Prevalence of Statin Intolerance: A Meta-Analysis

European Heart Journal (2022) 00, 1–16 META-ANALYSIS
https://doi.org/10.1093/eurheartj/ehac015 Dyslipidaemias
Prevalence of statin intolerance:

a meta-analysis
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Ibadete Bytyçi 1,2, Peter E. Penson 3,4, Dimitri P. Mikhailidis5, Nathan
D. Wong6, Adrian V. Hernandez7,8, Amirhossein Sahebkar9,10,11, Paul
D. Thompson12,13, Mohsen Mazidi14,15, Jacek Rysz16, Daniel Pella17,
Željko Reiner18, Peter P. Toth19,20, Maciej Banach 21,22*, and on behalf of the
Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group and the
International Lipid Expert Panel (ILEP)
1
Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden; 2Clinic of Cardiology, University Clinical Centre of Kosovo, Prishtina, Kosovo; 3School of
Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK; 4Liverpool Centre for Cardiovascular Science, Liverpool, UK; 5Department of Clinical
Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, UK; 6Heart Disease Prevention Program,
Division of Cardiology, University of California, Irvine School of Medicine Predictive Health Diagnostics, Irvine, CA, USA; 7Health Outcomes, Policy, and Evidence Synthesis
(HOPES) Group, University of Connecticut School of Pharmacy, Storrs, CT, USA; 8Vicerrectorado de Investigación, Universidad San Ignacio de Loyola (USIL), Lima, Peru;
9
Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; 10Applied Biomedical Research Center, Mashhad
University of Medical Sciences, Mashhad, Iran; 11School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; 12Division of Cardiology, Hartford Hospital, 80
Seymour Street, Hartford, CT, USA; 13Department of Internal Medicine, University of Connecticut, Farmington, CT, USA; 14Department of Twin Research and Genetic
Epidemiology, King’s College London, London, UK; 15Department of Nutritional Sciences, King’s College London, London, UK; 16Department of Hypertension, Nephrology and
Family Medicine, Medical University of Lodz (MUL), Lodz, Poland; 172nd Department of Cardiology, Faculty of Medicine, Pavol Jozef Safarik University and East Slovak Institute of
Cardiovascular Diseases, Kosice, Slovakia; 18Department of Internal Diseases, University Hospital Center Zagreb, School of Medicine, Zagreb University, Zagreb, Croatia; 19CGH
Medical Center, Sterling, IL, USA; 20Cicarrone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA;
21
Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Rzgowska 281/289, 93-338 Lodz, Poland; and 22Cardiovascular Research Centre,
University of Zielona Gora, Zielona Gora, Poland
Received 31 August 2021; accepted 10 January 2022
Aims Statin intolerance (SI) represents a significant public health problem for which precise estimates of prevalence are
needed. Statin intolerance remains an important clinical challenge, and it is associated with an increased risk of car-
diovascular events. This meta-analysis estimates the overall prevalence of SI, the prevalence according to different
diagnostic criteria and in different disease settings, and identifies possible risk factors/conditions that might increase
the risk of SI.
...............................................................................................................................................................................
Methods We searched several databases up to 31 May 2021, for studies that reported the prevalence of SI. The primary end-
and results point was overall prevalence and prevalence according to a range of diagnostic criteria [National Lipid Association
(NLA), International Lipid Expert Panel (ILEP), and European Atherosclerosis Society (EAS)] and in different disease
settings. The secondary endpoint was to identify possible risk factors for SI. A random-effects model was applied to
estimate the overall pooled prevalence. A total of 176 studies [112 randomized controlled trials (RCTs); 64 cohort
studies] with 4 143 517 patients were ultimately included in the analysis. The overall prevalence of SI was 9.1%
(95% confidence interval 8.0–10%). The prevalence was similar when defined using NLA, ILEP, and EAS criteria
[7.0% (6.0–8.0%), 6.7% (5.0–8.0%), 5.9% (4.0–7.0%), respectively]. The prevalence of SI in RCTs was significantly low-
er compared with cohort studies [4.9% (4.0–6.0%) vs. 17% (14–19%)]. The prevalence of SI in studies including both
primary and secondary prevention patients was much higher than when primary or secondary prevention patients
were analysed separately [18% (14–21%), 8.2% (6.0–10%), 9.1% (6.0–11%), respectively]. Statin lipid solubility did
not affect the prevalence of SI [4.0% (2.0–5.0%) vs. 5.0% (4.0–6.0%)]. Age [odds ratio (OR) 1.33, P = 0.04], female
gender (OR 1.47, P = 0.007), Asian and Black race (P , 0.05 for both), obesity (OR 1.30, P = 0.02), diabetes mellitus
(OR 1.26, P = 0.02), hypothyroidism (OR 1.37, P = 0.01), chronic liver, and renal failure (P , 0.05 for both) were
* Corresponding author. Tel: +48 422711124, Email: [email protected]

