NLA 2025: Understanding the Impact of Omega-3 Fatty Acids on LDL Cholesterol

As interest in omega-3 fatty acids continues to grow, so do questions about their clinical applications, safety, and efficacy. For pharmacists counseling patients, understanding the nuances of omega-3 therapy—ranging from potential effects on (low-density lipoprotein) LDL cholesterol (LDL-C) levels to the populations that benefit most from treatment—is critical for optimizing patient outcomes.

At the 2025 National Lipid Association (NLA) Scientific Sessions, Frank Qian, MD, MPH, a cardiovascular medicine fellow at Boston Medical Center in Massachusetts, delivered a presentation on the evolving science and clinical considerations surrounding omega-3 fatty acids. In this interview with Pharmacy Times®, Qian discusses the key takeaways from his presentation, including current evidence on LDL cholesterol changes, patient populations who may benefit most from therapy, and important safety considerations such as atrial fibrillation risk and bleeding concerns.

Pharmacy Times: What is the current consensus on the impact of omega-3 fatty acids on LDL-C levels, and how should pharmacists counsel patients about potential increases in LDL from these therapies?

Frank Qian, MD, MPH: To answer this question, it’s important to consider the differences in dosing. For lower doses—such as 1 gram per day, which is typically found in over-the-counter fish oil supplements or prescription formulations like [omega-3 acid ethyl esters [Lovaza; Waylis Therapeutics]), which is 1 gram per day of a mixture of [eicosapentaenoic acid (EPA)] and [docosahexaenoic acid (DHA)]—there is generally no significant change in LDL-C levels. However, at higher doses, particularly with mixtures of EPA and DHA—such as 4 grams per day of [omega-3 acid ethyl esters]—there is typically a small increase in LDL-C, usually around 5% to 10%. One meta-analysis reported about a 7% increase. In contrast, purified EPA formulations, such as icosapent ethyl, as studied in the REDUCE-IT trial, do not appear to increase LDL-C levels. Some in the field believe the increase in LDL is primarily due to DHA, as DHA has been shown to lower triglycerides more effectively than EPA. The hypothesis is that the triglyceride-lowering effect of DHA could lead to a compensatory increase in LDL-C through mechanisms related to triglyceride clearance.

Pharmacy Times: Are there specific patient populations-such as those with diabetes, chronic kidney disease (CKD), or elevated triglycerides-who derive the most benefit from omega-3 fatty acid therapy?

Cholesterol in the bloodstream. Image Credit: © Li - stock.adobe.com

Qian: This was observed in both the REDUCE-IT and [Japan EPA Lipid Intervention Study (JELIS)] trials. One of the reasons for the triglyceride inclusion criteria of 135 to 500 mg/dL in REDUCE-IT was based on a subgroup analysis from JELIS—a trial conducted in Japan that tested 1.8 grams per day of purified EPA. That analysis suggested that patients with low HDL cholesterol and high triglycerides derived the greatest benefit from EPA therapy compared to the overall study population. This finding led to a focus on studying higher-risk populations, such as those with elevated triglycerides, in subsequent trials. In REDUCE-IT, as you mentioned, patients with diabetes or CKD—conditions that increase atherosclerotic risk—appeared to derive even greater benefit, likely because their baseline risk is higher than the general population.

Pharmacy Times: What are the key safety considerations and potential adverse effects pharmacists should monitor for when initiating or continuing omega-3 fatty acid therapy in patients?

Qian: There are some minor side effects to be aware of, as well as more serious considerations. The more common side effects are gastrointestinal—such as dyspepsia, fishy aftertaste, or diarrhea—which tend to occur more frequently if patients take omega-3 fatty acids on an empty stomach. That’s why the recommendation for products like icosapent ethyl is to take them with a meal, which not only helps reduce GI side effects but also improves absorption. Omega-3 fatty acids are in the ethyl ester form, and they need to be processed by digestive enzymes for optimal absorption.

Beyond GI issues, there are other important safety concerns. Atrial fibrillation is one of the more clinically significant risks, and as more trials using high-dose omega-3 fatty acids have been conducted, it’s become clear that there is a small but consistent increase in the incidence of atrial fibrillation. The risk is usually in the range of 1% to 2%. While this is an important trade-off to discuss with patients—particularly those at higher risk for arrhythmias—it’s worth noting that in trials like REDUCE-IT, RESPECT-EPA, and others, although the risk of atrial fibrillation was increased, there was no corresponding increase in stroke risk. This is reassuring, as stroke is often the most feared complication of atrial fibrillation.

Another potential concern is bleeding risk. In REDUCE-IT, there was a borderline increase in minor bleeding events, but no significant increase in serious bleeding complications such as hemorrhagic stroke, intracranial hemorrhage, or major gastrointestinal bleeding. While bleeding is a possible side effect, it generally manifests as minor bleeding events, and high-dose omega-3 fatty acids do not appear to increase the risk of major bleeding events in clinical trials.