What is the management of elevated triglycerides (hypertriglyceridemia)?

Management of Elevated Triglycerides

Lifestyle intervention is the foundation of hypertriglyceridemia management, with pharmacotherapy decisions driven by triglyceride severity: fibrates are mandatory for levels ≥500 mg/dL to prevent pancreatitis, while statins are first-line for moderate elevation (200-499 mg/dL) when cardiovascular risk is ≥7.5%, and icosapent ethyl should be added for persistent elevation ≥150 mg/dL in patients with established cardiovascular disease or diabetes with additional risk factors on maximally tolerated statin therapy. 1, 2

Classification and Risk Stratification

Triglyceride levels are classified as: Normal (<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). 2 Severe hypertriglyceridemia carries a 14% risk of acute pancreatitis, with risk escalating dramatically as levels approach 1,000 mg/dL. 2 Persistently elevated nonfasting triglycerides ≥175 mg/dL constitute a cardiovascular risk-enhancing factor. 2

Initial Assessment for Secondary Causes

Before initiating treatment, aggressively evaluate for:

• Uncontrolled diabetes mellitus (check hemoglobin A1c and fasting glucose immediately, as poor glycemic control is often the primary driver of severe hypertriglyceridemia and optimizing glucose control can dramatically reduce triglycerides independent of lipid medications) 1, 2
• Hypothyroidism (check TSH) 2
• Excessive alcohol intake (even 1 ounce daily increases triglycerides by 5-10%, and alcohol can precipitate hypertriglyceridemic pancreatitis) 2
• Medications that raise triglycerides: thiazide diuretics, beta-blockers, estrogen therapy, corticosteroids, antiretrovirals, and antipsychotics (discontinue or substitute if possible) 2
• Chronic kidney disease and nephrotic syndrome 2
• Chronic liver disease 2

Lifestyle Interventions (All Patients)

Weight Loss and Physical Activity

• Target 5-10% body weight reduction over 6-12 months, which produces a 20% decrease in triglycerides (some patients experience up to 50-70% reduction). 2, 3
• Engage in at least 150 minutes per week of moderate-intensity aerobic activity (or 75 minutes per week vigorous activity), which reduces triglycerides by approximately 11%. 1, 2, 3

Dietary Modifications by Triglyceride Severity

For Mild-Moderate Hypertriglyceridemia (150-499 mg/dL):

• Restrict added sugars to <6% of total daily calories (sugar intake directly increases hepatic triglyceride production) 1, 2, 3
• Limit total fat to 30-35% of total daily calories 1, 2, 3
• Restrict saturated fats to <7% of total energy intake, replacing with monounsaturated or polyunsaturated fats 2, 3
• Increase soluble fiber to >10 g/day from sources like oats, beans, and vegetables 2, 3
• Consume at least 2 servings per week of fatty fish rich in EPA and DHA 2, 3
• Limit or avoid alcohol consumption 1, 2

For Severe Hypertriglyceridemia (500-999 mg/dL):

• Restrict total dietary fat to 20-25% of total daily calories 2
• Eliminate all added sugars completely 2
• Abstain completely from all alcohol consumption 2

For Very Severe Hypertriglyceridemia (≥1,000 mg/dL):

• Implement extreme dietary fat restriction (10-15% of total calories, or <5% until triglycerides fall below 1,000 mg/dL) 2
• Eliminate all added sugars and alcohol completely 2

Pharmacologic Treatment Algorithm

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, 5 Fenofibrate provides 30-50% triglyceride reduction. 2, 3 The FDA-approved initial dose for severe hypertriglyceridemia is 54-160 mg per day, with dosage individualized according to patient response and adjusted following repeat lipid determinations at 4-8 week intervals. 5

• Once triglycerides fall below 500 mg/dL, reassess LDL-C and consider adding statin therapy if LDL-C is elevated or cardiovascular risk is high. 2
• If triglycerides remain >200 mg/dL after 3 months of fenofibrate plus optimized lifestyle, add prescription omega-3 fatty acids (icosapent ethyl 2-4 g daily) as adjunctive therapy. 2
• Adjust fenofibrate dose based on renal function: initiate at 54 mg per day in patients with mild to moderately impaired renal function and increase only after evaluation of effects on renal function and lipid levels. 5

