Which PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor to add when Rosuvastatin (rosuvastatin) 40mg is not effectively lowering low-density lipoprotein (LDL) cholesterol?

From the Guidelines

If rosuvastatin 40mg is not adequately lowering LDL cholesterol, adding a PCSK9 inhibitor such as evolocumab (Repatha) would be the most effective option, as it has demonstrated safety, efficacy, and cardiovascular outcomes benefits in the FOURIER trial 1.

Key Considerations

• Evolocumab is usually given as 140mg every 2 weeks or 420mg monthly, and can lower LDL by an additional 50-70% 1.
• Before starting a PCSK9 inhibitor, you might consider adding ezetimibe 10mg daily as a less expensive first step, which can lower LDL by an additional 15-20% 1.
• PCSK9 inhibitors work by preventing the degradation of LDL receptors on liver cells, allowing more receptors to remain available to remove LDL from the bloodstream.
• These medications are generally well-tolerated with injection site reactions being the most common side effect.
• Insurance coverage can be challenging for PCSK9 inhibitors, so prior authorization will likely be required, and documentation of inadequate response to maximum statin therapy is typically necessary.

Additional Options

• Alirocumab (Praluent) is another PCSK9 inhibitor that can be considered, typically started at 75mg every 2 weeks and can be increased to 150mg if needed 1.
• Inclisiran may be considered in patients with demonstrated poor adherence to PCSK9 mAbs or those who may be unable to self-inject 1.

Clinical Decision Making

• The decision to add a PCSK9 inhibitor should be made after a clinician-patient discussion about the net benefit, safety, and cost 1.
• Referral to a lipid specialist may be necessary if the patient has a continued <50% reduction in LDL-C or LDL-C ≥70 mg/dL (or non–HDL-C ≥100 mg/dL) on maximally tolerated statin therapy with or without ezetimibe and/or bempedoic acid 1.

From the FDA Drug Label

To reduce the risk of major adverse cardiovascular (CV) events (CV death, myocardial infarction, stroke, unstable angina requiring hospitalization, or coronary revascularization) in adults with established cardiovascular disease as an adjunct to diet, alone or in combination with other low-density lipoprotein cholesterol (LDL-C)-lowering therapies, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce LDL-C The recommended dosage of REPATHA is either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously.

When Rosuvastatin 40mg is not effectively lowering low-density lipoprotein (LDL) cholesterol, Evolocumab (REPATHA) can be added as an adjunct to diet and other LDL-C-lowering therapies to reduce LDL-C. The recommended dosage is either 140 mg every 2 weeks or 420 mg once monthly administered subcutaneously 2.

From the Research

PCSK9 Inhibitors for LDL-Cholesterol Reduction

When Rosuvastatin 40mg is not effectively lowering low-density lipoprotein (LDL) cholesterol, adding a PCSK9 inhibitor can be considered. The following options are available:

• Alirocumab: a study 3 compared the efficacy of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients. The results showed that adding alirocumab to rosuvastatin provided incremental LDL-C lowering versus adding ezetimibe or doubling the rosuvastatin dose.
• Evolocumab: a study 4 compared the efficacy and safety of evolocumab and ezetimibe for atherogenic lipid reduction in four patient populations. The results showed that evolocumab reduced LDL-C by a mean 55-61% from baseline to week 12, while ezetimibe lowered LDL-C by 18-20% from baseline.

Comparison of PCSK9 Inhibitors and Ezetimibe

The following points compare the efficacy of PCSK9 inhibitors and ezetimibe:

• A study 4 showed that evolocumab outperformed ezetimibe in efficacy and lipid goal attainment.
• A study 3 showed that adding alirocumab to rosuvastatin provided greater LDL-C reductions compared to adding ezetimibe.
• A review 5 summarized the safety of statin alternatives, including PCSK9 inhibitors and ezetimibe, and found that they have an excellent safety profile.

Considerations for Choosing a PCSK9 Inhibitor

The following points should be considered when choosing a PCSK9 inhibitor:

• Efficacy: PCSK9 inhibitors have been shown to be more effective than ezetimibe in reducing LDL-C levels 3, 4.
• Safety: PCSK9 inhibitors have an excellent safety profile, with a low risk of adverse events 5.
• Cost and availability: the cost and availability of PCSK9 inhibitors may vary, and should be considered when making a decision.