Statin use and risk of new-onset diabetes: A meta-analysis of observational studies

  • M. Casula
    Corresponding author. Fax: +39 02 503 18386.
    Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy
    Search for articles by this author
  • F. Mozzanica
    Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy
    Search for articles by this author
  • L. Scotti
    Department of Statistics and Quantitative Methods, Division of Biostatistics, Epidemiology and Public Health, University of Milano-Bicocca, Via Bicocca degli Arcimboldi 8, 20126, Milan, Italy
    Search for articles by this author
  • E. Tragni
    Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy
    Search for articles by this author
  • A. Pirillo
    Center for the Study of Atherosclerosis, E. Bassini Hospital, Via M. Gorki 50, Cinisello Balsamo, 20092, Milan, Italy
    Search for articles by this author
  • G. Corrao
    Department of Statistics and Quantitative Methods, Division of Biostatistics, Epidemiology and Public Health, University of Milano-Bicocca, Via Bicocca degli Arcimboldi 8, 20126, Milan, Italy
    Search for articles by this author
  • A.L. Catapano
    Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy

    IRCCS MultiMedica, Via Milanese 300, 20099, Sesto S. Giovanni (MI), Italy
    Search for articles by this author


      • Trial meta-analyses showed an increased risk of statin-associated diabetes of 9–13%.
      • Our meta-analysis of observational studies showed an increased risk of 44%.
      • Our results confirm the need of a rigorous monitoring of patients taking statins.


      Background and aims

      Meta-analyses of randomized control trials investigating the association between incident diabetes and statin use showed an increased risk of new-onset diabetes (NOD) from 9% to 13% associated with statins. However, short follow-up period, unpowered sample size, and lack of pre-specified diagnostic criteria for diabetes detection could be responsible of an underestimation of this risk. We conducted a meta-analysis of published observational studies to evaluate the association between statins use and risk of NOD.

      Methods and results

      PubMed, EMBASE and MEDLINE databases were searched from inception to June 30, 2016 for cohort and case–control studies with risk of NOD in users vs nonusers, on ≥1000 subjects followed-up for ≥1 year. Two review authors assessed study eligibility and risk of bias and undertook data extraction independently. Pooled estimates were calculated by a random-effects model and between-study heterogeneity was tested and measured by I2 index. Furthermore, stratified analyses and the evaluation of publication bias were performed. Finally, the meta-analysis included 20 studies, 18 cohort and 2 case–control studies. Overall, NOD risk was higher in statin users than nonusers (RR 1.44; 95% CI 1.31–1.58). High between-study heterogeneity (I2 = 97%) was found. Estimates for all single statins showed a class effect, from rosuvastatin (RR 1.61; 1.30–1.98) to simvastatin (RR 1.38; 1.19–1.61).


      The present meta-analysis confirms and reinforces the evidence of a diabetogenic effect by statins utilization. These observations confirm the need of a rigorous monitoring of patients taking statins, in particular pre-diabetic patients or patients presenting with established risk factors for diabetes.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Nutrition, Metabolism and Cardiovascular Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Cholesterol Treatment Trialists C
        • Fulcher J.
        • O'Connell R.
        • Voysey M.
        • Emberson J.
        • Blackwell L.
        • et al.
        Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials.
        Lancet. 2015; 385: 1397-1405
        • Cholesterol Treatment Trialists C
        • Baigent C.
        • Blackwell L.
        • Emberson J.
        • Holland L.E.
        • Reith C.
        • et al.
        Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
        Lancet. 2010; 376: 1670-1681
        • Freeman D.J.
        • Norrie J.
        • Sattar N.
        • Neely R.D.
        • Cobbe S.M.
        • Ford I.
        • et al.
        Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study.
        Circulation. 2001; 103: 357-362
        • Downs J.R.
        • Clearfield M.
        • Weis S.
        • Whitney E.
        • Shapiro D.R.
        • Beere P.A.
        • 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.
        Jama. 1998; 279: 1615-1622
      1. 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). Ital Heart J Off J Ital Fed Cardiol 2000;1:810–820.

