What is the primary treatment for hypercholesterolemia (high cholesterol)?

Treatment of Hypercholesterolemia

Statins are the primary treatment for hypercholesterolemia, with high-intensity statins (atorvastatin or rosuvastatin) recommended as first-line therapy to achieve at least a 50% reduction in LDL-C from baseline. 1, 2

Initial Treatment Approach

First-Line: High-Intensity Statin Therapy

• Start with high-potency statins such as atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily 1, 2
• These agents reduce LDL-C by 35-61% depending on dose, with atorvastatin 80 mg achieving the maximum reduction 3
• Statins reduce myocardial infarction, stroke, and cardiovascular mortality in both primary and secondary prevention 1, 2

Treatment Goals Based on Risk Stratification

The LDL-C target depends on cardiovascular risk 1:

• LDL-C <100 mg/dL (2.6 mmol/L): For patients without clinical atherosclerotic cardiovascular disease (ASCVD) or other major risk factors 1
• LDL-C <70 mg/dL (1.8 mmol/L): For patients with imaging evidence of ASCVD or other major risk factors 1
• LDL-C <55 mg/dL (1.4 mmol/L): For patients with clinical ASCVD 1
• LDL-C <40 mg/dL (1.0 mmol/L): May be considered for recurrent ASCVD events within 2 years despite maximally tolerated statin therapy 1

Escalation Strategy When Goals Are Not Met

Second-Line: Add Ezetimibe

• Add ezetimibe 10 mg daily if LDL-C remains ≥100 mg/dL despite maximally tolerated statin therapy 1, 4
• Ezetimibe provides an additional 15-25% LDL-C reduction 5, 4
• The combination of ezetimibe with moderate-intensity statin reduces ASCVD risk more than statin monotherapy 1
• Ezetimibe is well-tolerated, available as a generic, and has minimal drug interactions 1, 4

Third-Line: Add Bempedoic Acid or PCSK9 Inhibitors

If LDL-C remains ≥100 mg/dL despite statin plus ezetimibe 1:

• Bempedoic acid provides additional LDL-C lowering without muscle-related side effects, making it particularly useful in statin-intolerant patients 5
• PCSK9 inhibitors (evolocumab, alirocumab, or inclisiran) should be added for patients requiring further LDL-C reduction 1
  • These agents provide an additional ≥50% LDL-C reduction 1
  • Evolocumab and alirocumab are monoclonal antibodies; inclisiran is a small interfering RNA 1, 5
  • Do not combine PCSK9 monoclonal antibodies with inclisiran—use one or the other 1

Fourth-Line: Bile Acid Sequestrants

• Colesevelam 3.75 g daily may be added if LDL-C goals are still not met 1
• Provides an additional 18.5% LDL-C reduction over 12 weeks 1
• Use is limited by gastrointestinal side effects, inconvenient dosing, and drug interactions 1
• Must be administered at least 2 hours before or 4 hours after ezetimibe 4

Special Populations

Severe Primary Hypercholesterolemia (LDL-C ≥190 mg/dL)

• Initiate high-intensity statin immediately without waiting for lifestyle modifications to fail 1
• Goal is ≥50% LDL-C reduction from baseline 1
• If LDL-C remains >100 mg/dL after maximal statin therapy, add ezetimibe 1
• Consider PCSK9 inhibitors for patients 30-75 years with LDL-C ≥100 mg/dL despite maximal statin plus ezetimibe 1
• Refer to a lipid specialist if combination therapy fails to achieve goals 1, 5

Familial Hypercholesterolemia

• Start with maximally tolerated high-potency statin plus ezetimibe 1, 5
• For extremely high-risk patients (post-MI, multivessel coronary disease), consider combination of high-potency statin, ezetimibe, and PCSK9 inhibitor as first-line treatment 1
• Specialized therapies (evinacumab, lomitapide, LDL apheresis) may be needed for homozygous familial hypercholesterolemia or inadequate response to standard therapy 1
• Genetic testing and family screening are recommended 5

Diabetes Mellitus

• All diabetic patients should receive at least moderate-intensity statin therapy for primary prevention 1
• LDL-C goal is <100 mg/dL (2.6 mmol/L) 1
• Initiate pharmacological therapy at LDL-C ≥130 mg/dL (3.35 mmol/L) 1
• For LDL-C 100-129 mg/dL with HDL <40 mg/dL, consider fibrates (fenofibrate preferred) 1

Monitoring and Safety

Laboratory Monitoring

• Measure hepatic aminotransferases, creatine kinase, glucose, and creatinine before starting therapy 1
• Monitor hepatic aminotransferases in patients at increased risk of hepatotoxicity 1, 4
• Measure creatine kinase if musculoskeletal symptoms develop 1
• Use non-fasting lipid profiles for stable patients; use fasting LDL-C when making treatment changes, especially with concomitant hypertriglyceridemia 1
• Assess LDL-C as early as 4 weeks after initiating or changing therapy 4

Common Pitfalls to Avoid

• Do not discontinue statins during acute illness (including COVID-19) unless specifically contraindicated 1
• Do not combine PCSK9 monoclonal antibodies with inclisiran—there is no evidence for additive benefit 1
• Avoid gemfibrozil with statins due to increased myopathy risk; fenofibrate is preferred for combination therapy 5
• Refer to lipid specialist if <50% LDL-C reduction or LDL-C ≥100 mg/dL persists despite maximal combination therapy 1, 5

Adjunctive Measures

• Lifestyle modifications including heart-healthy diet, regular exercise, smoking cessation, and weight management should be implemented alongside pharmacotherapy 1
• Low-dose aspirin may be considered for primary prevention in asymptomatic patients with elevated lipoprotein(a), diabetes, or adverse cardiovascular imaging findings 1, 5
• Assess and treat hypertriglyceridemia if triglycerides remain elevated despite LDL-lowering therapy, particularly if ≥500 mg/dL (pancreatitis risk) 1, 5