Meta-Analysis

. 2022 Sep 7;43(34):3213-3223.

doi: 10.1093/eurheartj/ehac015.

Prevalence of statin intolerance: a meta-analysis

Ibadete Bytyçi^{1

2}, Peter E Penson^{3

4}, Dimitri P Mikhailidis⁵, Nathan D Wong⁶, Adrian V Hernandez^{7

8}, Amirhossein Sahebkar^{9

10

11}, Paul D Thompson^{12

13}, Mohsen Mazidi^{14

15}, Jacek Rysz¹⁶, Daniel Pella¹⁷, Željko Reiner¹⁸, Peter P Toth^{19

20}, Maciej Banach^{21

22}

Affiliations

¹ Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
² Clinic of Cardiology, University Clinical Centre of Kosovo, Prishtina, Kosovo.
³ School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK.
⁴ Liverpool Centre for Cardiovascular Science, Liverpool, UK.
⁵ Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, UK.
⁶ Heart Disease Prevention Program, Division of Cardiology, University of California, Irvine School of Medicine Predictive Health Diagnostics, Irvine, CA, USA.
⁷ Health Outcomes, Policy, and Evidence Synthesis (HOPES) Group, University of Connecticut School of Pharmacy, Storrs, CT, USA.
⁸ Vicerrectorado de Investigación, Universidad San Ignacio de Loyola (USIL), Lima, Peru.
⁹ Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
¹⁰ Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
¹¹ School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
¹² Division of Cardiology, Hartford Hospital, 80 Seymour Street, Hartford, CT, USA.
¹³ Department of Internal Medicine, University of Connecticut, Farmington, CT, USA.
¹⁴ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
¹⁵ Department of Nutritional Sciences, King's College London, London, UK.
¹⁶ Department of Hypertension, Nephrology and Family Medicine, Medical University of Lodz (MUL), Lodz, Poland.
¹⁷ 2nd Department of Cardiology, Faculty of Medicine, Pavol Jozef Safarik University and East Slovak Institute of Cardiovascular Diseases, Kosice, Slovakia.
¹⁸ Department of Internal Diseases, University Hospital Center Zagreb, School of Medicine, Zagreb University, Zagreb, Croatia.
¹⁹ CGH Medical Center, Sterling, IL, USA.
²⁰ Cicarrone 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.
²² Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland.

PMID: 35169843
PMCID: PMC9757867
DOI: 10.1093/eurheartj/ehac015

Meta-Analysis

Prevalence of statin intolerance: a meta-analysis

Ibadete Bytyçi et al. Eur Heart J. 2022.

. 2022 Sep 7;43(34):3213-3223.

doi: 10.1093/eurheartj/ehac015.

Authors

Affiliations

¹ Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
² Clinic of Cardiology, University Clinical Centre of Kosovo, Prishtina, Kosovo.
³ School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK.
⁴ Liverpool Centre for Cardiovascular Science, Liverpool, UK.
⁵ Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, UK.
⁶ Heart Disease Prevention Program, Division of Cardiology, University of California, Irvine School of Medicine Predictive Health Diagnostics, Irvine, CA, USA.
⁷ Health Outcomes, Policy, and Evidence Synthesis (HOPES) Group, University of Connecticut School of Pharmacy, Storrs, CT, USA.
⁸ Vicerrectorado de Investigación, Universidad San Ignacio de Loyola (USIL), Lima, Peru.
⁹ Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
¹⁰ Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
¹¹ School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
¹² Division of Cardiology, Hartford Hospital, 80 Seymour Street, Hartford, CT, USA.
¹³ Department of Internal Medicine, University of Connecticut, Farmington, CT, USA.
¹⁴ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
¹⁵ Department of Nutritional Sciences, King's College London, London, UK.
¹⁶ Department of Hypertension, Nephrology and Family Medicine, Medical University of Lodz (MUL), Lodz, Poland.
¹⁷ 2nd Department of Cardiology, Faculty of Medicine, Pavol Jozef Safarik University and East Slovak Institute of Cardiovascular Diseases, Kosice, Slovakia.
¹⁸ Department of Internal Diseases, University Hospital Center Zagreb, School of Medicine, Zagreb University, Zagreb, Croatia.
¹⁹ CGH Medical Center, Sterling, IL, USA.
²⁰ Cicarrone 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.
²² Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland.

