Can Repatha (evolocumab) and ezetimibe be taken concurrently in patients with high cholesterol?

Can Repatha and Ezetimibe Be Taken Concurrently?

Yes, Repatha (evolocumab) and ezetimibe can and should be taken concurrently in high-risk patients who fail to achieve LDL-C goals despite maximally tolerated statin therapy plus ezetimibe. 1

Guideline-Supported Sequential Approach

The standard treatment algorithm for high-risk patients follows this stepwise intensification 1:

• Step 1: Maximize statin therapy (high-intensity statin to achieve ≥50% LDL-C reduction) 1
• Step 2: Add ezetimibe if LDL-C remains ≥70 mg/dL in very high-risk patients or ≥100 mg/dL in severe hypercholesterolemia 1
• Step 3: Add a PCSK9 inhibitor (evolocumab or alirocumab) if LDL-C remains ≥100 mg/dL despite maximally tolerated statin plus ezetimibe in very high-risk patients 1

Evidence for Combination Therapy

The combination of statin + ezetimibe + PCSK9 inhibitor is explicitly recommended by major guidelines 1:

• The European Society of Cardiology 2019 guidelines state that for very high-risk patients who do not achieve their LDL-C goal (<55 mg/dL) on maximum tolerated statin and ezetimibe, adding a PCSK9 inhibitor is recommended (Class I recommendation, Level A evidence for secondary prevention) 1
• The 2022 ACC Expert Consensus states it is reasonable to add a PCSK9 inhibitor when patients require >25% additional LDL-C lowering beyond what ezetimibe provides, or when LDL-C remains ≥100 mg/dL despite statin plus ezetimibe 1
• The 2018 ESC/EAS Task Force specifically evaluated patients on "statin with or without ezetimibe" as background therapy when adding PCSK9 inhibitors, confirming the safety and efficacy of triple therapy 1

Clinical Trial Evidence Supporting Concurrent Use

The FOURIER trial, which demonstrated cardiovascular outcomes benefit with evolocumab, included patients receiving background therapy of statins with or without ezetimibe 1, 2:

• Evolocumab reduced LDL-C by approximately 60% when added to statin therapy (with or without ezetimibe) 1, 2
• The safety profile was comparable whether patients were on statin monotherapy or statin plus ezetimibe 1
• No drug-drug interactions were identified between evolocumab and ezetimibe 2, 3

Complementary Mechanisms of Action

These medications work through entirely different mechanisms, making combination therapy rational 3:

• Statins inhibit HMG-CoA reductase to reduce cholesterol synthesis (20-45% LDL-C reduction) 3
• Ezetimibe inhibits NPC1L1 to block intestinal cholesterol absorption (18% LDL-C reduction as monotherapy, additional 15-25% when added to statins) 4, 5, 3
• Evolocumab binds PCSK9 to prevent LDL receptor degradation, enhancing hepatic LDL clearance (53-60% LDL-C reduction) 3, 6

Expected Lipid-Lowering Effects with Triple Therapy

When all three agents are combined, the cumulative LDL-C reduction can exceed 75-85% from baseline 4, 7:

• In the LAPLACE-2 trial, evolocumab 140 mg every 2 weeks added to statin therapy reduced LDL-C by 63%, and was 45% more effective than ezetimibe added to the same statin 2
• The complementary mechanisms allow for additive effects without increasing adverse events 3, 8

Safety Profile of Concurrent Use

The combination of evolocumab and ezetimibe with statins has been extensively studied and is well-tolerated 1, 2, 8:

• Adverse event rates with evolocumab were similar whether patients were on statin monotherapy or statin plus ezetimibe (muscle symptoms: 4.7% vs. 8.5% with standard of care) 1
• No evidence of increased risk of hemorrhagic stroke, even with very low LDL-C levels (<20 mg/dL achieved in 25% of FOURIER patients) 1
• Injection site reactions with evolocumab occurred in <5% of patients and were mild 1

When to Consider Simultaneous Addition

In select very high-risk patients, simultaneous addition of both ezetimibe and evolocumab may be reasonable 1:

• Patients with baseline LDL-C ≥190 mg/dL plus additional ASCVD risk factors who require >50% LDL-C reduction beyond statin alone 1
• Patients with established ASCVD and very high baseline LDL-C where rapid, aggressive reduction is needed 1
• Patients with familial hypercholesterolemia requiring maximal LDL-C lowering 1

Common Pitfalls to Avoid

• Do not delay adding a PCSK9 inhibitor if LDL-C remains substantially elevated (≥100 mg/dL) despite statin plus ezetimibe in very high-risk patients—the combination is guideline-recommended and safe 1
• Do not assume drug interactions exist between ezetimibe and evolocumab—they have completely different mechanisms and no pharmacokinetic interactions 2, 3
• Do not stop ezetimibe when starting evolocumab—maintaining triple therapy provides maximal LDL-C reduction through complementary pathways 1, 4
• Do not be concerned about achieving very low LDL-C levels (<20 mg/dL)—evidence from FOURIER and genetic studies shows no safety concerns with very low LDL-C 1

Practical Dosing for Concurrent Therapy

The standard regimen for triple therapy 1, 2:

• Statin: Maximally tolerated dose (typically atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily)
• Ezetimibe: 10 mg orally once daily 5
• Evolocumab: 140 mg subcutaneously every 2 weeks OR 420 mg subcutaneously once monthly 2