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Statin use and the risk of CVD events, stroke, and all-cause mortality in patients with diabetes: A systematic review and meta-analysis

Open AccessPublished:August 07, 2022DOI:https://doi.org/10.1016/j.numecd.2022.07.018

      Highlights

      • Statin use and the risk of cardiovascular disease (CVD) in patients with diabetes is uncertain.
      • Pooled results indicated that in comparison with statin non-users, patients who received statins showed a reduced risk of CVD.
      • No association was observed between statin users and non-statin users and the risk of all-cause mortality in diabetes.

      Abstract

      Aims

      Considering the lack of evidence on statin use and the risk of cardiovascular disease (CVD) in patients with diabetes in primary and secondary prevention, this study aimed to evaluate the effect of statin use in individuals with diabetes for primary and secondary prevention.

      Data synthesis

      The MEDLINE, Web of Science, Embase, ClinicalTrials.gov, and Cochrane Central Register for Controlled Trials databases were searched. We included studies that assessed the effect of statin use in individuals with diabetes for at least 1 year. The outcomes included CVD, all-cause mortality, and stroke. A total of 24 studies including 2,152,137 patients with diabetes were included in the meta-analysis. Compared with statin non-users, patients who received statins showed a lower risk of CVD events (primary prevention: risk ratio [RR] = 0.80, 95% confidence interval [CI] 0.69–0.94, P = 0.006; secondary prevention: RR = 0.75, 95% CI 0.65–0.87, P < 0.0001). No association was observed between statin and non-statin users and the risk of all-cause mortality. The pooled results also revealed that statin use reduced the risk of ischemic stroke in patients with diabetes (primary prevention: RR = 0.83, 95% CI 0.70–0.97, P = 0.020; secondary prevention: RR = 0.74, 95% CI 0.63–0.85, P < 0.0001).

      Conclusions

      Statin use significantly reduced the risk of CVD events and stroke, but not all-cause mortality, in individuals with diabetes undergoing both primary and secondary prevention. More data are required to verify the effects of statins in patients with diabetes.

      Systematic review registration

      PROSPERO CRD42021281132.

      Keywords

      Abbreviations:

      CI (confidence interval), CVD (cardiovascular disease), GRADE (Grading of Recommendations, Assessment, Development, and Evaluation), HbA1c (hemoglobin A1c), HD (hemodialysis), HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase), PCSK9 (proprotein convertase subtilisin/kexin type 9), RCT (randomized controlled trial), RR (risk ratio)

      1. Introduction

      Lipid disorders are traditional risk factors for cardiovascular diseases (CVDs), and lipid-lowering therapy using statins has been widely used in clinics for several years. Statin therapy is associated with a reduced risk of CVD events and all-cause mortality in the general population, both in primary and secondary prevention [
      • Taylor F.
      • Huffman M.D.
      • Macedo A.F.
      • et al.
      Statins for the primary prevention of cardiovascular disease.
      ,
      • Zhong P.
      • Wu D.
      • Ye X.
      • et al.
      Secondary prevention of major cerebrovascular events with seven different statins: a multi-treatment meta-analysis.
      ,
      • Mills E.J.
      • Wu P.
      • Chong G.
      • et al.
      Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials.
      ].
      Type 1 and type 2 diabetes are traditional risk factors for CVD. Lipid disorders frequently occur in patients with diabetes, and the prevalence of hypercholesterolemia ranges from 50% to 84% in Spain [
      • de la Sierra A.
      • Pintó X.
      • Guijarro C.
      • et al.
      Prevalence, treatment, and control of hypercholesterolemia in high cardiovascular risk patients: evidences from a systematic literature review in Spain.
      ]. A cross-sectional descriptive epidemiological study showed that the most common comorbidities were hypertension and hyperlipidemia (84.9% and 65.6%, respectively) [
      • Akın S.
      • Bölük C.
      Prevalence of comorbidities in patients with type-2 diabetes mellitus.
      ]. Considering that the coexistence of diabetes and lipid disorders may have an add-on effect on CVD outcomes, it is reasonable to recommend the use of statins in patients with diabetes. The 2018 American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines recommends moderate-intensity statin therapy for most adults with diabetes for primary prevention and continuously recommends high-intensity statins for secondary prevention. However, it also recommends ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors added to maximally tolerated statin therapy for a subgroup of very high-risk patients who do not achieve a low-density lipoprotein cholesterol (LDL-C) level below a threshold value of 70 mg/dl with statin therapy alone [
      • Goldberg R.B.
      • Stone N.J.
      • Grundy S.M.
      The 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guidelines on the management of blood cholesterol in diabetes.
      ].
      The 2018 guidelines were primarily based on the results of two meta-analyses [
      • Baigent C.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists’ (CTT) Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      ,
      • Kearney P.M.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaborators
      Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.
      ]. In comparison with more versus less intensive statin therapy from 26 randomized controlled trials (RCTs), more intensive regimens produced a highly significant 15% further reduction in major vascular events, consisting of significant reductions in coronary death or nonfatal myocardial infarction. However, this meta-analysis included all lipid-lowering therapies, and no diabetes subgroup was separated [
      • Baigent C.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists’ (CTT) Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      ]. In another 2008 meta-analysis [
      • Kearney P.M.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaborators
      Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.
      ] of 18,686 patients with diabetes, the pooled results of 14 RCTs indicated a 9% proportional reduction in all-cause mortality in patients with diabetes, similar to the 13% reduction in those without diabetes. Nevertheless, the conclusion of this meta-analysis was based only on mixed trials, regardless of the use of primary or secondary prevention. In another 2013 meta-analysis, statin treatment did not significantly reduce CVD events, and statin therapy had no benefit in primary or secondary prevention [
      • Chang Y.H.
      • Hsieh M.C.
      • Wang C.Y.
      • et al.
      Reassessing the benefits of statins in the prevention of cardiovascular disease in diabetic patients--a systematic review and meta-analysis.
      ]. Based on clinical trials reporting that a modest reduction in relative risk with statin treatment may provide substantial clinical benefits, it must be emphasized that treatment decisions should be based not on the reduction in relative risk but on the reduction in absolute risk. Considering the lack of strong evidence of statin use in primary and secondary prevention in patients with diabetes, rather than comparing statin users in individuals with and without diabetes, we performed a meta-analysis, including all clinical trials, to further confirm the effect of statins in primary and secondary prevention on the risk of CVD and mortality in patients with diabetes.

