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Deep Dive: A heartbreaking story of EPA, DHA, and CVD

A major study looking at how pharmaceutical-grade fish oil affects CVD risk came up empty-handed. We cover that trial here and discuss its possible ramifications.

Study under review: Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial


An estimated 25% of adults in the U.S[1] have elevated triglyceride (TG) levels (at least 150 mg/dL). This condition, also called hypertriglyceridemia[2], has long been known to be associated with cardiovascular disease (CVD)[3] as an independent risk factor increasing relative risk by 14% in men and 37% in women. Hypertriglyceridemia can be divided into moderate (TG levels of 150–1000 mg/dL) and severe (TG levels of more than 1000 mg/mL) forms. According to the American Heart Association’s recent guidelines, people with severe hypertriglyceridemia are at very high risk of CVD and require effective lipid-lowering treatment[4]. Even though a putative causal role[5] between triglycerides and heart disease is heavily debated, CVD prevention and treatment[6] in high-risk populations generally includes lowering TG levels. The two most effective ways to lower TG levels are medications and lifestyle modifications such as weight loss, cessation of alcohol consumption, and tighter blood sugar control. The former option usually involves the treatment with statins[7], which are low-density lipoprotein (LDL) lowering drugs that effectively reduce CVD risk[8]. Their effects on triglyceride levels[9] are limited, though, and high-risk people often benefit from additional treatment approaches[10] to prevent adverse events such as heart attack and stroke.

Omega-3 fatty acids[11] (O3FAs) have attracted considerable interest for their cardioprotective benefits[12]. These long-chain, polyunsaturated fatty acids play an essential role in the human diet and human physiology.[13] The two main O3FAs are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Observational[14] studies[15] found that the frequent consumption of fatty fish is associated with lower CVD risk. Furthermore, mechanistic studies identified EPA and DHA as the critical bioactive components[16] that convey the protective effects of O3FAs, and increased circulating levels of EPA and DHA are associated with a decreased CVD risk[17]. There’s also evidence that O3FA supplementation exerts a favorable impact on various risk factors[16] implicated in CVD, such as abnormal inflammatory, oxidative, thrombotic, and vascular blood markers.

Many mechanisms have been proposed concerning O3FA and lipid metabolism[18], yet research is still ongoing. What is known with reasonable certainty is that the liver, the hub of fatty acid synthesis and lipid circulation[19], seems to be the primary site of action where O3FAs may positively affect lipid metabolism. Mechanistic studies have found three possible pathways where O3FAs could positively impact lipid metabolism, summarized in Figure 1: synthesis, secretion, and clearance of certain kinds of lipids. First, O3FAs may attenuate the hepatic synthesis of triglycerides. Studies show that O3FAs reduce triglyceride synthesis by inhibiting the major hepatic triglyceride-synthesizing enzyme[20] called diacylglycerol acyltransferase. Second, O3FAs inhibit the secretion of triglyceride-rich lipoproteins. This mechanism is based on the findings that O3FAs induce the intracellular degradation of apoprotein-B[21], the primary organizing protein of many lipid particles such as LDL. In other words, O3FAs deplete the cell of the “package proteins” that transport these kinds of lipids out of the cell into blood circulation. The third potential mechanism is the increased clearance of blood triglycerides. To achieve this, O3FAs may upregulate lipoprotein lipase[22], which breaks down triglycerides and is involved in the cellular uptake of certain lipids from circulation. Overall, the putative mechanisms of action combined with the clinical evidence of the triglyceride-lowering benefits of O3FAs make a compelling case to use O3FA to prevent CVD.

Figure 1: Possible influences of O3FA on triglyceride metabolism

Reference: Skulas-Ray et al. Circulation. 2019 Sep.[18]

Here is the enigma: Even though the biological rationale for O3FA use for CVD prevention is clear, the clinical evidence is still inconsistent. Three[23] meta[24]-analyses[25] from 2008–2009 have shown modest reductions in the rates of cardiovascular events. In contrast, a recent meta-analysis of double-blinded RCTs from 2018 found no effect of low doses (less than 1–1.5 grams daily) of the O3FA agents EPA/DHA on cardiovascular outcomes. In contrast, a recent trial[26] used higher O3FA doses (more than 1.5–2 grams daily) and found significant cardiovascular benefits. This study, called the REDUCE-IT[26] trial, showed a significantly reduced relative risk reduction of 25% of adverse events in statin-treated participants taking about 3.8 grams of EPA daily, compared with placebo. However, the mineral oil placebo used in this trial has been criticized[27] for having adverse effects[28] on the control group, making the treatment group look more positive. Yet, a review by the US Food and Drug Administration (FDA) concluded that the harmful effects of the mineral oil could only explain a small fraction of the risk reduction. Nevertheless, this problem with oil placebos, and also supplement type and quality, will also become pivotal points when discussing the present study results in the “Bigger Picture” section below.

Why do all these trials show such inconsistent outcomes? There are various potential reasons: Most notably, the doses of O3FAs[27] may have been too low in some trials. Also, different studies use different EPA/DHA ratios and products. Some O3FAs products contain a mixture of both EPA and DHA. Other products only contain EPA, as some studies suggest that EPA is more potent[29] for cardiovascular benefits. Since 2019, the REDUCE-IT[26] trial is often quoted as further evidence for this claim. Another reason to explain the inconsistent outcomes is that O3FA products use different formulations[30]. The main ones used in pharmaceutical-grade products are usually ethyl EPA (E-EPA), also called icosapent ethyl, and carboxylic acid (CA-EPA), while those in supplements tend to be triglyceride or phospholipid forms among others, as shown in Figure 2. Even though all prescription formulations reduce TG levels effectively[30], head-to-head clinical trials directly comparing different O3FA products are lacking. Overall, it remains unclear as to what formulation and dosage of omega-3 is most efficacious (if any), and what the concrete benefits and risks are, especially for high-risk patients. However, answering this question is of paramount importance to optimize the treatment regime for optimal clinical outcomes.

Figure 2: The different forms of EPA and DHA

The present study[31] was designed to shed more light on this question. The trial carries the proud name STRENGTH, which stands for the less-catchy “Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia.” In this double-blind, multicenter randomized controlled trial, the researchers used a mixture of carboxylic acid EPA plus DHA. The rationale of using a carboxylic acid formulation is that it has a potentially higher bioavailability due to improved intestinal absorption. Two previous trials[32][33] already showed beneficial effects of the carboxylic acid formulation to lower blood triglycerides. Here, the researchers wanted to investigate cardiovascular outcomes.

The omega-3 fatty acids DHA and EPA have potential cardiovascular benefits which are thought to arise partly due to their triglyceride-lowering effects. This effect could be beneficial for statin-treated patients who are still at high risk of adverse cardiovascular events due to high triglyceride levels. Yet, the current body of evidence does not provide a clear picture of whether O3FAs improve clinical outcomes in people at high CVD risk. The present study investigated the effects of a pharmaceutical-grade omega-3 product using a carboxylic acid EPA plus DHA formulation in high cardiovascular risk participants.

What was studied?

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The bigger picture

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