Can a Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitor be used in patients intolerant to HMG-CoA reductase inhibitors (statins)?

From the Guidelines

PCSK9 inhibitors can be used in statin-intolerant patients as an effective alternative for lowering LDL cholesterol, as evidenced by the ODYSSEY ALTERNATIVE trial, which demonstrated the efficacy and safety of alirocumab in this population 1. The use of PCSK9 inhibitors, such as alirocumab and evolocumab, has been studied in patients with primary hypercholesterolemia and moderate, high, or very high cardiovascular risk who are intolerant to statins.

• The ODYSSEY ALTERNATIVE trial compared the LDL cholesterol–lowering efficacy of alirocumab with ezetimibe and the safety of each treatment compared with a statin rechallenge arm with 20 mg atorvastatin in 314 individuals with primary hypercholesterolemia and statin intolerance 1.
• The trial found that alirocumab lowered LDL cholesterol levels by 54.8% compared with 20.1% with ezetimibe, with similar rates of any adverse event for all treatments, but fewer events that led to treatment discontinuation for alirocumab 1.
• The study also found that individuals who received alirocumab had fewer skeletal muscle–related adverse events compared with those who received ezetimibe or atorvastatin 1.
• The open-label extension phase of the trial demonstrated that LDL cholesterol reductions of more than 50% were either achieved or maintained for the 281 individuals who either continued with or switched to alirocumab for the extension phase, and these reductions were sustained throughout the treatment period 1. The PCSK9 inhibitors, alirocumab and evolocumab, are typically administered as subcutaneous injections every 2-4 weeks, with dosages of 75-150 mg every 2 weeks or 300 mg monthly for alirocumab.
• These medications work by blocking the PCSK9 protein, which normally binds to LDL receptors and leads to their degradation, resulting in significant LDL reductions of 50-60% 1.
• While generally well-tolerated, with injection site reactions being the most common side effect, these medications are considerably more expensive than statins, which may affect accessibility depending on insurance coverage.

From the FDA Drug Label

To reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease (1) 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. (1)

Yes, a PCSK9 inhibitor can be used in statin intolerant patients as an adjunct to diet, alone or in combination with other LDL-C-lowering therapies. 2

From the Research

Use of PSK9 Inhibitors in Statin-Intolerant Patients

• PSK9 inhibitors can be used as an alternative treatment option for statin-intolerant patients, as they have been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) levels 3, 4, 5.
• Studies have demonstrated that PSK9 inhibitors, such as alirocumab and evolocumab, can achieve LDL-C reductions of 50% to 70% in statin-intolerant patients, while maintaining a favorable safety profile 3, 6.
• The efficacy and safety of PSK9 inhibitors have been confirmed in statin-intolerant patients, making them an attractive treatment option for this challenging clinical setting 3, 4.

Benefits of PSK9 Inhibitors

• PSK9 inhibitors have been shown to provide significant reductions in LDL-C levels, regress atherosclerosis, and lower the risk of major adverse cardiovascular events (MACE) 5.
• They have a benign side-effect profile and are generally well-tolerated, making them a suitable option for statin-intolerant patients 5.
• PSK9 inhibitors can be used in combination with other non-statin therapies, such as ezetimibe and bempedoic acid, to synergistically lower LDL-C levels and reduce the risk of MACE 5.

Clinical Evidence

• Multiple phase II and III studies have demonstrated the efficacy and safety of PSK9 inhibitors, such as alirocumab and evolocumab, in reducing LDL-C levels and ASCVD events 6, 7.
• Randomized controlled clinical trials have shown that PSK9 inhibitors reduce ASCVD events when used in combination with statin therapy compared to statin alone 7.
• The 2018 Cholesterol Guideline incorporated PSK9 inhibitors into the treatment algorithm for select secondary prevention patients unable to achieve an LDL-C below 70 mg/dL despite maximally tolerated statin plus ezetimibe 7.