Can Vascepa (icosapent ethyl) cause elevated triglycerides in adults with severe hypertriglyceridemia?

Vascepa Does Not Cause Elevated Triglycerides—It Lowers Them

Vascepa (icosapent ethyl) is specifically indicated to reduce triglyceride levels in adults with severe hypertriglyceridemia (≥500 mg/dL), not to elevate them. 1, 2

Mechanism and Effect on Triglycerides

Vascepa is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester that effectively lowers triglycerides through multiple mechanisms 3, 4:

• Inhibits hepatic triglyceride synthesis by reducing diacylglycerol acyltransferase activity and decreasing hepatic lipogenesis 5
• Increases triglyceride clearance through enhanced plasma lipoprotein lipase activity and increased hepatic β-oxidation 5
• Reduces median triglycerides by approximately 19-20% when used at the approved dose of 4 g/day 2
• In the pivotal MARINE trial, icosapent ethyl 4 g/day decreased placebo-corrected median triglyceride levels by 33.1% in patients with severe hypertriglyceridemia 3

FDA-Approved Indications

The FDA has approved Vascepa for two distinct purposes 1, 2:

1. As adjunct to diet to reduce triglyceride levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia 1

2. As adjunct to maximally tolerated statin therapy to reduce cardiovascular risk in adults with triglycerides ≥150 mg/dL who have either:

   • Established cardiovascular disease, OR
   • Diabetes mellitus and ≥2 additional cardiovascular risk factors 1, 2

Key Distinction from DHA-Containing Products

Unlike omega-3 products containing both EPA and docosahexaenoic acid (DHA), Vascepa contains ≥96% EPA ethyl ester without DHA 3, 4:

• DHA-containing formulations may increase LDL-C levels, which could be misinterpreted as worsening lipid profiles 5
• Vascepa does not increase LDL-C and has favorable effects on other lipid parameters including a 13% reduction in non-HDL-C 2, 3, 4
• The STRENGTH trial using a different omega-3 carboxylic acid formulation (containing both EPA and DHA) showed no cardiovascular benefit, highlighting that Vascepa's effects should not be extrapolated to other omega-3 products 2

Clinical Evidence for Triglyceride Reduction

The REDUCE-IT trial demonstrated robust cardiovascular benefits in patients with elevated triglycerides (135-499 mg/dL) on statin therapy 1, 2:

• 25% relative risk reduction in the primary composite cardiovascular endpoint 2
• 26% reduction in cardiovascular death, nonfatal MI, or nonfatal stroke 2
• 20% reduction in cardiovascular mortality 2
• Median triglyceride reduction of 19.7% compared with placebo at 1 year 1

Safety Considerations

While Vascepa effectively lowers triglycerides, clinicians should monitor for 1, 2:

• Increased risk of atrial fibrillation/flutter (3.1% vs 2.1% with placebo; P=0.004) 1, 2
• Slightly increased bleeding risk (2.7% vs 2.1% with placebo; P=0.06), though no fatal bleeding events occurred 1

Common Pitfall to Avoid

Do not confuse the mineral oil placebo used in REDUCE-IT with the active treatment. The trial used mineral oil as placebo, which may have increased LDL-C and triglycerides in the control group, potentially magnifying the apparent benefit of icosapent ethyl 1. However, this does not change the fact that icosapent ethyl itself lowers triglycerides, not raises them.