What are the alternatives to Repatha (evolocumab) for lowering LDL (low-density lipoprotein) cholesterol levels?

Alternatives to Repatha (Evolocumab)

Alirocumab (Praluent) is the most direct alternative to Repatha, offering equivalent LDL-C reduction of 50-65% with a similar safety profile and mechanism of action as another PCSK9 inhibitor. 1, 2

PCSK9 Inhibitor Alternative

Alirocumab represents a class-equivalent alternative with comparable efficacy to evolocumab, reducing LDL-C by 45-58% when added to maximally tolerated statin therapy. 2 Both agents are fully human monoclonal antibodies that bind circulating PCSK9, preventing LDL receptor degradation and increasing hepatic LDL clearance. 1, 3

Dosing and Administration

• Adults with established CVD or primary hyperlipidemia: Start with 75 mg every 2 weeks or 300 mg every 4 weeks subcutaneously 4
• If inadequate LDL-C response: Increase to 150 mg every 2 weeks 4
• Patients with HeFH undergoing apheresis or HoFH: 150 mg every 2 weeks 4

Safety Profile

Alirocumab is generally well-tolerated with adverse effects including nasopharyngitis, injection site reactions, influenza-like symptoms, noncardiac chest pain, and myalgia. 2 Both alirocumab and evolocumab show similar tolerability in statin-intolerant patients, with muscle-related adverse events comparable to ezetimibe. 1

Cardiovascular Outcomes

The ODYSSEY Outcomes trial demonstrated that alirocumab reduces cardiovascular events, similar to evolocumab's proven benefit. 2 Meta-analyses of Phase 2 and 3 trials found reduced total mortality with both PCSK9 inhibitors. 1

Non-PCSK9 Inhibitor Alternatives

Ezetimibe (First-Line Non-PCSK9 Alternative)

Ezetimibe should be the next consideration if PCSK9 inhibitors are unsuitable, offering oral administration and proven cardiovascular benefit. 2

• Mechanism: Inhibits NPC1L1 protein in the small intestine, reducing cholesterol absorption 2
• Efficacy: Monotherapy reduces LDL-C by approximately 18%; when combined with statins, provides an additional 25% reduction 2
• Safety: Generally well-tolerated with common side effects including upper respiratory tract infection, diarrhea, arthralgia, sinusitis, and extremity pain 2
• Cardiovascular outcomes: The IMPROVE-IT trial demonstrated reduction in cardiovascular events 2

Bempedoic Acid (For Statin-Intolerant Patients)

Bempedoic acid is particularly valuable for statin-intolerant patients as it inhibits ATP citrate lyase, reducing cholesterol synthesis without causing muscle-related side effects. 2 This agent can be used as monotherapy in statin-intolerant patients or as add-on therapy. 2

Bile Acid Sequestrants (Additional LDL-C Lowering)

• Mechanism: Bind bile acids in the intestine, promoting hepatic conversion of cholesterol to bile acids 2
• Efficacy: Reduce LDL-C by 15-30% 2
• Considerations: Gastrointestinal side effects and drug interactions limit use; best reserved as add-on therapy when additional LDL-C lowering is needed 2

Mipomersen (For Homozygous FH)

Mipomersen is an antisense oligonucleotide that binds apolipoprotein B mRNA, reducing LDL-C by approximately 30%. 1 This agent is particularly useful in homozygous FH patients as it does not require functional LDL receptors. 1 However, concerns include injection site reactions, influenza-like symptoms, transaminase elevations, and hepatic steatosis, limiting its use to severe cases. 1

Clinical Decision Algorithm

1. First alternative: Alirocumab if another PCSK9 inhibitor is acceptable (insurance, cost, or availability issues with evolocumab) 2

2. If PCSK9 inhibitors are not suitable: Ezetimibe as oral medication providing 18-25% LDL-C reduction 2

3. For statin-intolerant patients: Bempedoic acid alone or combined with ezetimibe 2

4. For additional LDL-C lowering: Add bile acid sequestrants to existing therapy 2

5. For homozygous FH with inadequate response: Consider mipomersen (US only) 1

Important Clinical Considerations

Always optimize statin therapy before adding non-statin agents, as recommended by the American College of Cardiology. 2 The goal is to achieve >50% LDL-C reduction in high-risk patients. 1

Common pitfall: In children on statins, discontinuing statin therapy when adding agents like colesevelam can paradoxically increase LDL-C despite the additional agent. 1 Maintain statin therapy when adding non-statin agents.

For combination therapy in statin-intolerant patients: Consider combining multiple non-statin therapies (ezetimibe + bempedoic acid) for greater efficacy rather than relying on monotherapy. 2