What are alternative medications for hyperlipidemia (high cholesterol) if a patient is unable to tolerate statins (HMG-CoA reductase inhibitors)?

Alternative Medications for Hyperlipidemia in Statin-Intolerant Patients

For patients unable to tolerate statins, ezetimibe should be considered as the first-line alternative medication for hyperlipidemia, followed by bempedoic acid and PCSK9 inhibitors based on cardiovascular risk and LDL-C targets. 1, 2, 3

First-Line Alternative: Ezetimibe

• Ezetimibe 10 mg daily is recommended as the initial therapy for statin-intolerant patients due to its favorable side effect profile (similar to placebo) and ability to reduce LDL-C by 15-20% 2, 3, 4
• Ezetimibe works by inhibiting intestinal cholesterol absorption, providing a complementary mechanism to statins 4
• Unlike other intestinally acting lipid-lowering agents, ezetimibe does not adversely affect triglyceride levels 4
• The IMPROVE-IT trial demonstrated that ezetimibe, when added to statin therapy, reduces cardiovascular outcomes in high-risk patients 5

Second-Line Options: Bempedoic Acid

• If ezetimibe monotherapy is insufficient, adding bempedoic acid is recommended 2, 3
• Bempedoic acid reduces LDL-C by 15-25% with low rates of muscle-related adverse effects 2
• The CLEAR Outcomes trial showed a 13% reduction in major adverse cardiovascular events in statin-intolerant patients 2
• A combination product of bempedoic acid with ezetimibe can lower LDL-C levels by approximately 35% 2, 3
• Monitor liver function tests when using bempedoic acid 2

Third-Line Options: PCSK9 Inhibitors

• PCSK9 inhibitors (alirocumab, evolocumab, inclisiran) reduce LDL-C by approximately 50% and are well-tolerated in statin-intolerant patients 1, 2, 3
• The ODYSSEY ALTERNATIVE trial showed alirocumab lowered LDL-C by 54.8% compared with 20.1% with ezetimibe in statin-intolerant patients 1
• Consider PCSK9 inhibitors for very high-risk patients with atherosclerotic cardiovascular disease if LDL-C remains ≥70 mg/dL despite maximally tolerated therapy with ezetimibe and bempedoic acid 1, 2
• For patients on PCSK9 inhibitors, assess LDL-C response every 3-6 months 2

Additional Options

• Bile acid sequestrants can be considered if triglycerides are <300 mg/dL, but are generally less preferred than the options above due to gastrointestinal side effects 2, 3
• Fibrates (fenofibrate) should be considered primarily for patients with triglycerides >500 mg/dL to prevent acute pancreatitis 3

Treatment Algorithm Based on Cardiovascular Risk

For Very High-Risk Patients (ASCVD or multiple risk factors):

1. Start with ezetimibe 10 mg daily 1
2. If inadequate response, add bempedoic acid or switch to bempedoic acid/ezetimibe combination 2, 3
3. If LDL-C remains ≥70 mg/dL, consider adding a PCSK9 inhibitor 1, 2

For High-Risk Patients:

1. Start with ezetimibe 10 mg daily 1, 3
2. If inadequate response, add bempedoic acid 2, 3
3. Consider PCSK9 inhibitor if LDL-C remains significantly elevated 2

For Moderate-Risk Patients:

1. Start with ezetimibe 10 mg daily 3
2. If inadequate response, consider bempedoic acid 3

Important Clinical Considerations

• Statin intolerance should be confirmed by attempting at least 2 different statins, including at least one at the lowest approved daily dose 2
• Alternative statin dosing strategies (e.g., every-other-day dosing) may be attempted before moving to non-statin therapies 1
• Combination therapy may be more effective than sequential monotherapy for achieving LDL-C targets in very high-risk patients 3
• Target LDL-C <70 mg/dL or even <55 mg/dL for secondary prevention in patients with very high cardiovascular risk 1, 3
• Reassess lipid profile 4-8 weeks after initiating therapy and adjust treatment as needed 3