What is the next step for a patient who cannot tolerate HMG-CoA reductase inhibitors (statins)?

From the Guidelines

If a patient cannot tolerate a statin, the next step is to consider ezetimibe or other alternatives such as PCSK9 inhibitor monoclonal antibodies, inclisiran, or bempedoic acid, as these options have been shown to be safe and effective in improving lipid parameters in statin-intolerant patients. According to the 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline for the management of patients with acute coronary syndromes 1, statin intolerance is frequent in clinical practice, and the most commonly reported cause is statin-associated muscle symptoms. To consider a patient as having statin intolerance, a minimum of 2 statins should be attempted, including at least 1 at the lowest approved daily dose.

The guideline suggests that ezetimibe and PCSK9 inhibitors have been demonstrated to be safe and well-tolerated and improve lipid parameters in statin-intolerant patients 1. Additionally, bempedoic acid, an ATP citrate lyase inhibitor, reduces LDL-C levels by 15% to 25% with low rates of muscle-related adverse effects 1. The CLEAR Outcomes trial compared bempedoic acid with placebo in statin-intolerant patients with or at high risk for ASCVD and found that bempedoic acid reduced MACE by 13% 1.

Some key points to consider when choosing an alternative therapy include:

• The patient's cardiovascular risk and LDL-cholesterol levels
• Specific statin intolerance symptoms
• Comorbidities
• The potential side effects of alternative therapies, such as increased uric acid levels and abnormal liver function tests with bempedoic acid 1
• The importance of lifestyle modifications, including a heart-healthy diet, regular exercise, weight management, smoking cessation, and limited alcohol consumption.

Overall, the choice of alternative therapy should be individualized based on the patient's specific needs and circumstances, and regular monitoring of lipid levels and side effects is essential to ensure the alternative treatment is effective and well-tolerated.

From the FDA Drug Label

As an adjunct to diet, alone or in combination with other low-density lipoprotein cholesterol (LDL-C)-lowering therapies, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce LDL-C. The recommended starting dosage of PRALUENT is either 75 mg once every 2 weeks or 300 mg once every 4 weeks administered subcutaneously o reduce the risk of major adverse cardiovascular (CV) events (CV death, myocardial infarction, stroke, unstable angina requiring hospitalization, or coronary revascularization) in adults with established cardiovascular disease As an adjunct to diet, alone or in combination with other low-density lipoprotein cholesterol (LDL-C)-lowering therapies, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce LDL-C

If a patient couldn't tolerate statin, the next step is to consider alternative LDL-C-lowering therapies.

• Alirocumab (PRALUENT) and Evolocumab (REPATHA) are two options that can be used as an adjunct to diet, alone or in combination with other LDL-C-lowering therapies, to reduce LDL-C in adults with primary hyperlipidemia, including HeFH.
• The recommended starting dosage of these medications varies, but they can be administered subcutaneously every 2 weeks or once monthly.
• It is essential to monitor LDL-C levels when clinically appropriate and adjust the dosage as needed to achieve a clinically meaningful response.
• Patients should be trained on how to prepare and administer these medications, and they should be instructed to read and follow the Instructions for Use each time they use the medication 2 3.

From the Research

Next Steps for Patients Who Cannot Tolerate Statins

If a patient cannot tolerate statins, the next steps involve several alternatives and considerations:

• Dose adjustment or intermittent dosing: Lowering the dose or using intermittent dosing of statins like atorvastatin or rosuvastatin may be tolerated and effective in some patients 4.
• Switching to a different statin: Trying a different statin, such as pravastatin or fluvastatin, which are less likely to cause muscle pain, may be an option 4.
• Non-statin therapies: For patients who cannot tolerate any statin, alternative drugs like ezetimibe and/or bile acid sequestrants can be used 4, 5.
• PCSK9 inhibitors: If LDL cholesterol targets are not reached with other treatments, PCSK9 inhibitors may be considered, especially in high-risk patients 4, 6.
• Lipoprotein apheresis: In patients with very high cardiovascular risk and sub-optimal LDL cholesterol levels despite lipid-lowering therapy, lipoprotein apheresis may be indicated 4.
• Combination therapy: Using a combination of lipid-lowering therapies, such as a lower dose of statin with another drug like ezetimibe, may be effective in some cases 6, 7.
• New and emerging therapies: Other options, including bempedoic acid, angiopoietin-like 3 protein inhibitors, and nutraceuticals, may also be considered for patients with statin intolerance 6, 7.