What is the management of hypertriglyceridemia?

Management of Hypertriglyceridemia

Lifestyle modification remains the foundation of hypertriglyceridemia management for all patients, with pharmacologic therapy selection determined by triglyceride severity: fibrates for severe hypertriglyceridemia (≥500 mg/dL) to prevent pancreatitis, statins for moderate levels (200-499 mg/dL) when cardiovascular risk is elevated, and icosapent ethyl as adjunctive therapy for patients with persistent elevation despite statin therapy who have established cardiovascular disease or diabetes with additional risk factors. 1, 2

Classification and Risk Stratification

Triglyceride levels must be classified by severity to determine the primary therapeutic goal 2, 3:

• Normal: <150 mg/dL 2, 4
• Mild: 150-199 mg/dL 2, 4
• Moderate: 200-499 mg/dL 2, 4
• Severe: 500-999 mg/dL 2, 4
• Very severe: ≥1,000 mg/dL 2, 4

Mild to moderate hypertriglyceridemia increases cardiovascular disease risk, while severe and very severe levels (≥500 mg/dL) dramatically increase the risk of acute pancreatitis, with a 14% incidence at severe levels. 1, 3

Initial Assessment: Identify Secondary Causes

Before initiating treatment, evaluate for reversible causes 2, 3, 5:

• Uncontrolled diabetes mellitus (often the primary driver of severe hypertriglyceridemia) 2, 3
• Hypothyroidism 2, 3
• Excessive alcohol intake (even 1 ounce daily increases triglycerides by 5-10%) 2, 3
• Chronic kidney disease or nephrotic syndrome 2, 3
• Chronic liver disease 2, 3
• Medications: estrogen therapy, thiazide diuretics, beta-blockers, corticosteroids, antiretrovirals, antipsychotics 2, 5

Lifestyle Interventions: First-Line for All Patients

Referral to a registered dietitian nutritionist is strongly recommended to individualize nutrition recommendations. 1

Weight Loss and Physical Activity

• Target 5-10% body weight reduction, which produces a 20% decrease in triglycerides (the single most effective lifestyle intervention) 1, 2, 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

Dietary Modifications by Triglyceride Level

For mild to moderate hypertriglyceridemia (150-499 mg/dL): 1, 2, 3

• Restrict added sugars to <6% of total daily calories 1, 2, 3
• Limit total dietary fat to 30-35% of total calories 1, 2, 3
• Restrict saturated fats to <7% of total energy intake, replacing with monounsaturated or polyunsaturated fats 1, 2, 3
• Consume ≥2 servings (8+ ounces) per week of fatty fish rich in omega-3 fatty acids (salmon, trout, sardines, anchovies) 2, 3
• Increase soluble fiber to >10 g/day 1, 2
• Limit or avoid alcohol consumption 1, 2, 3

For severe hypertriglyceridemia (500-999 mg/dL): 1, 2

• Restrict added sugars to <5% of total daily calories 1, 2
• Limit total fat to 20-25% of total daily calories 1, 2
• Complete abstinence from all alcohol 1, 2

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

• Eliminate all added sugars completely 1, 2
• Restrict total fat to 10-15% of daily calories 1, 2
• Complete abstinence from all alcohol 1, 2
• Medium-chain triglyceride oil can be added gradually for additional calories 1

Pharmacologic Therapy Algorithm

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

Initiate fenofibrate immediately as first-line therapy to prevent acute pancreatitis, regardless of LDL-C levels or cardiovascular risk. 2, 3, 4, 5

• Fenofibrate 54-160 mg daily (provides 30-50% triglyceride reduction) 2, 3, 4, 5
• Start at 54 mg daily in patients with mild to moderately impaired renal function 5
• Maximum dose: 160 mg once daily 5
• Take with meals to optimize bioavailability 5
• Monitor lipid levels 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, 4

Critical pitfall: 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

Moderate Hypertriglyceridemia (200-499 mg/dL)

For patients with elevated cardiovascular risk (10-year ASCVD risk ≥7.5%, established ASCVD, or diabetes): 1, 2, 4

• Initiate moderate-to-high intensity statin therapy as first-line (provides 10-30% dose-dependent triglyceride reduction and proven cardiovascular benefit) 1, 2, 4
• Calculate non-HDL-C (total cholesterol minus HDL-C) with target goal of <130 mg/dL 2, 6
• If triglycerides remain >200 mg/dL after 3 months of optimized lifestyle modifications and statin therapy, consider adding prescription omega-3 fatty acids (icosapent ethyl 2-4g daily) 2, 4

Mild Hypertriglyceridemia (150-199 mg/dL)

For patients with 10-year ASCVD risk ≥7.5%: 2

• Consider moderate-intensity statin therapy 2
• Persistently elevated nonfasting triglycerides ≥175 mg/dL constitute a cardiovascular risk-enhancing factor favoring statin therapy 2

For patients with 10-year ASCVD risk 5% to <7.5%: 2

• Patient-clinician discussion regarding statin initiation 2

Adjunctive Therapy: Icosapent Ethyl

Icosapent ethyl (pure EPA) 2g twice daily is indicated as adjunct to maximally tolerated statin therapy for patients with triglycerides ≥150 mg/dL and: 1, 2, 4

• Established cardiovascular disease, OR 1, 2, 4
• Diabetes with ≥2 additional cardiovascular risk factors 1, 2, 4

This provides a 25% reduction in major adverse cardiovascular events (number needed to treat = 21). 2, 4

Monitor for increased risk of atrial fibrillation (3.1% hospitalization rate versus 2.1% on placebo). 2

Special Considerations

Diabetes Management

Aggressively optimize glycemic control in diabetic patients with severe hypertriglyceridemia, as poor glucose control is often the primary driver and optimizing control can dramatically reduce triglycerides independent of lipid medications. 2, 3, 4

Combination Therapy Safety

When combining fenofibrate with statins: 2, 4

• Use lower statin doses to minimize myopathy risk, particularly in patients >65 years or with renal disease 2, 4
• Fenofibrate has a better safety profile than gemfibrozil when combined with statins 2, 4
• Monitor for muscle symptoms and obtain baseline and follow-up CPK levels 2

Critical pitfall: Avoid gemfibrozil when combining with statins—gemfibrozil has significantly higher myopathy risk. 2

Medications That Did NOT Show Cardiovascular Benefit

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

Monitoring and Follow-Up

• Reassess fasting lipid panel in 6-12 weeks after implementing lifestyle modifications 2, 3, 4
• Reassess lipids 4-8 weeks after initiating or adjusting pharmacotherapy 2, 3, 4, 5
• Monitor liver function tests and creatine kinase if fibrates are added, particularly at baseline and 3 months after initiation 2, 3
• 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 5

Treatment Goals by Severity

For severe/very severe hypertriglyceridemia (≥500 mg/dL): 2, 4

• Primary goal: Rapid reduction to <500 mg/dL to eliminate pancreatitis risk 2, 4
• Secondary goal: Further reduction to <200 mg/dL (ideally <150 mg/dL) to reduce cardiovascular risk 2, 4

For moderate hypertriglyceridemia (200-499 mg/dL): 2, 6

• Primary goal: Triglycerides <200 mg/dL (ideally <150 mg/dL) 2
• Secondary goal: Non-HDL-C <130 mg/dL 2, 6