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AHA: Prescription fish oil effectively lowers high triglycerides

Four grams per day of omega-3 fatty acids, specifically eicosapentaenoic acid and docosahexaenoic acid together or eicosapentaenoic acid alone, is clinically useful as monotherapy or in addition to other therapies to reduce triglycerides after implementing diet and lifestyle changes and addressing any underlying causes, according to an American Heart Association science advisory published in Circulation.

“From our review of the evidence from 17 randomized controlled clinical trials on high triglyceride levels, we concluded that treatment with 4 g daily of any of the available prescription choices is effective and can be used safely in conjunction with statin medicines that lower cholesterol,” Ann C. Skulas-Ray, PhD, assistant professor in the department of nutritional sciences at The University of Arizona College of Agriculture and Life Sciences in Tucson and member of the writing group, said in a press release.

FDA-approved medications

Several prescription versions of omega-3 fatty acids have been approved by the FDA including omega-3 acid-ethyl esters (Lovaza, SmithKline Beecham), omega-3 acid ethyl esters type A (Omtryg, Osmotica), icosapent ethyl (Vascepa, Amarin) and omega-3 carboxylic acid (Epanova, AstraZeneca), according to the science advisory. Omega-3 acid-ethyl esters, icosapent ethyl and omega-3 carboxylic acid have all been tested at 4 g per day and resulted in reductions in plasma triglyceride levels by 30% to 35% in patients with baseline levels of 600 mg/dL to 800 mg/dL.

Despite these benefits with omega-3 fatty acids, patients with very high triglycerides may need multiple mediations in addition to changes in lifestyle and diet to achieve acceptable triglyceride levels, according to the science advisory. Data are limited regarding the use of omega-3 fatty acids with nonstatin therapy for the treatment of these patients.

The writing group analyzed data from 17 trials that focused on patients with high triglycerides between 200 mg/dL and 499 mg/dL. Omega-3 fatty acids as monotherapy were found to reduce triglycerides in these patients, according to the science advisory.

Patients also had reductions in triglycerides between 22% and 31% when omega-3 fatty acids were added to a statin or ezetimibe. Data are limited on the effects of omega-3 fatty acids when combined with niacin and fibrates, according to the science advisory.

No head-to-head comparisons have been done to compare eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), although there have been some studies that comprised the triglyceride and LDL effects of omega-3 fatty acids in patients with high triglycerides.

“The lack of studies directly comparing the three prescription [omega-3 fatty acid] agents limits firm conclusions about the comparative effects of these agents on triglycerides and other lipid measures,” Skulas-Ray and colleagues wrote.

There has been some concern about DHA increasing LDL levels in patients with high triglycerides. The writing group confirmed in eight studies that there was no change in LDL in patients assigned omega-3 fatty acids compared with placebo. There was one study that showed a marginal increase in LDL.

“There is no strong evidence that DHA-containing prescription [omega-3 fatty acid] agents used as monotherapy or in combination with statins raise LDL in patients with [high triglycerides],” Skulas-Ray and colleagues wrote.

Data are also unclear regarding the effects of EPA on LDL in patients with high triglycerides, according to the science advisory. A determining factor of whether EPA and DHA affect LDL levels may be the magnitude of triglyceride reduction.

An AHA scientific statement released in 2002 previously recommended 2 g to 4 g per day of EPA and DHA for the reduction of triglycerides. Since then, several studies have shown greater efficacy with 4 g per day.

“Regardless of the type of agent, 4 g [per day] prescription [omega-3 fatty acid] agents (providing > 3 g [per day] EPA+DHA) have consistently reduced triglyceride levels in patients with elevated triglycerides,” Skulas-Ray and colleagues wrote.

Omega-3 fatty acids may also be safe in adolescents and children with elevated triglycerides, but there are few studies that focused on this patient population, according to the science advisory. Because of this, the recommended use of omega-3 fatty acids by the FDA are limited to adults.

