In a patient on the maximum tolerated statin dose whose LDL‑C remains above guideline targets, what is the first medication to add?

Add Ezetimibe First

For patients on maximum tolerated statin therapy whose LDL-C remains above target, add ezetimibe 10 mg daily as the first-line medication. 1, 2, 3, 4

Why Ezetimibe is the Clear First Choice

The 2018 ACC/AHA guidelines provide a Class IIa recommendation (reasonable to add) for ezetimibe in patients with clinical ASCVD on maximally tolerated statin therapy whose LDL-C remains ≥70 mg/dL. 1 This recommendation is even stronger for patients with severe hypercholesterolemia (LDL-C ≥190 mg/dL) who achieve less than 50% reduction or maintain LDL-C ≥100 mg/dL despite maximal statin therapy. 1

Ezetimibe lowers LDL-C by an additional 15-25% when added to statin therapy, is well-tolerated with minimal side effects, and is available as a generic medication making it cost-effective. 1, 2, 5 The IMPROVE-IT trial demonstrated that adding ezetimibe to moderate-intensity statin therapy in acute coronary syndrome patients produced significant cardiovascular benefit beyond statin monotherapy, with particularly robust effects in the diabetes subgroup. 1, 4

The Stepwise Algorithm After Maximal Statin

Step 1: Add Ezetimibe 10 mg Daily

• Provides 15-25% additional LDL-C reduction 2, 5
• Blocks intestinal cholesterol absorption via NPC1L1 protein 2
• Can be taken with or without food 2
• Reassess LDL-C in 4-12 weeks 3, 4

Step 2: If LDL-C Remains Above Target on Statin + Ezetimibe, Add Bempedoic Acid

• Bempedoic acid 180 mg daily provides an additional 15-25% LDL-C reduction 2
• The combination of ezetimibe + bempedoic acid achieves approximately 35-38% total LDL-C reduction 2
• Acts upstream of HMG-CoA reductase but is inactive in skeletal muscle, avoiding muscle-related adverse effects 2
• The CLEAR Outcomes trial showed 13% reduction in major adverse cardiovascular events in statin-intolerant patients, with 17% reduction in those with diabetes 2
• Monitor liver function tests when using bempedoic acid 2

Step 3: For Very High-Risk Patients Still Above Target, Add PCSK9 Inhibitor

• Reserve PCSK9 inhibitors (alirocumab, evolocumab, inclisiran) for very high-risk patients with LDL-C ≥70 mg/dL despite statin + ezetimibe ± bempedoic acid 1, 2
• PCSK9 inhibitors reduce LDL-C by approximately 50-60% 2, 6
• The 2018 ACC/AHA guidelines give a Class IIa recommendation for adding PCSK9 inhibitors in very high-risk ASCVD patients with LDL-C ≥70 mg/dL on maximally tolerated therapy 1
• Cost is significantly higher than ezetimibe or bempedoic acid, making them third-line 2, 3

Target LDL-C Goals by Risk Category

Very high-risk patients (recent MI, recurrent events, multivessel disease, diabetes with ASCVD): Target LDL-C <55 mg/dL with ≥50% reduction from baseline 2

High-risk patients (diabetes without complications, multiple risk factors): Target LDL-C <70 mg/dL 2, 4

Extremely high-risk patients (recurrent atherothrombotic events within 2 years despite optimal therapy): Consider target LDL-C <40 mg/dL 2

Critical Pitfalls to Avoid

Do not skip ezetimibe and go directly to PCSK9 inhibitors. Most patients achieve adequate LDL-C reduction with statin plus ezetimibe, making ezetimibe the cost-effective and evidence-based first choice. 3, 4 PCSK9 inhibitors should be reserved for very high-risk patients who fail combination therapy with statin + ezetimibe ± bempedoic acid. 2

Do not use bile acid sequestrants if triglycerides >300 mg/dL, as this can worsen hypertriglyceridemia. 1, 3 Bile acid sequestrants are generally less preferred due to gastrointestinal side effects, inconvenient dosing, and drug interactions. 1

When combining ezetimibe with bile acid sequestrants (if used), administer ezetimibe at least 2 hours before or 4 hours after the sequestrant to avoid binding. 2

Special Considerations

For patients on high-potency statins, ezetimibe addition produces the greatest LDL-C reductions because these patients have the lowest cholesterol synthesis markers and highest cholesterol absorption markers at baseline. 7 The high-potency statin group showed significantly greater LDL-C reductions with ezetimibe (-29.1%) compared to medium/low-potency groups (-25.0% and -22.7%). 7

Fixed-dose combination tablets of statin/ezetimibe produce greater LDL-C reduction (28.4%) compared to separate pills (19.4%), likely due to improved adherence. 8