Fenofibrate is the Best Drug for Hypertriglyceridemia
For severe hypertriglyceridemia (triglycerides ≥500 mg/dL), fenofibrate 54-160 mg daily should be initiated immediately as first-line therapy to prevent acute pancreatitis, providing a 30-50% reduction in triglyceride levels. 1, 2 For moderate hypertriglyceridemia (200-499 mg/dL) with elevated cardiovascular risk, statins are first-line, but fenofibrate becomes the preferred agent when triglycerides remain elevated despite lifestyle modifications or when LDL-C is already controlled. 3, 1
Treatment Algorithm by Triglyceride Level
Severe Hypertriglyceridemia (≥500 mg/dL)
Initiate fenofibrate 54-160 mg daily immediately, before addressing LDL cholesterol, as this level carries significant risk for acute pancreatitis (14% incidence in severe hypertriglyceridemia). 1, 2
Fenofibrate reduces triglycerides by 30-50% in clinical trials, with patients having baseline triglycerides of 500-1,500 mg/dL experiencing reductions from 726 mg/dL to 308 mg/dL (-54.5%). 2
Do not start with statin monotherapy at this level—statins provide only 10-30% triglyceride reduction and are insufficient for preventing pancreatitis. 1
Once triglycerides fall below 500 mg/dL with fenofibrate therapy, reassess LDL-C and add statin therapy if LDL-C is elevated or cardiovascular risk is high. 1
Moderate Hypertriglyceridemia (200-499 mg/dL)
For patients with 10-year ASCVD risk ≥7.5%, initiate moderate-to-high intensity statin therapy first (atorvastatin 10-40 mg or rosuvastatin 5-20 mg daily), which provides 10-30% dose-dependent triglyceride reduction plus proven cardiovascular benefit. 3, 1
If triglycerides remain >200 mg/dL after 3 months of optimized lifestyle modifications and statin therapy, add fenofibrate 54-160 mg daily as second-line therapy. 1
Alternative second-line option: prescription omega-3 fatty acids (icosapent ethyl 2-4g daily) for patients with established cardiovascular disease or diabetes with ≥2 additional risk factors. 3, 1
Mild Hypertriglyceridemia (150-199 mg/dL)
For patients with 10-year ASCVD risk ≥7.5% and persistently elevated nonfasting triglycerides ≥175 mg/dL, consider statin initiation as triglycerides represent a cardiovascular risk-enhancing factor. 1
Fenofibrate is generally not first-line at this level unless statins are contraindicated or LDL-C is already at goal. 1
Critical Dietary and Lifestyle Interventions
These must be implemented immediately alongside pharmacotherapy:
Complete alcohol abstinence is mandatory for severe hypertriglyceridemia (≥500 mg/dL), as alcohol synergistically increases triglycerides and can precipitate hypertriglyceridemic pancreatitis. 3, 1
For severe hypertriglyceridemia (500-999 mg/dL), restrict total dietary fat to 20-25% of total calories and eliminate all added sugars completely. 3, 1
For very severe hypertriglyceridemia (≥1,000 mg/dL), implement extreme dietary fat restriction (<5-15% of total calories) until triglycerides fall below 1,000 mg/dL. 3, 1
Target 5-10% body weight reduction, which produces a 20% decrease in triglycerides and is the single most effective lifestyle intervention. 1
Engage in ≥150 minutes/week of moderate-intensity aerobic activity, which reduces triglycerides by approximately 11%. 1
Why Fenofibrate Over Other Fibrates
Fenofibrate has a superior safety profile compared to gemfibrozil when combined with statins, as fenofibrate does not inhibit statin glucuronidation, resulting in significantly lower myopathy risk. 1 Gemfibrozil should be avoided when combining with statins due to increased risk of rhabdomyolysis. 1
Dosing and Administration
Initial dose for severe hypertriglyceridemia: 54-160 mg daily with meals to optimize bioavailability. 2
Dose adjustment based on renal function: Start at 54 mg daily in patients with mild-to-moderate renal impairment and increase only after evaluating effects on renal function and lipid levels. 2
Avoid fenofibrate in severe renal impairment. 2
Reassess lipid levels at 4-8 week intervals after initiating or adjusting fenofibrate dose. 1, 2
Combination Therapy Considerations
When combining fenofibrate with statins (necessary for patients with both elevated triglycerides and LDL-C):
Use lower statin doses to minimize myopathy risk, particularly in patients >65 years or with renal disease. 3, 1
Monitor for muscle symptoms and obtain baseline and follow-up creatine kinase (CPK) levels. 1
The combination of high-dose statin plus fibrate significantly increases myopathy risk—keep statin doses relatively low (e.g., atorvastatin 10-20 mg maximum). 3, 1
Secondary Causes to Address First
Before or alongside fenofibrate initiation, aggressively evaluate and treat:
Uncontrolled diabetes mellitus: Poor glycemic control is often the primary driver of severe hypertriglyceridemia, and optimizing glucose control can dramatically reduce triglycerides independent of lipid medications. 3, 1
Hypothyroidism: Check TSH and treat if elevated. 1
Medications that raise triglycerides: Discontinue or substitute thiazide diuretics, beta-blockers, oral estrogen therapy, corticosteroids, antiretrovirals, and atypical antipsychotics if possible. 3, 1
Chronic kidney disease, nephrotic syndrome, and chronic liver disease: These conditions elevate triglycerides and require management. 1
Monitoring Strategy
Liver enzymes (AST/ALT): Check every 2-4 weeks for the first 2 months, then every 3 months. Discontinue fenofibrate if transaminases exceed 3 times upper normal limit. 3, 2
Fasting lipid panel: Reassess at 4-8 weeks after initiating or adjusting therapy. 1, 2
Creatine kinase and muscle symptoms: Monitor when combining with statins, especially in patients >65 years or with renal disease. 1
Target goals: Triglycerides <200 mg/dL (ideally <150 mg/dL) and non-HDL-C <130 mg/dL. 1
Common Pitfalls to Avoid
Do not delay fenofibrate initiation while attempting lifestyle modifications alone when triglycerides are ≥500 mg/dL—pharmacologic therapy is mandatory at this level. 1
Do not ignore secondary causes of hypertriglyceridemia, particularly uncontrolled diabetes and hypothyroidism, as treating these may be more effective than additional medications. 3, 1
Do not use gemfibrozil when combining with statins—fenofibrate has a better safety profile. 1
Do not use over-the-counter fish oil supplements as substitutes for prescription omega-3 fatty acids—they are not equivalent. 1
Do not use bile acid sequestrants when triglycerides are >200 mg/dL, as they are relatively contraindicated and can worsen hypertriglyceridemia. 1
Alternative and Adjunctive Therapies
Prescription Omega-3 Fatty Acids (Icosapent Ethyl)
Indicated for patients with triglycerides ≥150 mg/dL on maximally tolerated statin with established cardiovascular disease or diabetes with ≥2 additional risk factors. 3, 1
Provides 25% reduction in major adverse cardiovascular events (number needed to treat = 21) based on the REDUCE-IT trial. 1
Dose: 2g twice daily (total 4g/day). 1
Monitor for increased risk of atrial fibrillation. 1
Statins
Provide 10-30% dose-dependent triglyceride reduction and are first-line for moderate hypertriglyceridemia with elevated LDL-C or high cardiovascular risk. 3, 1
Should be restricted to patients with both high LDL cholesterol and high triglycerides when used primarily for triglyceride lowering. 1