What is the recommended PSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) inhibitor and dosing regimen for reducing LDL (Low-Density Lipoprotein) cholesterol levels?

From the Guidelines

The recommended PSK9 inhibitors for reducing LDL cholesterol are evolocumab (Repatha) and alirocumab (Praluent), with evolocumab typically administered as a 140 mg subcutaneous injection every two weeks or 420 mg once monthly, and alirocumab given as 75 mg or 150 mg subcutaneous injection every two weeks, with the option to increase to 150 mg if needed, as supported by the most recent evidence from 1.

Key Points

• These medications are generally prescribed for patients with familial hypercholesterolemia, established atherosclerotic cardiovascular disease, or those who cannot achieve adequate LDL reduction with maximum tolerated statin therapy.
• PCSK9 inhibitors work by blocking the PCSK9 protein that normally binds to LDL receptors, preventing their degradation and allowing more receptors to remain on liver cells to remove LDL from the bloodstream, as described in 1.
• This mechanism can reduce LDL cholesterol by 50-70%, with evidence from 1 showing a 59% reduction in LDL cholesterol from a median of 92 to 30 mg/dL in the treatment arm.
• Side effects are generally mild and include injection site reactions and flu-like symptoms, as noted in 1.
• These medications should be used in conjunction with a heart-healthy diet, regular exercise, and other lipid-lowering medications as prescribed, with regular lipid panel monitoring recommended to assess treatment efficacy, as suggested in 1.

Considerations

• The choice between evolocumab and alirocumab should be based on individual patient factors, including tolerance, cost, and administration preferences, as discussed in 1.
• Inclisiran, a siRNA PCSK9 inhibitor, may be considered in patients with demonstrated poor adherence to PCSK9 mAbs or adverse effects from both PSCK9 mAbs, as mentioned in 1.
• Combination therapy with a PSCK9 mAb and inclisiran is not recommended, as there is currently no evidence for additional efficacy in LDL-C lowering or cardiovascular outcomes benefit, as stated in 1.

From the FDA Drug Label

To reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease. As 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. PRALUENT 75 mg or placebo once every two weeks. At month 2, if additional LDL-C lowering was required based on pre-specified LDL-C criteria (LDL-C ≥50 mg/dL), PRALUENT was adjusted to 150 mg every 2 weeks

The recommended PSK9 inhibitor is alirocumab (PRALUENT). The dosing regimen for reducing LDL cholesterol levels is:

• 75 mg every 2 weeks
• Adjusted to 150 mg every 2 weeks if additional LDL-C lowering is required based on pre-specified LDL-C criteria (LDL-C ≥50 mg/dL) 2 Key points:
• Indications: Reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease
• Adjunct therapy: To diet, alone or in combination with other LDL-C-lowering therapies, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH) 2

From the Research

PSK9 Inhibitors for Reducing LDL Cholesterol Levels

• PSK9 inhibitors, such as evolocumab and alirocumab, are effective in reducing low-density lipoprotein (LDL) cholesterol levels by approximately 60% 3, 4.
• These inhibitors work by blocking the action of proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that helps remove LDL receptors from the liver, leading to increased LDL cholesterol levels in the blood.

Recommended PSK9 Inhibitor and Dosing Regimen

• Evolocumab is recommended at a dose of 140 mg every 2 weeks or 420 mg monthly, administered subcutaneously 3, 4.
• Alirocumab is recommended at a dose of 75 mg to 150 mg subcutaneously every 2 weeks 5.

Efficacy and Safety of PSK9 Inhibitors

• PSK9 inhibitors have been shown to significantly reduce the risk of cardiovascular events, including cardiovascular death, myocardial infarction, and stroke 3, 4.
• The most common adverse events associated with PSK9 inhibitors are injection-site reactions, which are generally mild and transient 3, 4.
• PSK9 inhibitors are generally well-tolerated and have a benign side-effect profile, making them a suitable option for patients who are intolerant of statins 6, 7.

Comparison of PSK9 Inhibitors

• Both evolocumab and alirocumab have been shown to be effective in reducing LDL cholesterol levels and cardiovascular risk 3, 4, 5.
• The choice of PSK9 inhibitor may depend on individual patient factors, such as dosing regimen and potential side effects 5.
• Further research is needed to fully compare the efficacy and safety of different PSK9 inhibitors and to determine their optimal use in clinical practice 5, 6, 7.