What are the guidelines for treating hypercholesterolemia?

Guidelines for Treating Hypercholesterolemia

Begin with maximally tolerated high-potency statins (atorvastatin, rosuvastatin, or pitavastatin) combined with lifestyle modifications as first-line therapy for most adults with hypercholesterolemia, targeting LDL-C goals based on cardiovascular risk stratification. 1

Risk-Stratified LDL-C Treatment Goals

The treatment targets depend on atherosclerotic cardiovascular disease (ASCVD) risk level:

• No ASCVD or major risk factors: LDL-C <2.5 mmol/L (<100 mg/dL) 1
• Imaging evidence of ASCVD or major risk factors: LDL-C <1.8 mmol/L (<70 mg/dL) 1
• Clinical ASCVD: LDL-C <1.4 mmol/L (<55 mg/dL) 1
• Recurrent ASCVD within 2 years on maximal statin: Consider LDL-C <1.0 mmol/L (<40 mg/dL) 1

All patients should achieve approximately 50% reduction in LDL-C from baseline. 1

Stepwise Treatment Algorithm for Adults

Step 1: Lifestyle Modifications (All Patients)

• Fat-modified, heart-healthy diet with reduced saturated fat and cholesterol 1
• Regular physical exercise and weight reduction if applicable 1
• Smoking cessation, blood pressure control, and management of diabetes/metabolic syndrome 1
• Plant sterols/stanols 2-3g daily can reduce LDL-C by 9-20% 2

Step 2: Initial Pharmacotherapy

Start high-potency statin (atorvastatin, rosuvastatin, or pitavastatin) at maximally tolerated dose 1

• Assess LDL-C response at 4-12 weeks after initiation 1
• Monitor hepatic aminotransferases, creatine kinase, glucose, and creatinine before starting therapy 1
• Use fasting LDL-C when making treatment decisions, especially with concomitant hypertriglyceridemia 1

Step 3: Add Ezetimibe

If LDL-C goals not achieved, add ezetimibe 10mg daily to statin therapy 1

Step 4: Add Bempedoic Acid

If still not at goal, add bempedoic acid (if available) 1

Step 5: Consider Adjunctive Therapies

Plant sterols/stanols (2g daily) or bile acid sequestrants (colesevelam) may be added 1, 2

Step 6: PCSK9-Targeted Therapy

Add PCSK9 inhibitor (monoclonal antibody or inclisiran) if LDL-C goals remain unachieved despite maximal tolerated statin, ezetimibe, bempedoic acid, and adjunctive therapies 1

High-Risk Exception: Aggressive First-Line Therapy

For extremely high-risk patients (recent myocardial infarction, multivessel coronary atherosclerosis, or polyvascular disease), initiate triple therapy immediately: high-potency statin + ezetimibe + PCSK9 inhibitor 1

Pediatric Patients (≥10 Years) with Familial Hypercholesterolemia

Treatment Initiation Criteria

• LDL-C ≥4.9 mmol/L (≥190 mg/dL) on two occasions: Consider starting at age 8-10 years 1
• LDL-C >4.0 mmol/L (>160 mg/dL) with multiple ASCVD risk factors or family history of premature ASCVD: Start at age ≥10 years 1

Pediatric Treatment Goals

• No additional risk factors: LDL-C <3.5 mmol/L (<135 mg/dL) or 50% reduction 1
• With additional risk factors: LDL-C <2.5 mmol/L (<100 mg/dL) 1

Pediatric Treatment Algorithm

1. Lifestyle modifications for 3-6 months 1
2. Statin therapy (approved for pediatric use) if goals not met 1
3. Add ezetimibe or bile acid sequestrants if needed 1
4. PCSK9 inhibitor may be considered per regulatory approvals (limited long-term safety data) 1

Monitor growth, liver enzymes, creatine kinase, glucose, and creatinine annually 1

Homozygous Familial Hypercholesterolemia (HoFH)

Begin treatment at diagnosis, ideally by age 2 years 1

HoFH Treatment Sequence

1. High-potency statin with rapid up-titration to maximal tolerated dose 1
2. Add ezetimibe within 8 weeks 1
3. Add colesevelam if tolerated 1
4. Add PCSK9 inhibitor within further 8 weeks (only in patients without biallelic LDLR null mutations; continue only if ≥15% additional LDL-C reduction) 1
5. Lipoprotein apheresis at age 3 years (no later than age 8) if goals not achieved 1
6. Lomitapide or evinacumab for markedly elevated LDL-C or rapidly progressive ASCVD, especially if apheresis unavailable 1

Older Adults (≥75 Years)

Initiating moderate-intensity statin may be reasonable in adults ≥75 years with LDL-C 70-189 mg/dL (1.7-4.8 mmol/L) 1

Consider stopping statin therapy when functional decline (physical or cognitive), multimorbidity, frailty, or reduced life expectancy limits potential benefits 1

For ages 76-80 years, measuring coronary artery calcium (CAC) may be reasonable to reclassify those with CAC score of zero to avoid statin therapy 1

Monitoring and Safety

• Assess LDL-C at 4-12 weeks after initiation or dose adjustment, then every 3-12 months 1
• Monitor hepatic aminotransferases in patients at increased risk of hepatotoxicity 1
• Measure creatine kinase if musculoskeletal symptoms develop 1
• Monitor glucose/HbA1c if diabetes risk factors present 1
• Use non-fasting lipid profiles for monitoring stable therapy; use fasting LDL-C for treatment decisions 1

Critical Dosing Restrictions for Simvastatin

Maximum recommended dose is 40mg daily 3

Simvastatin 80mg daily is restricted to patients taking it chronically (≥12 months) without muscle toxicity 3

Drug Interaction Dose Limits

• With lomitapide: Reduce simvastatin by 50%; maximum 20mg daily 3
• With verapamil, diltiazem, or dronedarone: Maximum 10mg daily 3
• With amiodarone, amlodipine, or ranolazine: Maximum 20mg daily 3

Common Pitfalls to Avoid

Do not use simvastatin 80mg as initial therapy or in patients requiring high-intensity statin therapy; prescribe alternative LDL-C-lowering treatment instead 3

Do not delay PCSK9 inhibitor therapy in patients with familial hypercholesterolemia who fail to reach goals on maximal conventional therapy, as this directly impacts cardiovascular morbidity and mortality 1

Do not rely solely on total cholesterol for treatment decisions; always use LDL-C as the primary target 1