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail:
[email protected]
2 I. Bytyçi et al.
significantly associated with SI in the meta-regression model. Antiarrhythmic agents, calcium channel blockers, alco-
hol use, and increased statin dose were also associated with a higher risk of SI.
...............................................................................................................................................................................
Conclusion Based on the present analysis of .4 million patients, the prevalence of SI is low when diagnosed according to inter-
national definitions. These results support the concept that the prevalence of complete SI might often be overesti-
mated and highlight the need for the careful assessment of patients with potential symptoms related to SI.
Key question

What is the overall prevalence of statin intolerance (SI) worldwide? What are the main risk factors of SI?
...............................................................................................................................................................................
Key finding
The overall prevalence of SI is 9.1% and even lower using the international definitions: National Lipid Association, International Lipid Expert
Panel, European Atherosclerosis Society (7.0, 6.7, 5.9%). Female gender, hypothyroidism, high statin dose, advanced age, antiarrhythmics,
and obesity are the main factors that increase the risk of SI.
...............................................................................................................................................................................
Take-home message
Clinicians should use these results to encourage adherence to statin therapy in the patients they treat.
----------------------------------------------------------------------------------------------------------------------------------------------------------
Structured Graphical Abstract The worldwide prevalence of statin intolerance and risk factors/conditions that effect or do not effect
the risk of statin intolerance.
...............................................................................................................................................................................
Keywords Cardiovascular disease • Prevalence • Risk factors • Statin intolerance
Prevalence and risk factors of statin intolerance 3
Introduction from inception through 31 May 2021: PubMed-Medline, EMBASE,

Scopus, Google Scholar, the Cochrane Central Registry of
Cardiovascular (CV) disease (CVD) is the leading cause of morbid- Controlled Trials, and ClinicalTrial.gov. The following keywords
ity and mortality worldwide, despite continuous improvement of were used: statin intolerance, statin toxicity, statin adverse effects, sta-
tin side effects, statin-associated muscle symptoms, SAMS, statin-
medical treatment, diagnosis, and risk factor control.1 It has
related myopathy, statin-related side effects, statin-related myalgia,
been clearly demonstrated that statin therapy confers significant
statin discontinuation, statin withdrawal, prevalence, occurrence
mortality and morbidity benefits in both the primary and second-
rate, and frequency rate (see Supplementary material online,
ary prevention of CVD.2 Although statins are among the most

