What is the treatment for a patient with hypertriglyceridemia?

Treatment for High Triglycerides

For severe hypertriglyceridemia (≥500 mg/dL), initiate fenofibrate 54-160 mg daily immediately to prevent acute pancreatitis, while for moderate elevations (200-499 mg/dL), start with aggressive lifestyle modifications and consider statins if cardiovascular risk is elevated (10-year ASCVD risk ≥7.5%). 1, 2

Classification Determines Treatment Urgency

• Normal triglycerides are <150 mg/dL, mild 150-199 mg/dL, moderate 200-499 mg/dL, severe 500-999 mg/dL, and very severe ≥1,000 mg/dL 1, 2, 3
• Severe hypertriglyceridemia (≥500 mg/dL) carries a 14% risk of acute pancreatitis and requires immediate pharmacologic intervention 1, 3
• Mild to moderate hypertriglyceridemia primarily increases cardiovascular disease risk rather than pancreatitis risk 1, 3

Evaluate and Address Secondary Causes First

Before initiating any lipid-lowering medication, aggressively evaluate for reversible causes:

• Check hemoglobin A1c and fasting glucose immediately—uncontrolled diabetes is often the primary driver of severe hypertriglyceridemia, and optimizing glucose control can reduce triglycerides by 20-50% independent of lipid medications 1, 3
• Measure TSH to rule out hypothyroidism, which must be treated before expecting full response to lipid therapy 1, 3
• Assess for excessive alcohol intake—even 1 ounce daily increases triglycerides by 5-10%, and alcohol can precipitate hypertriglyceridemic pancreatitis at severe levels 1, 3
• Review medications that raise triglycerides: thiazide diuretics, beta-blockers, estrogen therapy, corticosteroids, antiretrovirals, and antipsychotics—discontinue or substitute if possible 1, 3
• Check renal function (creatinine, eGFR) and liver function (AST, ALT), as chronic kidney disease and liver disease contribute to hypertriglyceridemia 1, 3

Lifestyle Modifications: The Foundation

Target a 5-10% body weight reduction, which produces a 20% decrease in triglycerides—this is the single most effective lifestyle intervention 1, 2, 3

Dietary Changes

• Restrict added sugars to <6% of total daily calories for mild-moderate hypertriglyceridemia (150-499 mg/dL), as sugar intake directly increases hepatic triglyceride production 1, 2, 3
• Limit total dietary fat to 30-35% of total calories for mild-moderate hypertriglyceridemia 1, 2, 3
• For severe hypertriglyceridemia (500-999 mg/dL), restrict dietary fat to 20-25% of total calories and eliminate all added sugars completely 1, 2
• For very severe hypertriglyceridemia (≥1,000 mg/dL), implement a very low-fat diet (10-15% of calories) until triglycerides fall below 1,000 mg/dL 1, 2
• Restrict saturated fats to <7% of total energy intake, replacing with monounsaturated or polyunsaturated fats 1, 3
• Increase soluble fiber to >10 g/day from sources like oats, beans, and vegetables 1, 3
• Consume ≥2 servings (8+ ounces) per week of fatty fish rich in omega-3 fatty acids (salmon, trout, sardines) 1, 3

Alcohol and Physical Activity

• Complete abstinence from alcohol is mandatory for severe hypertriglyceridemia (≥500 mg/dL) to prevent hypertriglyceridemic pancreatitis 1, 2, 3
• For mild-moderate hypertriglyceridemia, limit or completely avoid alcohol consumption 1, 3
• Engage in ≥150 minutes/week of moderate-intensity aerobic activity (or 75 minutes/week vigorous activity), which reduces triglycerides by approximately 11% 1, 2, 3

Pharmacologic Treatment Algorithm

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

Initiate fenofibrate 54-160 mg daily immediately as first-line therapy to prevent acute pancreatitis, regardless of LDL-C levels or cardiovascular risk 1, 2, 4

