What alternative lipid‑lowering medication can be used in a patient who cannot tolerate or is contraindicated for statins?

Alternative Lipid-Lowering Medications for Statin-Intolerant Patients

For patients who cannot tolerate statins, ezetimibe 10 mg daily should be initiated first, followed by the addition of bempedoic acid 180 mg daily if LDL-C targets are not met, with PCSK9 inhibitors reserved for very high-risk patients who remain above goal despite combination therapy. 1, 2, 3

First-Line Alternative: Ezetimibe

• Ezetimibe 10 mg once daily is the recommended initial non-statin therapy, reducing LDL-C by 15-20% with a side-effect profile similar to placebo 1, 2
• Before starting ezetimibe, confirm true statin intolerance by documenting that the patient has attempted at least 2 different statins, including at least one at the lowest approved daily dose, with adverse effects that resolved upon discontinuation 2, 3
• Ezetimibe works by inhibiting intestinal cholesterol absorption without affecting fat-soluble vitamins, triglycerides, or bile acids 4
• Reassess lipid profile 4-6 weeks after initiating ezetimibe and monitor liver enzymes (ALT/AST) at baseline and as clinically indicated 2

Second-Line Addition: Bempedoic Acid

• If LDL-C targets are not achieved with ezetimibe alone, add bempedoic acid 180 mg daily, which provides an additional 15-25% LDL-C reduction 1, 3
• The combination of bempedoic acid plus ezetimibe lowers LDL-C by approximately 35% total 1, 3
• Bempedoic acid has low rates of muscle-related adverse effects because it works upstream from statins in the liver and is only activated in hepatocytes, not muscle cells 1, 3
• The CLEAR Outcomes trial demonstrated a 13% reduction in major adverse cardiovascular events in statin-intolerant patients 1, 3
• Monitor liver function tests when using bempedoic acid 3

Third-Line Option: PCSK9 Inhibitors

• PCSK9 inhibitors (alirocumab, evolocumab, inclisiran) should be considered for very high-risk patients with LDL-C ≥55 mg/dL despite ezetimibe plus bempedoic acid 1, 3
• PCSK9 inhibitors reduce LDL-C by approximately 50-60% and are well-tolerated in statin-intolerant patients with minimal muscle-related side effects 1, 3
• For high-risk patients (not very high-risk), consider PCSK9 inhibitors only if LDL-C remains ≥70 mg/dL despite combination therapy 2, 3
• The ODYSSEY ALTERNATIVE trial showed alirocumab reduced LDL-C by 54.8% in statin-intolerant patients with fewer skeletal muscle-related adverse events (32.5%) compared to ezetimibe (41.1%) 3

Alternative Options for Specific Situations

Bile Acid Sequestrants

• Bile acid sequestrants (colesevelam, cholestyramine) are reasonable alternatives if triglycerides are <300 mg/dL and the patient cannot tolerate bempedoic acid, reducing LDL-C by 15-30% 5, 1
• These agents have significant gastrointestinal side effects and drug interactions, making them generally less preferred 3
• Bile acid sequestrants can provide a modest hypoglycemic effect beneficial in diabetic patients 3

Niacin

• Niacin is reasonable for LDL-C lowering in statin-intolerant patients, particularly those with low HDL cholesterol or elevated Lp(a) 5, 1
• Monitor uric acid levels as niacin can cause hyperuricemia 1

Fibrates

• Fibrates (fenofibrate preferred over gemfibrozil) should be started for patients with triglycerides >500 mg/dL to prevent acute pancreatitis 5, 1
• Fibrates have mild LDL-lowering action and randomized controlled trials do not support their use as add-on drugs to other LDL-lowering therapy for LDL-C reduction 3

Omega-3 Fatty Acids

• For patients with elevated triglycerides (135-499 mg/dL) on optimized lipid therapy, consider icosapent ethyl 2 grams twice daily 1, 3
• Omega-3 fatty acids from fish or fish oil capsules (1 g/day) may be reasonable for cardiovascular disease risk reduction 5, 1

Treatment Targets Based on Risk

Very High-Risk Patients (established ASCVD, recurrent events)

• Target LDL-C <55 mg/dL with ≥50% reduction from baseline 1, 2, 3
• Non-HDL-C secondary target <85 mg/dL 3
• For patients with recurrent events within 2 years despite optimal therapy, consider aggressive target of LDL-C <40 mg/dL 3

High-Risk Patients (diabetes without complications, multiple risk factors)

• Target LDL-C <70 mg/dL 1, 2, 3
• Non-HDL-C secondary target <100 mg/dL 3

Moderate-Risk Patients

• Target LDL-C <100 mg/dL or at least 50% reduction from baseline 3

Essential Lifestyle Modifications

• Reduce saturated fat intake to <7% of total calories, trans fatty acids to <1% of total calories, and cholesterol to <200 mg/day 5, 1
• Daily physical activity of 30-60 minutes at least 5 days per week (preferably 7 days) 5, 1
• Target BMI 18.5-24.9 kg/m² and waist circumference <35 inches for women, <40 inches for men 5, 1

Critical Pitfalls to Avoid

• Do not prescribe PCSK9 inhibitors as first-line therapy after ezetimibe without trying bempedoic acid first, except in very high-risk patients with markedly elevated LDL-C, due to high cost and the need for stepwise therapy 3
• Do not use fibrates as add-on therapy for LDL-C lowering—they are indicated only for severe hypertriglyceridemia (>500 mg/dL) to prevent pancreatitis 3
• Avoid all lipid-lowering drugs except bile acid sequestrants when pregnancy is planned, during pregnancy, or during breastfeeding 3
• Do not combine gemfibrozil with other lipid-lowering agents due to increased risk of myopathy; fenofibrate is preferred if fibrate therapy is needed 1

Monitoring Schedule

• Obtain baseline lipid profile and liver enzymes (ALT/AST) before initiating therapy 1, 3
• Reassess lipid profile 4-8 weeks after initiating or adjusting therapy 1, 2
• Once at goal, monitor lipids annually unless there are adherence concerns 3
• For patients on PCSK9 inhibitors, assess LDL-C response every 3-6 months 3

When to Refer to a Lipid Specialist

• Refer patients with complex mixed dyslipidemia, severe hypertriglyceridemia (>500 mg/dL), or baseline LDL-C ≥190 mg/dL not due to secondary causes 3
• Mandatory referral for patients with coronary artery calcium (CAC) score >1,000 3
• Consider referral for familial hypercholesterolemia patients who cannot tolerate statins 3