Table S2). In addition, the references from the selected articles and re-
commonly prescribed drugs, non-adherence and discontinuation levant review articles, and the abstracts from selected congresses:
of statin therapy is an ongoing problem worldwide.3 The most com- scientific sessions of the European Society of Cardiology, the
mon cause of discontinuation of statin therapy is statin-associated American Heart Association (AHA), American College of
muscle symptoms (SAMS).4,5 Other possible statin-related adverse Cardiology (ACC), NLA, and European Atherosclerosis Society
effects include neurocognitive disorders, hepatotoxicity, haemor- (EAS) were screened for additional relevant articles. The wild-card
rhagic stroke, and renal toxicity.6,7 These conditions may lead to dis- term ‘*’ was used to increase the sensitivity of the search strategy.
continuation, but causality has been confirmed only for SAMS, Articles were eligible if they reported the prevalence of SI ei-
ther in primary or secondary prevention and met the following
temporary elevation of aminotransferase alanine, and newly diag-
inclusion criteria: (i) trials or cohorts reporting SI, (ii) at least
nosed diabetes.6 According to the International Lipid Expert Panel
100 participants included in the analysis, and (iii) available criteria
(ILEP), statin intolerance (SI) is an inability to tolerate a dose of sta-
for SI diagnosis. Exclusion criteria were as follows: (i) studies with
tin required to sufficiently reduce an individual’s CV risk, limiting the unclear methodologies to obtain the estimates of SI frequency,
effective treatment of patients at risk of, or with, CVD.7 The (ii) studies that investigated a statin that has been withdrawn
National Lipid Association (NLA) has a wider definition, including from the market, (iii) ongoing trials (unless they reported relevant
any adverse effects relating to the quality of life and leading to the interim results), (iv) studies only investigating statin discontinu-
decision to decrease or stop the use of an otherwise beneficial ation without specifying intolerance, and (v) short follow-up
drug.8 The Luso-Latin American Consortium (LLAC) definition of (,1.5 month/6 weeks).
SI is similar to that of the Canadian Consensus Working Group The search, screening, and data extraction were performed inde-
(CCWG). It refers to an inability to tolerate ≥2 statins at any pendently by two reviewers (I.B. and J.R.); any disagreements were re-
solved through discussion with senior investigators (M.B. and P.E.P.).
dose or an inability to tolerate increasing doses. The symptoms
Non-relevant articles were excluded on the basis of title and abstract
must not be attributable to drug–drug interactions or conditions
screening. For each trial, the risk of bias was independently assessed by
known to increase SI.9,10 They indicate that symptomatic criteria in-
the same investigators using the revised Cochrane RoB2 tool involving
clude intolerable muscle symptoms [pain, weakness, or cramps with five domains (randomization process, deviation from intended inter-
or without creatine kinase (CK) changes] or severe myopathy, and ventions, missing outcome data, outcome measurement, and selection
they must appear in the first 12 weeks after initiating treatment or of reported results). The risk of bias in each study was judged to be
following an increase in dose.9,10 ‘low’, ‘high’, or ‘unclear’.14 For the assessment of the risk of bias in co-
The prevalence of SI is widely debated, in part because of diffi- hort studies, the Newcastle-Ottawa Scale (NOS) was used. Three do-
culties in identification and diagnosis, possible interaction of differ- mains were evaluated with the following items: (i) selection, (ii)
ent risk factors, different diseases, drugs, and other clinical and comparability, and (iii) exposure. The risk of bias in each study was
demographic indices.11 In contrast with randomized controlled judged to be ‘good’, ‘fair’, or ‘poor’.15
trials (RCTs) (prevalence usually 5–7%), cohort studies suggest
that SI occurs in as many as 30% of treated patients.8,12
However, this is likely to be an overestimate or underestimate
Outcome measures
The primary endpoint was the overall prevalence and the prevalence
and in many cases, the symptoms are likely to be attributable to
based on each of the international diagnostic criteria: NLA, EAS, and
the nocebo/drucebo effect.11 ILEP. The secondary endpoint was the prevalence of SI in groups of pa-
Because of these inconsistent findings, the present meta-analysis tients with different diseases and the analysis of the association between
aimed to estimate the overall prevalence of SI, its prevalence ac- possible risk factors/conditions and the risk of SI. According to the NLA,
cording to various diagnostic criteria, in different disease settings, SI is defined as adverse effects relating to the quality of life, leading to
and to identify possible risk factors for SI. decisions to decrease or stop the use of an otherwise beneficial
drug.8 The ILEP definition stated that SI is an inability to tolerate a
dose of statin required to reduce a person’s CV risk sufficiently from
Methods their baseline risk and could result from different statin-related side ef-
fects.7 The EAS definition focused only on SAMS: the assessment of the
Search strategy and selection criteria probability of SAMS being due to a statin considering the nature of the
We followed the methods recommended by the Cochrane muscle symptoms, the elevation in CK levels, and their temporal asso-
Collaboration and complied with the reporting standards of the ciation with statin initiation, discontinuation, and re-challenge.16 As sta-
Preferred Reporting Items for Systematic Review and Meta-analysis ted by the CCWG and LLAC, SI was defined as a clinical syndrome
(PRISMA) guideline of 2020.13 A PECOS (population, exposure, com- characterized by significant symptoms and biomarker abnormalities
parison, outcomes, study design) model was used to shape the clinical that is documented by challenge/dechallenge/re-challenge using ≥2 sta-
question and to design the search strategy (see Supplementary tins that is not due to drug interactions or untreated risk factors for in-
material online, Table S1). The following databases were searched tolerance9,10 (see Supplementary material online, Figure S1). Because
4 I. Bytyçi et al.
the main outcome was not limited by the type of statin, the CCWG and I2 = 98%; 5.9% (4.0–7.0%), I2 = 93%, respectively; see
LLAC criteria were not used in further analyses. Supplementary material online, Figures S3–S5]. The prevalence of
SI in RCTs was significantly lower compared with cohort studies
Data synthesis and statistical analyses [4.9% (4.0–6.0%), I2 = 93% vs. 17% (14–19%), I2 = 98%;
The meta-analysis was conducted using R Statistical Software (v3.5.1, P , 0.001, see Supplementary material online, Figures S6 and S7].
Boston, MA, USA), using the packages ‘meta’ and ‘metafor’ for In an analysis stratified by the type of disease prevention, SI was
meta-analysis. A random-effects model (DerSimonian and Laird meth- more common in pooled analyses of studies which included both
od) was applied to estimate the pooled prevalence across the studies.
primary and secondary prevention [18% (14–21%), I2 = 99%] pa-

