What alternative treatments can be given to patients who cannot take statins (HMG-CoA reductase inhibitors) for hyperlipidemia?

Alternative Treatments for Statin-Intolerant Patients

Start with ezetimibe 10 mg daily as first-line therapy for patients who cannot tolerate statins, then add bempedoic acid if LDL-C targets are not met, and reserve PCSK9 inhibitors for very high-risk patients with persistent LDL-C elevation. 1, 2

Defining Statin Intolerance

Before proceeding with alternatives, confirm true statin intolerance by ensuring the patient has:

• Attempted at least 2 different statins (preferably 3), including one trial at the lowest FDA-approved dose 1, 2
• Tried alternative dosing regimens such as every-other-day dosing 1
• Experienced adverse effects that resolved or improved with dose reduction or discontinuation 2

First-Line Alternative: Ezetimibe

Ezetimibe 10 mg daily should be the initial non-statin therapy for all statin-intolerant patients. 1, 2, 3

• Reduces LDL-C by approximately 15-20% as monotherapy 1, 3, 4
• Can be taken with or without food, once daily 3
• Has a side-effect profile comparable to placebo 4, 5
• Works by inhibiting cholesterol absorption in the small intestine without affecting fat-soluble vitamins or bile acids 1, 4
• Demonstrated cardiovascular outcomes benefit in the IMPROVE-IT trial when added to statin therapy in post-ACS patients 1

Ezetimibe Monitoring and Precautions:

• Not recommended in moderate to severe hepatic impairment 1
• Monitor liver function tests if considering future combination therapy 1
• Avoid during pregnancy and breastfeeding 3

Second-Line: Bempedoic Acid

If LDL-C targets are not achieved with ezetimibe alone, add bempedoic acid 180 mg daily. 2

• Reduces LDL-C by 15-25% with low rates of muscle-related adverse effects 2
• Works upstream from statins in the liver, making it particularly valuable for statin-intolerant patients 2
• The CLEAR Outcomes trial demonstrated a 13% reduction in major adverse cardiovascular events in statin-intolerant patients 2
• Combination of ezetimibe plus bempedoic acid lowers LDL-C by approximately 35% 2
• Requires monitoring of liver function tests 2

Third-Line: PCSK9 Inhibitors

Reserve PCSK9 inhibitors (evolocumab, alirocumab, or inclisiran) for very high-risk patients with persistent LDL-C elevation despite ezetimibe and bempedoic acid. 1, 2

• Reduce LDL-C by approximately 50-60% 2
• Well-tolerated in statin-intolerant patients with minimal muscle-related side effects 2
• FDA-approved for statin-intolerant patients with primary hyperlipidemia or established ASCVD 2
• Monitor LDL-C response every 3-6 months 2

Important Caveat:

Try ezetimibe and bempedoic acid first before PCSK9 inhibitors due to cost considerations, unless the patient has very high risk with markedly elevated LDL-C. 2

Risk-Based Treatment Algorithm

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

• Target: LDL-C <55 mg/dL with ≥50% reduction from baseline 2
• Start ezetimibe 10 mg daily 2
• Add bempedoic acid 180 mg daily if not at goal 2
• Add PCSK9 inhibitor if LDL-C remains ≥55 mg/dL 2
• Consider referral to lipid specialist if goals not met 1, 2

High-Risk Patients (diabetes, familial hypercholesterolemia phenotype):

• Target: LDL-C <70 mg/dL 2
• Start ezetimibe 10 mg daily 2
• Add bempedoic acid 180 mg daily if not at goal 2
• Consider PCSK9 inhibitor only if LDL-C remains significantly elevated 2

Moderate-Risk Patients (primary prevention):

• Target: LDL-C <100 mg/dL or at least 50% reduction 2
• Start ezetimibe 10 mg daily 2
• Add bempedoic acid as preferred next agent 2
• PCSK9 inhibitors do not have an established role in primary prevention without ASCVD or baseline LDL-C ≥190 mg/dL 2

Alternative Options (Less Preferred)

Bile Acid Sequestrants (Cholestyramine, Colesevelam):

Consider only if triglycerides are <300 mg/dL and the patient cannot tolerate bempedoic acid. 1, 2, 6

• Provide modest LDL-C reduction of 15-30% 2
• May cause gastrointestinal side effects 1
• Can provide beneficial hypoglycemic effect in diabetic patients 2
• Take ezetimibe either ≥2 hours before or ≥4 hours after bile acid sequestrants if used in combination 1

Special Situations:

For severe hypertriglyceridemia (>500 mg/dL):

• Consider fibrates (fenofibrate preferred over gemfibrozil) to prevent acute pancreatitis 1, 2
• Refer to lipid specialist 2

For moderate hypertriglyceridemia (135-499 mg/dL) in high-risk patients:

• Consider icosapent ethyl (omega-3 fatty acid) 2

Lifestyle Modifications

Implement intensive dietary therapy alongside pharmacologic treatment: 1, 2

• Saturated fats <7% of total calories 1
• Trans fatty acids <1% of total calories 1
• Cholesterol <200 mg/day 1
• Daily physical activity and weight management 1

Common Pitfalls to Avoid

1. Don't assume statin intolerance without adequate trials - Ensure at least 2-3 different statins have been attempted, including lowest doses and alternative regimens 1, 2

2. Don't jump directly to PCSK9 inhibitors - Follow the stepwise approach (ezetimibe → bempedoic acid → PCSK9 inhibitor) unless dealing with extremely high-risk patients 2

3. Don't forget to reassess lipid profile - Check lipids 4-8 weeks after initiating therapy and adjust treatment accordingly 2

4. Don't overlook referral indications - Refer to lipid specialist for: baseline LDL-C ≥190 mg/dL, intolerance to ≥3 statins, complex mixed dyslipidemia, or failure to achieve goals on combination therapy 1, 2

5. Don't use bile acid sequestrants if triglycerides ≥300 mg/dL - They can worsen hypertriglyceridemia 2, 6