An Overview of the National Lipid Association’s New Recommendations for Managing Statin Intolerance

Cardiovascular disease (CVD) is the leading cause of death in the United States.¹ Statin medications have been effective in lowering this risk by their ability to reduce atherogenic lipoprotein levels.

However, approximately 5%-30% of statin users encounter statin intolerance, which contributes to challenges in adequately reducing atherosclerotic CVD (ASCVD) risk. The National Lipid Association (NLA) released a new statin intolerance statement in June 2022, which is an update of the previous guidance published in 2014.^2,3

According to the most recent update, statin intolerance is defined as the condition of experiencing adverse effects (AEs) from at least 2 statin medications that can be improved by either discontinuing or reducing the dose of the statin. One of these statins must have been taken at the lowest approved daily dose.² Statin users may experience either complete intolerance to any statin dose or regimen or partial intolerance toward the required statin dose.²

The new definition emphasizes the AEs correlated with statins that lead to statin intolerance. This rare clinical syndrome can impact patients on statin therapy and lead to adherence difficulties and, ultimately, discontinuation of therapy.

Statin intolerance has been known to be mainly driven by statin-associated muscle symptoms (SAMS). Myalgias are the most common AEs experienced by statin users, followed by myopathy and rhabdomyolysis. Some less common AEs of statins include elevated transaminase levels, increased blood glucose levels, confusion, and memory loss.²

The new guidance also recognizes the exclusion criteria, mentioned in the previous definition, as modifiable risk factors that are linked to statin intolerance. These should be assessed when patients begin treatment with statins and when statin intolerance is identified.²

These modifiable risk factors include:

• Alcohol use
• Diabetes
• Drug-drug interactions involving gemfibrozil, protease inhibitors, amiodarone, calcium channel blockers, azole antifungals, macrolides, immunosuppressants, colchicine
• Hypothyroidism
• Obesity
• Strenuous exercise
• Vitamin D deficiency

Statin intolerance may be resolved by making changes in dose, dosing regimen, or switching to a different statin to improve tolerance; however, these changes may not be sufficient for all patients. If patients are unable to achieve tolerance despite therapy changes and addressing modifiable risk factors, or if a maximally tolerated statin with lifestyle changes fails to reduce atherogenic lipoproteins, additional options to consider include non-statin medications.²

Non-statin medications are selected based on randomized trials showing efficacy in lowering ASCVD risk. Patients who have a high or very high risk for ASCVD must be on a non-statin therapy while finding a tolerable statin to prevent fluctuations in atherogenic lipoprotein levels.

Non-statin therapy is recommended for patients who experience complete or partial statin intolerance.² The following are non-statin therapy options:

• ATP citrate lyase inhibitor
• Bile acid sequestrants
• Cholesterol absorption inhibitor
• Fibrates
• Omega-3 fatty acid
• PCSK9-targeting agents

Bempedoic acid is an ATP citrate lyase inhibitor that reduces low-density lipoprotein cholesterol (LDL-C) levels by 13%-25% and can be added with ezetimibe for a 38% reduction. There are currently no studies that found cardiovascular outcomes with bempedoic acid therapy. A favorable aspect of this drug is that as a prodrug, there is a lower occurrence of muscle-related AEs due to its activated state in the liver.²

The bile acid sequestrants cholestyramine, colestipol, and colesevelam can reduce LDL-C by 13%-25%. Although data supporting cardiovascular outcomes are lacking, the LRC-CPPT study observed patients with hypercholesterolemia taking either cholestyramine or placebo and found a 19% reduction in CVD.⁴

Ezetimibe is a cholesterol absorption inhibitor that is efficient in reducing LDL-C by 15%-20% when taken alone and has additive reductions by 20%-25% when taken with a statin. In the IMPROVE-IT study, participants who had acute coronary syndrome took either ezetimibe 10 mg plus simvastatin 40 mg or simvastatin 40 mg alone. The group who took the additional ezetimibe was found to have a 6% reduction in cardiovascular events for 7 years.⁵

Fibrates include fenofibrate, fenofibric acid, and gemfibrozil, but studies measuring cardiovascular outcomes have not been reliable due to mixed data results.²

Icosapent ethyl is an omega-3 fatty acid that can be used for secondary prevention of ASCVD. The REDUCE-IT study included participants who took a statin along with icosapent ethyl and concluded that although icosapent ethyl has some impact in reducing ASCVD risk, it is likely not solely responsible for the improved cardiovascular outcomes as other factors may have played a role.⁶

PCSK9 inhibitors include monoclonal antibodies and a small interfering RNA (siRNA) agent. Evolocumab and alirocumab are monoclonal antibodies and are the only PCSK9 inhibitorsthat have been tested to lower ASCVD risk.

Inclisiran is a newer option that is an siRNA agent also in this class, but it has not been studied to produce cardiovascular outcomes. When used alone, a PCSK9 inhibitor can reduce LDL-C by 20%-25% and when combined with a statin by 50%-60%.

Studies on the monoclonal antibodies included patients with ASCVD and showed a 15% reduction in cardiovascular events. The literature has not tested evolocumab or alirocumab as monotherapy for reducing ASCVD risk.²

Final selection of an agent is individualized based on patient preference, ASCVD risk, benefits, AE profile, and cost determined by patient and provider discussion. The available non-statin therapies give prescribers different avenues to reduce ASCVD risk in patients with statin intolerance.

Pharmacists have a key role in monitoring patients on statin therapy and identifying statin intolerance. Pharmacists can help patients by suggesting strategies to overcome statin intolerance, such as addressing modifiable risk factors, and also by recommending these patients to consider non-statin therapies when appropriate.

References

1. FASTSTATS - leading causes of death. Centers for Disease Control and Prevention.Published January 13, 2022. Accessed July 1, 2022.https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm
2. Cheeley M, Saseen J, Agarwala A et al. NLA scientific statement on statin intolerance: a new definition and key considerations for ASCVD risk reduction in the statin intolerant patient. J Clin Lipidol. Published online June 9, 2022. doi:10.1016/j.jacl.2022.05.068
3. Association NL. NLA release: Scientific statement on statin intolerance: A new definition and key considerations for ASCVD risk reduction in the statin intolerant patient. National Lipid Association Online. Accessed July 1, 2022.https://www.lipid.org/node/2836
4. Rifkind BM. Lipid Research Clinics Coronary Primary Prevention Trial: results and implications. The American Journal of Cardiology. 1984;54(5):30-34. doi:10.1016/0002-9149(84)90854-3
5. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397. doi:10.1056/nejmoa1410489
6. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. doi:10.1056/nejmoa1812792