The 95% confidence intervals (CIs) for the prevalence reported in the
tients than in either pooled analyses of studies which only included
individual studies (see Supplementary material online, Table S1) were
estimated from the proportion of cases of SI and sample size using the primary or secondary prevention patients [8.2% (6.0–10%, I2 =
binomial exact method (Clopper–Pearson method). An inverse var- 98%), 9.1% (6.0–11%, I2 = 98%), respectively; Figures 2–4].
iance method was used for weighting each study in the meta-analysis. In the subgroup analysis according to disease states, in primary
For the difference of subgroup analysis, we employed post hoc analysis. prevention patients with familial hypercholesterolaemia (FH),
To investigate the differences between groups, we used the signifi- hypercholesterolaemia, dyslipidaemia, and Type 2 diabetes melli-
cance test. An I2 statistic was also computed for subgroup differ- tus (T2DM), the prevalence of SI was 9.0% (6.0–13%, I2 = 96%),
ences.14 With the inverse variance method, when the estimated 12% (11–13%, I2 = 99%), 13% (7.0–18%, I2 = 98%), and 6.0%
probability of the condition of a single study approaches 0 or 1, the (2.0–10%, I2 = 99%) (see Supplementary material online,
variance of the study approaches zero, which in turn causes the inverse Figure S8), respectively. In secondary prevention: stable coronary
variance to approach infinity; subsequently, the inflated inverse var-
artery disease (CAD), acute coronary syndrome (ACS), myocar-
iance substantially increases the adjusted weight of the study in the
dial infarction (MI), and stroke/transient ischaemic attack were as-
pooled mean, resulting in an over-contribution of the study in the final
pooled estimation of the meta-analysis. Therefore, to avoid the over- sociated with SI prevalence of 8% (2.0–18%, I2 = 98%), 13% (2.0–
estimated results, we conducted the Freeman–Tukey double arcsine. 24%, I2 = 98%), 13% (2.0–24%, I2 = 98%), and 5.4% (3.9–9.1%, I2 =
The final pooled result and 95% CIs were then back-transformed 96%), respectively (see Supplementary material online, Figure S9).
and expressed as percentages for ease of interpretation. The baseline We also compared the prevalence of SI in patients treated with
characteristics are reported as the median and range. The mean and lipophilic (atorvastatin, simvastatin, lovastatin, fluvastatin, and pita-
standard deviation values were estimated using the method described vastatin) and hydrophilic statins (pravastatin and rosuvastatin). The
by Hozo et al.16 Heterogeneity between studies was assessed using pooled prevalence was similar in these two types [4.0% (2.0–5.0%,
Cochrane’s Q-test and the I2 index. As a guide, I2 , 25% indicated I2 = 97%) vs. 5.0% (4.0–6.0%, I2 = 98%), respectively; P = 0.33, see
low, 25–50% moderate, and .50% high heterogeneity.17 Supplementary material online, Figures S10 and S11]. A summary of
Potential demographic, clinical, and drugs as modifiers of SI were
SI prevalence is shown in Figure 5. Between-study heterogeneity
further explored by meta-regression. Meta-regression coefficients
was large (I2 ≥ 93%). Tests assessing bias were non-significant
and corresponding P-values are reported. For summary estimates,
P , 0.05 (two-tailed) was considered statistically significant.18 (P . 0.28).
Interaction of demographic indices with

