What are the treatment options for dyslipidemia in patients intolerant to statins (HMG-CoA reductase inhibitors)?

Treatment of Dyslipidemia in Statin-Intolerant Patients

For statin-intolerant patients, ezetimibe should be initiated first (10 mg daily), followed by the addition of bempedoic acid if LDL-C targets are not met, with PCSK9 inhibitors reserved for very high-risk patients with persistent LDL-C elevation despite combination therapy. 1, 2

Defining Statin Intolerance

Before pursuing alternative therapies, confirm true statin intolerance by documenting:

• Adverse effects that resolve or improve with dose reduction or discontinuation 2
• Failed trials of at least 2 different statins, including at least one at the lowest approved daily dose 2

First-Line Alternative: Ezetimibe

Ezetimibe (10 mg daily) is the recommended initial therapy for statin-intolerant patients, providing 15-20% LDL-C reduction with a placebo-like side effect profile. 1, 2

• Ezetimibe inhibits intestinal cholesterol absorption and has demonstrated cardiovascular event reduction in the IMPROVE-IT trial when added to statins in acute coronary syndrome patients 3
• This agent is particularly appropriate when elevated LDL-C is the primary lipid abnormality 3, 1
• For patients with diabetes or metabolic disorders, ezetimibe does not negatively impact glycemic control, making it especially suitable 1

Second-Line: Adding Bempedoic Acid

If LDL-C targets are not achieved with ezetimibe alone, add bempedoic acid (180 mg daily) to achieve approximately 35% total LDL-C reduction. 1, 2

• Bempedoic acid monotherapy reduces LDL-C by 15-25% with minimal muscle-related adverse effects because it acts upstream from statins in the liver and requires activation by an enzyme not present in skeletal muscle 1, 2
• The CLEAR Outcomes trial demonstrated a 13% reduction in major adverse cardiovascular events in statin-intolerant patients 2
• A fixed-dose combination product of bempedoic acid with ezetimibe is available and may improve adherence 1
• Monitor liver function tests (ALT/AST) when using bempedoic acid 1

Third-Line: PCSK9 Inhibitors

For very high-risk patients (atherosclerotic CVD, LDL-C ≥70 mg/dL despite maximal tolerated ezetimibe and bempedoic acid), add a PCSK9 inhibitor. 3, 1, 2

• PCSK9 inhibitors (evolocumab, alirocumab, inclisiran) reduce LDL-C by approximately 50% and are well-tolerated in statin-intolerant patients 3, 1, 2
• The combination of evolocumab with ezetimibe achieves the greatest LDL-C reduction (approximately 49% additional reduction beyond ezetimibe alone) with comparable safety 4
• Assess LDL-C response every 3-6 months when using PCSK9 inhibitors 2
• Important caveat: PCSK9 inhibitors lack an established role for primary prevention in the absence of ASCVD or baseline LDL-C ≥190 mg/dL; bempedoic acid should be tried first in these patients 2

Alternative Agents for Specific Situations

Bile Acid Sequestrants

Consider bile acid sequestrants (colesevelam, cholestyramine, colestipol) if triglycerides are <300 mg/dL and the patient cannot tolerate bempedoic acid. 1, 2, 5

• Provide 15-30% LDL-C reduction with good evidence for cardiovascular event reduction (approximately 20% in primary prevention trials) 3, 1
• Offer a modest hypoglycemic effect beneficial in diabetic patients 2
• May be used in pregnancy or breastfeeding when other agents are contraindicated 2

Niacin

Niacin is reasonable for LDL-C lowering and may be particularly beneficial for patients with low HDL-C or elevated Lp(a). 1

• Reduces LDL-C by 20-25% with approximately 20% cardiovascular risk reduction in placebo-controlled trials 3, 1
• Monitor uric acid levels due to risk of hyperuricemia 1
• Note that the AIM-HIGH and HPS2-THRIVE trials did not show clinical benefit when niacin was added to statins, but these trials did not specifically study statin-intolerant patients 3

Fibrates for Severe Hypertriglyceridemia

For patients with triglycerides >500 mg/dL, initiate fenofibrate (54-160 mg daily with meals) to prevent acute pancreatitis. 1, 6

• Fenofibrate is preferred over gemfibrozil due to lower drug interaction risk 2
• Particularly appropriate when hypertriglyceridemia and/or low HDL-C is the principal abnormality 3
• Adjust dose in renal impairment: start at 54 mg daily in mild-to-moderate renal dysfunction; avoid in severe renal impairment 6
• Critical warning: Fenofibrate at 160 mg was not shown to reduce coronary heart disease morbidity and mortality in a large randomized trial of type 2 diabetes patients 6

Omega-3 Fatty Acids

For patients with elevated triglycerides (135-499 mg/dL) at high cardiovascular risk, consider icosapent ethyl (omega-3 fatty acid). 2

• Standard fish oil capsules (1 g/day) may be reasonable for cardiovascular risk reduction in patients with elevated triglycerides 1

Treatment Targets Based on Cardiovascular Risk

Very High-Risk Patients (Secondary Prevention, ASCVD)

• Target LDL-C <55 mg/dL with at least 50% reduction from baseline 3
• Secondary target: non-HDL-C <85 mg/dL 3
• Consider combination therapy immediately rather than sequential monotherapy to achieve targets more rapidly 1

High-Risk Patients

• Target LDL-C <70 mg/dL 1, 2
• Secondary target: non-HDL-C <100 mg/dL 3

Moderate-Risk Patients

• Target LDL-C <100 mg/dL or at least 50% reduction from baseline 2
• PCSK9 inhibitors do not have an established role for primary prevention in this population 2

Essential Lifestyle Modifications

All patients must implement intensive dietary therapy and lifestyle changes regardless of pharmacotherapy. 1, 2

• Reduce saturated fats to <7% of total calories 1, 2
• Reduce trans fatty acids to <1% of total calories 1, 2
• Limit cholesterol intake to <200 mg/day 1, 2
• Daily physical activity and weight management 1
• Mediterranean diet pattern appears beneficial 1

Monitoring Protocol

Obtain baseline lipid panel and liver enzymes (ALT/AST) before initiating therapy. 2

• Reassess lipid profile 4-8 weeks after initiating or adjusting therapy 1, 2
• Once at goal, perform annual lipid monitoring unless adherence concerns exist 2
• Monitor for medication-specific adverse effects (liver function with bempedoic acid, uric acid with niacin) 1

When to Refer to a Lipid Specialist

Refer patients with the following conditions: 2

• Complex mixed dyslipidemia
• Severe hypertriglyceridemia
• Baseline LDL-C ≥190 mg/dL not due to secondary causes
• Failure to achieve targets despite combination therapy

Special Populations

Transplant Patients

In transplant patients intolerant to statins with significant dyslipidemia and high residual risk, consider ezetimibe for high LDL-C or fibrates for hypertriglyceridemia/low HDL-C as the principal abnormality. 3

Women of Childbearing Potential

Avoid all lipid-lowering drugs except bile acid sequestrants when pregnancy is planned, during pregnancy, or during breastfeeding. 3, 2