      2. Methods

      We developed and followed a standard protocol according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. This study was registered with International Prospective Register of Systematic Reviews (number: CRD42021281132).

      2.1 Search strategy and study selection

      Relevant literature was searched in several databases, including MEDLINE (PubMed, January 1, 1966, to April 1, 2022), Web of Science, Embase (January 1, 1966, to April 1, 2022), ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials. The keywords used were as follows: statins AND diabetes AND (cardiovascular disease OR coronary heart disease OR stroke OR all-cause death OR all-cause mortality). Manual searches for references cited by the identified original studies and relevant review articles were also performed and evaluated. All studies in this meta-analysis were published in English. The detailed steps are shown in Fig. 1.

      2.2 Inclusion and exclusion criteria

      Studies that met the following criteria were included in our meta-analysis: (1) studies with duration of more than 1 year; (2) RCTs, nonrandomized trials, and prospective, observational cohort studies; (3) studies with statins being compared with a control group in patients with diabetes; and (4) studies with availability of an outcome (CVD events, all-cause mortality, or stroke).
      Studies were excluded if they met any of the following criteria: (1) studies not comparing the outcomes between the statin and control groups, (2) studies comprising patients with a combination of diabetes and kidney disease (chronic kidney disease or dialysis), and (3) studies with different publications analyzing the same population or duplicates.

      2.3 Data collection

      Three researchers (Yang XH, Zhang BL, and Cheng Y) performed the search and reviewed the results. Data were collected by all authors and independently extracted by the three researchers (Yang XH, Zhang BL, and Cheng Y) who reviewed all the study characteristics (i.e., first author's surname, year of publication, study design, sample size, follow-up, and outcomes). Any disagreement in data extraction was resolved through discussion among these researchers in consultation with other authors (Jin HM and Fun SK).

      2.4 Assessment of heterogeneity

      Heterogeneity was evaluated using Cochran's Q test and I2 statistics. The study was deemed heterogeneous if the P-value was <0.1 (Cochran Q). Studies with I2 values < 50% were considered non-heterogeneous; thus, a fixed-effects model was used in their analysis, whereas studies with I2 values > 50% were considered heterogeneous and were analyzed using a random-effects model.

      2.5 Quality assessment

      Two of the previously mentioned researchers (Yang XH and Zhang BL) assessed the quality of each selected study using the Newcastle–Ottawa scale, which assigns a maximum of nine stars to a study based on the quality of patient selection, study design, comparability, exposure, and outcome. We considered a study to be of “high quality” if it scored nine stars on this scale and “medium quality” if it scored seven or eight stars. Discrepancies between the two researchers were resolved through discussion.
      The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system (https://gdt.gradepro.org/app/) was used to evaluate the quality of evidence. The evaluation included the study design, risk of bias, inconsistency, indirectness, imprecision, and other considerations. Four quality levels were developed: “very low,” low,” “moderate,” and “high.”

      2.6 Outcome measures

      The primary outcome was the occurrence of CVD events, and the secondary outcomes were coronary heart disease (CHD), all-cause mortality, and ischemic stroke. CVD events were defined based on the diagnostic codes in the International Classification of Diseases, Ninth Revision, Clinical Modification as the occurrence of CHD (including myocardial infarction, angina, and other CHDs), heart failure, or cerebrovascular diseases (including stroke, transient cerebral ischemic attack, cerebrovascular accident, and other cerebrovascular diseases).

      2.7 Statistical analyses

      Data were analyzed using STATA version 14.0 (StataCorp, TX, USA). The risk ratios (RRs) for the association between statins and CVD events, all-cause mortality, and stroke in patients with diabetes were calculated or extracted from individual studies. We also performed a sensitivity analysis, in which each study was extracted to evaluate its effect on the estimate. Egger's test was used to examine the presence of publication bias. Statistical significance for all analyses was set at P < 0.05.

