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Prevalence of Statin Intolerance: A Meta-Analysis
Prevalence of Statin Intolerance: A Meta-Analysis
https://doi.org/10.1093/eurheartj/ehac015 Dyslipidaemias
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
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
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
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-
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-
62.9 + 9.1
1 166 745
3.3
2.9
4.5
0.3
54
85
81
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
3.2
5.4
0.3
64
80
11
59.2 + 8.12
6.2
6.1
1.7
78
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)
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 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
Other
Asian
Black
NLA
ILEP
Figure 2 Prevalence of statin intolerance in primary prevention studies. Note: D–L random-effects model was used.
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I. Bytyçi et al.
Figure 3 Prevalence of statin intolerance in secondary prevention studies. Note: D–L random-effects model was used.
8
Prevalence and risk factors of statin intolerance 9
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 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.
Prevalence and risk factors of statin intolerance 11
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
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