Results statin intolerance
In meta-regression analyses, age (as a continuous variable) was
Study selection and patient population
found to be significantly associated with the higher risk for SI
A total of 3569 articles were retrieved from the search after dupli-
[odds ratio (OR) 1.33, 95% CI 1.25–1.41; P = 0.04, see
cates from the different databases were discarded. These articles
Supplementary material online, Figure S12A]. Likewise, the older
were first screened by title and abstract, leading to 271 articles
age ≥65 years (OR 1.31, 95% CI 1.22–1.45; P = 0.04, see
that underwent full-text review. After a stringent selection process,
Supplementary material online, Figure S12B) and female sex were
a total of 176 studies with 4 143 517 patients and a mean follow-up
associated with a higher risk of SI (OR 1.47, 95% CI 1.38–1.53;
of 19 + 7.3 months were included in the analysis.19–194 Out of 176
P = 0.007) (see Supplementary material online, Figure S12C).
articles, 112 were RCTs (195 575 patients) and the remaining 64
Analysis of demographic indices revealed that the prevalence
were cohort studies with 3 947 942 patients. The PRISMA flow dia-
of SI was associated with the percentage of participants of
gram is shown in Figure 1 and the key characteristics of the included
Asian and African-American race (P , 0.05 for both, see
studies are presented in Supplementary material online, Table S3.
Supplementary material online, Figure S12G and H). However, no
The mean age of patients was 60.5 + 8.9 and 40.9% were females.
association was observed with White, Caucasian, and Hispanic
The White or Caucasian race made up a greater proportion
races with SI (P . 0.05 for all, see Supplementary material
of participants than Afro-American, Asian, Hispanic, or others
online, Figure S12D–F). A summary of the meta-regression of
(81.1, 8.25.1, 4.5, and 1.2%, respectively; P , 0.001; Table 1).
demographic indices on SI is shown in Figure 6A.
Prevalence of statin intolerance

The pooled prevalence of SI was 9.1% (95% CI 8.0–10%, see Interaction of clinical indices with statin
Supplementary material online, Figure S2). The prevalence based intolerance
on NLA criteria was similar compared with using the ILEP A range of potential factors was tested for possible interaction
or EAS definitions [7.0% (6.0–8.0%), I2 = 98%; 6.7% (5.0–8.0%), with SI. Positive associations were found for obesity (OR 1.30,

