Management of Triglycerides 375 mg/dL
For a patient with triglycerides of 375 mg/dL (moderate hypertriglyceridemia), immediately implement aggressive lifestyle modifications while simultaneously initiating moderate-to-high intensity statin therapy if the patient has diabetes (age 40-75), a 10-year ASCVD risk ≥7.5%, or elevated LDL-C—do not delay pharmacotherapy while attempting lifestyle changes alone in high-risk patients. 1
Classification and Risk Assessment
A triglyceride level of 375 mg/dL falls into the moderate hypertriglyceridemia category (200-499 mg/dL), which increases cardiovascular risk through atherogenic VLDL remnant particles but remains below the 500 mg/dL threshold that mandates immediate fibrate therapy for pancreatitis prevention. 1, 2
This level is classified as a cardiovascular risk-enhancing factor that should influence treatment decisions, particularly when combined with other risk factors. 1
The primary concern at this level is long-term cardiovascular disease risk, not acute pancreatitis, which becomes significant only when triglycerides exceed 500 mg/dL. 1, 3
Urgent Assessment for Secondary Causes
Before initiating any triglyceride-lowering therapy, systematically evaluate for reversible contributors:
Check hemoglobin A1c and fasting glucose immediately—uncontrolled diabetes is often the primary driver of hypertriglyceridemia, and optimizing glycemic control can reduce triglycerides by 20-50% independent of lipid medications. 1, 3
Measure thyroid-stimulating hormone (TSH) to exclude hypothyroidism, which must be treated before expecting full response to lipid therapy. 1, 3
Obtain a detailed alcohol history—even 1 ounce daily raises triglycerides by 5-10%, and the effects are synergistically exaggerated when coupled with high saturated-fat meals; complete abstinence may be required as levels approach 500 mg/dL. 1, 3
Review all current medications for agents that raise triglycerides: thiazide diuretics, beta-blockers, estrogen therapy, corticosteroids, antiretrovirals, and antipsychotics—discontinue or substitute when possible. 1, 3, 4
Assess renal function (creatinine, eGFR) and liver function (AST, ALT), as chronic kidney disease and liver disease contribute to hypertriglyceridemia and affect medication dosing. 1
Intensive Lifestyle Modifications (First-Line for All Patients)
Lifestyle interventions can lower triglycerides by 20-50% and must be implemented immediately:
Weight Management
- Target 5-10% body weight reduction, which produces approximately 20% decrease in triglycerides—this is the single most effective lifestyle intervention. 1, 5
- In some individuals, weight loss alone can reduce triglyceride levels by 50-70%. 1
Dietary Interventions
Restrict added sugars to <6% of total daily calories (approximately 30 grams on a 2,000-calorie diet) because sugar intake directly increases hepatic triglyceride production. 1, 3
Limit total dietary fat to 30-35% of total calories for moderate hypertriglyceridemia. 1, 3
Restrict saturated fats to <7% of total energy intake and replace with monounsaturated or polyunsaturated fats (olive oil, nuts, avocado, fatty fish). 1, 3, 5
Eliminate trans fatty acids completely, as they increase triglycerides and atherogenic lipoproteins. 1
Increase soluble fiber to >10 g/day from sources like oats, beans, lentils, and vegetables. 1, 3
Consume at least 2 servings per week of fatty fish (salmon, trout, sardines, mackerel) to provide dietary omega-3 fatty acids. 1, 5
Lower carbohydrate intake, especially refined carbohydrates, as low-carbohydrate diets are more effective at lowering triglycerides than low-fat diets. 1, 5
Physical Activity
- Engage in ≥150 minutes per week of moderate-intensity aerobic activity (or 75 minutes per week of vigorous activity), which reduces triglycerides by approximately 11%. 1, 3, 5
Alcohol Restriction
- Limit or completely avoid alcohol consumption—even modest intake raises triglycerides by 5-10%, and complete abstinence is mandatory when levels approach 500 mg/dL. 1, 3
Pharmacologic Therapy Decision Algorithm
For High-Risk Patients (Diabetes Age 40-75,10-Year ASCVD Risk ≥7.5%, or Elevated LDL-C)
Initiate moderate-to-high intensity statin therapy immediately alongside lifestyle modifications—do not postpone pharmacotherapy:
Start atorvastatin 10-20 mg daily or rosuvastatin 5-10 mg daily, which provides a dose-dependent 10-30% triglyceride reduction plus proven cardiovascular mortality benefit through LDL-C lowering. 1, 2, 5
Statins possess the strongest evidence for reducing cardiovascular events and mortality among lipid-lowering agents and should be the foundation of therapy. 1, 6
Lipid targets while on statin therapy:
For Lower-Risk Patients (10-Year ASCVD Risk <7.5%, No Diabetes, No Elevated LDL-C)
Prioritize aggressive lifestyle modification for at least 3 months before considering pharmacotherapy. 1, 2
Reassess fasting lipid panel in 6-12 weeks after implementing lifestyle changes. 1
If triglycerides remain elevated despite documented adherence to lifestyle changes, consider moderate-intensity statin therapy after shared decision-making, particularly if persistently elevated triglycerides ≥175 mg/dL are present as a risk-enhancing factor. 1
Add-On Therapy When Triglycerides Remain >200 mg/dL After 3 Months
If triglycerides stay above 200 mg/dL despite optimized lifestyle modifications and statin therapy:
Icosapent Ethyl (Preferred Add-On for Specific High-Risk Patients)
Add icosapent ethyl 2 g twice daily (total 4 g/day) for patients with established cardiovascular disease OR diabetes with ≥2 additional cardiovascular risk factors (e.g., hypertension, smoking, family history, age >50 years for men or >60 years for women). 1, 5
Icosapent ethyl is the only triglyceride-lowering agent FDA-approved for cardiovascular risk reduction, demonstrating a 25% reduction in major adverse cardiovascular events (number needed to treat = 21) in the REDUCE-IT trial. 1, 5
Monitor for increased risk of atrial fibrillation (3.1% vs 2.1% with placebo) when prescribing prescription omega-3 at 2-4 g daily. 1
Fenofibrate (Alternative When Icosapent Ethyl Criteria Not Met)
Consider fenofibrate 54-160 mg daily if the patient does not meet icosapent ethyl criteria but triglycerides remain >200 mg/dL after optimized lifestyle and statin therapy. 1, 2, 4
Fenofibrate provides 30-50% triglyceride reduction but has not demonstrated cardiovascular outcome benefit when added to statins in major trials (ACCORD, AIM-HIGH). 1, 6
When combining fenofibrate with a statin, use fenofibrate (NOT gemfibrozil) because fenofibrate does not inhibit statin glucuronidation and has a significantly better safety profile. 1, 2
Consider lower statin doses (atorvastatin ≤20 mg or rosuvastatin ≤10 mg) when combining with fenofibrate to minimize myopathy risk, particularly in patients >65 years or with renal impairment. 1, 2
Fenofibrate dosing must be adjusted for renal function: start at 54 mg daily and do not exceed this dose if eGFR is 30-59 mL/min/1.73 m²; fenofibrate is contraindicated if eGFR <30 mL/min/1.73 m². 1, 4
Monitoring Strategy
Calculate non-HDL-C (total cholesterol minus HDL-C) and aim for <130 mg/dL as the secondary lipid target when triglycerides are elevated. 1, 3
Reassess fasting lipid panel 4-8 weeks after initiating or adjusting statin therapy. 1
If fenofibrate is added, monitor lipid levels at 4-8 week intervals after initiation or dose adjustment. 1, 4
Monitor renal function at baseline, 3 months, and every 6 months when fenofibrate is used, as the drug is substantially excreted by the kidney. 1, 4
Obtain baseline and follow-up creatine kinase (CPK) levels and monitor for muscle symptoms when combining fenofibrate with statins. 1, 2
Critical Pitfalls to Avoid
Do not delay statin initiation while attempting lifestyle modifications alone in high-risk patients (diabetes, 10-year ASCVD risk ≥7.5%)—pharmacotherapy and lifestyle optimization should occur concurrently. 1, 2
Do not overlook secondary causes (uncontrolled diabetes, hypothyroidism, offending medications)—correcting these may eliminate the need for additional lipid agents and can reduce triglycerides by 20-50%. 1, 3
Do not start with fibrate monotherapy when cardiovascular risk is elevated—statins provide proven mortality benefit and should be the foundation of therapy. 1, 2
Do not use gemfibrozil when combining with statins—fenofibrate has a superior safety profile with lower myopathy risk. 1, 2
Do not use over-the-counter fish oil supplements expecting cardiovascular benefit—only prescription formulations (icosapent ethyl) have proven cardiovascular outcomes. 1