What alternative lipid-lowering therapies can be considered for a patient with severe hypercholesterolemia who is not responding adequately to Repatha (evolocumab) and cannot tolerate statins?

Alternative Lipid-Lowering Therapies When Repatha Is Insufficient

Add bempedoic acid 180 mg daily to your current Repatha regimen, and if LDL-C targets remain unmet, add ezetimibe 10 mg daily to create a triple non-statin combination therapy. 1, 2

Understanding Your Current Situation

You are already on Repatha (evolocumab), a PCSK9 inhibitor that typically reduces LDL-C by approximately 50-60% 3, 1. If this is not achieving adequate cholesterol control and statins are not an option, you need additional non-statin therapies that work through different mechanisms.

Recommended Treatment Algorithm

First Addition: Bempedoic Acid

• Add bempedoic acid 180 mg daily to your current Repatha therapy 1, 2
• Bempedoic acid reduces LDL-C by an additional 15-25% and works upstream from statins in the liver, making it ideal for statin-intolerant patients 1, 4
• The CLEAR Outcomes trial demonstrated a 13% reduction in major adverse cardiovascular events in statin-intolerant patients 1
• Monitor liver function tests when starting bempedoic acid 1, 2

Second Addition: Ezetimibe

• If LDL-C targets are still not met after adding bempedoic acid, add ezetimibe 10 mg daily 1, 2, 4
• Ezetimibe reduces LDL-C by approximately 15-20% by blocking cholesterol absorption in the intestine 2, 4
• The combination of bempedoic acid plus ezetimibe provides approximately 35% LDL-C reduction 3, 1
• Triple therapy (Repatha + bempedoic acid + ezetimibe) achieves the greatest LDL-C reduction in statin-intolerant patients 2

Your LDL-C Targets Based on Risk

Very High-Risk Patients (established ASCVD, recurrent events, diabetes with complications)

• Target LDL-C <55 mg/dL with ≥50% reduction from baseline 1, 2, 4
• Secondary target: non-HDL-C <85 mg/dL 1, 2
• For patients with recurrent events within 2 years despite optimal therapy, consider targeting LDL-C <40 mg/dL 2

High-Risk Patients (diabetes without complications, multiple risk factors)

• Target LDL-C <70 mg/dL 1, 2, 4
• Secondary target: non-HDL-C <100 mg/dL 2

Alternative Options If Above Therapies Fail or Are Not Tolerated

Bile Acid Sequestrants (Third-Line)

• Consider colesevelam 3.8 g daily or cholestyramine only if triglycerides are <300 mg/dL and you cannot tolerate bempedoic acid 1, 2, 4
• These reduce LDL-C by approximately 15-30% but have significant gastrointestinal side effects 1, 5, 6
• Generally less preferred due to tolerability issues 1

For Severe Hypertriglyceridemia

• If triglycerides >500 mg/dL, add fenofibrate 160 mg daily to prevent acute pancreatitis 1, 2
• If triglycerides 135-499 mg/dL in high-risk patients, consider icosapent ethyl 2 grams twice daily 2

Monitoring Strategy

• Obtain lipid profile 4-8 weeks after initiating or changing therapy 1, 2
• Monitor LDL-C response every 3-6 months once on PCSK9 inhibitor 1
• Annual lipid monitoring once at goal 1
• Check liver enzymes (ALT/AST) at baseline when using bempedoic acid 2

Essential Lifestyle Modifications

Even with aggressive pharmacotherapy, lifestyle modifications remain critical:

• Reduce saturated fats to <7% of total calories 1, 2, 4
• Limit trans fatty acids to <1% of total calories 1, 2
• Restrict cholesterol to <200 mg/day 1, 2
• Daily physical activity (at least 30 minutes, 5-7 days per week) 1
• Target BMI 18.5-24.9 kg/m² 1

Critical Pitfalls to Avoid

• Don't assume Repatha has failed without checking adherence and proper injection technique 1
• Don't overlook secondary causes of hypercholesterolemia (poorly controlled diabetes, hypothyroidism, nephrotic syndrome, obstructive liver disease) 5
• Don't use fibrates if triglycerides are <500 mg/dL unless specifically for pancreatitis prevention 2
• Avoid all lipid-lowering drugs except bile acid sequestrants if pregnancy is planned, during pregnancy, or breastfeeding 1, 2

When to Refer to a Lipid Specialist

Refer immediately if: 1

• Baseline LDL-C ≥190 mg/dL not due to secondary causes
• Complex mixed dyslipidemia
• Severe hypertriglyceridemia
• Coronary artery calcium (CAC) score >1,000

Why This Approach Works

The combination of Repatha (PCSK9 inhibitor) + bempedoic acid + ezetimibe targets three different mechanisms of cholesterol metabolism: 7

1. Repatha increases LDL receptor availability by blocking PCSK9 3, 8
2. Bempedoic acid inhibits cholesterol synthesis in the liver upstream from statins 1, 4
3. Ezetimibe blocks cholesterol absorption in the intestine 2, 4

This triple non-statin combination provides the most potent LDL-C lowering available for statin-intolerant patients and has been shown to be well-tolerated with minimal muscle-related side effects 1, 2, 9.