increased risk of major adverse cardiovascular events and the role of omega-3 fatty acids, particularly icosapent ethyl, on reducing the risk of major adverse cardiovascular events in patients with hypertriglyceridemia.
Dr. Ballantyne initiated the presentation, taking up the subject of TG, TG-rich lipoproteins (TRL), and their association with ASCVD. He noted that even when LDL-C of <20 mg/dL is achieved, risk of CV death, MI, or stroke remains substantial. A key reason for this, Dr. Ballantyne said, is that management strategies that focus solely on LDL ignore other atherogenic lipids.
“We need to pay more attention to the fact that triglyceride-rich lipoproteins and their remnants are causally related to ASCVD,” he said.
By way of support, Dr. Ballantyne noted that residual hypertriglyceridemia (HTG) predicts residual ASCVD risk even when LDL-C has been reduced to goal on a high-intensity statin monotherapy.
“We know that lower triglyceride levels are better and that there is a direct association between average triglyceride level and CVD,” he said, presenting a graph showing that CVD events increase steeply across the range of TG levels up to ~200 mg/dL.
Unfortunately, elevated TG levels are pervasive in the U.S., Dr. Ballantyne noted. The good news, he said, is that guidelines are evolving to reflect the increasingly recognized importance of TG levels.
Healthcare providers interested in learning more in greater detail should refer to the American College of Cardiology’s 2021 “Expert Consensus Decision Pathway on the Management of ASCVD Risk Reduction in Patients With Persistent Hypertriglyceridemia: A Report of the American College of Cardiology Solution Set Oversight Committee.”
The Clinical Perspective: REDUCE-IT vs STRENGTH
Dr. Toth followed Dr. Ballantyne with a presentation focused on reducing CV events in patients with high TGs through use of icosapent ethyl (IPE). He called on the findings of the REDUCE-IT and STRENGTH trials to support the discussion.
The REDUCE-IT trial showed that use of IPE 2 g twice daily was superior to placebo in reducing TGs, CV events, and CV death among patients with high TGs and either known CVD or those at high risk for developing it, and who were already on statin therapy with relatively well-controlled LDL levels.
By contrast, the STRENGTH trial failed to show that omega-3 CA was superior to placebo at reducing adverse cardiovascular outcomes. In fact, the trial was terminated early due to interim analysis revealing low probability for benefit with omega-3 CA. The primary outcome of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina occurred in 12.0% of the omega-3 CA group compared with 12.2% of the placebo group (p = 0.84). Cardiovascular events were similar between the treatment groups.
However, Dr. Toth explained that the reason for the neutral finding of this trial and the positive REDUCE-IT trial is likely due to the different drugs studied: The latter trial studied a purified formulation of high-dose EPA, which resulted in much higher EPA levels. The prior JELIS trial had also studied pure EPA and was positive. The STRENGTH trial instead used omega-3 CA, a combination of EPA and DHA. It is thought possible that DHA counteracts the benefits of EPA.
Dr. Toth provided support for that position by noting that four trials that evaluated EPA (REDUCE-IT, JELIS, CHERRY, and EVAPORATE) all showed a reduction in CV risk while four trials that employed EPA/DHA instead of EPA (ASCEND, VITAL, STRENGTH, and OMEMI) did not. He went on to list the known differences between the marine omega-3 fatty acids EPA and DHA:
- Membrane stabilization and fluidity are very different
- Different resolvins are engaged
- Activity on oxidized LDL-C is different
- Different effects on anti-inflammatory biomarkers such as hsCRP
Dr. Toth concluded by labeling REDUCE-IT a “landmark trial” that showed that icosapent ethyl 4 g/day in addition to maximally tolerated statin therapy could reduce ASCVD events significantly, but warned clinicians to be sure to prescribe pure IPE.