• Fenofibrate provides 30-50% triglyceride reduction 1, 2, 3
• Do NOT start with statin monotherapy when triglycerides are ≥500 mg/dL—statins provide only 10-30% triglyceride reduction and are insufficient for preventing pancreatitis at this level 1, 2
• For patients with mild to moderately impaired renal function (eGFR 30-59 mL/min/1.73 m²), start fenofibrate at 54 mg daily and do not exceed this dose 4
• Fenofibrate is contraindicated in severe renal impairment (eGFR <30 mL/min/1.73 m²) 4
• Once triglycerides fall below 500 mg/dL with fenofibrate therapy, reassess LDL-C and consider adding statin therapy if LDL-C is elevated or cardiovascular risk is high 1, 2

For Moderate Hypertriglyceridemia (200-499 mg/dL)

Treatment depends on cardiovascular risk and LDL-C levels:

• For patients aged 40-75 years with 10-year ASCVD risk ≥7.5%, established ASCVD, or diabetes, initiate moderate-to-high intensity statin therapy as first-line, which provides 10-30% dose-dependent triglyceride reduction plus proven cardiovascular benefit 1, 2, 3
• Target LDL-C <100 mg/dL (or <70 mg/dL for very high-risk patients) and non-HDL-C <130 mg/dL 1, 2
• If triglycerides remain >200 mg/dL after 3 months of optimized lifestyle modifications and statin therapy, add prescription omega-3 fatty acids (icosapent ethyl 2-4g daily) if the patient has established cardiovascular disease OR diabetes with ≥2 additional cardiovascular risk factors 1, 2
• Icosapent ethyl demonstrated a 25% reduction in major adverse cardiovascular events in the REDUCE-IT trial (number needed to treat = 21) 1, 2
• Alternatively, consider fenofibrate 54-160 mg daily if icosapent ethyl criteria are not met 1, 2

For Mild Hypertriglyceridemia (150-199 mg/dL)

• Persistently elevated nonfasting triglycerides ≥175 mg/dL constitute a cardiovascular risk-enhancing factor 1
• For patients aged 40-75 years with 10-year ASCVD risk ≥7.5%, consider initiating moderate-intensity statin therapy 1, 2
• For patients with 10-year ASCVD risk 5% to <7.5%, engage in patient-clinician discussion regarding statin initiation 1
• Focus primarily on lifestyle modifications for this group 2, 3

Combination Therapy Safety Considerations

When combining fenofibrate with statins, use lower statin doses to minimize myopathy risk, particularly in patients >65 years or with renal disease 1, 2, 3

• Use fenofibrate, NOT gemfibrozil, when combining with statins—fenofibrate has a significantly better safety profile because it does not inhibit statin glucuronidation 1, 2
• Monitor creatine kinase levels at baseline and if muscle symptoms develop 1, 2
• Consider taking fenofibrate in the morning and statins in the evening to minimize peak dose concentrations 1

Monitoring Strategy

• Reassess fasting lipid panel in 6-12 weeks after implementing lifestyle modifications 1, 2, 3
• Reassess lipids 4-8 weeks after initiating or adjusting pharmacotherapy 1, 2, 4
• Monitor liver function tests (AST/ALT) at baseline, 3 months, then annually on fenofibrate 1, 2
• Monitor renal function within 3 months after fenofibrate initiation and every 6 months thereafter—if eGFR persistently decreases to <30 mL/min/1.73 m², fenofibrate must be discontinued immediately 1, 4
• Monitor for increased risk of atrial fibrillation with prescription omega-3 fatty acids (icosapent ethyl) 1, 2

Treatment Goals

• Primary goal: Rapid reduction of triglycerides to <500 mg/dL to eliminate pancreatitis risk 1, 2
• Secondary goal: Further reduction to <200 mg/dL (ideally <150 mg/dL) to reduce cardiovascular risk 1, 2
• Tertiary goal: Non-HDL-C <130 mg/dL once triglycerides are controlled 1, 2

Critical Pitfalls to Avoid

• Do NOT delay fenofibrate therapy while attempting lifestyle modifications alone in patients with triglycerides ≥500 mg/dL—pharmacologic therapy is mandatory to prevent pancreatitis 1, 2
• Do NOT use over-the-counter fish oil supplements expecting cardiovascular benefit—only prescription omega-3 fatty acids (icosapent ethyl) have proven cardiovascular outcomes benefit 1, 5
• Do NOT discontinue statins in favor of fibrate monotherapy for patients with cardiovascular risk or established disease—statins provide proven mortality benefit through LDL-C reduction 1
• Therapy should be withdrawn 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