From the Guidelines
Patients who refuse statins should be considered for alternative treatments such as ezetimibe, PCSK9 inhibitors, or bempedoic acid, as these options have been shown to be safe and effective in reducing LDL cholesterol levels and cardiovascular risk. When a patient refuses a statin, it is essential to discuss the potential benefits and risks of alternative treatments. According to the 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline for the management of patients with acute coronary syndromes 1, ezetimibe and PCSK9 inhibitors have been demonstrated to be safe and well-tolerated and improve lipid parameters in statin-intolerant patients.
Some key alternative treatment options include:
- Ezetimibe (10mg daily), which reduces cholesterol absorption in the intestine, lowering LDL by 15-20% with minimal side effects 1
- PCSK9 inhibitors (evolocumab, alirocumab), which can lower LDL cholesterol by 50-60% when administered subcutaneously every 2-4 weeks
- Bempedoic acid (180mg daily), which works similarly to statins but with fewer muscle-related side effects and has been shown to reduce LDL-C levels by 15% to 25% 1
- Bile acid sequestrants like cholestyramine (4g 1-2 times daily) or colesevelam (625mg tablets, 6 tablets daily), which can reduce LDL by 15-25% but may cause gastrointestinal side effects
- Lifestyle modifications, including a Mediterranean or DASH diet, regular exercise, weight management, and smoking cessation, which remain essential regardless of medication choice
It is crucial to note that the choice of alternative therapy should be based on the patient's cardiovascular risk, LDL targets, medication tolerance, and cost considerations, as most alternatives are less effective than statins at reducing cardiovascular events. The 2014 guidelines for the primary prevention of stroke also suggest considering niacin or fibric acid derivatives for patients with specific lipid profiles, but their efficacy in preventing ischemic stroke is not established 1. However, the most recent and highest-quality study 1 prioritizes ezetimibe, PCSK9 inhibitors, and bempedoic acid as alternative treatments for patients who refuse statins.
From the FDA Drug Label
The initial treatment of dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. The use of drugs should be considered only when reasonable attempts have been made to obtain satisfactory results with non-drug methods. If the decision is made to use drugs, the patient should be instructed that this does not reduce the importance of adhering to diet.
For a patient who refuses to take a statin, alternative treatments may include:
- Dietary therapy specific to the type of lipoprotein abnormality
- Lifestyle modifications, such as:
- Addressing excess body weight
- Reducing alcoholic intake
- Increasing physical exercise
- Treatment of underlying diseases that may be contributing to hyperlipidemia, such as hypothyroidism or diabetes mellitus
- Consideration of other lipid-lowering drugs, such as fenofibrate, but only after reasonable attempts have been made to obtain satisfactory results with non-drug methods 2
From the Research
Alternative Treatments for Patients Refusing Statins
When a patient refuses to take a statin, there are several alternative treatments that can be considered. These alternatives aim to reduce low-density lipoprotein cholesterol (LDL-C) levels and decrease the risk of cardiovascular events.
- Ezetimibe: Ezetimibe is a safe and efficacious choice for further lowering LDL-C levels 3. It can be used in combination with other lipid-lowering agents or as a monotherapy.
- PCSK9 Inhibitors: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to significantly reduce the risk of non-fatal myocardial infarction, stroke, and coronary revascularization when added to statin therapy 4.
- Fibrates: Fibrates, such as fenofibrate, can be effective in normalizing high-density lipoprotein (HDL) and triglyceride levels persisting after statin therapy 3.
- Omega-3 Fatty Acids: The REDUCE-IT trial reported a 25% relative risk reduction in primary endpoints with the use of EPA, a pure omega-3 fatty acid 5.
- Bile Acid Sequestrants: Colesevelam is a moderately effective and well-tolerated bile acid sequestrant that can be used to further lower LDL-C levels 3.
- Niacin: Niacin, particularly extended-release niacin, can be effective in normalizing HDL and triglyceride levels persisting after statin therapy 3.
Considerations for Alternative Treatments
When selecting an alternative treatment, it is essential to consider the patient's individual needs and circumstances. This includes:
- Residual Lipoprotein Abnormalities: The choice of added agent depends on the residual lipoprotein abnormalities after statin therapy 3.
- Efficacy and Safety: The efficacy and safety of the alternative treatment should be carefully evaluated, taking into account the patient's medical history and potential drug interactions 6, 4.
- Cost and Compliance: The cost and compliance issues associated with the alternative treatment should be considered, as well as the availability of approved combined preparations 3.
- Patient Preferences: Patient preferences and values should be taken into account when selecting an alternative treatment, ensuring that the chosen therapy aligns with the patient's goals and expectations.
Combination Therapies
Combination therapies, such as moderate-intensity statin plus ezetimibe, may offer a viable alternative to high-intensity statin therapy 7. This approach can provide considerable efficacy and effectiveness, along with better safety and adherence compared to statin intensification alone.