What is the best medication for reducing hypertriglyceridemia?

Best Medication for Reducing Triglycerides

For severe hypertriglyceridemia (≥500 mg/dL), fenofibrate is the best first-line medication to prevent acute pancreatitis, while for moderate hypertriglyceridemia (135-499 mg/dL) in patients already on statin therapy with established cardiovascular disease or diabetes plus risk factors, icosapent ethyl is the best medication for reducing cardiovascular events. 1, 2, 3

Treatment Algorithm by Triglyceride Level

Severe to Very Severe Hypertriglyceridemia (≥500 mg/dL)

Fenofibrate is the mandatory first-line medication at doses of 54-200 mg daily, initiated immediately before addressing LDL cholesterol, as this triglyceride level carries a 14% risk of acute pancreatitis. 2, 3 Fenofibrate reduces triglycerides by 30-50% and is considered the most potent triglyceride-lowering agent available. 1, 2

• Start fenofibrate immediately without waiting for lifestyle modifications alone, as pharmacologic therapy is mandatory at this level to prevent pancreatitis. 2, 3
• Do not start with statin monotherapy when triglycerides are ≥500 mg/dL, as statins provide only 10-30% triglyceride reduction and are insufficient for preventing pancreatitis. 2, 3
• Once triglycerides fall below 500 mg/dL with fenofibrate therapy, then add or optimize statin therapy to address LDL-C and cardiovascular risk. 2, 3

Moderate Hypertriglyceridemia (135-499 mg/dL) on Statin Therapy

Icosapent ethyl 2g twice daily is the best medication for patients with triglycerides 135-499 mg/dL who are on maximally tolerated statin therapy with LDL-C 41-100 mg/dL and have either established cardiovascular disease OR diabetes with ≥2 additional risk factors. 1, 3

• The REDUCE-IT trial demonstrated a 25% reduction in major adverse cardiovascular events when icosapent ethyl was added to statin therapy in high-risk patients with elevated triglycerides. 1, 3
• Icosapent ethyl is specifically indicated as adjunctive therapy to statins, not as monotherapy. 2, 3
• Monitor for increased risk of atrial fibrillation with icosapent ethyl therapy. 2

Moderate Hypertriglyceridemia (200-499 mg/dL) Not on Statin

Statins are first-line pharmacologic therapy for patients with moderate hypertriglyceridemia and 10-year ASCVD risk ≥7.5%, as they provide 10-30% triglyceride reduction plus proven cardiovascular risk reduction. 2, 4

• If triglycerides remain >200 mg/dL after 3 months of optimized lifestyle modifications and statin therapy, add icosapent ethyl 2-4g daily. 1, 2
• Fenofibrate can be considered as an alternative if icosapent ethyl criteria are not met, particularly in diabetic patients with poor glycemic control. 3

Critical Considerations for Specific Populations

Diabetic Patients

Optimizing glycemic control is the highest priority before adding additional lipid medications, as poor glucose control is often the primary driver of severe hypertriglyceridemia, and improving diabetes management can dramatically reduce triglycerides independent of lipid-lowering medications. 1, 2

• Fenofibrate is particularly useful in diabetic patients with combined hyperlipidemia and can be used without adversely affecting glycemic control. 3, 5
• In the ACCORD trial, fenofibrate plus simvastatin reduced progression of diabetic retinopathy compared to simvastatin alone. 4

Combination Therapy Safety

When combining fenofibrate with statins, fenofibrate has a better safety profile than gemfibrozil and lower risk of rhabdomyolysis. 1

• Use lower statin doses when combining with fibrates to minimize myopathy risk, particularly in patients >65 years or with renal disease. 1, 2
• Monitor creatine kinase levels and muscle symptoms regularly with combination therapy. 2
• Avoid combining gemfibrozil with statins due to significantly higher risk of rhabdomyolysis. 1

Medications That Did NOT Show Cardiovascular Benefit

Niacin should generally not be used, as the HPS2-THRIVE trial showed no cardiovascular benefit when added to statin therapy, with increased risk of new-onset diabetes, gastrointestinal disturbances, and possibly increased ASCVD risk. 1

• Over-the-counter fish oil supplements are not recommended and are not equivalent to prescription omega-3 formulations. 1, 2
• Fenofibrate alone (without statin) did not significantly reduce coronary heart disease events in the FIELD trial, though subgroup analyses suggested benefit in patients with triglycerides ≥200 mg/dL and HDL-C ≤40 mg/dL. 1, 4

Common Pitfalls to Avoid

• Never delay fenofibrate initiation while attempting lifestyle modifications alone in patients with triglycerides ≥500 mg/dL—pharmacologic therapy is mandatory. 2, 3
• Never use bile acid sequestrants when triglycerides are >200 mg/dL, as they are relatively contraindicated and can worsen hypertriglyceridemia. 2
• Never prescribe icosapent ethyl as monotherapy—it is only indicated as adjunctive therapy to maximally tolerated statin therapy. 2, 3
• Never overlook secondary causes including uncontrolled diabetes, hypothyroidism, excessive alcohol intake, renal disease, and medications (thiazide diuretics, beta-blockers, estrogen, corticosteroids) before escalating pharmacotherapy. 1, 2