      3. Results

      3.1 Study flow and characteristics

      The decision-making process for inclusion is shown in Fig. 1. Overall, 24 studies including 2,152,137 patients with diabetes were included [
      • Pyŏrälä K.
      • Pedersen T.R.
      • Kjekshus J.
      • et al.
      Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S).
      ,
      • Downs J.R.
      • Clearfield M.
      • Weis S.
      • et al.
      Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.
      ,
      • Goldberg R.B.
      • Mellies M.J.
      • Sacks F.M.
      • et al.
      Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators.
      ,
      • Hoogwerf B.J.
      • Waness A.
      • Cressman M.
      • et al.
      Effects of aggressive cholesterol lowering and low-dose anticoagulation on clinical and angiographic outcomes in patients with diabetes: the Post Coronary Artery Bypass Graft Trial.
      ,
      Results of the low-dose (20 mg) pravastatin GISSI Prevenzione trial in 4271 patients with recent myocardial infarction: do stopped trials contribute to overall knowledge? GISSI Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico).
      ,
      ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group
      The antihypertensive and lipid-lowering treatment to prevent heart attack trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT-LLT).
      ,
      • Serruys P.W.
      • de Feyter P.
      • Macaya C.
      • et al.
      Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial.
      ,
      • Shepherd J.
      • Blauw G.J.
      • Murphy M.B.
      • et al.
      Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.
      ,
      • Collins R.
      • Armitage J.
      • Parish S.
      • et al.
      MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.
      ,
      • Keech A.
      • Colquhoun D.
      • Best J.
      • et al.
      Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial.
      ,
      • Colhoun H.M.
      • Betteridge D.J.
      • Durrington P.N.
      • et al.
      Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.
      ,
      • Sever P.S.
      • Poulter N.R.
      • Dahlöf B.
      • et al.
      Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial--lipid-lowering arm (ASCOT-LLA).
      ,
      • Knopp R.H.
      • d'Emden M.
      • Smilde J.G.
      • et al.
      Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN).
      ,
      • Kjekshus J.
      • Apetrei E.
      • Barrios V.
      • et al.
      Rosuvastatin in older patients with systolic heart failure.
      ,
      • Tavazzi L.
      • Maggioni A.P.
      • Marchioli R.
      • et al.
      Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.
      ,
      • Tajima N.
      • Kurata H.
      • Nakaya N.
      • et al.
      Pravastatin reduces the risk for cardiovascular disease in Japanese hypercholesterolemic patients with impaired fasting glucose or diabetes: diabetes subanalysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study.
      ,
      • Ting R.Z.
      • Yang X.
      • Yu L.W.
      • et al.
      Lipid control and use of lipid-regulating drugs for prevention of cardiovascular events in Chinese type 2 diabetic patients: a prospective cohort study.
      ,
      • Callahan A.
      • Amarenco P.
      • Goldstein L.B.
      • et al.
      Risk of stroke and cardiovascular events after ischemic stroke or transient ischemic attack in patients with type 2 diabetes or metabolic syndrome: secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.
      ,
      • Sheng X.
      • Murphy M.J.
      • MacDonald T.M.
      • Wei L.
      Effect of statins on total cholesterol concentrations and cardiovascular outcomes in patients with diabetes mellitus: a population-based cohort study.
      ,
      • Simmons R.K.
      • Carlsen A.H.
      • Griffin S.J.
      • et al.
      Variation in prescribing of lipid-lowering medication in primary care is associated with incidence of cardiovascular disease and all-cause mortality in people with screen-detected diabetes: findings from the ADDITION-Denmark trial.
      ,
      • Hero C.
      • Rawshani A.
      • Svensson A.M.
      • et al.
      Association between use of lipid-lowering therapy and cardiovascular diseases and death in individuals with type 1 diabetes.
      ,
      • Fung C.S.C.
      • Wan E.Y.F.
      • Chan A.K.C.
      • Lam C.L.K.
      Statin use reduces cardiovascular events and all-cause mortality amongst Chinese patients with type 2 diabetes mellitus: a 5-year cohort study.
      ,
      • Ramos R.
      • Comas-Cufí M.
      • Martí-Lluch R.
      • et al.
      Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study.
      ,
      • Kim M.K.
      • Han K.
      • Joung H.N.
      • et al.
      Cholesterol levels and development of cardiovascular disease in Koreans with type 2 diabetes mellitus and without pre-existing cardiovascular disease.
      ]. Table 1 shows the characteristics of the 24 included studies on statins in individuals with diabetes. Fifteen studies recorded CVD events in primary prevention (eight RCTs), and 11 evaluated CVD events in secondary prevention (10 RCTs). Eight studies assessed all-cause mortality in primary prevention (four RCTs), and eight assessed all-cause mortality in secondary prevention (seven RCTs). Nine studies evaluated strokes in primary prevention (four RCTs), and six evaluated strokes in secondary prevention (five RCTs). Five and three patients were evaluated for CHD in primary and secondary prevention, respectively. The quality assessment results indicated that 17 and seven studies were of high and medium quality, respectively, in the meta-analysis.
      Table 1Characteristics of the included studies.
      StudyPreventionSample size (N)Age (years)Sex (male%)Pre-existing conditionStudy typeFollow up (year)StatinOutcomesBaseline LDL-C

      Level (mmol/L)
      quality
      4S 1997 [
      • Pyŏrälä K.
      • Pedersen T.R.
      • Kjekshus J.
      • et al.
      Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S).
      ]
      Secondary20259.9 ± 6.672.0DMdouble-blind,

      multicenter

      RCT
      5.4Lovastatin 20-40 mg/dCVD

      CHD

      All-cause mortality
      4.8 ± 0.67high
      AFCAPS/TexCAPS 1998 [
      • Downs J.R.
      • Clearfield M.
      • Weis S.
      • et al.
      Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.
      ]
      Primary15558.0 ± 7.085.0DMdouble-blind,

