What are alternative pill options to Repatha (evolocumab) for a patient with a history of high cholesterol or cardiovascular disease?

Oral Alternatives to Repatha for Cholesterol Management

Yes, there are effective pill alternatives to Repatha, with bempedoic acid and ezetimibe being the primary oral options recommended by current guidelines. 1

First-Line Oral Alternative: Bempedoic Acid

Bempedoic acid is the most direct oral alternative to Repatha, specifically designed for patients who cannot tolerate statins or need additional LDL-C lowering beyond maximally tolerated statin therapy. 1

Efficacy Profile

• Bempedoic acid reduces LDL-C by 24% when used without statins and 15% when added to existing statin therapy 1
• When combined with ezetimibe, it provides an additional 19% reduction in LDL-C 1
• The CLEAR Outcomes trial demonstrated a 13% reduction in major adverse cardiovascular events compared to placebo in patients with established ASCVD or high cardiovascular risk 1

Key Advantages Over Injectable PCSK9 Inhibitors

• Oral administration eliminates the need for subcutaneous injections 1
• No skeletal muscle activity, which limits muscle-related adverse effects that commonly occur with statins 1, 2
• No major drug interactions and no increased risk of new-onset diabetes 2

Important Caveat

• Bempedoic acid is associated with a small increase in plasma uric acid and slightly increased frequency of gout episodes in susceptible patients 2
• Monitor uric acid levels in patients with history of gout 1

Second-Line Oral Alternative: Ezetimibe

Ezetimibe should be tried before considering PCSK9 inhibitors like Repatha, as it is the guideline-recommended second-line therapy after statins. 1, 3

Efficacy Profile

• Provides 18% LDL-C reduction as monotherapy 4
• Adds 25% incremental LDL-C reduction when combined with statins 1, 4
• The IMPROVE-IT trial demonstrated that adding ezetimibe to moderate-intensity statin therapy reduced cardiovascular events in patients with recent acute coronary syndrome over 6 years of follow-up 1

Mechanism and Administration

• Inhibits cholesterol absorption in the small intestine by blocking the NPC1L1 protein 1
• Dosed at 10 mg orally daily, with or without food 1, 4
• Generally well-tolerated with adverse effects similar to placebo 1

Treatment Algorithm for Statin-Intolerant Patients

For patients who cannot tolerate statins, the recommended sequence is: 1, 3

1. First attempt: Try different statins at various doses or alternate-day dosing 1
2. Second step: Initiate ezetimibe 10 mg daily 1, 3
3. Third step: Add bempedoic acid to ezetimibe if LDL-C remains ≥70 mg/dL 1
4. Fourth step: Consider PCSK9 inhibitors (Repatha, inclisiran) only if oral therapies fail to achieve goals 1, 3

When Oral Alternatives May Not Be Sufficient

Injectable PCSK9 inhibitors like Repatha remain superior for maximal LDL-C reduction, providing 50-60% reductions compared to 24% with bempedoic acid. 1, 2, 5

Situations Favoring Injectable Therapy

• Very high-risk patients with recurrent cardiovascular events requiring LDL-C <55 mg/dL 6
• Familial hypercholesterolemia with extremely elevated baseline LDL-C 1, 7
• Failure to achieve LDL-C goals despite maximally tolerated oral therapy 1, 3

Practical Considerations for Choosing Between Options

Cost and Access

• Ezetimibe is available as a generic and is generally well-covered by insurance 1
• Bempedoic acid and PCSK9 inhibitors require prior authorization demonstrating failure of less expensive alternatives 3, 2
• Insurance typically requires documentation of ezetimibe trial before approving bempedoic acid or PCSK9 inhibitors 3

Patient Preference

• Oral medications (bempedoic acid, ezetimibe) avoid injection site reactions that occur in 2-5% of patients on PCSK9 inhibitors 1, 2, 5
• Injection frequency with Repatha (every 2 weeks or monthly) versus daily oral pills may influence adherence 1, 8

Combination Therapy Strategy

The most effective approach for high-risk patients combines multiple mechanisms: 1, 4

• Maximally tolerated statin + ezetimibe + bempedoic acid can achieve substantial LDL-C reduction without injections 1
• This triple oral therapy should be optimized before considering injectable PCSK9 inhibitors 1, 3