What alternative treatment with minimal side effects can be used for a patient with hyperlipidemia who is hesitant to take statins (HMG-CoA reductase inhibitors)?

Alternative to Statins for Hyperlipidemia with Minimal Side Effects

Ezetimibe 10 mg daily is the best first-line alternative for your statin-hesitant patient, offering 15-20% LDL-C reduction with a side effect profile comparable to placebo. 1, 2, 3

Why Ezetimibe is the Optimal Choice

Ezetimibe should be your go-to alternative because it has the most favorable tolerability profile of all lipid-lowering agents, with adverse effects essentially matching placebo rates. 3, 4 The drug works by selectively blocking cholesterol absorption in the small intestine without affecting fat-soluble vitamins, triglycerides, or bile acids—a mechanism that avoids the muscle-related side effects your patient fears from statins. 3

Key Advantages:

• Minimal side effects: In clinical trials involving 2,396 patients, the most common adverse reactions (upper respiratory infection 4.3%, diarrhea 4.1%, arthralgia 3.0%) occurred at rates barely above placebo. 2
• No muscle toxicity: Unlike statins, ezetimibe has minimal systemic absorption and does not cause the myopathy that concerns many patients. 3
• Simple dosing: One 10 mg tablet daily, with or without food, no dose adjustments needed. 2
• Few drug interactions: Does not interact with most medications except cyclosporine, fibrates, and bile acid sequestrants. 5, 2

If Ezetimibe Alone is Insufficient

For High to Very High-Risk Patients:

Add bempedoic acid 180 mg daily to ezetimibe if LDL-C targets are not met. 1 This combination provides approximately 35% LDL-C reduction and is particularly valuable because bempedoic acid works upstream from statins in the liver, causing minimal muscle-related adverse effects. 1 The CLEAR Outcomes trial demonstrated a 13% reduction in major adverse cardiovascular events with bempedoic acid in statin-intolerant patients. 1

Important monitoring: Check liver function tests when using bempedoic acid. 1

For Very High-Risk Patients with Persistent Elevation:

Consider adding a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) if LDL-C remains ≥70 mg/dL despite ezetimibe plus bempedoic acid. 1 PCSK9 inhibitors reduce LDL-C by approximately 50% and are well-tolerated in statin-intolerant patients, though they require injections (every 2 weeks, monthly, or twice yearly depending on the agent). 1

Treatment Algorithm Based on Risk:

Moderate Risk:

1. Start ezetimibe 10 mg daily 1
2. Recheck lipids in 4-8 weeks 2
3. Add bempedoic acid if needed 1

High Risk (established ASCVD or diabetes with risk factors):

1. Start ezetimibe 10 mg daily 1
2. Add bempedoic acid 180 mg if LDL-C remains >100 mg/dL or <50% reduction from baseline 1
3. Consider PCSK9 inhibitor if still not at goal 1

Very High Risk (recent ACS, recurrent events):

1. Start ezetimibe 10 mg daily 1
2. Add bempedoic acid 180 mg immediately 1
3. Add PCSK9 inhibitor if LDL-C ≥70 mg/dL (target <55 mg/dL) 1

Common Pitfalls to Avoid:

Do not use bile acid sequestrants as a first alternative—they cause significant GI side effects (bloating, constipation, nausea) and require multiple daily doses, making them poorly tolerated compared to ezetimibe. 1 Only consider them if triglycerides are <300 mg/dL and the patient cannot tolerate bempedoic acid. 1

Do not jump directly to PCSK9 inhibitors—while highly effective, they lack an established role in primary prevention and should not be used before trying bempedoic acid in patients without established ASCVD or baseline LDL-C ≥190 mg/dL. 1

Avoid fenofibrate combinations initially—when ezetimibe was studied with fenofibrate, cholecystectomy rates were 1.7% versus 0.6% with fenofibrate alone, and this combination is generally reserved for specific mixed dyslipidemia cases. 2

Monitoring Schedule:

• Baseline: Obtain complete lipid panel, liver enzymes (ALT/AST) 6
• 4-8 weeks after starting: Recheck lipid panel to assess response 2
• If adding bempedoic acid: Monitor liver function tests 1
• Once at goal: Annual lipid monitoring unless adherence concerns 6

Reassurance for Your Patient:

Emphasize that ezetimibe's side effect profile in clinical trials was essentially identical to placebo, with no increased risk of muscle pain, weakness, or the symptoms they're trying to avoid with statins. 3, 4 The drug has been extensively studied in over 11,000 patients and has demonstrated excellent long-term tolerability. 2, 4