What are the treatment options for hypertriglyceridemia?

Treatment of Hypertriglyceridemia

The treatment approach for hypertriglyceridemia is stratified by triglyceride level severity: for levels ≥500 mg/dL, immediately initiate fibrate therapy (fenofibrate 54-160 mg daily) to prevent acute pancreatitis; for levels 200-499 mg/dL, intensify lifestyle modifications and consider adding prescription omega-3 fatty acids (icosapent ethyl 2-4g/day) if on maximally tolerated statin therapy; for levels 150-199 mg/dL with cardiovascular risk factors, initiate or intensify statin therapy. 1, 2

Classification and Risk Assessment

Hypertriglyceridemia severity determines treatment urgency 2, 3:

• Normal: <150 mg/dL
• Mild: 150-199 mg/dL (cardiovascular risk-enhancing factor)
• Moderate: 200-499 mg/dL (increased cardiovascular risk)
• Severe: 500-999 mg/dL (pancreatitis risk)
• Very severe: ≥1,000 mg/dL (high pancreatitis risk, requires immediate intervention)

Before initiating treatment, evaluate for secondary causes including excessive alcohol intake, uncontrolled diabetes mellitus, hypothyroidism, renal disease, liver disease, and medications (thiazide diuretics, beta-blockers, estrogen therapy, corticosteroids, antiretrovirals, antipsychotics). 1, 2, 4

Lifestyle Interventions (Foundation for All Levels)

Weight Loss and Physical Activity

• Target 5-10% body weight reduction, which produces a 20% decrease in triglycerides—the single most effective lifestyle intervention. 2, 3 In some patients, weight loss can reduce triglyceride levels by up to 50-70%. 2

• Engage in ≥150 minutes/week of moderate-intensity aerobic activity (or 75 minutes/week vigorous activity), which reduces triglycerides by approximately 11%. 2, 3

Dietary Modifications (Severity-Based)

For mild to moderate hypertriglyceridemia (150-499 mg/dL): 2, 3

• Restrict added sugars to <6% of total daily calories
• Limit total fat to 30-35% of total daily calories
• Restrict saturated fats to <7% of total calories
• Eliminate trans fats completely

For severe hypertriglyceridemia (500-999 mg/dL): 2, 3

• Restrict added sugars to <5% of total daily calories
• Limit total fat to 20-25% of total daily calories
• Completely eliminate alcohol consumption

For very severe hypertriglyceridemia (≥1,000 mg/dL): 1, 2, 3

• Eliminate all added sugars completely
• Restrict total fat to 10-15% of daily calories
• In some cases, implement extreme dietary fat restriction (<5% of total calories) until triglycerides fall to <1,000 mg/dL, where medications become more effective

Alcohol Restriction

• Complete abstinence from alcohol is mandatory for patients with severe hypertriglyceridemia (≥500 mg/dL) to prevent hypertriglyceridemic pancreatitis. 1, 2 Alcohol consumption of just 1 ounce per day corresponds to a 5-10% higher triglyceride concentration, and effects are synergistically exaggerated when coupled with high saturated fat meals. 2

Pharmacologic Therapy Algorithm

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

Immediate intervention required to prevent acute pancreatitis: 1, 2, 4

• Initiate fenofibrate 54-160 mg daily immediately as first-line therapy, before addressing LDL cholesterol. 2, 4 Fibrates reduce triglycerides by 30-50%. 2

• 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 at this level. 2

• For patients with uncontrolled diabetes mellitus, aggressively optimize glycemic control first, as poor glucose control is often the primary driver of severe hypertriglyceridemia and can dramatically reduce triglycerides independent of lipid medications. 1, 2

• Once triglycerides fall below 500 mg/dL with fenofibrate and lifestyle optimization, initiate or optimize statin therapy to address LDL-C and cardiovascular risk. 2

• If triglycerides remain elevated after fenofibrate and lifestyle optimization, add prescription omega-3 fatty acids (icosapent ethyl 2-4g/day) as adjunctive therapy. 1, 2

Moderate Hypertriglyceridemia (200-499 mg/dL)

Focus on cardiovascular risk reduction: 1, 2

• If LDL-C is elevated or 10-year ASCVD risk is ≥7.5%, initiate or intensify statin therapy, which provides 10-30% dose-dependent triglyceride reduction. 2

• Target non-HDL-C <130 mg/dL (calculated as total cholesterol minus HDL-C). 2

• If triglycerides remain >200 mg/dL after 3 months of optimized lifestyle modifications and maximally tolerated statin therapy, add prescription omega-3 fatty acids (icosapent ethyl 2-4g/day). 1, 2

• Fenofibrate can be considered if triglycerides remain significantly elevated and cardiovascular risk is high, but combination therapy with statins increases myopathy risk. 2

Mild Hypertriglyceridemia (150-199 mg/dL)

Cardiovascular risk-based approach: 2

• For patients with 10-year ASCVD risk ≥7.5% or persistently elevated nonfasting triglycerides ≥175 mg/dL, consider initiating moderate-intensity statin therapy. 2

• For patients with 10-year ASCVD risk 5% to <7.5%, engage in patient-clinician discussion regarding statin initiation. 2

Special Considerations

Prescription Omega-3 Fatty Acids

• Icosapent ethyl (prescription EPA) is specifically indicated as adjunct to maximally tolerated statin therapy for patients with triglycerides ≥150 mg/dL and established cardiovascular disease OR diabetes with ≥2 additional risk factors. 1, 2 This is based on the REDUCE-IT trial showing 25% reduction in major adverse cardiovascular events. 2

• Monitor for increased risk of atrial fibrillation with prescription omega-3 fatty acids. 2

• Over-the-counter fish oil supplements are not equivalent to prescription formulations and should not be substituted. 2

Combination Therapy Safety

• When combining fenofibrate with statins, use lower statin doses to minimize myopathy risk, particularly in patients >65 years or with renal disease. 2, 5 Fenofibrate has a better safety profile than gemfibrozil when combined with statins. 2

• Monitor creatine kinase (CK) levels and muscle symptoms when using combination therapy. 2

Renal Impairment

• Initiate fenofibrate at 54 mg daily in patients with mild to moderately impaired renal function and increase only after evaluating effects on renal function and lipid levels. 4

• Avoid fenofibrate in patients with severe renal impairment, including those receiving dialysis. 4

Monitoring and Follow-Up

• Reassess fasting lipid panel in 6-12 weeks after implementing lifestyle modifications or starting pharmacotherapy. 2, 5

• For patients on fenofibrate, monitor lipid levels at 4-8 week intervals and adjust dosage accordingly. 4

• Withdraw therapy in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of fenofibrate 160 mg once daily. 4

Critical Pitfalls to Avoid

• Do NOT delay fibrate initiation while attempting lifestyle modifications alone in patients with triglyceride levels ≥500 mg/dL—pharmacologic therapy is mandatory to prevent pancreatitis. 2

• Do NOT use bile acid sequestrants when triglycerides are >200 mg/dL, as they are relatively contraindicated and can worsen hypertriglyceridemia. 2

• Do NOT overlook secondary causes, particularly uncontrolled diabetes and alcohol consumption, as addressing these can be more effective than additional medications. 1, 2, 4

• Niacin should generally not be used, as it showed no cardiovascular benefit when added to statin therapy in the AIM-HIGH and ACCORD trials, with increased risk of new-onset diabetes and gastrointestinal disturbances. 2