PMID: 35169843
PMCID: PMC9757867
DOI: 10.1093/eurheartj/ehac015

Abstract

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 cardiovascular 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 and results: We searched several databases up to 31 May 2021, for studies that reported the prevalence of SI. The primary endpoint 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 lower 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, alcohol 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 international definitions. These results support the concept that the prevalence of complete SI might often be overestimated and highlight the need for the careful assessment of patients with potential symptoms related to SI.

Keywords: Cardiovascular disease; Prevalence; Risk factors; Statin intolerance.

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Conflict of interest statement

Conflict of interest: P.E.P. has received honoraria and/or travel reimbursement for events sponsored by AKCEA, Amgen, AMRYT, Link Medical, Mylan, Napp, Sanofi; D.P.M. has given talks, acted as a consultant, or attended conferences sponsored by Amgen and Novo Nordisk; P.P.T.: speaker for Amgen, Esperion, Merck, Novo Nordisk; consultant to Amarin, Amgen, Kowa, Merck, Resverlogix, and Theravance; Ž.R. has given talks sponsored by Sanofi-Aventis and Novartis; M.B.: speakers bureau: Amgen, Herbapol, Kogen, KRKA, Polpharma, Mylan/Viatris, Novartis, Novo Nordisk, Sanofi-Aventis, Teva, Zentiva; consultant to Abbott Vascular, Amgen, Daichii Sankyo, Esperion, FreiaPharmaceuticals, Novartis, Polfarmex, Sanofi-Aventis; Grants from Amgen, Mylan/Viatris, Sanofi, and Valeant; CMO at Nomi Biotech Corporation; all other authors have no conflict of interest.

Figures

**Structured Graphical Abstract**
The worldwide prevalence of statin intolerance and risk factors/conditions that effect or do not effect the risk of statin intolerance.

**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.

**Figure 2**
Prevalence of statin intolerance in primary prevention studies. *Note:* D–L random-effects model was used.

**Figure 3**
Prevalence of statin intolerance in secondary prevention studies. *Note:* D–L random-effects model was used.

**Figure 4**
Prevalence of statin intolerance in combined primary and secondary prevention studies. *Note:* D–L random-effects model was used.

**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.

See this image and copyright information in PMC

Comment in

Statin intolerance: how common is it and how do we work with patients to overcome it?
Cannon CP. Cannon CP. Eur Heart J. 2022 Sep 7;43(34):3224-3226. doi: 10.1093/eurheartj/ehac156. Eur Heart J. 2022. PMID: 35325103 No abstract available.

References

1. Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al. . Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 study. J Am Coll Cardiol 2020;76:2982–3021. - PMC - PubMed
1. Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. . 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889–2934. - PubMed
1. Banach M, Stulc T, Dent R, Toth PP. Statin non-adherence and residual cardiovascular risk: there is need for substantial improvement. Int J Cardiol 2016;225:184–196. - PubMed
1. Toth PP, Patti AM, Giglio RV, Nikolic D, Castellino G, Rizzo M, et al. . Management of statin intolerance in 2018: still more questions than answers. Am J Cardiovasc Drugs 2018;18:157–173. - PMC - PubMed
1. Rosenson RS, Baker S, Banach M, Borow KM, Braun LT, Bruckert E, et al. . Optimizing cholesterol treatment in patients with muscle complaints. J Am Coll Cardiol 2017;70:1290–1301. - PubMed

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Prevalence of statin intolerance: a meta-analysis

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Prevalence of statin intolerance: a meta-analysis

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Conflict of interest statement

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