Can Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors be used with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins)?

PCSK9 Inhibitors Can Be Used with Statins

Yes, PCSK9 inhibitors can be used in combination with statins and are specifically indicated as add-on therapy to maximally tolerated statin therapy in patients who require additional LDL-cholesterol reduction. 1, 2

Mechanism and Efficacy of Combination Therapy

PCSK9 inhibitors work synergistically with statins by:

• Binding to PCSK9 protein in the bloodstream, preventing it from binding to LDL receptors
• Preserving LDL receptors on liver cells, enhancing clearance of LDL cholesterol
• Providing additional 50-60% LDL-C reduction beyond what statins alone can achieve 3, 4

This complementary mechanism is particularly valuable because statin therapy actually increases PCSK9 levels through negative feedback, which can limit statin efficacy over time 5.

FDA-Approved Indications for Combination Therapy

Both FDA-approved PCSK9 inhibitors are specifically indicated for use with statins:

• Alirocumab (Praluent): "As adjunct to diet, alone or in combination with other LDL-C-lowering therapies, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia, to reduce LDL-C" 1

• Evolocumab (Repatha): "As an adjunct to diet, alone or in combination with other LDL-C-lowering therapies, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia, to reduce LDL-C" 2

Clinical Scenarios for Adding PCSK9 Inhibitors to Statins

According to current guidelines, PCSK9 inhibitors should be added to statin therapy in the following situations:

1. Secondary Prevention (Established ASCVD)

• For very high-risk patients with established ASCVD who don't achieve LDL-C goal <55 mg/dL (<1.4 mmol/L) despite maximum tolerated statin plus ezetimibe 6
• Class I recommendation (strong) for secondary prevention 6

2. Primary Prevention (High-Risk Without ASCVD)

• For patients with heterozygous familial hypercholesterolemia (HeFH) with substantially elevated LDL-C despite maximum tolerated statin plus ezetimibe 6
• Class IIb recommendation (weaker) for primary prevention 6

3. Statin Intolerance

• For patients who cannot tolerate appropriate doses of at least three statins but require LDL-C reduction 6

Clinical Outcomes of Combination Therapy

The FOURIER trial demonstrated that adding evolocumab to statin therapy:

• Reduced LDL-C by 59% from a median of 92 to 30 mg/dL
• Significantly reduced cardiovascular events in high-risk patients with ASCVD 6

Similarly, the ODYSSEY OUTCOMES trial showed that adding alirocumab to maximally tolerated statin therapy:

• Reduced the composite primary endpoint (death from CHD, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) by 15% (HR 0.85) 6

Safety Considerations

The combination of PCSK9 inhibitors with statins appears to be well-tolerated:

• No significant increase in muscle-related adverse events compared to statin monotherapy
• No excess adverse events observed in patients achieving very low LDL-C levels (<25 mg/dL) 6
• Common side effects include injection site reactions and influenza-like symptoms 1, 2

Treatment Algorithm

1. Start with maximally tolerated high-intensity statin therapy (e.g., atorvastatin 40-80 mg or rosuvastatin 20-40 mg)
2. Assess LDL-C response after 4-12 weeks
3. If LDL-C remains above target:
   • For very high-risk ASCVD: LDL-C ≥55 mg/dL
   • For FH without ASCVD: LDL-C ≥100 mg/dL (2.6 mmol/L)
4. Add ezetimibe and reassess in 4-12 weeks
5. If LDL-C still remains above target despite statin + ezetimibe:
   • Consider adding PCSK9 inhibitor (evolocumab or alirocumab)
   • Evolocumab: 140 mg every 2 weeks or 420 mg monthly
   • Alirocumab: 75-150 mg every 2 weeks or 300 mg monthly 6

Key Considerations for Optimal Use

• Assess LDL-C levels 4-12 weeks after initiating PCSK9 inhibitor therapy to evaluate response
• For patients receiving alirocumab 300 mg every 4 weeks, measure LDL-C just prior to the next scheduled dose 1
• Rotate injection sites between thigh, abdomen, and upper arm areas
• PCSK9 inhibitors can be used in patients undergoing LDL apheresis 2

In summary, PCSK9 inhibitors are specifically designed and FDA-approved to be used in combination with statins, providing substantial additional LDL-C lowering and cardiovascular risk reduction in high-risk patients who cannot achieve target LDL-C levels on statin therapy alone.