Next Step: Add a PCSK9 Inhibitor to Your Current Regimen
If your LDL cholesterol remains ≥70 mg/dL (1.8 mmol/L) on maximally tolerated statin plus ezetimibe therapy, adding a PCSK9 inhibitor (evolocumab or alirocumab) is the recommended next step. 1
Risk Assessment and Treatment Targets
Your current combination of statin and ezetimibe suggests you are either:
- Very high-risk patient (established atherosclerotic cardiovascular disease): Target LDL-C <70 mg/dL with ≥50% reduction from baseline 1
- High-risk patient with diabetes: Target LDL-C <70 mg/dL if 10-year ASCVD risk ≥20% or very high-risk features present 1
Algorithmic Treatment Approach
Step 1: Verify Current Therapy is Optimized
- Confirm you are on maximally tolerated statin dose (high-intensity preferred for very high-risk patients) 1
- Confirm ezetimibe 10 mg daily is being taken consistently 1
- Assess medication adherence and lifestyle modifications 1, 2
- Check lipid panel to document current LDL-C level 1
Step 2: Add PCSK9 Inhibitor if LDL-C Goals Not Met
PCSK9 inhibitors are indicated when:
- LDL-C remains ≥70 mg/dL on statin plus ezetimibe in very high-risk patients 1
- LDL-C remains ≥100 mg/dL on statin plus ezetimibe in some high-risk scenarios 1
Expected additional LDL-C reduction: 50-60% beyond statin-ezetimibe combination 2, 1
Options include:
- Evolocumab 140 mg subcutaneously every 2 weeks 2
- Alirocumab 75-150 mg subcutaneously every 2 weeks 1
- Inclisiran 284 mg subcutaneously every 6 months (after initial dosing) 1
Step 3: Alternative Considerations
If PCSK9 inhibitors are not accessible due to cost or availability:
- Consider bempedoic acid as an additional agent, particularly if you have statin-associated muscle symptoms 1
- Bempedoic acid provides modest additional LDL-C lowering (15-25%) 1
- Note: At the time of the 2022 ACC guidelines, cardiovascular outcomes data for bempedoic acid was pending 1
If triglycerides are <300 mg/dL:
- Bile acid sequestrants may be considered as an alternative if ezetimibe-intolerant, though less commonly used 1
Important Clinical Considerations
Monitoring Requirements
- Obtain lipid panel 4-12 weeks after adding any new therapy 1
- Monitor liver enzymes (AST/ALT) as clinically indicated 3
- Assess for muscle symptoms at each visit 3
- Continue annual lipid monitoring once LDL-C goal achieved 1
Safety Profile
- PCSK9 inhibitors are generally well-tolerated with low rates of adverse effects 1
- Ezetimibe plus statin combination has similar safety profile to statin monotherapy 4, 5
- Risk of myopathy/rhabdomyolysis remains low but monitor for unexplained muscle pain, weakness, or fatigue 3
Special Populations
If you have diabetes:
- High-intensity statin therapy is preferred if you have established ASCVD or multiple risk factors 1
- Ezetimibe addition is reasonable if LDL-C ≥70 mg/dL on maximally tolerated statin 1
If you are >75 years old:
- Continue current statin-ezetimibe therapy if already established 1
- PCSK9 inhibitor addition follows same criteria but requires careful risk-benefit discussion 1
Common Pitfalls to Avoid
- Don't assume treatment failure without checking adherence first - non-adherence is a common cause of inadequate LDL-C response 2
- Don't delay PCSK9 inhibitor addition in very high-risk patients - the absolute benefit is greatest in those at highest risk 1
- Don't forget to continue lifestyle modifications - diet, exercise, and weight management remain essential adjuncts 1, 2
- Don't overlook secondary causes of hyperlipidemia - hypothyroidism, nephrotic syndrome, or other conditions may need treatment 1
Cost Considerations
Ezetimibe is preferred as the first add-on to statins due to lower cost (generic availability), proven cardiovascular outcomes benefit, and ease of use as a once-daily oral medication 1. PCSK9 inhibitors, while highly effective, are significantly more expensive but provide substantial additional LDL-C lowering when needed 1.