What are the first‑line pharmacologic options for lowering elevated triglycerides and their recommended dosing regimens?

First-Line Pharmacologic Options for Lowering Elevated Triglycerides

Treatment Algorithm Based on Triglyceride Severity

For severe to very severe hypertriglyceridemia (≥500 mg/dL), fenofibrate 54-160 mg daily is the mandatory first-line therapy to prevent acute pancreatitis, initiated immediately before any LDL-lowering agents. 1, 2 Fibrates provide 30-50% triglyceride reduction and must be started regardless of LDL-cholesterol level or cardiovascular risk when triglycerides reach this threshold. 3, 1

For moderate hypertriglyceridemia (200-499 mg/dL) with elevated cardiovascular risk (10-year ASCVD risk ≥7.5%, diabetes age 40-75, or established ASCVD), moderate-to-high intensity statin therapy is first-line pharmacologic treatment. 1, 2 Statins provide 10-30% dose-dependent triglyceride reduction plus proven cardiovascular mortality benefit through LDL-cholesterol lowering. 3, 1, 4

Specific Dosing Regimens by Drug Class

Fibrates (First-Line for Severe Hypertriglyceridemia ≥500 mg/dL)

• Fenofibrate: 54-160 mg once daily is the preferred fibrate formulation when combining with statins due to superior safety profile compared to gemfibrozil. 1, 2 Fenofibrate does not inhibit statin glucuronidation, minimizing myopathy risk. 1

• Dose adjustment required for renal impairment: limit to 54 mg daily if eGFR 30-59 mL/min/1.73 m²; contraindicated if eGFR <30 mL/min/1.73 m². 1

• Monitor renal function at baseline, 3 months, then every 6 months during fenofibrate therapy. 1

Statins (First-Line for Moderate Hypertriglyceridemia with Cardiovascular Risk)

• Atorvastatin 10-20 mg daily (moderate-intensity) or 40-80 mg daily (high-intensity) provides 10-30% triglyceride reduction. 1, 2

• Rosuvastatin 5-10 mg daily (moderate-intensity) or 20-40 mg daily (high-intensity) achieves ≥50% LDL-cholesterol reduction with additional triglyceride lowering. 1

• Statins should be initiated concurrently with lifestyle modifications—do not delay pharmacotherapy in high-risk patients. 1, 2

Prescription Omega-3 Fatty Acids (Add-On Therapy)

• Icosapent ethyl (pure EPA): 2 g twice daily (total 4 g/day) is indicated for patients with triglycerides ≥150 mg/dL on maximally tolerated statin therapy who have established cardiovascular disease OR diabetes with ≥2 additional risk factors. 1, 2, 4 This is the only triglyceride-lowering agent FDA-approved for cardiovascular risk reduction, demonstrating 25% reduction in major adverse cardiovascular events (NNT=21). 1, 4

• Omega-3-acid ethyl esters (EPA+DHA): 4 g daily are FDA-approved only for severe hypertriglyceridemia (≥500 mg/dL) as adjunct to diet, not for cardiovascular risk reduction. 1, 4

• Monitor for increased atrial fibrillation risk (3.1% vs 2.1% with placebo) when prescribing prescription omega-3 at therapeutic doses. 1, 4

Niacin (Limited Role)

• Immediate-release niacin: 1.5-3 g daily provides 20-50% triglyceride reduction but showed no cardiovascular benefit when added to statin therapy in major trials (AIM-HIGH, ACCORD). 3, 1 Niacin should generally not be used due to lack of proven benefit and increased risk of new-onset diabetes and gastrointestinal disturbances. 1

Sequential Treatment Approach

Step 1: Classify triglyceride severity and assess cardiovascular risk

• Severe/very severe (≥500 mg/dL): immediate fenofibrate to prevent pancreatitis 1, 2
• Moderate (200-499 mg/dL) with high CV risk: statin as first-line 1, 2
• Moderate (200-499 mg/dL) with low CV risk: intensive lifestyle modification for 3 months before considering pharmacotherapy 1

Step 2: Optimize lifestyle interventions concurrently

• 5-10% weight loss produces 20% triglyceride reduction (most effective single intervention) 1, 2
• Restrict added sugars to <6% of total calories 1
• Limit saturated fat to <7% of energy, replace with monounsaturated/polyunsaturated fats 3, 1
• Engage in ≥150 minutes/week moderate-intensity aerobic activity (reduces triglycerides by ~11%) 1
• Complete alcohol abstinence for severe hypertriglyceridemia 3, 1

Step 3: Add-on therapy if triglycerides remain >200 mg/dL after 3 months

• For patients meeting icosapent ethyl criteria: add icosapent ethyl 2 g twice daily 1, 2, 4
• For patients not meeting icosapent ethyl criteria: consider fenofibrate 54-160 mg daily 1
• When combining fenofibrate with statin, use lower statin doses (atorvastatin ≤20 mg or rosuvastatin ≤10 mg) to minimize myopathy risk, especially in patients >65 years or with renal disease 1

Treatment Targets

• Primary goal: Reduce triglycerides to <200 mg/dL (ideally <150 mg/dL) 1, 2
• Secondary goal: Non-HDL-cholesterol <130 mg/dL 3, 1
• LDL-cholesterol goal: <100 mg/dL (or <70 mg/dL for very high-risk patients) 1

Critical Pitfalls to Avoid

• Do not start statin monotherapy when triglycerides are ≥500 mg/dL—statins provide insufficient triglyceride reduction to prevent pancreatitis; fibrates must be initiated first. 1, 2

• Do not use gemfibrozil when combining with statins—fenofibrate has significantly better safety profile due to lack of statin glucuronidation inhibition. 1

• Do not delay statin therapy while attempting lifestyle modifications alone in high-risk patients—pharmacotherapy and lifestyle optimization should occur simultaneously. 1, 2

• Do not use over-the-counter fish oil supplements expecting therapeutic benefit—only prescription omega-3 formulations at 2-4 g daily provide adequate dosing and purity. 1, 4

• Do not overlook secondary causes (uncontrolled diabetes, hypothyroidism, excessive alcohol, medications)—optimizing glucose control can reduce triglycerides by 20-50% independent of lipid medications. 1, 2