Figure 1 The Preferred Reporting Items for Systematic Review and Meta-analysis flow-chart of studies included in the meta-analysis.
Incomplete data: Studies that reported only statin discontinuation without specifying the reasons for discontinuation.
P = 0.02), diabetes mellitus (OR 1.26, P = 0.02), hypothyroidism Figure S14). A summary of the results of meta-regression with re-
(OR 1.37, P = 0.01), chronic liver disease (OR 1.24, P = 0.03), spect to associations between risk factors and drugs on SI is shown
and chronic renal failure (OR 1.25, P = 0.03), whereas the percen- in Figure 6B.
tage of individuals with depression was found to have a negative
association with SI (OR 0.88, P = 0.04). Conversely, arterial hyper- Risk of bias assessment
tension was not associated with the prevalence of SI (see The assessment of the risk of bias in the included studies using
Supplementary material online, Figure S13). RoB2 for RCTs and NOS for cohort studies showed that most stu-
dies had moderate to high-quality level in defining objectives and
Interaction of drugs and addiction the main outcomes (see Supplementary material online, Tables
S4 and S5).
diseases with statin intolerance
The percentage of smokers was not significantly associated with
the prevalence of SI (OR 1.03, P = 0.60), whereas the percentage Discussion
of alcohol users used showed a significant association with the pre-
valence of SI (OR 1.22, P = 0.03). Moreover, exercise (OR 1.23, To the best of our knowledge, the present meta-analysis is the first
P = 0.03), calcium channel blockers (CCB) (OR 1.31, P = 0.03), to evaluate the overall prevalence of SI worldwide, the prevalence
and antiarrhythmic agents (OR 1.35, P = 0.03) were associated based on different diagnostic criteria and in different disease set-
with higher risk of SI, whereas warfarin use was not (OR 1.04, tings. The results of our meta-analysis of 176 studies with 4 143
P = 0.15). In addition, increased statin dose was associated with 517 patients and a mean follow-up of 19 + 7.3 months showed
a higher prevalence of SI (OR 1.37, P = 0.01), whereas the duration that the worldwide prevalence of SI is 9.1%, irrespective of
of study follow-up was not associated with the occurrence of the definition applied. Older age, female gender, Asian and
SI (OR 1.06, P = 0.48, see Supplementary material online, African-American races, obesity, T2DM, alcohol use, hypothyroidism,
6 I. Bytyçi et al.
chronic liver, and renal diseases were associated with a higher risk of
Combined patientsa
..................................................................................................................................................................................................................................... SI, as were increased statin doses and the concomitant administration
of antiarrhythmic agents (Structured Graphical abstract).
Statin intolerance and the discontinuation of statin therapy is an
15.3 (10–18)
ongoing clinical problem worldwide.1–3 Statin intolerance is asso-
12 (9.1–17)
18 (14–21)
16 (11–19)
62.9 + 9.1
1 250 388
ciated with suboptimal lipid-lowering therapy and a high risk of
first and recurrent CVD events.176 Numerous studies, systematic
47.3
11.9
5.1
0.6
0.4
29
82
CI, confidence interval; NLA, National Lipid Association; ILEP, International Lipid Expert Panel; EAS, European Atherosclerosis Society; RCT, randomized controlled trial; SD, standard deviation.
reviews, and meta-analyses have demonstrated an association be-

tween statin non-adherence and discontinuation and the risk of
CVD and mortality.195,196
Secondary prevention
Although a wide range of values for the prevalence of SI has

been reported in the literature (from 2 to 3% to as high as
50%),3,11,91,117 our findings show that the pooled overall world-
wide prevalence ranges from 8.1 to 10% (1 in every 10–12 pa-
5.5 (4.0–9.1)
9.1 (6.0–11)
8.7 (5.9–11)
8.1 (6.0–11)
62.9 + 9.1
1 166 745
tients). There is debate on the definition of SI. We compared

the prevalence of SI according to all major definitions. Despite
31.2
3.3
2.9
4.5
0.3
54
85
the fact that the EAS definition of SI is focused solely on SAMS,

the pooled prevalence in our analysis did not show significant dif-
ferences between the EAS, NLA, and ILEP definitions.
Primary prevention
The prevalence of SI in cohort studies was significantly higher

than that reported in RCTs. This is associated with large difficulties
of correct SI diagnosis in clinical practice and lack of possibility of
7.5 (5.0–9.8)
7.3 (5.0–9.1)
6.2 (4.8–8.9)
8.2 (6.0–10)
using of new one-of-trial approach or even cross-over design as it

58.3 + 7.12
1 726 384
was applied, e.g. in PCSK9 inhibitors trials.197–199 This also suggests

44.4
Table 1. Summary of main characteristics of studies included in the present meta-analysis
that the prevalence of SI is overestimated in real-life data. It is also