Moderate Hypertriglyceridemia (200-499 mg/dL)

For patients with 10-year ASCVD risk ≥7.5%, initiate moderate-to-high intensity statin therapy as first-line pharmacologic treatment (atorvastatin 20-40 mg or rosuvastatin 10-20 mg daily), which provides 10-30% dose-dependent triglyceride reduction and proven cardiovascular benefit. 1, 2

• For patients with 10-year ASCVD risk 5% to <7.5%, patient-clinician discussion regarding statin initiation is recommended, as persistently elevated triglycerides ≥175 mg/dL constitute a cardiovascular risk-enhancing factor. 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 patient has established cardiovascular disease OR diabetes with ≥2 additional risk factors. 1, 2
• Alternatively, consider fenofibrate 54-160 mg daily if icosapent ethyl criteria are not met, particularly for isolated hypertriglyceridemia with low HDL-C (<40 mg/dL in men). 2, 4, 3

Mild Hypertriglyceridemia (150-199 mg/dL)

• For patients with 10-year ASCVD risk ≥7.5%, consider moderate-intensity statin therapy. 1, 2
• Pharmacological therapy is generally not indicated unless other cardiovascular risk factors are present. 4
• Focus on intensive lifestyle modifications. 1, 2

Prescription Omega-3 Fatty Acids (Icosapent Ethyl)

Icosapent ethyl (prescription EPA) is indicated as adjunct to maximally tolerated statin therapy for patients with triglycerides ≥150 mg/dL who have either established cardiovascular disease OR diabetes with ≥2 additional risk factors. 1, 2 The REDUCE-IT trial demonstrated a 25% reduction in major adverse cardiovascular events (number needed to treat = 21). 2

• Dose: 2 g twice daily (4 g total daily) 2
• Monitor for increased risk of atrial fibrillation (3.1% hospitalization rate versus 2.1% on placebo). 2
• Over-the-counter fish oil supplements are not equivalent to prescription formulations and should not be substituted. 2

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 Fenofibrate has a better safety profile than gemfibrozil when combined with statins, as fenofibrate does not inhibit statin glucuronidation. 2 Monitor creatine kinase levels and muscle symptoms, especially at baseline and 3 months after initiation. 2

Treatment Goals

• Primary goal: Triglycerides <200 mg/dL (ideally <150 mg/dL) 2, 3
• Secondary goal: Non-HDL-C <130 mg/dL (calculated as total cholesterol minus HDL-C) 1, 2
• For severe hypertriglyceridemia: Rapid reduction to <500 mg/dL to eliminate pancreatitis risk 2

Monitoring Strategy

• Reassess fasting lipid panel in 6-12 weeks after implementing lifestyle modifications. 2
• Recheck lipid panel 4-8 weeks after initiating or adjusting pharmacotherapy. 2
• Monitor liver function tests and creatine kinase if fenofibrate is added, particularly at baseline and 3 months after initiation. 2
• Once goals are achieved, follow-up every 6-12 months. 2

Critical Pitfalls to Avoid

• Do not delay fibrate therapy while attempting lifestyle modifications alone in patients with triglycerides ≥500 mg/dL—pharmacologic therapy is mandatory to prevent pancreatitis. 2
• 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. 2
• Do not use gemfibrozil instead of fenofibrate—gemfibrozil has significantly higher myopathy risk when combined with statins. 2, 3
• Do not ignore secondary causes of hypertriglyceridemia, particularly uncontrolled diabetes and hypothyroidism, as treating these can dramatically reduce triglycerides independent of lipid medications. 1, 2
• Do not use bile acid sequestrants when triglycerides are >200 mg/dL—they are relatively contraindicated. 2
• Do not use niacin routinely—it showed no cardiovascular benefit when added to statin therapy and increases risk of new-onset diabetes. 2