New AHA Guidance on Omega-3 Fatty Acids for High Triglycerides

Prescription-strength omega-3 fatty acids, available at the US Food and Drug Administration-approved dose of 4 g/day, are a safe and effective treatment for reducing triglycerides among individuals with hypertriglyceridemia, according to a new scientific statement from the American Heart Association (AHA).

Before omega-3 fatty acids are prescribed, however, physicians should first address any potential secondary causes of high triglycerides, such as hyperthyroidism or poorly managed type 2 diabetes, as well as implement a strategy to modify diet and lifestyle.

“If these changes are not possible or not effective, initiating triglyceride-lowering pharmacotherapy may be required,” write Ann Skulas-Ray, PhD (University of Arizona, Tucson), and colleagues in a paper published online August 19, 2019, in Circulation.

The science advisory updates prior AHA documents focused on omega-3 fatty acids, dating back to 2002 and 2011, that predate the advent of purified, prescription-strength formulations. The document also focuses specifically on their effects on hypertriglyceridemia, rather than atherosclerotic vascular disease.

To TCTMD, Skulas-Ray stressed that the degree of treatment response to omega-3 prescriptions is determined by the severity of an individual’s triglyceride levels prior to treatment. She also noted that levels are highly variable day-to-day, so the determination of response shouldn’t be based on a single triglyceride measurement.

For managing hypertriglyceridemia (200-499 mg/dL), the AHA experts state that prescription-strength omega-3 fatty acids, either with eicosapentaenoic acid (EPA) or EPA plus docosapentaenoic acid (DHA), would be expected to yield a 20% to 30% reduction in triglycerides without any increase in LDL cholesterol. For individuals with severe hypertriglyceridemia, 4 g/day of omega-3 fatty acids will reduce triglycerides by more than 30%, but LDL cholesterol may increase in agents that contain DHA. The goal for patients with severe hypertriglyceridemia is to reduce decrease triglycerides to less than 500 mg/dL and decrease the risk of pancreatitis.

“One of the surprising findings of this analysis is that the prescription omega-3 fatty acids containing DHA did not increase LDL cholesterol in studies of people with triglycerides less than 500 mg/dL,” said Skulas-Ray. In prior studies suggesting that DHA-containing agents may increase LDL cholesterol, researchers did not stratify by patient populations, such as those with and without severe hypertriglyceridemia. “The results we reviewed suggest to me that LDL increases proportionally to the degree of triglyceride reduction, not as a result of the prescription agent containing DHA,” she said.  

Since 2004, several types of prescription-strength omega-3 fatty acid products have been approved by the FDA for lowering triglycerides, including Vascepa (Amarin), Lovaza (GlaxoSmithKline), Epanova (AstraZeneca), and two generic products. Their use in the treatment of high triglycerides recently received a massive boost with the publication of REDUCE-IT, a 2018 study testing 4 g/day of Amarin’s icosapent ethyl, a highly purified EPA ethyl ester. In that trial of patients with high triglycerides (135 to 499 mg/dL) also at high risk for cardiovascular disease, the addition of the omega-3 fatty acid on top of statin therapy reduced major adverse cardiovascular events by 25%.

“When we began writing this advisory, the results of REDUCE-IT were not yet available,” Skulas-Ray told TCTMD. “We delayed publication in order to include results of this trial. Omega-3 fatty acids are not always part of the discussion regarding triglyceride management, and this was likely due to the lack of studies evaluating effects prescription dosing of omega-3 fatty acids on hard endpoints in a population with elevated triglycerides. The results of REDUCE-IT changed that.”

Icosapent ethyl is currently approved for lowering triglyceride levels in patients with severe hypertriglyceridemia (≥ 500 mg/dL) but not yet for those with triglyceride levels in the range tested in the REDUCE-IT trial. It also is not yet approved for the prevention of cardiovascular events, but an FDA advisory committee is planned for November 14, 2019, to review REDUCE-IT and discuss the potential for an expanded indication to include cardiovascular event reduction.

Another large-scale cardiovascular outcomes study in patients with hypertriglyceridemia is currently underway. The STRENGTH trial, testing a 4 g/day of omega-3 carboxylic acid (containing both EPA and DHA) in patients with hypertriglyceridemia and low HDL cholesterol levels currently treated with statins, is expected to be completed and presented in 2020.

In the new statement, the AHA lays out various clinical conditions and drugs associated with hypertriglyceridemia and the efficacy of other drugs for lowering triglyceride levels. For example, fibrates lower triglyceride levels by 30% to 50%, while immediate- and extended-release niacin lower levels anywhere from 10% to 50%. In addition, they cite clinical evidence highlighting the effectiveness of prescription-strength omega-3 fatty acids as a monotherapy and when added to other lipid-lowering therapies. Statin therapy, according to the experts, does not appear to influence the degree of triglyceride-lowering with omega-3 fatty acid therapy.

“All forms of omega-3 fatty acid products have relatively benign side-effect profiles and are generally safe,” the AHA document states, but the safety data largely comes from short-term randomized trials. The drugs do have an antiplatelet effect, so the FDA prescribing information reminds physicians to watch for bleeding among patients concomitantly treated with anticoagulant or antiplatelet therapy.