What is the next step in managing a patient with hypercholesterolemia who cannot take statins or fenofibrate?

Management of Hypercholesterolemia in Statin and Fenofibrate Intolerant Patients

For patients with hypercholesterolemia who cannot take statins or fenofibrate, bile acid sequestrants and/or niacin should be the first-line therapy, followed by ezetimibe if needed. 1

First-Line Options for Statin/Fenofibrate Intolerant Patients

Bile Acid Sequestrants and Niacin

• According to the American Heart Association/American College of Cardiology Foundation guidelines, for patients who cannot tolerate statins, LDL-C-lowering therapy with bile acid sequestrants and/or niacin is reasonable (Level of Evidence: B) 1
• These agents can reduce LDL-C by approximately 18-25% when used as monotherapy

Ezetimibe

• Ezetimibe may be considered for patients who do not tolerate statins or bile acid sequestrants 1
• Mechanism: Inhibits Niemann-Pick C1 like 1 (NPC1L1) protein, reducing cholesterol absorption in small intestine
• Efficacy: Monotherapy reduces LDL-C by approximately 18%; well-tolerated with minimal side effects 1
• Generally well tolerated with few drug interactions (except with cyclosporine, fibrates, and bile acid sequestrants) 1

Second-Line Options

PCSK9 Inhibitors

• For patients with established cardiovascular disease or heterozygous familial hypercholesterolemia who cannot achieve adequate LDL-C reduction with first-line agents 1, 2
• Evolocumab dosing: 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously 2
• Provides substantial LDL-C reduction (typically 50-60%) 3
• FDA approved for use as monotherapy or in combination with other LDL-C-lowering therapies 2

Bempedoic Acid

• Particularly useful in statin-intolerant patients 3
• Can be used in combination with ezetimibe for enhanced LDL-C reduction 3
• Should be used with caution in patients with history of gout or tendon rupture 3

Treatment Algorithm for Statin/Fenofibrate Intolerant Patients

1. Start with lifestyle modifications:

   • Daily physical activity and weight management 1
   • Dietary therapy: reduced intake of saturated fats (<7% of total calories), trans fatty acids (<1% of total calories), and cholesterol (<200 mg/d) 1

2. First-line pharmacotherapy:

   • Bile acid sequestrants and/or niacin 1
   • Monitor for side effects: constipation with bile acid sequestrants; flushing with niacin

3. If inadequate response or intolerance to first-line therapy:

   • Add ezetimibe 10 mg daily 1, 4
   • Ezetimibe can be used as monotherapy or in combination with bile acid sequestrants (take ezetimibe either ≥2 hours before or ≥4 hours after bile acid sequestrants) 1

4. For high-risk patients with inadequate response to above therapies:

   • Consider PCSK9 inhibitors (evolocumab or alirocumab) 1, 3, 2
   • For very high-risk patients with established cardiovascular disease, PCSK9 inhibitors may be considered earlier in the treatment algorithm 3

5. Additional options for specific scenarios:

   • Omega-3 fatty acids (1 g/day) may be reasonable for cardiovascular disease risk reduction 1
   • Consider bempedoic acid, especially in combination with ezetimibe for statin-intolerant patients 3

Monitoring and Follow-up

• Assess LDL-C levels 4-12 weeks after initiating therapy 2
• For patients on PCSK9 inhibitors administered monthly, measure LDL-C just prior to the next scheduled dose 2
• Monitor for adverse effects specific to each medication class

Important Considerations and Pitfalls

• Avoid combining gemfibrozil with any remaining statin therapy due to higher risk of myopathy compared to fenofibrate 5
• If partial statin tolerance exists (lower doses), consider combining low-dose statin with non-statin therapies rather than using higher statin doses 3
• Consider referral to a lipid specialist for patients with complex lipid disorders or multiple medication intolerances 1
• When using combination therapy, be vigilant for potential drug interactions and monitor for adverse effects 3
• For patients with mixed hyperlipidemia (elevated LDL-C and triglycerides), a combination approach may be particularly beneficial 6

By following this algorithm, most patients with hypercholesterolemia who cannot tolerate statins or fenofibrate should be able to achieve significant LDL-C reduction and cardiovascular risk reduction.