Cardiometabolic Chronicle

Addressing Statin Intolerance In Practice: Moving Beyond the Controversy

Low-density lipoprotein cholesterol (LDL-C) has been shown to be atherogenic and likely have a causal relationship for the development of atherosclerotic cardiovascular disease (ASCVD).1 Thus, reducing LDL-C levels is imperative in decreasing the impacts of ASCVD, as demonstrated in several studies.2 Since their introduction more than 30 years ago, statins, along with lifestyle modifications, have been the treatment of choice in lowering cholesterol. They decrease cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), a rate-limiting step in cholesterol synthesis.3 Multiple large outcomes trials have demonstrated the efficacy of statins in not only lowering LDL-C but more importantly, reducing major adverse cardiovascular events both in the primary and secondary prevention of ASCVD.4 Given the strength of evidence and the cost-effectiveness, statins remain the first-line treatment of patients with elevated LDL-C, which was also highlighted in the updated 2018 AHA/ACC cholesterol guidelines.2

However, a large gap remains between guideline recommendations and use of statins in actual practice, with studies showing that a large number of eligible patients are not on statin therapy, or are not adherent to therapy.5-9 This includes patients at high-risk for primary or secondary events, including patients with diabetes or cardiometabolic risk, and statin underutilization and non-adherence can increase ASCVD morbidity and mortality.8 Even when patients are initiated on statins, many discontinue statin therapy within the year of starting it.6 Real-world studies have shown that less than 40% of patients persist in taking statins for primary prevention at the 3-year post-initiation mark, while these number is only 45% for secondary prevention.8 One of the many reasons that lead to discontinuation of statin therapy can be statin intolerance, which is most frequently attributed to muscle-related adverse events.10 Often patients will discontinue statins without consulting their physician, which increases their cardiovascular risk.10



  1. Ference, Brian A., et al. “Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.” European Heart Journal 38.32 (2017): 2459-2472.
  2. Grundy, Scott M., et al. “2018 AHA/ACC/AACVPR/ AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/ PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.” Journal of the American College of Cardiology (2018): 25709.
  3. Istvan, Eva S., and Johann Deisenhofer. “Structural mechanism for statin inhibition of HMG-CoA reductase.” Science 292.5519 (2001): 1160-1164.
  4. Baigent, C., et al. “Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.” (2010): 1670-1681.
  5. Bradley, Corey K., et al. “Patient-reported reasons for declining or discontinuing statin therapy: insights from the PALM registry.” Journal of the American Heart Association 8.7 (2019): e011765.
  6. Brinton, Eliot A. “Understanding Patient Adherence and Concerns with STatins and MedicatION Discussions With Physicians (ACTION): A survey on the patient perspective of dialogue with healthcare providers regarding statin therapy.” Clinical Cardiology 41.6 (2018): 710-720.
  7. McClellan, Mark, et al. “Call to Action: Urgent Challenges in Cardiovascular Disease: A Presidential Advisory From the American Heart Association.” Circulation 139.9 (2019): e44-e54.
  8. Spence, J. David, and George K. Dresser. “Overcoming challenges with statin therapy.” Journal of the American Heart Association 5.1 (2016): e002497.
  9. Ueda, Peter, et al. “Treatment gaps and potential cardiovascular risk reduction from expanded statin use in the US and England.” PloS One 13.3 (2018): e0190688.
  10. Toth, Peter P., et al. “Management of statin intolerance in 2018: still more questions than answers.” American Journal of Cardiovascular Drugs 18.3 (2018): 157-173.
  11. Bruckert, Eric, et al. “Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study.” Cardiovascular Drugs and Therapy 19.6 (2005): 403-414.
  12. Mampuya, Warner M., et al. “Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience.” American Heart Journal 166.3 (2013): 597-603.
  13. Nissen, Steven E., et al. “Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial.” JAMA 315.15 (2016): 1580- 1590.
  14. Ahmadizar, Fariba, et al. “Associations of statin use with glycaemic traits and incident type 2 diabetes.” British Journal of Clinical Pharmacology 85.5 (2019): 993-1002.
  15. Thakker, Divyesh, et al. “Statin use and the risk of developing diabetes: a network meta-analysis.” Pharmacoepidemiology and Drug Safety 25.10 (2016): 1131-1149.
  16. Blumenthal, Roger and Francoise A. Marvel. “AHA’s statement on the safety profile of statins: big benefit with low risk.” December 10, 2018. Available at jsp, accessed August 2, 2019.
  17. Arnett, Donna K., et al. “2019 ACC/AHA guideline on the primary prevention of cardiovascular disease.” Journal of the American College of Cardiology (2019): 26029.
  18. Ridker, Paul M. “The JUPITER trial: results, controversies, and implications for prevention.” Circulation: Cardiovascular Quality and Outcomes 2.3 (2009): 279-285.


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