      RCT
      5.2Simvastatin 20-40 mg/dCVD4.04 ± 0.63high
      CARE 1998 [
      • Goldberg R.B.
      • Mellies M.J.
      • Sacks F.M.
      • et al.
      Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators.
      ]
      Secondary58661.0 ± 8.080.4DMdouble-blind, RCT5.0Pravastatin 40 mg/dCVD

      CHD

      All-cause mortality

      Ischaemic stroke
      136 ± 14 (mg/dL)high
      Post-CABG 1999 [
      • Hoogwerf B.J.
      • Waness A.
      • Cressman M.
      • et al.
      Effects of aggressive cholesterol lowering and low-dose anticoagulation on clinical and angiographic outcomes in patients with diabetes: the Post Coronary Artery Bypass Graft Trial.
      ]
      Secondary11663.1 (21–74)/T2DMdouble-blind,

      multicenter

      RCT
      4.3LovastatinCVD

      All-cause mortality
      3.93high
      GISSI-P 2000 [
      Results of the low-dose (20 mg) pravastatin GISSI Prevenzione trial in 4271 patients with recent myocardial infarction: do stopped trials contribute to overall knowledge? GISSI Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico).
      ]
      Secondary58269.0 ± 9.079.1DMdouble-blind,

      RCT
      1.9Pravastatin 20-40 mg/dAll-cause mortality< 250 mg/dlhigh
      ALLHAT-LLT 2002 [
      ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group
      The antihypertensive and lipid-lowering treatment to prevent heart attack trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT-LLT).
      ]
      Primary363866.4 ± 7.651.4T2DMMulticenter

      RCT
      4.8Pravastatin 40 mg/dCVD

      All-cause mortality
      3.8high
      LIPS 2002 [
      • Serruys P.W.
      • de Feyter P.
      • Macaya C.
      • et al.
      Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial.
      ]
      Secondary20260 (18–80)84.2T1DM and T2DMdouble-blind,

      multinational

      RCT
      3.9Fluvastatin 80 mg/dCVD3.4 ± 0.8high
      PROSPER 2002 [
      • Shepherd J.
      • Blauw G.J.
      • Murphy M.B.
      • et al.
      Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.
      ]
      Primary and Secondary62375.3 ± 3.448.0DMdouble-blind,

      RCT
      3.2Pravastatin 40 mg/dCVD3.8 ± 0.8high
      HPS 2003 [
      • Collins R.
      • Armitage J.
      • Parish S.
      • et al.
      MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.
      ]
      Primary and Secondary596362.1 ± 8.970.0T1DM and T2DMMulticenter

      RCT
      5.0Simvastatin 40 mg/dCVD

      CHD

      Ischaemic stroke
      3.2 ± 0.82high
      LIPID 2003 [
      • Keech A.
      • Colquhoun D.
      • Best J.
      • et al.
      Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial.
      ]
      Secondary107764 (57–68)81.0T1DM and T2DMdouble-blind,

      RCT
      6.1Pravastatin 40 mg/dCVD

      All-cause mortality

      Ischaemic stroke
      3.7high
      CARDS 2004 [
      • Colhoun H.M.
      • Betteridge D.J.
      • Durrington P.N.
      • et al.
      Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.
      ]
      Primary283861.5 ± 8.368.0T2DMdouble-blind,

      multicenter

      RCT
      3.9Atorvastatin 10 mg/dCVD

      CHD

      All-cause mortality

      Ischaemic stroke
      3.04 ± 0.72high
      ASCOT-LLA 2005 [
      • Sever P.S.
      • Poulter N.R.
      • Dahlöf B.
      • et al.
      Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial--lipid-lowering arm (ASCOT-LLA).
      ]
      Primary253263.6 ± 8.576.3T2DMdouble-blind,

      RCT
      3.3Atorvastatin 10 mg/dCVD

      Ischaemic stroke
      3.3 ± 0.7high
      ASPEN 2006 [
      • Knopp R.H.
      • d'Emden M.
      • Smilde J.G.
      • et al.
      Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN).
      ]
      Primary and Secondary241061.1 ± 8.166.3T2DMdouble-blind,

      multinational

      RCT
      4.0Atorvastatin 10 mg/dCVD

      All-cause mortality

      Ischaemic stroke
      113 ± 25 (mg/dL)high
      CORON 2007 [
      • Kjekshus J.
      • Apetrei E.
      • Barrios V.
      • et al.
      Rosuvastatin in older patients with systolic heart failure.
      ]
      Secondary147773 ± 7.176.0DMsingle-blind,

      RCT
      2.7Rosuvastatin 10 mg/dCVD3.54 ± 0.95high
      GISSI-HF 2008 [
      • Tavazzi L.
      • Maggioni A.P.
      • Marchioli R.
      • et al.
      Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.
      ]
      Secondary119668 ± 1177.4DMdouble-blind,

      multicenter

      RCT
      3.9Rosuvastatin 10 mg/dAll-cause mortality122 (mg/dL)high
      MEGA 2008 [
      • Tajima N.
      • Kurata H.
      • Nakaya N.
      • et al.
      Pravastatin reduces the risk for cardiovascular disease in Japanese hypercholesterolemic patients with impaired fasting glucose or diabetes: diabetes subanalysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study.
      ]
      Primary174659 ± 742DMmulticenter