7.5
6.2
4.9
0.4
93
81
possible that RCTs underestimate the prevalence by excluding

older patients and those with comorbidities such as chronic liver
and kidney diseases and abnormal laboratory values that may in-
Cohort studies
crease the risk of SI. Some previous studies have reported substan-
tially lower adherence rates in primary prevention compared with
8.4 (5.7–11)
61.9 + 7.89
11 (6.0–16)
10 (7.2–15)
17 (14–19)
3 947 942
patients with CVD or after MI.61,87,100,200 In contrast, our sub-

analysis of the pooled prevalence of SI in primary prevention (93
43.1
3.2
5.4
0.3
64
80
11
papers with 1 762 384 participants) and secondary prevention

(54 papers with 1 166 745 participants) did not find a significant dif-
ference (8.2 vs. 9.1%). However, in observational cohort studies
RCT studies
which included mixed patients (both primary and secondary pre-

4.9 (4.0–6.0)
4.8 (3.0–6.0)
4.9 (3.5–6.2)
3.8 (2.4–5.4)
59.2 + 8.12
vention), the pooled prevalence of SI was twice as high (18%).

195 575
This finding suggests that such studies overestimate the prevalence

38.6
112
6.2
6.1
1.7
78
of SI. Similarly, in the subgroup analysis based on different diseases

8
in the primary prevention cohorts (FH, hypercholesterolaemia,

dyslipidaemia, and T2DM) and secondary prevention (stable
60.54 + 8.88
All studies
7.0 (6.0–8.0)
6.7 (5.0–8.0)
5.9 (4.0–7.0)
CAD, ACS, and MI), the mean overall SI prevalence was not signif-
9.1 (8.0–10)
Combined: primary and secondary prevention patients.

4 143 517
icantly different. Likewise, regarding the safety of different classes

of statins, we found no difference between lipophilic and hydro-
40.9
81.1
176
8.2
5.1
4.5
1.2
philic statins.
Because statins are the gold standard for the treatment of dys-
lipidaemia and in the management of elevated CV risk, the most
Overall prevalence, % (95% CI)
important issue during the diagnosis and management of patients

with SI is the urgent need to continue statin therapy. To predict
Age, years, mean + SD
the risk of SI and to be effective in lipid management, it is critically

White or Caucasian
important to know the risk factors and conditions that might in-
crease the risk of SI.4 It is now 20 years since the ACC/AHA/
Sample size, n
Female sex, %
No. of studies
National Heart Lung and Blood Institute first identified risk factors
Hispanic
in their recommendations for statin safety; however, there has

Race, %
Other
Asian
Black
NLA
ILEP
been no attempt to validate their suggested risk factors using

EAS
data from clinical trials or observational studies.201 In this

a
meta-analysis, we have attempted to investigate what risk

Figure 2 Prevalence of statin intolerance in primary prevention studies. Note: D–L random-effects model was used.
I. Bytyçi et al.
Figure 3 Prevalence of statin intolerance in secondary prevention studies. Note: D–L random-effects model was used.
8
Figure 4 Prevalence of statin intolerance in combined primary and secondary prevention studies. Note: D–L random-effects model was used.
factors/conditions might be linked to SI prevalence using obesity, diabetes mellitus, hypothyroidism, chronic liver disease,
meta-regression. Pooled analysis demonstrated that many demo- and renal failure. Depression was negatively associated
graphic, clinical, and other risk factors are associated with SI. with SAMS, perhaps because of under-reporting in these pa-
Older age, female gender, Asian, and African-American races tients.202–205 Smoking and anticoagulant drugs were not associated
were associated with a higher incidence of SI, whereas White, with SI; however, the use of alcohol, exercise, antiarrhythmic
Caucasian, and Hispanic races were not associated with higher SI agents, and CCB was positively associated with SI. Finally, as pre-
risk. Many commonly observed risk factors and conditions may viously reported, higher doses of statins were associated with a
also be significantly associated with SI occurrence, including greater prevalence of SI.5,7
10 I. Bytyçi et al.

