What is the recommended management for a 45‑year‑old adult with hypercholesterolemia (total cholesterol 206 mg/dL), hypertriglyceridemia (222 mg/dL), borderline low high‑density lipoprotein (HDL 43 mg/dL) and elevated low‑density lipoprotein (LDL 124 mg/dL) without known atherosclerotic cardiovascular disease?

Management of Hyperlipidemia with Elevated Triglycerides and Borderline LDL

Initial Assessment and Risk Stratification

This 45-year-old patient has moderate hypertriglyceridemia (222 mg/dL) with borderline-high LDL-C (124 mg/dL), borderline-low HDL-C (43 mg/dL), and elevated total cholesterol (206 mg/dL), creating an atherogenic dyslipidemia pattern that warrants immediate intervention. 1

• Calculate the 10-year ASCVD risk using the Pooled Cohort Equations, incorporating age, sex, race, blood pressure, smoking status, diabetes status, and current lipid values to determine treatment intensity. 2
• The triglyceride level of 222 mg/dL falls into the moderate hypertriglyceridemia range (200-499 mg/dL), which is associated with increased cardiovascular risk through atherogenic VLDL remnant particles but is below the 500 mg/dL threshold requiring immediate fibrate therapy for pancreatitis prevention. 1
• Persistently elevated triglycerides ≥175 mg/dL constitute a cardiovascular risk-enhancing factor that should influence statin initiation decisions. 1
• The non-HDL-C (calculated as total cholesterol minus HDL-C) is 163 mg/dL, which exceeds the target of <130 mg/dL for patients with moderate hypertriglyceridemia, reflecting the total burden of atherogenic lipoproteins. 1

Evaluation for Secondary Causes (Critical First Step)

Before initiating any lipid-lowering therapy, systematically screen for reversible contributors that can lower triglycerides by 20-50% independent of pharmacotherapy. 1

• Check hemoglobin A1c and fasting glucose immediately; uncontrolled diabetes is often the primary driver of hypertriglyceridemia, and optimizing glycemic control can dramatically reduce triglycerides independent of lipid medications. 1
• Measure TSH to exclude hypothyroidism, which must be treated before expecting a full lipid-lowering response. 1
• Obtain a detailed alcohol history; even 1 oz daily can raise triglycerides by 5-10%, and the effects are synergistically exaggerated when coupled with high saturated-fat meals. 1
• Review all current medications for agents that raise triglycerides (thiazide diuretics, beta-blockers, oral estrogen, corticosteroids, antiretrovirals, atypical antipsychotics) and discontinue or substitute when possible. 1
• Assess renal function (creatinine, eGFR) and hepatic function (AST, ALT) because chronic kidney or liver disease contributes to hypertriglyceridemia and influences medication dosing. 1

Intensive Lifestyle Modifications (Start Immediately)

Comprehensive lifestyle changes can lower triglycerides by 20-70% and LDL-C by 15-25 mg/dL, and should be initiated immediately alongside pharmacotherapy in high-risk patients—not sequentially. 1, 2

Weight Management

• Target a 5-10% body weight reduction, which produces an approximate 20% decrease in triglycerides—the single most effective lifestyle intervention; in some individuals, weight loss alone can achieve 50-70% triglyceride reduction. 1
• If BMI ≥25 kg/m², aim for 10% body-weight reduction in the first year through caloric restriction and increased physical activity. 2

Dietary Interventions

• Restrict added sugars to <6% of total daily calories (approximately 30 g on a 2,000-kcal diet) because sugar intake directly increases hepatic triglyceride production. 1
• Limit total dietary fat to 30-35% of total calories for moderate hypertriglyceridemia. 1
• Restrict saturated fat to <7% of total energy intake and replace with monounsaturated fats (olive oil, canola oil, avocados) or polyunsaturated fats (nuts, seeds, fatty fish). 1, 2
• Eliminate trans fatty acids completely, as they increase triglycerides and atherogenic lipoproteins. 1
• Limit dietary cholesterol to <200 mg per day. 2
• Increase soluble fiber intake to >10 g/day from sources such as oats, beans, lentils, and vegetables, which can provide an additional 5-10% LDL-C reduction. 1, 2
• Add 2 g/day of plant stanols/sterols (via fortified margarines, orange juice, or supplements), which can lower LDL-C by approximately 6-15%. 2
• Consume ≥2 servings per week of fatty fish (salmon, trout, sardines, mackerel) to provide dietary omega-3 fatty acids. 1

Physical Activity

• Engage in ≥150 minutes/week of moderate-intensity aerobic activity (or 75 minutes/week of vigorous activity), which reduces triglycerides by approximately 11%. 1
• Add resistance training: 8-10 exercises, 1-2 sets of 10-15 repetitions at moderate intensity, twice weekly. 2

Alcohol Restriction

• Limit or avoid alcohol; even modest intake (approximately 1 oz daily) raises triglycerides by 5-10%, especially when levels approach 500 mg/dL. 1

Pharmacologic Therapy Algorithm

Statin Therapy (First-Line for Moderate Hypertriglyceridemia with Elevated LDL-C)

Initiate moderate-to-high intensity statin therapy immediately alongside lifestyle changes if the patient has any of the following: 10-year ASCVD risk ≥7.5%, diabetes mellitus (age 40-75 years), established ASCVD, or LDL-C ≥190 mg/dL. 1, 2