      RCT
      5.3Pravastatin 10-20 mg/dCVD

      All-cause mortality

      Ischaemic stroke
      156.6 ± 18.8 (mg/dL)high
      Ting RZ et al., 2010 [
      • Ting R.Z.
      • Yang X.
      • Yu L.W.
      • et al.
      Lipid control and use of lipid-regulating drugs for prevention of cardiovascular events in Chinese type 2 diabetic patients: a prospective cohort study.
      ]
      Primary45215446.3T2DMprospective

      cohort study
      4.9statinsCVD3.0medium
      SPARCL 2011 [
      • Callahan A.
      • Amarenco P.
      • Goldstein L.B.
      • et al.
      Risk of stroke and cardiovascular events after ischemic stroke or transient ischemic attack in patients with type 2 diabetes or metabolic syndrome: secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.
      ]
      Secondary79464.4 ± 0.4961.1T2DMRCT4.9Atorvastatin 80 mg/dCVD

      All-cause mortality

      Ischaemic stroke
      130.8 (mg/dL)high
      Sheng X et al., 2012 [
      • Sheng X.
      • Murphy M.J.
      • MacDonald T.M.
      • Wei L.
      Effect of statins on total cholesterol concentrations and cardiovascular outcomes in patients with diabetes mellitus: a population-based cohort study.
      ]
      Primary and Secondary669760.9 ± 11.854.4DMpopulation-based cohort study14statinsCVD

      All-cause mortality

      Ischaemic stroke
      /medium
      Simmons RK et al., 2014 [
      • Simmons R.K.
      • Carlsen A.H.
      • Griffin S.J.
      • et al.
      Variation in prescribing of lipid-lowering medication in primary care is associated with incidence of cardiovascular disease and all-cause mortality in people with screen-detected diabetes: findings from the ADDITION-Denmark trial.
      ]
      Primary150940–6956.9T2DMObservational cohort study5statinsCVD

      All-cause mortality

      Ischaemic stroke
      /medium
      Hero C et al., 2016 [
      • Hero C.
      • Rawshani A.
      • Svensson A.M.
      • et al.
      Association between use of lipid-lowering therapy and cardiovascular diseases and death in individuals with type 1 diabetes.
      ]
      Primary805048.4 ± 11.754.9T1DMpropensity

      score–based study.
      6statinsCVD

      CHD

      All-cause mortality

      Ischaemic stroke
      2.71 ± 0.86medium
      Fung CSC et al., 2017 [
      • Fung C.S.C.
      • Wan E.Y.F.
      • Chan A.K.C.
      • Lam C.L.K.
      Statin use reduces cardiovascular events and all-cause mortality amongst Chinese patients with type 2 diabetes mellitus: a 5-year cohort study.
      ]
      Primary2020864.8 ± 10.341.7T2DMretrospective cohort study5statinsCVD

      CHD

      All-cause mortality

      Ischaemic stroke
      3.76 ± 0.63medium
      Ramos R et al., 2018 [
      • Ramos R.
      • Comas-Cufí M.
      • Martí-Lluch R.
      • et al.
      Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study.
      ]
      Primary7880>7539.7T2DMretrospective cohort study5.6statinsCVD

      CHD

      All-cause mortality

      Ischaemic stroke
      3.7 ± 0.9medium
      Kim MK et al., 2019 [
      • Kim M.K.
      • Han K.
      • Joung H.N.
      • et al.
      Cholesterol levels and development of cardiovascular disease in Koreans with type 2 diabetes mellitus and without pre-existing cardiovascular disease.
      ]
      Primary207713558.3 ± 10.556.6T2DMprospective

      cohort study
      7.1statinsCVD

      Ischaemic stroke
      113.4 ± 10.5 (mg/dL)medium
      AKI, acute kidney injury; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; RCT, randomized controlled trial; 4S: Scandinavian Simvastatin Survival Study; AFCAPS/TexCAPS, the Air Force/Texas Coronary Atherosclerosis Prevention Study; CARE, the Cholesterol And Recurrent Events; Post-CABG, the Post Coronary Artery Bypass Graft; ALLHAT-LLT, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; LIPS, Lescol Intervention Prevention Study; PROSPER, the PROspective Study of Pravastatin in the Elderly at Risk; LIPID, the Long-Term Intervention with Pravastatin in Ischemic Disease trial; CARDS, the Collaborative Atorvastatin Diabetes Study; ASCOT-LLA, Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm; ASPEN, the Atorvastatin Study for Prevention of Coronary Heart DiseaseEndpoints in Non-Insulin-Dependent Diabetes Mellitus; SPARCL, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trial; GISSI-HF, the Gruppo Italiano per lo Studio della Sopravvivenza nell’Insuffi cienza cardiac-heart failure; MEGA, the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese Study; GISSI-P, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico Prevenzione.