Figure 5 Prevalence of statin intolerance—summary figure. NLA, National Lipid Association; ILEP, International Lipid Expert Panel; EAS,
European Atherosclerosis Society; RCTs, randomized controlled trials; DM, diabetes mellitus; sCAD, stable coronary artery disease; ASC,
acute coronary syndrome; MI, myocardial infarction; TIA, transient ischaemic attack; SI, statin intolerance.
Figure 6 Summary meta-regression of (A) demographic and (B) risk factors and drugs with statin intolerance. SI, statin intolerance; BMI, body
mass index; CLD, chronic liver disease; CRF, chronic renal failure; CCB, calcium channel blockers.
Strength and limitations August). This meta-analysis was written independently; no company
Our meta-analysis has some limitations. Heterogeneity between or institution supported it financially. No professional writer was in-
volved in the preparation of this position paper.
studies was present in our analysis (I2 = 93–99%; unknown con-
founding may have led to this), although this was anticipated be- Conflict of interest: P.E.P. has received honoraria and/or travel re-
cause of the broad scope of this systematic analysis, and due to imbursement for events sponsored by AKCEA, Amgen, AMRYT, Link
very large data, we could not test the influence analysis that would Medical, Mylan, Napp, Sanofi; D.P.M. has given talks, acted as a consult-
resolve the effect size of different weight across the studies. The ant, or attended conferences sponsored by Amgen and Novo Nordisk;
statistical examination of potential publication bias through Egger P.P.T.: speaker for Amgen, Esperion, Merck, Novo Nordisk; consultant

and funnel plots is not appropriate because studies with ,100 pa- to Amarin, Amgen, Kowa, Merck, Resverlogix, and Theravance; Ž.R.
has given talks sponsored by Sanofi-Aventis and Novartis; M.B.: speak-
tients were excluded from this systematic review.
ers bureau: Amgen, Herbapol, Kogen, KRKA, Polpharma, Mylan/
Our analysis depended upon data reported in published studies.
Viatris, Novartis, Novo Nordisk, Sanofi-Aventis, Teva, Zentiva; con-
Some potential risk factors for SI were not reported with ideal de- sultant to Abbott Vascular, Amgen, Daichii Sankyo, Esperion,
tail or precision, such as the amount of alcohol consumption, types FreiaPharmaceuticals, Novartis, Polfarmex, Sanofi-Aventis; Grants
of exercise, and physical activity endurance. In this line, race distri- from Amgen, Mylan/Viatris, Sanofi, and Valeant; CMO at Nomi
bution was not similar with predominantly Caucasian/White race Biotech Corporation; all other authors have no conflict of interest.
(81.1%). It is also important to emphasize the importance of the
nocebo/drucebo effect that was not examined in the included stu-
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Prevalence of Statin Intolerance: A Meta-Analysis

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Prevalence of statin intolerance:

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Received 31 August 2021; accepted 10 January 2022

* Corresponding author. Tel: +48 422711124, Email: [email protected]

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Introduction from inception through 31 May 2021: PubMed-Medline, EMBASE,

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Interaction of demographic indices with

Prevalence of statin intolerance

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Although a wide range of values for the prevalence of SI has

tients). There is debate on the deﬁnition of SI. We compared

the fact that the EAS deﬁnition of SI is focused solely on SAMS,

The prevalence of SI in cohort studies was signiﬁcantly higher

using of new one-of-trial approach or even cross-over design as it

was applied, e.g. in PCSK9 inhibitors trials.197–199 This also suggests

that the prevalence of SI is overestimated in real-life data. It is also

possible that RCTs underestimate the prevalence by excluding

patients with CVD or after MI.61,87,100,200 In contrast, our sub-

papers with 1 762 384 participants) and secondary prevention

which included mixed patients (both primary and secondary pre-

vention), the pooled prevalence of SI was twice as high (18%).

This ﬁnding suggests that such studies overestimate the prevalence

of SI. Similarly, in the subgroup analysis based on different diseases

in the primary prevention cohorts (FH, hypercholesterolaemia,

Combined: primary and secondary prevention patients.

icantly different. Likewise, regarding the safety of different classes

important issue during the diagnosis and management of patients

the risk of SI and to be effective in lipid management, it is critically

in their recommendations for statin safety; however, there has

been no attempt to validate their suggested risk factors using

data from clinical trials or observational studies.201 In this

meta-analysis, we have attempted to investigate what risk

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