What is the recommended treatment for patients with hypercholesterolemia who require additional low-density lipoprotein (LDL) cholesterol lowering beyond statins, using bempedoic acid (Nexletol) and Repatha (evolocumab)?

Treatment Strategy for Hypercholesterolemia: Bempedoic Acid and Repatha (Evolocumab)

For patients requiring additional LDL-cholesterol lowering beyond statins, add ezetimibe first, then Repatha (evolocumab) second, and reserve bempedoic acid as third-line therapy—except in statin-intolerant patients where bempedoic acid moves up in the treatment hierarchy. 1, 2

Hierarchical Treatment Algorithm

First-Line Non-Statin: Ezetimibe

• Add ezetimibe 10 mg daily as the initial non-statin agent when maximally tolerated statin therapy fails to achieve target LDL-C levels (LDL-C ≥70 mg/dL for ASCVD patients or <50% LDL-C reduction). 1, 2
• Ezetimibe provides approximately 18% additional LDL-C reduction as monotherapy and 25% when combined with statins, with proven cardiovascular outcomes benefit in the IMPROVE-IT trial. 2
• This agent has demonstrated safety, tolerability, generic availability, and cardiovascular death/MI reduction when added to moderate-intensity statins in acute coronary syndrome patients. 2

Second-Line Non-Statin: Repatha (Evolocumab)

• Add Repatha (evolocumab) 140 mg subcutaneously every 2 weeks or 420 mg monthly if LDL-C remains ≥70 mg/dL or <50% reduction despite statin plus ezetimibe. 1, 2
• Repatha reduces LDL-C by 40-65% when added to statin therapy and has proven cardiovascular outcomes benefit in the FOURIER trial, demonstrating reduction in cardiovascular death, MI, and stroke. 2, 3
• The American College of Cardiology prioritizes PCSK9 monoclonal antibodies (evolocumab, alirocumab) over other PCSK9 inhibitors due to established cardiovascular outcomes data. 3

Third-Line Non-Statin: Bempedoic Acid

• Consider adding bempedoic acid 180 mg daily if LDL-C remains elevated despite statin, ezetimibe, and Repatha, or if the patient cannot tolerate these therapies. 1
• Bempedoic acid reduces LDL-C by approximately 23% as monotherapy and 15-17.8% when added to statin therapy. 1
• The 2024 American Diabetes Association guidelines note that bempedoic acid demonstrated a 13% reduction in four-point major adverse cardiovascular events in the CLEAR Outcomes trial, with particularly strong benefit in primary prevention (32% reduction in HR 0.68). 1

Special Consideration: Statin-Intolerant Patients

In patients truly intolerant to statins, bempedoic acid moves to first-line therapy, followed by ezetimibe, then Repatha. 1

• Bempedoic acid is activated only in the liver (not skeletal muscle) by very-long-chain acyl-CoA synthetase-1, avoiding statin-associated muscle symptoms. 1
• In the CLEAR Outcomes trial, 70% of participants had established ASCVD and 30% were at high risk, with 19% on very-low-dose statin therapy at baseline, demonstrating efficacy in statin-intolerant populations. 1
• The FDA specifically approves bempedoic acid "to reduce the risk of myocardial infarction and coronary revascularization in adults who are unable to take recommended statin therapy." 4

Combination Therapy for Severe Hypercholesterolemia

For patients with ASCVD and baseline LDL-C ≥190 mg/dL requiring rapid, aggressive LDL-C reduction, consider simultaneous addition of ezetimibe plus Repatha to maximally tolerated statin. 1

• The fixed-dose combination of bempedoic acid 180 mg plus ezetimibe 10 mg provides 38% additional LDL-C reduction when added to statin therapy. 1, 5
• This combination approach is reasonable when any single additional agent cannot achieve the required LDL-C reduction to prevent recurrent cardiovascular events. 1

Adding Bempedoic Acid to Existing Repatha Therapy

Bempedoic acid can be safely added to background Repatha therapy and provides an additional 30.3% LDL-C reduction beyond the PCSK9 inhibitor alone. 6

• A randomized controlled trial demonstrated that bempedoic acid added to evolocumab (Repatha) background therapy significantly lowered LDL-C by 30.3% (P < .001) versus placebo, with comparable safety profiles. 6
• This combination also significantly reduced apolipoprotein B, non-HDL cholesterol, total cholesterol, and high-sensitivity C-reactive protein. 6
• The safety profile of bempedoic acid when added to Repatha was comparable to placebo, with no clinically meaningful increase in muscle-related symptoms. 6, 7

Critical Safety Monitoring

Bempedoic Acid-Specific Monitoring

• Monitor serum uric acid levels as bempedoic acid increases uric acid by a mean of 0.8 mg/dL, with gout occurring in 1.5% versus 0.4% with placebo. 1, 7
• Counsel patients about tendon rupture risk (0.5% versus 0% with placebo), particularly in those with prior tendon disorders. 1
• Monitor for benign prostatic hyperplasia (1.3% vs 0.1%), atrial fibrillation (1.7% vs 1.1%), and creatine kinase elevation (1.0% vs 0.6%). 1

Repatha-Specific Considerations

• Repatha requires subcutaneous injection every 2 weeks or monthly, which may affect adherence compared to oral bempedoic acid. 1
• Refrigeration storage may be required, though room temperature storage is permitted for limited periods per prescribing information. 1

Common Pitfalls to Avoid

• Do not skip ezetimibe and proceed directly to Repatha or bempedoic acid unless the patient has documented ezetimibe intolerance—ezetimibe has proven cardiovascular outcomes benefit, is generic, and should be tried first. 2
• Do not use inclisiran instead of Repatha expecting equivalent cardiovascular outcomes benefit—inclisiran lacks completed cardiovascular outcomes data until 2026-2027, while Repatha has proven benefit in FOURIER. 3
• Do not combine Repatha with inclisiran—there is no evidence or mechanistic plausibility for additional benefit, and if inclisiran is used, it must replace (not supplement) the PCSK9 mAb. 3
• Refer to a lipid specialist if the patient has ASCVD with baseline LDL-C ≥190 mg/dL not achieving targets on maximally tolerated statin plus nonstatin therapy, or if the patient is intolerant to ≥2-3 different statins. 2

Cost and Access Considerations

• Bempedoic acid is commercially available as a branded product; prior authorization may be required, but patient assistance programs and discount copay cards are available for eligible patients. 1
• Repatha similarly requires prior authorization in most insurance plans, with patient assistance programs available. 1
• The availability of fixed-dose combination bempedoic acid/ezetimibe may improve adherence in patients requiring multiple agents. 1, 5