Analysis Suggests Statin Intolerance is Overdiagnosed


A meta-analysis of data from more than 4 million patients suggests the prevalence of statin therapy may be overdiagnosed and provides insight into risk factors associated with increased risk of intolerance.

Prof. Maciej Banach

Prof. Maciej Banach

A meta-analysis of data from more than 175 studies including more than 4 million patients suggests the prevalence of statin intolerance may be lower than previously thought.

Leveraging data from more than 100 randomized clinical trials, and 60 cohort studies, results of the meta-analysis suggest the overall prevalence of statin intolerance was 9.1%, but this figure was even lower when assessed using criteria from the National Lipid Association (NLA), the International Lipid Expert Panel (ILEP), and the European Atherosclerosis Society (EAS).

“These results were not a surprise to me but they were for many other experts. They show that in most cases statin intolerance is over-estimated and over-diagnosed, and they mean that around 93% of patients on statin therapy can be treated effectively, with very good tolerability and without any safety issues,” said Maciej Banach, of the Medical University of Lodz and the University of Zielona Góra in Poland, in a statement.

An important and perplexing problem facing clinicians, statin intolerance represents a unique issue in the care of patients with dyslipidemia. The current study was designed with the intent of describing the prevalence of statin intolerance according to different diagnostic criteria and in different disease settings as well as provide insight into risk factors associated with increased risk on behalf of the Lipid and Blood Pressure Meta-Analysis Collaboration Group and the ILEP.

With this in mind, Banach and colleagues designed the current study as a meta-analysis of data published in the PubMed/Medline, EMBASE, Scopus, Google Scholar, the Cochrane Central Registry of Controlled Trials, and databases from inception through May 31, 2021. Search terms used by investigators included statin intolerance, statin toxicity, statin adverse effects, statin side effects, statin-associated muscle symptoms, statin-related myopathy, statin-related side effects, statin-related myalgia, statin discontinuation, and statin withdrawal. Studies were considered eligible if they reported prevalence of statin intolerance in either the primary or secondary prevention, included at least 100 participants, and reported criteria used to define the diagnosis of statin intolerance.

The primary outcome of interest was the overall prevalence and the prevalence of statin intolerance based on criteria from the NLA, ILEP, and EAS. The secondary outcome of interest was prevalence of statin intolerance in groups of patients with different disease and analysis of association between risk factors and risk of statin intolerance.

NLA criteria defined intolerance as adverse effects relating to the quality of life, leading to decisions to decrease or stop the use of an otherwise beneficial drug. ILEP criteria defined intolerance as an inability to tolerate a dose of statin required to reduce a person’s cardiovascular risk sufficiently from their baseline risk and could result from different statin-related side effects. EAS criteria focused on statin-associated muscle symptoms and was defined as the assessment of probability of statin-associated muscle symptoms being due to a statin considering the nature of the muscle symptoms, the elevation in creatine kinase levels, and their temporal association with statin initiation, discontinuation, and re-challenge.

A total of 176 studies, including 112 randomized controlled trials and 64 cohort studies, with 4,143,517 patients were identified for inclusion in the analysis. Of the 4,143,517 patients, 195,575 patients were from the trials and 3,947,942 patients were from the cohort studies. The mean age of the overall study cohort was 60.5±8.9 years, 40.9% were females, and 81.1% were White. The pooled prevalence of statin intolerance among the study population was 9.1% (95% CI, 8.0-10).

When using NLA, ILEP, and EAS criteria, the prevalence rates of statin intolerance were 7.0% (95% CI, 6.0-8.0), 6.7% (95% CI, 5.0-8.0), 5.9% (95% CI, 4.0-7.0), respectively. Results of the investigators’ analyses suggested the prevalence rate in randomized controlled trials was significantly lower than the rate observed in cohort studies, with rates of 4.9% (95% CI, 4.0-6.0) and 17% (95% CI, 14-19). Additionally, results suggested rates of prevalence among studies including both primary and secondary prevention patients were much higher than when primary or secondary prevention patients were evaluated separately (18% [95% CI, 14-21]; 8.2% [95% CI, 6.0-10]; 9.1% [95% CI, 6.0-11], respectively).

Investigators pointed out statin lipid solubility did not influence prevalence of statin intolerance. Further analysis of risk factors indicated age (OR, 1.33; P=.04), female gender (OR, 1.47; P=.007), Asian and Black race (P <.05 for both), obesity (OR, 1.30; P=.02), diabetes mellitus (OR, 1.26; P=.02), hypothyroidism (OR, 1.37; P=.01), and chronic liver and renal failure (P <.05 for both) in meta-regression model. Investigators noted use of antiarrhythmic agents, calcium channel blockers, and alcohol as well as increased statin dose were associated with greater risk of intolerance.

“These results clearly show that patients needn’t be afraid of statin therapy as it is very well tolerated in as much as 93%, which is similar or even better than other cardiology drugs, including ones for reducing blood pressure and clotting or blocking of blood vessels. What is more, patients need to know that statins may prolong their life, and in cases where side effects appear, we have enough knowledge to manage these effectively,” Banach added. The most important message to patients as a result of this study is that they should keep on taking statins according to the prescribed dose, and discuss any side effects with their doctor, rather than discontinuing the medication.

This study, “Prevalence of statin intolerance: a meta-analysis,” was published in the European Heart Journal.

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