SI can be defined as any side effect considered unacceptable by the patient, and/or some laboratory abnormalities, both attributed to statin treatment and leading to its discontinuation.⁴

The International Lipid Expert Panel defines SI as ‘an inability to tolerate a dose of statin required to sufficiently reduce an individual’s CV risk, limiting the effective treatment of patients at risk of, or with, CVD’.⁵

The Canadian Consensus Working Group is more specific and refers to SI as ‘an inability to tolerate ≥2 statins at any dose or an inability to tolerate increasing doses. The symptoms must not be attributable to drug–drug interactions or conditions known to increase SI’.⁶

The working group indicates that symptomatic criteria include intolerable muscle symptoms (pain, weakness, or cramps with or without creatine kinase changes) or severe myopathy, and they must appear in the first 12 weeks after initiating treatment or following an increase in dose.⁶

Statin intolerance is real, but greatly exaggerated

A major challenge in establishing SI is to distinguishing statin- from non-statin-associated muscle symptoms. Many patients diagnosed with statin-associated muscle symptoms likely have nonspecific musculoskeletal pain, unrelated to statin therapy.⁷

Two rechallenge crossover studies, the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3 (GAUSS-3) and the Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE trials, have established SI as a real and verifiable phenomenon.^8,9

However, according to a 2022 review, which included 176 studies involving >4 million patients, the prevalence of SI is greatly exaggerated. Cohort studies suggest that SI occurs in as many as 30% of treated patients.²

Interestingly, the Self-Assessment Method for Statin Side-effects or Nocebo trial found that 90% of side effects experienced on statin therapy were also experienced while taking placebo.¹⁰

The aim of the study by Bytyçi et al was to determine the overall prevalence of SI, the prevalence according to different diagnostic criteria and in different disease settings, and to identify possible risk factors/conditions that might increase the risk of SI.²

The team found that the pooled prevalence of SI was 9.1%. In the subgroup analysis according to disease states, in primary prevention patients with familial hypercholesterolaemia, hypercholesterolaemia, dyslipidaemia, and type 2 diabetes, the prevalence of SI was 9%, 12% 13%, and 6% respectively.²

In secondary prevention, stable coronary artery disease, acute coronary syndrome, myocardial infarction, and stroke/transient ischaemic attack were associated with SI prevalence of 8%, 13%, 13%, and 5.4%, respectively.²

Bytyçi et al also compared the prevalence of SI in patients treated with lipophilic (atorvastatin, simvastatin, lovastatin, fluvastatin, and pitavastatin) and hydrophilic statins (pravastatin and rosuvastatin). The pooled prevalence was similar in these two types (4% vs 5%), respectively.²

In another sub-analysis, the team found that SI was significantly associated with age. Patients ≥65-years had a higher risk for SI (odds ratio [OR] 1.31).  Furthermore, women (OR 1.47), patients living with obesity (OR 1.30), diabetes (OR 1.26), hypothyroidism (OR 1.37), chronic liver disease (OR 1.24), and chronic renal failure (OR 1.25), had the highest risk of SI.²

Interestingly, patients living with depression were found to have a negative association with SI (OR 0.88). Arterial hypertension and smoking were not associated with the prevalence of SI.²

Alcohol use showed a significant association with the prevalence of SI (OR 1.22). Exercise (OR 1.23), calcium channel blockers (OR 1.31), and antiarrhythmic agents (OR 1.35) were also associated with a higher risk of SI, whereas warfarin use was not (OR 1.04).

Furthermore, increased statin dose was associated with a higher prevalence of SI (OR 1.37), whereas the duration of study follow-up was not associated with the occurrence of SI (OR 1.06).²

How do you manage statin intolerance?

According to Alonso et al, to avoid premature discontinuation of treatment, it is important to emphasise the CV benefits of statins and to explain to patients that muscle pain is a very rare side effect.⁴

When a patient on statin develops muscle symptoms, it is necessary to assess whether the symptoms are due to statin use or not by measuring creatine kinase levels and evaluating risk factors for intolerance.⁴

Different statin-based approaches can be used such as switching to a different statin, lowering the dose or frequency, or re-challenging with the same statin following a drug-holiday.⁴

If the new regime is tolerated, doses can be up-titrated slowly to achieve LDL-C goals with minimal or no muscle complaints. For patients who do not tolerate statins daily, alternate day or twice-weekly dosing is a good option.⁴

Rosuvastatin and atorvastatin have longer half-lives, permitting their use on a non-daily regime. Different studies have shown that administering rosuvastatin once or twice-weekly in patients with previous side effects produces a modest reduction (up to 26%) in LDL-C levels, but it is tolerated by more than 70% of patients.⁴

If statins are not tolerated at all, other lipid-lowering drugs, in monotherapy or in addition to the maximum tolerated statin dose, are recommended to achieve LDL-C goals. The first option is adding ezetimibe to a lower statin dose or ezetimibe monotherapy that decreases LDL-C by 20% and is usually well tolerated. Adding fibrates or resins may be considered if ezetimibe is not enough to achieve LDL-C goals.⁴

Reduction in LDL-C level by fibrates is around 15% and its cardiovascular benefit has been demonstrated in post-hoc analysis of RCTs in hypertriglyceridemia patients. However, using gemfibrozil must be avoided with statins because of the risk of myopathy. Other fibrates with less interaction profile, like fenofibrate, are preferable.⁴

Conclusion

Statins are the gold standard for the treatment of dyslipidaemia and in the management of elevated CV risk, the most important issue during the diagnosis and management of patients with SI is the urgent need to continue statin therapy. To predict the risk of SI and to be effective in lipid management, it is critically important to know the risk factors and conditions that might increase the risk of SI.²

REFERENCES

1. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet,2005.
2. Bytyçi I, Penson PE, Mikhailidis DP, et al. Prevalence of statin intolerance: a meta-analysis. Eur Heart J, 2022.
3. Stroes ES, Thompson PD, Corsini A, et al.Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J, 2015.
4. Alonso R, Cuevas A, Cafferata A. Diagnosis and Management of Statin Intolerance. J Atheroscler Thromb, 2019.
5. Banach M, Rizzo M, Toth PP, et al. Statin intolerance: an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci,
6. Mancini GB, Baker S, Bergeron J, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Consensus Working Group Update (2016). Can J Cardiol,2016
7. Rosenson RS, Baker SK, Jacobson TA, et al.  The National Lipid Association’s Muscle Safety Expert Panel. An assessment by the Statin Muscle Safety Task Force: 2014 update. J Clin Lipidol, 2014.
8. Nissen SE, Stroes E, Dent-Acosta RE, et al.Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA, 2016.
9. Moriarty PM, Thompson PD, Cannon CP, et al.Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol, 2015.
10. Wood FA, Howard JP, Finegold JA, et al.N-of-1 trial of a statin, placebo, or no treatment to assess side effects. N Engl J Med, 2020.