Can Nexlizet (bempedoic acid and ezetimibe) and Repatha (evolocumab) be used together?

Can Nexlizet and Repatha Be Used Together?

Yes, Nexlizet (bempedoic acid/ezetimibe) and Repatha (evolocumab) can be used together safely and effectively for patients requiring intensive LDL-C lowering who have not achieved target goals on maximally tolerated statin therapy with initial non-statin agents.

Guideline-Supported Combination Strategy

The 2022 ACC Expert Consensus explicitly addresses this combination approach for very high-risk patients:

• If patients with clinical ASCVD at very high risk require additional LDL-C lowering after adding a single nonstatin agent (ezetimibe or PCSK9 mAb) to maximally tolerated statin therapy, the addition of a second evidence-based nonstatin agent (e.g., ezetimibe plus PCSK9 mAb) should be considered 1

• If additional LDL-C lowering is warranted despite maximally tolerated statin therapy, ezetimibe, and a PCSK9 mAb, the addition of bempedoic acid may be considered 1

This creates a clear pathway where all three components of Nexlizet (bempedoic acid + ezetimibe) can be combined with Repatha (evolocumab).

Algorithmic Approach to Triple Therapy

Step 1: Identify Appropriate Candidates

• Patients with clinical ASCVD at very high risk who have achieved <50% reduction in LDL-C and LDL-C ≥55 mg/dL (or non-HDL-C ≥85 mg/dL) despite maximally tolerated statin therapy 1
• Patients with recurrent atherothrombotic events on maximally tolerated statin therapy, where LDL-C goal of <40 mg/dL may be considered 1

Step 2: Sequential vs. Simultaneous Addition

European guidelines support that in some very high-risk patients requiring greater LDL-C reduction than any single additional agent can achieve, it may be reasonable to consider the simultaneous addition of 2 agents to reduce the risk of recurrent events more rapidly 1

The 2024 ILEP recommendations advocate for initiating therapy with multiple drugs (double or even triple therapy) immediately during hospitalization or during the first visit in the highest-risk patients to increase the number of patients achieving LDL-C goals and reduce discontinuation risk 1

Step 3: Expected LDL-C Reduction

When combining these agents on background statin therapy:

• Ezetimibe provides additional 20-25% LDL-C reduction 1
• PCSK9 inhibitors (Repatha) provide 50-60% LDL-C reduction 1
• Bempedoic acid provides approximately 17% additional LDL-C reduction 1

The fixed-dose combination of bempedoic acid/ezetimibe (Nexlizet) demonstrated 36.2% LDL-C reduction when added to maximally tolerated statin therapy 2

Safety Considerations

No Mechanistic Drug Interactions

• Bempedoic acid is a prodrug activated only in the liver (not muscle), which explains its low incidence of musculoskeletal adverse events unlike statins 3
• PCSK9 inhibitors work by increasing hepatic LDL receptor expression through a completely different mechanism 1
• Ezetimibe reduces intestinal cholesterol absorption via a distinct pathway 1
• These complementary mechanisms allow safe combination without overlapping toxicity profiles 4

Specific Safety Profile

The combination of bempedoic acid/ezetimibe has been shown to have:

• A generally similar safety profile compared with individual components or placebo 2
• Non-significant increased risk of drug-related adverse events (RR 1.61) but lower incidence of therapy discontinuation (RR 0.75) 5
• Acceptable safety profile when lowering LDL-C to very low levels (<30 mg/dL) 1

Important Caveats

Bempedoic acid should be used with caution in patients with:

• History of gout (can increase uric acid levels) 1
• History of tendon rupture 1

Clinical Context for Triple Therapy

The 2024 ESC Guidelines for Chronic Coronary Syndromes provide the treatment hierarchy:

1. High-intensity statin up to highest tolerated dose (Class I, Level A) 1
2. If goal not achieved: add ezetimibe (Class I, Level B) 1
3. If goal not achieved: add PCSK9 inhibitor (Class I, Level A) 1
4. If goal not achieved: consider adding bempedoic acid (Class IIa, Level C) 1

This sequential approach supports the combination of Nexlizet with Repatha when earlier steps have not achieved target LDL-C levels 1

Practical Implementation

• The combination is particularly valuable for statin-intolerant patients, as bempedoic acid has demonstrated cardiovascular risk reduction in this population through the CLEAR Outcomes trial 3
• Fixed-dose combinations like Nexlizet improve adherence by reducing pill burden 1
• Regular monitoring of LDL-C levels at 4-12 weeks after initiation or dose adjustment is appropriate to assess response 1
• Referral to a lipid specialist should be considered for patients requiring this level of intensive therapy who remain above goal 1