What medications can be used as alternatives for patients intolerant to statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor) medications?

Alternative Medications for Statin-Intolerant Patients

For patients who are intolerant to statin medications, bempedoic acid, ezetimibe, and PCSK9 inhibitors (alirocumab, evolocumab, and inclisiran) are the recommended alternative lipid-lowering therapies, with bempedoic acid being the preferred first-line option based on the most recent evidence. 1

First-Line Options for Statin-Intolerant Patients

Bempedoic Acid

• Recommended as first-line therapy for statin-intolerant patients 1
• Reduces LDL-C levels by 15-25% 1
• Demonstrated 13% reduction in major adverse cardiovascular events (MACE) in the CLEAR Outcomes trial 1
• Works upstream from statins in the liver with low rates of muscle-related adverse effects 1
• Caution: May raise uric acid levels and increase risk of gout, abnormal liver function tests, and gallstones 1

Ezetimibe

• Alternative for statin-intolerant patients 1
• Reduces LDL-C by 15-20% by blocking intestinal cholesterol absorption 1, 2
• Well-tolerated with adverse event profile similar to placebo 2, 3
• Can be used as monotherapy or in combination with other non-statin agents 4
• Does not adversely affect triglyceride levels unlike some other intestinally acting agents 2, 5

Second-Line Options

PCSK9 Inhibitors

• Monoclonal antibodies (alirocumab, evolocumab) and small interfering RNA (inclisiran)
• Powerful LDL-C reduction of approximately 50% 1
• Safe and well-tolerated in statin-intolerant patients 1
• Alirocumab demonstrated superior LDL-C reduction (45% vs 14.6%) compared to ezetimibe in statin-intolerant patients in the ODYSSEY ALTERNATIVE trial 6
• Less frequent skeletal muscle-related events compared to atorvastatin rechallenge 6
• Inclisiran offers convenient dosing schedule (every 6 months after initial doses) 1

Combination Approaches

For patients not achieving LDL-C goals on a single non-statin agent:

1. Bempedoic acid + ezetimibe combination:

   • Provides approximately 35% LDL-C reduction 1
   • Recommended for patients not achieving goals on either agent alone 1

2. Multiple non-statin therapy:

   • Consider adding PCSK9 inhibitor if LDL-C remains elevated despite bempedoic acid and ezetimibe 1

Algorithm for Statin-Intolerant Patients

1. Confirm true statin intolerance:

   • Try at least 2 different statins, including one at lowest approved dose 1
   • Most common manifestation is statin-associated muscle symptoms 1

2. First-line therapy:

   • Start with bempedoic acid (preferred based on recent evidence) 1
   • Alternative: ezetimibe if bempedoic acid not tolerated or contraindicated 1

3. If inadequate response:

   • Add ezetimibe to bempedoic acid 1
   • OR consider PCSK9 inhibitor (alirocumab, evolocumab, or inclisiran) 1

4. For very high-risk patients:

   • Consider starting with PCSK9 inhibitor or combination therapy immediately 1

Important Considerations

• Assess cardiovascular risk to determine appropriate LDL-C targets 1
• Monitor for side effects specific to each medication class
• Combine pharmacological therapy with lifestyle modifications including diet and physical activity 1
• Regularly reassess lipid profile to evaluate treatment efficacy 1

Caveats and Pitfalls

• Long-term safety data for newer agents like bempedoic acid and inclisiran are still accumulating 1
• Cost and insurance coverage may limit access to PCSK9 inhibitors
• Ezetimibe has been associated with rare cases of myopathy despite generally good tolerability 3
• Bempedoic acid may not be suitable for patients with history of gout or gallstones 1
• Ensure adequate washout period between statin discontinuation and initiation of alternative therapy to accurately assess response