What infusions can be used to augment statin therapy for additional lipid-lowering?

From the Guidelines

PCSK9 inhibitors, including evolocumab and alirocumab, are the most commonly used infusion therapies to augment statin therapy for additional lipid-lowering effects, typically administered subcutaneously every 2-4 weeks. These therapies work through different mechanisms than statins, preventing LDL receptor degradation and allowing more LDL cholesterol to be removed from circulation. According to the most recent study 1, placebo-controlled trials evaluating the addition of PCSK9 inhibitors to maximally tolerated doses of statin therapy demonstrated an average reduction in LDL cholesterol ranging from 36% to 59%.

Key points to consider when using these therapies include:

• They are typically reserved for patients with very high cardiovascular risk, those with familial hypercholesterolemia, or individuals who cannot achieve target LDL levels with maximum tolerated statin therapy plus ezetimibe.
• Side effects are generally mild, with injection site reactions being most common for the PCSK9 inhibitors.
• Other options, such as evinacumab for patients with homozygous familial hypercholesterolemia, may be considered in specialized cases.
• The choice of therapy should be based on individual patient needs and risk factors, as well as the potential for adverse effects and interactions with other medications.

As noted in the 2022 study 1, the effects of PCSK9 inhibition on ASCVD outcomes were investigated in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, which demonstrated a significant reduction in LDL cholesterol and major adverse cardiovascular events with evolocumab therapy. Similarly, the 2022 ACC expert consensus decision pathway 1 recommends the use of nonstatin therapies, including PCSK9 inhibitors, for patients with ASCVD or familial hypercholesterolemia who require additional lowering of LDL cholesterol.

From the FDA Drug Label

In combination with a statin, or alone when additional low-density lipoprotein cholesterol (LDL-C) lowering therapy is not possible, as an adjunct to diet to reduce elevated LDL-C in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH) The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was −71% (95% CI: −74%, −67%; p < 0.0001) and −63% (95% CI: −68%, −57%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively.

Infusions to Augment Statin Therapy:

• Evolocumab (IV): can be used to augment statin therapy for additional lipid-lowering, with a mean percent change in LDL-C from baseline to Week 12 of −71% (95% CI: −74%, −67%; p < 0.0001) and −63% (95% CI: −68%, −57%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively 2.
• Ezetimibe (PO): can be used in combination with a statin to reduce elevated LDL-C levels, but it is not an infusion 3.

From the Research

Infusions to Augment Statin Therapy

To augment statin therapy for additional lipid-lowering, several infusions can be considered:

• PCSK9 inhibitors, such as alirocumab and evolocumab, which have been shown to reduce LDL-C levels by up to 60% when used in combination with statins 4, 5, 6, 7
• Ezetimibe, a cholesterol absorption inhibitor, which can lead to additional LDL-C reduction and decreased ASCVD risk when added to statin therapy 5, 8

Mechanism of Action

The mechanism of action of these infusions involves:

• PCSK9 inhibitors: binding to and inhibiting the PCSK9 enzyme, which plays a key role in lipoprotein metabolism, leading to increased LDL-receptor expression and enhanced LDL-C clearance 4, 7
• Ezetimibe: inhibiting the intestinal absorption of cholesterol, leading to a decrease in the amount of cholesterol available for incorporation into LDL particles 5

Clinical Evidence

Clinical trials have demonstrated the efficacy and safety of these infusions in reducing LDL-C levels and ASCVD risk:

• PCSK9 inhibitors: have been shown to reduce LDL-C levels by 54-74% versus placebo and 26-46% versus ezetimibe, with a significant reduction in ASCVD events 6, 7
• Ezetimibe: has been shown to reduce LDL-C levels and ASCVD risk when added to statin therapy, with a significant reduction in major vascular events 5, 8

Safety and Tolerability

The safety and tolerability of these infusions have been evaluated in clinical trials:

• PCSK9 inhibitors: have been shown to be generally well-tolerated, with a low incidence of adverse events, although injection site reactions have been reported 4, 7
• Ezetimibe: has been shown to be safe and well-tolerated, with a low incidence of adverse events 5, 8