Mechanisms of triglyceride lowering

Several mechanisms may explain omega-3 fatty acids and lipoprotein metabolism such a reduction in hepatic secretion of triglyceride-rich lipoproteins, inhibition of diacylglycerol acyltransferase, inhibition of phosphatidic acid phosphatase and reduction in de novo lipogenesis, according to the science advisory. Triglyceride synthesis may also be reduced by omega-3 fatty acids through sterol regulatory element-binding protein 1 (SREBP-1) activity suppression and activation via posttranslational mechanisms.

All forms of omega-3 fatty acids have been shown to be safe, although data to confirm this are mainly from trials with short-term follow-up, according to the science advisory. Some of the adverse effects include eructation, fishy taste, nausea and diarrhea. Patients who are also taking an anticoagulant or antiplatelet should also be monitored periodically when taking omega-3 fatty acids.

The REDUCE-IT trial was presented at AHA Scientific Sessions in 2018. As Healio previously reported, icosapent ethyl was superior to placebo for reducing the risk for ischemic events in patients with elevated triglycerides at high CV risk despite statin therapy. Another trial — STRENGTH — is currently being conducted to assess omega-3 carboxylic acid in approximately 13,000 patients and is expected to be completed in 2020, according to the science advisory.

“Dietary supplements containing omega-3 fatty acids are not regulated by the FDA,” Skulas-Ray said in a press release. “They should not be used in place of prescription medication for the long-term management of high triglycerides.” – by Darlene Dobkowski and Erik Swain

Disclosures: Skulas-Ray reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

Four grams per day of omega-3 fatty acids, specifically eicosapentaenoic acid and docosahexaenoic acid together or eicosapentaenoic acid alone, is clinically useful as monotherapy or in addition to other therapies to reduce triglycerides after implementing diet and lifestyle changes and addressing any underlying causes, according to an American Heart Association science advisory published in Circulation.

“From our review of the evidence from 17 randomized controlled clinical trials on high triglyceride levels, we concluded that treatment with 4 g daily of any of the available prescription choices is effective and can be used safely in conjunction with statin medicines that lower cholesterol,” Ann C. Skulas-Ray, PhD, assistant professor in the department of nutritional sciences at The University of Arizona College of Agriculture and Life Sciences in Tucson and member of the writing group, said in a press release.

FDA-approved medications

Several prescription versions of omega-3 fatty acids have been approved by the FDA including omega-3 acid-ethyl esters (Lovaza, SmithKline Beecham), omega-3 acid ethyl esters type A (Omtryg, Osmotica), icosapent ethyl (Vascepa, Amarin) and omega-3 carboxylic acid (Epanova, AstraZeneca), according to the science advisory. Omega-3 acid-ethyl esters, icosapent ethyl and omega-3 carboxylic acid have all been tested at 4 g per day and resulted in reductions in plasma triglyceride levels by 30% to 35% in patients with baseline levels of 600 mg/dL to 800 mg/dL.

Despite these benefits with omega-3 fatty acids, patients with very high triglycerides may need multiple mediations in addition to changes in lifestyle and diet to achieve acceptable triglyceride levels, according to the science advisory. Data are limited regarding the use of omega-3 fatty acids with nonstatin therapy for the treatment of these patients.

The writing group analyzed data from 17 trials that focused on patients with high triglycerides between 200 mg/dL and 499 mg/dL. Omega-3 fatty acids as monotherapy were found to reduce triglycerides in these patients, according to the science advisory.

Patients also had reductions in triglycerides between 22% and 31% when omega-3 fatty acids were added to a statin or ezetimibe. Data are limited on the effects of omega-3 fatty acids when combined with niacin and fibrates, according to the science advisory.

No head-to-head comparisons have been done to compare eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), although there have been some studies that comprised the triglyceride and LDL effects of omega-3 fatty acids in patients with high triglycerides.

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“The lack of studies directly comparing the three prescription [omega-3 fatty acid] agents limits firm conclusions about the comparative effects of these agents on triglycerides and other lipid measures,” Skulas-Ray and colleagues wrote.

There has been some concern about DHA increasing LDL levels in patients with high triglycerides. The writing group confirmed in eight studies that there was no change in LDL in patients assigned omega-3 fatty acids compared with placebo. There was one study that showed a marginal increase in LDL.