• Do not postpone statin initiation while attempting lifestyle modifications alone in high-risk patients; pharmacotherapy and lifestyle optimization should occur concurrently. 1
• Recommended statin regimens:
  • Atorvastatin 10-20 mg daily (moderate-intensity, provides 30-40% LDL-C reduction) 1, 2
  • Rosuvastatin 5-10 mg daily (moderate-intensity, provides 30-40% LDL-C reduction) 1, 2
• Statins provide a dose-dependent 10-30% reduction in triglycerides in addition to proven cardiovascular mortality benefit via LDL-C lowering. 1

Lipid Targets While on Statin Therapy

• LDL-C <100 mg/dL (or <70 mg/dL for very high-risk patients) 1, 2
• Non-HDL-C <130 mg/dL 1
• Triglycerides <200 mg/dL (ideally <150 mg/dL) 1

Add-On Therapy When Triglycerides Remain >200 mg/dL After 3 Months

If triglycerides stay >200 mg/dL after 3 months of optimized lifestyle modifications and statin therapy, add prescription omega-3 fatty acids or fenofibrate based on specific criteria. 1

Icosapent Ethyl (Prescription EPA) – Preferred Add-On

• Indicated for patients with established cardiovascular disease OR diabetes plus ≥2 additional cardiovascular risk factors (e.g., hypertension, smoking, family history of premature ASCVD, age >50 years for men or >60 years for women, chronic kidney disease). 1
• Dose: 2 g twice daily (total 4 g/day) 1
• The REDUCE-IT trial demonstrated a 25% relative risk reduction in major adverse cardiovascular events (NNT = 21 over 4.9 years)—this is Level A evidence from a large randomized controlled trial. 1
• Icosapent ethyl is the only triglyceride-lowering agent FDA-approved for cardiovascular risk reduction. 1
• Monitor for a modest increased risk of atrial fibrillation (3.1% vs 2.1% with placebo). 1

Fenofibrate – Alternative Add-On

• Add fenofibrate 54-160 mg daily if the patient does NOT meet icosapent ethyl criteria but triglycerides remain >200 mg/dL after 3 months of optimized lifestyle and statin therapy. 1
• Fenofibrate provides a 30-50% triglyceride reduction. 1, 3
• When combining fenofibrate with statins, use fenofibrate (NOT gemfibrozil) because fenofibrate does not inhibit statin glucuronidation and has a markedly better safety profile with lower myopathy risk. 1
• Consider lower statin doses (atorvastatin ≤20 mg or rosuvastatin ≤10 mg) when combined with fenofibrate, especially in patients >65 years or with renal impairment. 1
• Fenofibrate dosing with renal impairment: Start at 54 mg daily if eGFR 30-59 mL/min/1.73 m²; contraindicated if eGFR <30 mL/min/1.73 m². 1, 3

Patients with Lower Cardiovascular Risk

• For individuals with 10-year ASCVD risk <7.5% and no diabetes or established ASCVD, prioritize intensive lifestyle modification for at least 3 months before considering pharmacotherapy. 1
• Re-measure fasting lipid panel 6-12 weeks after lifestyle implementation. 1
• Consider a moderate-intensity statin after shared decision-making if risk-enhancing factors are present (family history of premature ASCVD, chronic kidney disease, metabolic syndrome, triglycerides ≥175 mg/dL). 1

Monitoring Strategy

• Reassess fasting lipid panel 6-12 weeks after implementing lifestyle modifications to evaluate response. 1
• Recheck lipids 4-8 weeks after initiating or adjusting statin therapy to confirm adequate LDL-C reduction and triglyceride response. 1
• Calculate non-HDL-C (total cholesterol minus HDL-C) and aim for <130 mg/dL as a secondary target when triglycerides are elevated. 1
• Measure baseline hepatic transaminases (ALT/AST) before starting a statin and repeat as clinically indicated. 2
• Screen for muscle symptoms at each visit; obtain creatine kinase only if musculoskeletal complaints develop. 1
• If fenofibrate is added, monitor renal function at baseline, at 3 months, and then every 6 months; obtain baseline and follow-up creatine kinase levels when combining with statins. 1
• Once lipid goals are achieved and stable, conduct annual fasting lipid assessments. 2

Treatment Goals

• Primary goal: Reduce triglycerides to <200 mg/dL (ideally <150 mg/dL) to lower cardiovascular risk. 1
• Secondary goal: Achieve non-HDL-C <130 mg/dL. 1
• Tertiary goal: Attain LDL-C <100 mg/dL (or <70 mg/dL for very high-risk patients). 1, 2

Critical Pitfalls to Avoid

• Do not delay statin initiation while attempting lifestyle changes alone in high-risk patients (ASCVD risk ≥7.5%, diabetes, established ASCVD); both should be started concurrently. 1
• Do not overlook secondary causes (uncontrolled diabetes, hypothyroidism, excess alcohol, offending medications); correcting these can lower triglycerides by 20-50% and may obviate the need for additional lipid agents. 1
• Do not start with fenofibrate monotherapy for moderate hypertriglyceridemia (200-499 mg/dL) with elevated LDL-C; statins provide superior cardiovascular benefit and are first-line. 1
• Do not combine gemfibrozil with statins; fenofibrate has a markedly better safety profile with lower myopathy risk when combined with statins. 1
• Do not rely on over-the-counter fish oil supplements for cardiovascular benefit; only prescription icosapent ethyl has proven outcome data. 1
• Do not add fibrates or omega-3 agents before completing at least 3 months of intensive lifestyle and statin therapy (unless triglycerides exceed 500 mg/dL). 1