What is the role of non-statin medications, such as ezetimibe, fibrates (e.g. fenofibrate), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (e.g. alirocumab, evolocumab), in the management of hyperlipidemia?

Role of Non-Statin Medications in Hyperlipidemia Management

Non-statin medications play a critical role as adjunctive therapy when statins alone are insufficient to reach LDL-C goals or as alternative therapy in statin-intolerant patients, with ezetimibe being the preferred first-line non-statin agent followed by PCSK9 inhibitors for high-risk patients requiring additional LDL-C reduction. 1

Stepwise Approach to Non-Statin Therapy

The American College of Cardiology recommends a clear hierarchy for non-statin medications in hyperlipidemia management:

1. Maximally tolerated statin therapy (first-line for most patients)
2. Ezetimibe (first-line non-statin)
3. PCSK9 inhibitors (for high-risk patients not at goal)
4. Bempedoic acid (newer option for additional LDL-C lowering)
5. Other specialized therapies (for specific conditions)

Ezetimibe

Ezetimibe is the preferred first-line non-statin agent for several reasons:

• Provides 18-25% additional LDL-C reduction 1
• Demonstrated cardiovascular benefit in the IMPROVE-IT trial with ~7% reduction in cardiovascular events 1
• Oral administration with convenient once-daily dosing 2
• Well-tolerated with minimal side effects 2
• Available as generic, improving cost-effectiveness 1
• FDA-approved for use alone or in combination with statins for primary hyperlipidemia, HeFH, and HoFH 2

PCSK9 Inhibitors (Evolocumab, Alirocumab)

PCSK9 inhibitors are powerful second-line agents for specific high-risk populations:

• Provide 50-65% additional LDL-C reduction 3
• Reduce cardiovascular events by approximately 15% in high-risk patients 3
• Particularly valuable for:
  • Patients with clinical ASCVD at very high risk 1
  • Patients with baseline LDL-C ≥190 mg/dL 1
  • Patients not achieving adequate LDL-C reduction despite maximally tolerated statin plus ezetimibe 1

Bempedoic Acid

Bempedoic acid represents a newer non-statin option:

• Provides approximately 17% additional LDL-C reduction 1
• Particularly useful in statin-intolerant patients with myalgias 1
• Oral administration (advantage over injectable PCSK9 inhibitors) 1
• Should be used with caution in patients with history of gout or tendon rupture 1

Other Non-Statin Options

• Inclisiran: A newer PCSK9 inhibitor administered twice yearly, beneficial for patients with adherence issues to PCSK9 mAbs 1
• Fibrates: Limited role in pure hypercholesterolemia; primarily for hypertriglyceridemia (TG >500 mg/dL) or mixed dyslipidemia 4
• Bile acid sequestrants: Provide 18-25% LDL-C reduction but limited use due to poor tolerability 1, 4
• Specialized therapies for homozygous FH (evinacumab, lomitapide) 1

Patient-Specific Treatment Algorithms

1. Patients with Clinical ASCVD at Very High Risk

For patients with ASCVD who have not achieved ≥50% LDL-C reduction or LDL-C <55 mg/dL on maximally tolerated statin:

1. Add ezetimibe as first-line non-statin therapy
2. If still not at goal, add PCSK9 inhibitor
3. Consider bempedoic acid if additional lowering needed

2. Patients with Clinical ASCVD Not at Very High Risk

For patients with ASCVD who have not achieved ≥50% LDL-C reduction or LDL-C <70 mg/dL on maximally tolerated statin:

1. Add ezetimibe as first-line non-statin therapy
2. If still not at goal, consider PCSK9 inhibitor
3. Consider bempedoic acid if additional lowering needed

3. Patients with Baseline LDL-C ≥190 mg/dL

For patients with severe hypercholesterolemia not achieving ≥50% LDL-C reduction or LDL-C <100 mg/dL on maximally tolerated statin:

1. Add ezetimibe and/or PCSK9 inhibitor
2. Consider bempedoic acid if additional lowering needed
3. For homozygous FH, consider specialized therapies (evinacumab, lomitapide, LDL apheresis)

4. Statin-Intolerant Patients

For patients unable to tolerate statins who require LDL-C lowering:

1. Ezetimibe as first-line therapy 1
2. PCSK9 inhibitors for high-risk patients (ASCVD or LDL-C ≥190 mg/dL) 1
3. Bempedoic acid as an additional option 1, 5

Clinical Pearls and Pitfalls

• Don't delay intensification: When patients don't reach LDL-C goals on statins, promptly add non-statin therapy rather than continuing to titrate statins beyond tolerability
• Consider combination initiation: For very high-risk patients requiring substantial LDL-C reduction, consider initiating statin plus ezetimibe simultaneously 1
• Monitor adherence: Poor adherence is a common cause of apparent treatment failure before adding non-statin therapy
• Recognize statin intolerance: True statin intolerance affects approximately 5-10% of patients and requires alternative strategies
• Cost considerations: PCSK9 inhibitors are significantly more expensive than ezetimibe; ensure appropriate prior authorization and patient assistance programs are utilized

By following these evidence-based recommendations, clinicians can effectively utilize non-statin medications to achieve target LDL-C levels and reduce cardiovascular risk in patients with hyperlipidemia.