What is the best medication to treat hypertriglyceridemia in an adult?

Best Medication to Lower Triglycerides

For severe hypertriglyceridemia (≥500 mg/dL), fenofibrate 54-160 mg daily is the best first-line medication to prevent acute pancreatitis, while for moderate hypertriglyceridemia (150-499 mg/dL) with elevated cardiovascular risk, statins are the best medication providing both triglyceride reduction and proven mortality benefit. 1, 2, 3

Treatment Algorithm Based on Triglyceride Severity

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

Fenofibrate is the medication of choice because it provides 30-50% triglyceride reduction and must be initiated immediately to prevent acute pancreatitis, regardless of LDL-C levels or cardiovascular risk. 1, 2, 3 The risk of pancreatitis is 14% at these levels and escalates dramatically as triglycerides approach 1,000 mg/dL. 1

• Start fenofibrate 54-160 mg daily immediately as first-line therapy before addressing LDL cholesterol 1, 2
• Do NOT start with statin monotherapy at this level—statins provide only 10-30% triglyceride reduction, which is insufficient for preventing pancreatitis 1, 3
• Once triglycerides fall below 500 mg/dL with fenofibrate, reassess LDL-C and add statin therapy if LDL-C is elevated or cardiovascular risk is high 1

Moderate Hypertriglyceridemia (200-499 mg/dL)

Statins are the best medication for patients with elevated cardiovascular risk (10-year ASCVD risk ≥7.5%, diabetes age 40-75, or established ASCVD) because they provide 10-30% dose-dependent triglyceride reduction PLUS proven cardiovascular mortality benefit through LDL-C lowering. 1, 4, 3

• Initiate moderate-to-high intensity statin therapy (atorvastatin 10-20 mg or rosuvastatin 5-10 mg daily) as first-line 1, 4
• Target LDL-C <100 mg/dL (or <70 mg/dL for very high-risk patients) and non-HDL-C <130 mg/dL 1, 4
• Do NOT delay statin initiation while attempting lifestyle modifications alone in high-risk patients—both should proceed concurrently 1

Mild Hypertriglyceridemia (150-199 mg/dL)

Statins are reasonable if 10-year ASCVD risk ≥7.5%, as persistently elevated triglycerides ≥175 mg/dL constitute a cardiovascular risk-enhancing factor. 1 For lower-risk patients, aggressive lifestyle modifications for 3 months before considering pharmacotherapy is appropriate. 1

Add-On Therapy When Triglycerides Remain Elevated

After 3 Months of Optimized Statin Therapy

Icosapent ethyl 2g twice daily is the best add-on medication for patients with triglycerides ≥150 mg/dL who have established cardiovascular disease OR diabetes with ≥2 additional risk factors, because it demonstrated a 25% reduction in major adverse cardiovascular events (NNT=21) and is the ONLY triglyceride-lowering agent FDA-approved for cardiovascular risk reduction. 1, 3

• Monitor for increased risk of atrial fibrillation (3.1% vs 2.1% with placebo) 1
• This is NOT the same as over-the-counter fish oil supplements 1

Fenofibrate 54-160 mg daily can be added if icosapent ethyl criteria are not met but triglycerides remain >200 mg/dL after optimized lifestyle and statin therapy. 1, 2

• When combining fenofibrate with statins, use fenofibrate (NOT gemfibrozil) because it has a significantly better safety profile and does not inhibit statin glucuronidation 1, 2
• Use lower statin doses (atorvastatin ≤20 mg or rosuvastatin ≤10 mg) to minimize myopathy risk, particularly in patients >65 years or with renal disease 1
• Monitor creatine kinase levels and muscle symptoms at baseline and follow-up 1, 4

Why NOT Niacin

Niacin should generally not be used because it showed no cardiovascular benefit when added to statin therapy in the AIM-HIGH trial, with increased risk of new-onset diabetes and gastrointestinal disturbances. 1, 5 While niacin can reduce triglycerides by 20-50%, the lack of outcome benefit makes it inferior to other options. 5, 6

Critical Pitfalls to Avoid

• Never start with statin monotherapy when triglycerides are ≥500 mg/dL—fibrates must be initiated first to prevent pancreatitis 1, 3
• Never use gemfibrozil instead of fenofibrate when combining with statins—gemfibrozil has significantly higher myopathy risk 1, 2
• Never overlook secondary causes (uncontrolled diabetes, hypothyroidism, excessive alcohol, certain medications)—optimizing glycemic control alone can reduce triglycerides by 20-50% independent of lipid medications 1, 4
• Never substitute over-the-counter fish oil for prescription omega-3 fatty acids—they are not equivalent and lack proven cardiovascular benefit 1

Expected Outcomes by Medication

Medication	Triglyceride Reduction	Cardiovascular Benefit
Fenofibrate	30-50% [1,2]	Not proven in outcome trials [2]
Statins	10-30% (dose-dependent) [1,4]	Proven mortality benefit [1,4]
Icosapent ethyl	20-50% [1]	25% reduction in MACE [1,3]
Niacin	20-50% [5,6]	No benefit when added to statins [1,5]

Monitoring Strategy

• Reassess fasting lipid panel 4-8 weeks after initiating or adjusting pharmacotherapy 1, 4
• For fenofibrate: monitor renal function at baseline, 3 months, and every 6 months thereafter; contraindicated if eGFR <30 mL/min/1.73 m² 1
• When combining statin with fenofibrate: monitor creatine kinase and muscle symptoms, especially in patients >65 years or with renal disease 1, 4