What alternative injections are recommended for individuals with statin (HMG-CoA reductase inhibitors) intolerance who require cholesterol management?

From the Guidelines

For individuals with statin intolerance who require cholesterol management, PCSK9 inhibitors like alirocumab are recommended as an alternative injectable option, given their ability to lower LDL cholesterol levels by 54.8% compared to ezetimibe, as demonstrated in the ODYSSEY ALTERNATIVE trial 1.

Key Points to Consider

• The ODYSSEY ALTERNATIVE trial showed that alirocumab had a higher LDL cholesterol–lowering efficacy compared to ezetimibe, with a reduction of 54.8% versus 20.1% respectively 1.
• Alirocumab also had fewer skeletal muscle–related adverse events and fewer events leading to treatment discontinuation compared to ezetimibe and atorvastatin 1.
• The use of PCSK9 inhibitors like alirocumab can be particularly beneficial for patients with statin intolerance, as they provide a mechanism to lower LDL cholesterol levels without the need for statins.
• These medications are typically administered as subcutaneous injections, with alirocumab given as 75-150 mg every 2 weeks, and can be used alongside other cholesterol-lowering approaches such as diet and exercise.

Mechanism and Efficacy

• PCSK9 inhibitors work by increasing the liver's ability to remove LDL cholesterol from the bloodstream, providing a different mechanism of action compared to statins.
• The ODYSSEY ALTERNATIVE trial demonstrated the efficacy and safety of alirocumab in individuals with primary hypercholesterolemia and statin intolerance, with sustained LDL cholesterol reductions of more than 50% over a 3-year treatment period 1.
• The use of alirocumab can help reduce the risk of cardiovascular events in individuals with statin intolerance, particularly those with established cardiovascular disease or familial hypercholesterolemia.

From the FDA Drug Label

Ezetimibe Tablet + all doses of lovastatin pooled (10-40 mg) significantly reduced total-C, LDL-C, Apo B, and non-HDL-C compared to all doses of lovastatin pooled (10-40 mg) Ezetimibe Tablet coadministered with fenofibrate significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to fenofibrate administered alone The effects of ezetimibe tablet coadministered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in males and females with HeFH. Ezetimibe tablet, administered with atorvastatin or simvastatin (40- and 80-mg statin groups, pooled), significantly reduced LDL-C (21%) compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg (7%).

Alternative injections for statin intolerance are not directly mentioned in the provided drug label. However, the label discusses the use of ezetimibe in combination with other cholesterol-lowering medications, including fenofibrate and bile-acid-binding resins, as an alternative to statin monotherapy.

• Ezetimibe can be used in combination with fenofibrate or bile-acid-binding resins to lower cholesterol levels.
• Ezetimibe can also be used in combination with a low-dose statin to minimize the risk of statin intolerance. 2

From the Research

Alternative Injections for Statin Intolerance

• For individuals with statin intolerance, alternative injections recommended for cholesterol management include:
  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, such as alirocumab and evolocumab, which have been shown to achieve significant reductions in low-density lipoprotein (LDL) cholesterol levels 3, 4, 5, 6, 7
  • PCSK9 inhibitors have been found to be effective in reducing LDL cholesterol levels by 50-70% across various patient populations and background lipid-lowering therapies, while maintaining a favorable safety profile 3
  • Ezetimibe, a cholesterol absorption inhibitor, can also be used in combination with statin therapy to achieve additional LDL cholesterol reduction and reduce cardiovascular risk 4, 5, 7
  • Bempedoic acid, which reduces hepatic cholesterol synthesis, is another alternative that has been shown to be effective in lowering LDL-C levels and reducing the risk of major adverse cardiovascular events (MACE) 5, 6

Safety and Efficacy

• The safety and efficacy of these alternative injections have been evaluated in several studies, with results indicating that they are generally well-tolerated and effective in reducing LDL cholesterol levels and cardiovascular risk 3, 4, 5, 6, 7
• PCSK9 inhibitors have been associated with a small increase in injection site reactions, but these are usually mild or moderate in intensity 6
• Bempedoic acid has been associated with a small increase in plasma uric acid and slightly increased frequency of episodes of gout in susceptible subjects 6