      3.2 Association between statin use and risk of cardiovascular events and coronary heart disease in patients with diabetes in primary and secondary prevention

      In the analysis of primary prevention, the pooled results from 15 studies indicated that compared with statin non-users, statin users showed a lower risk of CVD events (RR = 0.80, 95% confidence interval [CI] 0.69–0.94, P = 0.006 [Fig. 2A]). Similarly, the pooled results from eight RCTs also indicated that those receiving statins showed a lower risk of CVD events (RR = 0.76, 95% CI 0.69–0.85, P < 0.0001) compared to statin non-users.
      Figure 2
      Figure 2RRs for CVD events associated with statin use from pooled studies in patients with diabetes.(A) Pooled results of statin use for CVD events in primary prevention in patients with diabetes.(B) Pooled results of statin use for CVD events in secondary prevention in patients with diabetes.
      In the analysis of secondary prevention, the results of 11 studies showed that statin therapy was more effective in the prevention of CVD events than no statin therapy (RR = 0.75, 95% CI 0.65–0.87, P < 0.0001 [Fig. 2B]). The pooled results from 10 RCTs also indicated that statin therapy was significantly associated with a reduced risk of CVD (RR = 0.79, 95% CI 0.68–0.90, P = 0.001). Thus, publication bias was found in CVD prevention (primary prevention, P = 0.001; secondary prevention, P = 0.013).
      In the analysis of primary and secondary prevention, statin users also showed a reduced risk of CHD (RR = 0.78, 95% CI 0.72–0.85 and RR = 0.59, 95% CI 0.42–0.84, respectively [Fig. 5]).
      Figure 3
      Figure 3RRs for all-cause mortality associated with statin use from pooled studies in patients with diabetes.(A) Pooled results of statin use for all-cause mortality in primary prevention in patients with diabetes(B) Pooled results of statin use for all-cause mortality in secondary prevention in patients with diabetes.
      Figure 4
      Figure 4RRs for ischaemic stroke associated with statin use from pooled studies in patients with diabetes. (A) Pooled results of statin use for ischaemic stroke in primary prevention in patients with diabetes.(B) Pooled results of statin use for ischaemic stroke in secondary prevention in patients with diabetes.
      Figure 5
      Figure 5RRs for CHD associated with statin use from pooled studies in patients with diabetes.

      3.3 Association between statins use and the risk of all-cause mortality in patients with diabetes in primary and secondary prevention

      As shown in Fig. 3A, the pooled results from all trials dealing with all-cause mortality were inconclusive, indicating that statin use was not associated with decreased all-cause mortality compared with statin non-users among patients with diabetes in primary prevention (RR = 0.85, 95% CI 0.71–1.01, P = 0.079). Pooled results from four RCTs also indicated that compared to statin non-users, those receiving statins were not associated with all-cause mortality (RR = 0.89, 95% CI 0.68–1.16, P = 0.396).
      Similarly, there was no significant association between statin use and the incidence of all-cause mortality in secondary prevention (RR = 0.85, 95% CI 0.70–1.03, P = 0.065 [Fig. 3B]). The pooled results from seven RCTs also indicated that compared to statin non-users, statins users were not associated with all-cause mortality (RR = 0.97, 95% CI 0.86–1.09, P = 0.600 [Fig. 3B]). No publication bias was found (primary prevention, P = 0.440; secondary prevention, P = 0.245).

      3.4 Association between statin use and the risk of ischemic stroke in patients with diabetes in primary and secondary prevention

      Compared to no statin therapy, the results from nine studies showed that statin therapy resulted in significantly lower risk of ischemic stroke in the primary prevention of patients with diabetes (RR = 0.83, 95% CI 0.70–0.97, P = 0.020 [Fig. 4A]). The pooled results from the four RCTs also indicated that statin therapy was effective in reducing the risk of ischemic stroke in the primary prevention of patients with diabetes (RR = 0.69, 95% CI 0.53–0.90, P = 0.007 [Fig. 4A]).
      In the analysis of secondary prevention, the results of six studies showed that statin therapy was more effective than no statin therapy (RR = 0.74, 95% CI 0.63–0.85, P < 0.0001 [Fig. 4B]). The pooled results from five RCTs also indicated that statin therapy was effective in the secondary prevention of stroke (RR = 0.74, 95% CI 0.64–0.86, P = 0.007 [Fig. 4B]). Consequently, publication bias was found in the primary prevention group (P = 0.035), but no publication bias was found in the secondary prevention group (P = 0.578).

      3.5 Quality of evidence assessment

      The GRADE system was used to assess the quality of evidence, and the results are presented in Table 2. In summary, the quality of evidence was rated as high for CVD events in primary prevention, all-cause mortality in secondary prevention, stroke in both primary and secondary prevention, and moderate for CVD events in secondary prevention and all-cause mortality in primary prevention.
      Table 2Statin users compared to Statin non-users for CVD/All-cause mortality/Stroke in patients with diabetes.
      OutcomesNo of participants (studies)

      Follow up
      Certainty of the evidence (GRADE)Relative effect (95% CI)Anticipated absolute effects
      Risk with Statin non-usersRisk difference with Statin users
      CVD events primary prevention21713 (8 RCTs)

      HIGH
      RR 0.76 (0.69–0.85)96 per 100023 fewer per 1000 (30 fewer to 14 fewer)
      CVD events

      secondary prevention
      7167 (10 RCTs)

      MODERATE
      RR 0.79 (0.68–0.90)343 per 100072 fewer per 1000 (110 fewer to 34 fewer)
      All-cause mortality primary prevention8727 (4 RCTs)

      MODERATE
      RR 0.89 (0.68–1.16)83 per 10009 fewer per 1000 (27 fewer to 13 more)
      All-cause mortality

      Secondary prevention
      3981 (7 RCTs)