“There is no strong evidence that DHA-containing prescription [omega-3 fatty acid] agents used as monotherapy or in combination with statins raise LDL in patients with [high triglycerides],” Skulas-Ray and colleagues wrote.

Data are also unclear regarding the effects of EPA on LDL in patients with high triglycerides, according to the science advisory. A determining factor of whether EPA and DHA affect LDL levels may be the magnitude of triglyceride reduction.

An AHA scientific statement released in 2002 previously recommended 2 g to 4 g per day of EPA and DHA for the reduction of triglycerides. Since then, several studies have shown greater efficacy with 4 g per day.

“Regardless of the type of agent, 4 g [per day] prescription [omega-3 fatty acid] agents (providing > 3 g [per day] EPA+DHA) have consistently reduced triglyceride levels in patients with elevated triglycerides,” Skulas-Ray and colleagues wrote.

Omega-3 fatty acids may also be safe in adolescents and children with elevated triglycerides, but there are few studies that focused on this patient population, according to the science advisory. Because of this, the recommended use of omega-3 fatty acids by the FDA are limited to adults.

Mechanisms of triglyceride lowering

Several mechanisms may explain omega-3 fatty acids and lipoprotein metabolism such a reduction in hepatic secretion of triglyceride-rich lipoproteins, inhibition of diacylglycerol acyltransferase, inhibition of phosphatidic acid phosphatase and reduction in de novo lipogenesis, according to the science advisory. Triglyceride synthesis may also be reduced by omega-3 fatty acids through sterol regulatory element-binding protein 1 (SREBP-1) activity suppression and activation via posttranslational mechanisms.

All forms of omega-3 fatty acids have been shown to be safe, although data to confirm this are mainly from trials with short-term follow-up, according to the science advisory. Some of the adverse effects include eructation, fishy taste, nausea and diarrhea. Patients who are also taking an anticoagulant or antiplatelet should also be monitored periodically when taking omega-3 fatty acids.

The REDUCE-IT trial was presented at AHA Scientific Sessions in 2018. As Healio previously reported, icosapent ethyl was superior to placebo for reducing the risk for ischemic events in patients with elevated triglycerides at high CV risk despite statin therapy. Another trial — STRENGTH — is currently being conducted to assess omega-3 carboxylic acid in approximately 13,000 patients and is expected to be completed in 2020, according to the science advisory.

“Dietary supplements containing omega-3 fatty acids are not regulated by the FDA,” Skulas-Ray said in a press release. “They should not be used in place of prescription medication for the long-term management of high triglycerides.” – by Darlene Dobkowski and Erik Swain

Disclosures: Skulas-Ray reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

    Perspective

    Triglycerides are an important risk factor for CVD and are highly prevalent in the population. The first step in treating elevated triglycerides is controlling risk factors, including weight loss, tight control of diabetes, exercise, avoiding refined carbohydrates and decreasing alcohol consumption. Triglyceride-lowering agents can be used with other medications such as statins and fibrates in a safe and efficacious way. We know that omega-3 fatty acids have indications beyond just lowering triglycerides, and based on recent trials like REDUCE-IT, they might be associated with a mortality benefit and significant reduction in CV events in patients with established CVD and high-risk patients requiring primary prevention.

    We live in an era where multiple medications have been shown to improve cardiac outcomes. A clinician has to choose right medication for each patient. That comes down to shared decision making with the patient about type of medication to choose, in addition to looking at cost and figuring out what payers will cover.

    We need more studies looking at benefits of using these medications in high vs. low risk patients for primary and secondary prevention. We need to find out more about those differences. Head-to-head studies comparing these medications would be something to look forward to. We know these medications are safe and well tolerated, but we need to be careful about over-the-counter products that are not FDA-approved in terms of their safety profile long-term.

    We live in exciting time where there are multiple medications and multiple treatment options to lower lipids, which translates to lower CV risk factors, which results in longer, healthier lives.

    • Khaled A. Dajani, MD, MBA
    • Associate Professor of Medicine
      Division of Cardiology
      Loyola University Medical Center

    Disclosures: Dajani reports no relevant financial disclosures.