For a very high‑risk adult with elevated LDL‑cholesterol and hypertriglyceridemia, what is the recommended triple‑therapy regimen using a high‑intensity statin (atorvastatin or rosuvastatin), fenofibrate, and a non‑statin LDL‑lowering agent (ezetimibe), and how should the treatment be monitored?

Triple Therapy for Cholesterol: Statin + Fenofibrate + Ezetimibe

For very high-risk adults with elevated LDL-cholesterol and hypertriglyceridemia, initiate upfront triple therapy with high-intensity statin (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) plus ezetimibe 10 mg plus fenofibrate 160 mg daily, targeting LDL-C <55 mg/dL and triglycerides <150 mg/dL. 1

Treatment Algorithm

Step 1: Initiate High-Intensity Statin Plus Ezetimibe

• Start with atorvastatin 40-80 mg or rosuvastatin 20-40 mg combined with ezetimibe 10 mg as the foundation of triple therapy 1, 2
• This dual combination achieves 50-60% LDL-C reduction from baseline, with the statin providing the majority of reduction and ezetimibe adding an additional 20-25% 2, 3
• For patients with diabetes or metabolic syndrome, consider pitavastatin plus ezetimibe as an alternative to minimize new-onset diabetes risk 2

Step 2: Add Fenofibrate for Hypertriglyceridemia

• Add fenofibrate 160 mg daily to the statin-ezetimibe combination when triglycerides remain >200 mg/dL or HDL-C remains low despite statin therapy 4
• Fenofibrate is preferred over gemfibrozil due to significantly lower myopathy risk when combined with statins 4
• Start with lower statin doses (atorvastatin 20-40 mg or rosuvastatin 10-20 mg) when initiating triple therapy to minimize myopathy risk, then uptitrate as tolerated 4

Step 3: Target Goals for Very High-Risk Patients

• Primary target: LDL-C <55 mg/dL (or non-HDL-C <85 mg/dL) with ≥50% reduction from baseline 1
• Secondary target: Triglycerides <150 mg/dL to address residual cardiovascular risk 1, 4
• Very high-risk is defined as multiple major ASCVD events or 1 major ASCVD event plus multiple high-risk conditions 1

Monitoring Protocol

Initial Monitoring (4-6 Weeks)

• Measure lipid panel (total cholesterol, LDL-C, HDL-C, triglycerides, non-HDL-C) at 4-6 weeks after initiating triple therapy 1, 4
• Check liver enzymes (ALT/AST) and creatine kinase (CK) for safety monitoring 4
• Assess renal function (eGFR, creatinine) especially critical with fenofibrate, which requires dose adjustment in chronic kidney disease 4

Ongoing Monitoring

• If LDL-C <55 mg/dL achieved, continue therapy and follow up at 3 months, then every 6-12 months 1
• If LDL-C remains ≥55 mg/dL on triple therapy, consider adding a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) for additional 50-60% LDL-C reduction 1, 2
• Monitor liver enzymes every 3-6 months; discontinue ezetimibe if ALT/AST ≥3× upper limit of normal persists 2

Critical Safety Considerations

Contraindications to Fenofibrate

• Avoid fenofibrate in severe renal impairment (eGFR <30 mL/min/1.73 m²), active liver disease, preexisting gallbladder disease, or known hypersensitivity 4
• Never combine gemfibrozil with statins due to significantly elevated myopathy risk; fenofibrate is the only fibrate safe for statin combination 4

Myopathy Risk Management

• The combination of ezetimibe plus statin carries similar myopathy risk to statin monotherapy 2
• Fenofibrate-statin combinations have acceptable myopathy risk when dosed appropriately, but start with lower statin doses 4
• Educate patients to report unexplained muscle pain, tenderness, or weakness immediately 4

Dose Adjustments for Renal Impairment

• Fenofibrate requires dose reduction in moderate renal impairment (eGFR 30-59 mL/min/1.73 m²); start with 54 mg daily 4
• Monitor renal function closely as fenofibrate can transiently increase creatinine 4

When to Escalate Beyond Triple Therapy

• If LDL-C remains ≥55 mg/dL despite maximally tolerated triple therapy (statin + ezetimibe + fenofibrate), add a PCSK9 inhibitor as quadruple therapy 1
• For extreme cardiovascular risk patients (recurrent ASCVD events despite optimal therapy), target LDL-C <40 mg/dL with quadruple therapy 1
• Bempedoic acid 180 mg daily is an alternative add-on option if PCSK9 inhibitors are not accessible or tolerated 1

Common Pitfalls to Avoid

• Do not deescalate therapy if very low LDL-C levels (<40 mg/dL) are achieved and well-tolerated; maintain therapy for "lower is better for longer" benefit 1
• Do not use fenofibrate primarily for LDL-C lowering; its role is triglyceride reduction and HDL-C elevation in mixed dyslipidemia 4
• Do not abandon statin therapy prematurely due to perceived intolerance without trying multiple statins at varying doses 5
• Avoid simvastatin 80 mg in any combination due to excessive myopathy risk 5

Special Populations

Patients >75 Years

• Continue triple therapy if already tolerating it, as data support continuation beyond age 75 years 1
• For new initiation, consider moderate-intensity statin (atorvastatin 20-40 mg or rosuvastatin 10-20 mg) plus ezetimibe plus fenofibrate based on expected benefit and competing comorbidities 1

Diabetes with Mixed Dyslipidemia

• Triple therapy is particularly beneficial in type 2 diabetes with persistent hypertriglyceridemia (135-499 mg/dL) and LDL-C not at goal 1
• Consider adding icosapent ethyl 4 g daily if triglycerides remain 135-499 mg/dL despite triple therapy, as it provides additional 25% cardiovascular event reduction 1