      HIGH
      RR 0.97 (0.86–1.09)268 per 10008 fewer per 1000 (38 fewer to 24 more)
      Stroke primary prevention9021 (4 RCTs)

      HIGH
      RR 0.69 (0.53–0.90)29 per 10009 fewer per 1000 (14 fewer to 3 fewer)
      Stroke-Secondary prevention8902 (5 RCTs)

      HIGH
      RR 0.74 (0.64–0.86)81 per 100021 fewer per 1000 (29 fewer to 11 fewer)
      Patient or population: Diabetic patients.
      Intervention: Statin users.
      Comparison: Statin non-users.
      ∗The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)·CI: Confidence interval; RR: Risk ratio.
      GRADE Working Group grades of evidence.
      High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
      Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
      Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
      Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

      4. Discussion

      This meta-analysis is the largest in terms of pooling results from the largest number of articles and sample size. The main results indicate that statin use in patients with diabetes is associated with a reduced risk of CVD events and ischemic stroke in primary and secondary prevention, but is not associated with reduced all-cause mortality in either group.
      The results of this meta-analysis differ from those of several previous meta-analyses [
      • Baigent C.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists’ (CTT) Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      ,
      • Kearney P.M.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaborators
      Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.
      ,
      • Chang Y.H.
      • Hsieh M.C.
      • Wang C.Y.
      • et al.
      Reassessing the benefits of statins in the prevention of cardiovascular disease in diabetic patients--a systematic review and meta-analysis.
      ]. First, several previous meta-analyses compared statin use in diabetes versus non-diabetes or less versus more intensive statin therapy between patients with and without diabetes. Our pooled results were obtained from individuals with diabetes and compared statin use with non-statin use. It is reasonable to believe that such results are reliable when comparing statin and non-statin use in the same disease condition. Second, there have been several meta-analyses of patients with diabetic kidney disease and those undergoing hemodialysis (HD). There is a counter-epidemiological phenomenon in patients undergoing HD; therefore, it is readily comprehensible that statin use in patients on HD is not associated with a positive reduction in CVD risk and mortality. Third, the number of patients in some large lipid-lowering therapy studies was high; however, the subgroups of individuals with diabetes, such as 4S (n = 202), WOSCOPS (n = 76), LIPS (n = 202), and post-CABG (n = 116), were relatively small. The pooled results from small trials were not statistically robust. However, our meta-analysis included RCTs, prospective cohort trials, and retrospective studies, and the overall result is the same as the pooled RCT result, indicating that the overall results are reliable.
      The American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines published their 2018 recommendations for the management of LDL-C in patients with diabetes [
      • Goldberg R.B.
      • Stone N.J.
      • Grundy S.M.
      The 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guidelines on the management of blood cholesterol in diabetes.
      ]. For primary prevention, moderate-intensity statin therapy is recommended for those aged 40–75 years, with a preference for high-intensity statin treatment for older subjects and those with higher estimated risk or risk-enhancing factors. This recommendation is mainly based on a meta-analysis of 14 randomized trials comparing statin use in patients with and without diabetes [
      • Kearney P.M.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaborators
      Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.
      ]. However, this conclusion is insufficiently strong; statin users should be compared with statin non-users in the same individuals with diabetes, rather than statin use in patients with diabetes and those without diabetes. Of the 24 papers included in this meta-analysis, 17, 4, and 3 were RCTs, prospective cohort studies, and retrospective studies, respectively. Placebo served as a control in all RCTs on primary and secondary prevention. In both prospective and retrospective studies, expectedly, non-statin users were used as controls compared with statin users. Therefore, it is easy to understand that some patients with diabetes did not receive statin therapy.
      If an individual is intolerable to statins, is an alternative drug available? PCSK9 is a circulating protein that binds to the LDL receptor to regulate cholesterol metabolism. PCSK9 monoclonal antibody therapy, which reduces LDL-C level, has been used clinically for many years and may be a substitute for patients with diabetes who are intolerant or resistant to statins. A previous study has shown that the PCSK9 monoclonal antibody alirocumab could decrease the risk of stroke, irrespective of baseline LDL-C level and history of cerebrovascular disease in patients with recent acute coronary syndrome and dyslipidemia despite intensive statin therapy [
      • Jukema J.W.
      • Zijlstra L.E.
      • Bhatt D.L.
      • et al.
      Effect of alirocumab on stroke in ODYSSEY OUTCOMES.
      ]. Therefore, combination therapy with statins and PCSK9 inhibitors or PCSK9 inhibitors alone for those who are intolerable to statins may further reduce CVD events, stroke, and mortality in individuals with diabetes.
      The mechanism by which statins reduce the risk of CVD and stroke in diabetes is related to the potential protection of endothelial cell injuries induced by hyperglycemia. Hyperglycemia is an important factor associated with cardiovascular damage. Hyperglycemia-induced mitochondrial dysfunction and endoplasmic reticulum stress can promote reactive oxygen species accumulation, subsequently promoting cellular damage [
      • Bertoluci M.C.
      • Cé G.V.
      • da Silva A.M.
      • et al.
      Endothelial dysfunction as a predictor of cardiovascular disease in type 1 diabetes.
      ,
      • Fiorentino T.V.
      • Prioletta A.
      • Zuo P.
      • et al.
      Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases.
      ,
      • Madonna R.
