What are the alternative treatments for a patient with elevated Low-Density Lipoprotein (LDL) who is not tolerating statin therapy?

Alternative Treatments for Patients Not Tolerating Statins with Elevated LDL

For patients not tolerating statins and with elevated LDL, ezetimibe should be considered as the first-line alternative medication, followed by bempedoic acid and PCSK9 inhibitors based on cardiovascular risk and LDL-C targets. 1, 2

First-Line Options After Statin Intolerance

• Ezetimibe (10 mg daily) is recommended as the initial non-statin therapy due to its demonstrated safety, tolerability, convenience, and single-tablet daily dose, reducing LDL-C by 15-20% 3, 1
• Bempedoic acid should be considered if there is inadequate response to ezetimibe, as it reduces LDL-C by 15-25% with low rates of muscle-related adverse effects 3, 1
• A combination of bempedoic acid with ezetimibe can lower LDL-C levels by approximately 35% and should be considered for patients requiring greater LDL-C reduction 1, 2

Second-Line Options

• PCSK9 inhibitors (alirocumab, evolocumab, inclisiran) are highly effective in statin-intolerant patients, reducing LDL-C by approximately 50%, and should be considered 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 3, 1, 2
• Bile acid sequestrants (such as colesevelam) are reasonable for LDL-C lowering in statin-intolerant patients and may be considered as alternative agents if triglycerides are <300 mg/dL 1, 4
• Niacin can be considered for LDL-C lowering in statin-intolerant patients and may be particularly beneficial for those with low HDL cholesterol or elevated Lp(a) 1, 5

Treatment Algorithm Based on Cardiovascular Risk

For Very High-Risk Patients (with ASCVD)

• Start with ezetimibe 10 mg daily 3, 1
• If inadequate response, add bempedoic acid 3, 2
• If LDL-C remains ≥70 mg/dL, consider adding a PCSK9 inhibitor 3
• Target LDL-C <70 mg/dL or even <55 mg/dL for secondary prevention 1, 2

For High-Risk Patients (without ASCVD but with risk factors)

• Start with ezetimibe 10 mg daily 1, 2
• If inadequate response, add bempedoic acid 3, 1
• Consider PCSK9 inhibitor if LDL-C remains significantly elevated 1, 2
• Target LDL-C <100 mg/dL 3

Lifestyle Modifications

• Lifestyle modification focusing on weight loss (if indicated), Mediterranean or DASH eating pattern, reduction of saturated fat and trans fat, increase of dietary n-3 fatty acids, viscous fiber, and plant stanol/sterol intake, and increased physical activity should be recommended alongside pharmacological therapy 3
• Dietary therapy should include reduced intake of saturated fats (<7% of total calories), trans fatty acids (<1% of total calories), and cholesterol (<200 mg/d) 1

Monitoring Recommendations

• Obtain a lipid profile at initiation of lipid-lowering therapy, 4-12 weeks after initiation or a change in dose, and annually thereafter 3
• Monitor liver function tests when using bempedoic acid 1
• For patients on PCSK9 inhibitors, assess LDL-C response every 3-6 months 1

Important Considerations and Pitfalls

• Women appear to have a greater response to lipid-lowering therapies than men but are less likely to achieve LDL-C targets 5, 6
• Combination therapy increases the likelihood of achieving LDL-C goals but may also increase the risk of adverse events 4, 7
• For patients with diabetes, ezetimibe may be preferred as first-line therapy as it does not negatively impact glycemic control 1
• Despite optimal therapy, LDL-C target attainment remains low in patients with statin intolerance, especially among women 6
• The definition of statin intolerance should include attempting at least 2 different statins, including at least one at the lowest approved daily dose, before considering alternative therapies 2