What are the alternatives to statins (HMG-CoA reductase inhibitors) for lowering low-density lipoprotein (LDL) cholesterol levels?

Alternatives to Statins for LDL Cholesterol Lowering

Ezetimibe 10 mg daily is the preferred first-line alternative to statins for patients who cannot tolerate statins or need additional LDL-C lowering beyond maximally tolerated statin therapy. 1, 2

Hierarchical Approach to Non-Statin Therapy

First-Line: Ezetimibe

• Ezetimibe should be initiated as the initial non-statin agent, providing 18-25% LDL-C reduction when used alone or an additional 15-20% reduction when added to statins 3, 1, 4
• The IMPROVE-IT trial demonstrated strong evidence with a 7% relative risk reduction (2% absolute risk reduction) in cardiovascular events when added to statin therapy in acute coronary syndrome patients 3
• Ezetimibe is FDA-approved for use alone when additional LDL-C lowering therapy is not possible, or in combination with statins for primary hyperlipidemia including heterozygous familial hypercholesterolemia 4
• Take once daily with or without food, making adherence straightforward 4

Second-Line: PCSK9 Inhibitors

• PCSK9 inhibitors (evolocumab, alirocumab, inclisiran) should be added when LDL-C goals are not achieved with maximally tolerated statin plus ezetimibe, particularly in very high-risk patients 1, 2
• These agents reduce LDL-C by 40-65% and demonstrated a 15-20% reduction in major cardiovascular events in the FOURIER and ODYSSEY OUTCOMES trials 3, 2
• The 2019 ACC/AHA guidelines assign a Class IIa recommendation for PCSK9 inhibitors in very high-risk patients with LDL-C ≥70 mg/dL on maximally tolerated statin plus ezetimibe 3
• Cost and prior authorization requirements are significant barriers, though patient assistance programs exist 2

Third-Line: Bempedoic Acid

• Bempedoic acid lowers LDL-C by 24% in statin-intolerant patients and 15% when added to statins 1, 2
• This agent works in the same cholesterol synthesis pathway as statins but lacks activity in skeletal muscle, making it suitable for patients with statin-associated muscle symptoms 1
• Recent evidence shows a 13% reduction in major adverse cardiovascular events in statin-intolerant patients with established ASCVD or high ASCVD risk 2

Alternative Options: Bile Acid Sequestrants

• Bile acid sequestrants (cholestyramine, colestipol, colesevelam) reduce LDL-C by 18-25% with good evidence showing ~20% cardiovascular risk reduction in primary prevention 3
• These should be considered only if patients have inadequate response to ezetimibe or are ezetimibe-intolerant 1
• Critical caveat: Do not use in patients with triglycerides >300 mg/dL 1

Clinical Decision Algorithm for Statin-Intolerant Patients

Step 1: Confirm True Statin Intolerance

• Before abandoning statins, try switching to a different high-intensity statin (pravastatin or fluvastatin are better tolerated), lowering the dose, or using non-daily dosing (e.g., atorvastatin or rosuvastatin twice weekly) 2, 5
• At least 3 different statins should be tested before declaring complete statin intolerance 5

Step 2: Initiate Ezetimibe

• Start ezetimibe 10 mg daily as first-line non-statin therapy 1, 2, 4
• Monitor lipid levels 4-6 weeks after initiation 2

Step 3: Add PCSK9 Inhibitor if Needed

• If LDL-C goals not achieved with ezetimibe alone, add PCSK9 inhibitor for very high-risk or high-risk patients 1, 2
• Very high-risk is defined as: history of multiple major ASCVD events OR one major ASCVD event plus multiple high-risk conditions (age ≥65, diabetes, hypertension, CKD, current smoking, persistently elevated LDL-C ≥100 mg/dL) 3

Step 4: Consider Bempedoic Acid

• For patients who cannot afford or access PCSK9 inhibitors, bempedoic acid provides moderate additional LDL-C lowering 1, 2

Treatment Targets Based on Risk

Very High-Risk Patients (Secondary Prevention)

• Target LDL-C <55 mg/dL with ≥50% reduction from baseline 2
• This includes patients with recent ACS, history of MI, ischemic stroke, or symptomatic peripheral arterial disease 3

High-Risk Patients (Primary Prevention)

• Target LDL-C <70 mg/dL (<1.8 mmol/L) for patients with diabetes aged 40-75 years with additional ASCVD risk factors 3
• For primary prevention without diabetes, target LDL-C <100 mg/dL, with minimum therapeutic goal of 30-40% reduction from baseline 2

Common Pitfalls to Avoid

• Failing to optimize statin therapy before adding non-statin agents is a frequent error—always attempt multiple statins at various doses and schedules first 1
• Do not use niacin or fibrates as primary alternatives for LDL-C lowering in statin-intolerant patients, as these have neutral outcomes when added to well-treated patients on statins and are less effective than ezetimibe or PCSK9 inhibitors 3
• If LDL-C drops below 25 mg/dL on PCSK9 inhibitors, consider de-intensification as long-term safety of extremely low LDL-C levels remains unknown 3
• Monitor for liver enzyme elevations when using ezetimibe, particularly in combination with other lipid-lowering agents 4

Special Populations

Patients with Diabetes

• Ezetimibe is the preferred initial non-statin therapy despite limited RCT evidence for outcomes benefits in this population 1
• For diabetes patients aged 40-75 years at higher cardiovascular risk with LDL-C ≥70 mg/dL, it is reasonable to add ezetimibe or PCSK9 inhibitor to maximum tolerated statin 3

Pediatric Patients

• Ezetimibe is approved in combination with statins for children ≥10 years old with heterozygous or homozygous familial hypercholesterolemia 4
• For homozygous familial sitosterolemia, ezetimibe is approved for children ≥9 years old 4