      • De Caterina R.
      Cellular and molecular mechanisms of vascular injury in diabetes--part I: pathways of vascular disease in diabetes.
      ]. Elevated glucose levels might also increase pro-inflammatory and procoagulant factor expression, induce apoptosis, and impair nitric oxide release. Oxidative stress-induced phenotypic alterations were observed in vascular smooth muscle cell (37). A previous study showed that statins could directly regulate extracellular signal-regulated kinase 5, stimulate tight junction formation, and reduce permeability of human cardiac endothelial cells [
      • Wilkinson E.L.
      • Sidaway J.E.
      • Cross M.J.
      Statin regulated ERK5 stimulates tight junction formation and reduces permeability in human cardiac endothelial cells.
      ]. Statins can reduce endothelial lipase expression in vitro and in vivo by inhibiting RhoA activity [
      • Kojima Y.
      • Ishida T.
      • Sun L.
      • et al.
      Pitavastatin decreases the expression of endothelial lipase both in vitro and in vivo.
      ].
      In this meta-analysis, our pooled results showed that statin use is effective in the primary and secondary prevention of stroke in patients with diabetes. Whether statins play different roles in stroke prevention in primary and secondary prevention settings is controversial. A previous meta-analysis [
      • Milionis H.
      • Ntaios G.
      • Korompoki E.
      • et al.
      Statin-based therapy for primary and secondary prevention of ischemic stroke: a meta-analysis and critical overview.
      ] indicated that lipid-lowering therapy using statins in the general population was associated with a lower risk of ischemic stroke in primary and secondary prevention. The curve estimation procedure revealed a linear association between the absolute risk reduction of ischemic stroke in secondary prevention, and the cubic model indicated a greater absolute risk reduction in high-risk CVD-free individuals in primary prevention. Considering the relatively few trials (nine papers on primary prevention and six on secondary prevention) in our pooled stroke prevention studies, more trials are required to further confirm these significant results in patients with diabetes.
      It is unclear why statins had no significant effect on all-cause mortality in patients with diabetes in the pooled results. Early meta-analysis also showed that there was a slight and insignificant reduction in the relative risk of non-cardiovascular mortality and fatal strokes in primary and secondary prevention in individuals without diabetes [
      • Vrecer M.
      • Turk S.
      • Drinovec J.
      • et al.
      Use of statins in primary and secondary prevention of coronary heart disease and ischemic stroke. Meta-analysis of randomized trials.
      ]. However, its precise mechanism of action remains unclear. Elevated inflammation and coronary plaque progression have been proposed in statin users [
      • Scott C.
      • Lateef S.S.
      • Hong C.G.
      • et al.
      Inflammation, coronary plaque progression, and statin use: a secondary analysis of the risk stratification with image guidance of HMG CoA reductase inhibitor therapy (RIGHT) study.
      ]. In a subgroup analysis of 142 participants from the Risk Stratification with Image Guidance of HMG CoA Reductase Inhibitor Therapy study, the authors found that systemic inflammation played a role in coronary calcification, which probably led to increased side effects in statin users [
      • Scott C.
      • Lateef S.S.
      • Hong C.G.
      • et al.
      Inflammation, coronary plaque progression, and statin use: a secondary analysis of the risk stratification with image guidance of HMG CoA reductase inhibitor therapy (RIGHT) study.
      ]. Diabetes may increase systemic inflammation, and increased inflammation and coronary calcification may counteract the effects of statins in patients with diabetes. Therefore, it seems reasonable to explain the negative results for mortality in patients with statin use and diabetes. However, there are only eight papers on primary and secondary prevention, and more perspective-controlled studies are required to confirm this conclusion.
      This meta-analysis has some potential limitations. First, RCTs were relatively small for each endpoint event, the sample size was relatively small, and many trials were published several years previously, several of which were prospective or retrospective cohort studies. However, the overall results are consistent with the pooled results of the RCTs, and the conclusions are reliable. Second, heterogeneity was relatively high in pooled all-cause mortality and stroke in primary prevention, with 75.5% and 73.6% heterogeneity, respectively. This significant heterogeneity was due to the different study designs (RCT, prospective cohort, or retrospective cohort) included in this meta-analysis. Third, there are several publication biases in primary and secondary prevention, and negative results are probably difficult to publish. However, publication bias did not affect the overall results. Fourth, the types of diabetes cannot be separated because most of the studies did not clearly state whether the study subjects had type 1 or 2 diabetes.

      5. Conclusions

      In conclusion, this meta-analysis indicates that statin use is associated with a reduced risk of CVD events and stroke, but not with reduced all-cause mortality, in patients with diabetes in primary and secondary prevention.

      Authors' contributions

      HM Jin and SK Fu conceived and designed the study. XH Yang, BL Zhang and Y Chen selected the articles, extracted and analyzed the data. XH Yang, BL Zhang and Y Chen wrote the first draft of the manuscript. XH Yang and BL Zhang interpreted the data and contributed to the writing of the final version of the manuscript. All authors agreed with the results and conclusions of this Article.

      Funding

      This study was supported by Discipline Construction Promoting Project of Shanghai Pudong Hospital in Nephrology ( Zdxk2020-10 ), Key Specialty of Plasma Purification in Shanghai Pudong Hospital ( Zdzk2020-12 ). All authors have approved the final version of the manuscript and have agreed to submit it to this journal. Zhang BL, Cheng Y and Yang XH contributed equally to this paper.

      Declaration of competing interest

      The authors declare no competing interests.

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