        • Keech A.
        • Colquhoun D.
        • Best J.
        • Kirby A.
        • Simes R.J.
        • Hunt D.
        • et al.
        Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial.
        Diabetes Care. 2003; 26: 2713-2721
        • Ridker P.M.
        • Danielson E.
        • Fonseca F.A.
        • Genest J.
        • Gotto Jr., A.M.
        • Kastelein J.J.
        • et al.
        Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
        N Engl J Med. 2008; 359: 2195-2207
        • Culver A.L.
        • Ockene I.S.
        • Balasubramanian R.
        • Olendzki B.C.
        • Sepavich D.M.
        • Wactawski-Wende J.
        • et al.
        Statin use and risk of diabetes mellitus in postmenopausal women in the women's health initiative.
        Archives Intern Med. 2012; 172: 144-152
        • Park Z.H.
        • Juska A.
        • Dyakov D.
        • Patel R.V.
        Statin-associated incident diabetes: a literature review.
        Consult Pharm J Am Soc Consult Pharm. 2014; 29: 317-334
        • Rajpathak S.N.
        • Kumbhani D.J.
        • Crandall J.
        • Barzilai N.
        • Alderman M.
        • Ridker P.M.
        Statin therapy and risk of developing type 2 diabetes: a meta-analysis.
        Diabetes Care. 2009; 32: 1924-1929
        • Sattar N.
        • Preiss D.
        • Murray H.M.
        • Welsh P.
        • Buckley B.M.
        • de Craen A.J.
        • et al.
        Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.
        Lancet. 2010; 375: 735-742
        • Mills E.J.
        • Wu P.
        • Chong G.
        • Ghement I.
        • Singh S.
        • Akl E.A.
        • et al.
        Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials.
        QJM Mon J Assoc Physicians. 2011; 104: 109-124
        • Preiss D.
        • Seshasai S.R.
        • Welsh P.
        • Murphy S.A.
        • Ho J.E.
        • Waters D.D.
        • et al.
        Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.
        Jama. 2011; 305: 2556-2564
        • Cai R.
        • Yuan Y.
        • Zhou Y.
        • Xia W.
        • Wang P.
        • Sun H.
        • et al.
        Lower intensified target LDL-c level of statin therapy results in a higher risk of incident diabetes: a meta-analysis.
        Plos One. 2014; 9: e104922
        • Thakker D.
        • Nair S.
        • Pagada A.
        • Jamdade V.
        • Malik A.
        Statin use and the risk of developing diabetes: a network meta-analysis.
        Pharmacoepidemiol Drug Saf. 2016 Oct; 25: 1131-1149
        • Mansi I.
        • Frei C.R.
        • Wang C.P.
        • Mortensen E.M.
        Statins and new-onset diabetes mellitus and diabetic complications: a retrospective cohort study of US healthy adults.
        J General Intern Med. 2015; 30: 1599-1610
        • Moher D.
        • Shamseer L.
        • Clarke M.
        • Ghersi D.
        • Liberati A.
        • Petticrew M.
        • et al.
        Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
        Syst Rev. 2015; 4: 1
        • Stroup D.F.
        • Berlin J.A.
        • Morton S.C.
        • Olkin I.
        • Williamson G.D.
        • Rennie D.
        • et al.
        Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group.
        Jama. 2000; 283: 2008-2012
      2. Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses.

        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • Egger M.
        • Davey Smith G.
        • Schneider M.
        • Minder C.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • Bhattacharya R.
        • Ajmera M.
        • Bhattacharjee S.
        • Sambamoorthi U.
        Use of antidepressants and statins and short-term risk of new-onset diabetes among high risk adults.
        Diabetes Res Clin Pract. 2014; 105: 251-260
        • Cederberg H.
        • Stancakova A.
        • Yaluri N.
        • Modi S.
        • Kuusisto J.
        • Laakso M.
        Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort.
        Diabetologia. 2015; 58: 1109-1117
        • Chen C.W.
        • Chen T.C.
        • Huang K.Y.
        • Chou P.
        • Chen P.F.
        • Lee C.C.
        Differential impact of statin on new-onset diabetes in different age groups: a population-based case-control study in women from an asian country.
        Plos One. 2013; 8: e71817
        • Currie O.
        • Mangin D.
        • Williman J.
        • McKinnon-Gee B.
        • Bridgford P.
        The comparative risk of new-onset diabetes after prescription of drugs for cardiovascular risk prevention in primary care: a national cohort study.
        BMJ Open. 2013; 3: e003475
        • Danaei G.
        • Garcia Rodriguez L.A.
        • Fernandez Cantero O.
        • Hernan M.A.
        Statins and risk of diabetes: an analysis of electronic medical records to evaluate possible bias due to differential survival.
        Diabetes Care. 2013; 36: 1236-1240
        • Izzo R.
        • de Simone G.
        • Trimarco V.
        • Giudice R.
        • De Marco M.
        • Di Renzo G.
        • et al.
        Primary prevention with statins and incident diabetes in hypertensive patients at high cardiovascular risk.
        Nutr Metab Cardiovasc Dis NMCD. 2013; 23: 1101-1106
        • Lichtenstein K.A.
        • Hart R.L.
        • Wood K.C.
        • Bozzette S.
        • Buchacz K.
        • Brooks J.T.
        • et al.
        Statin use is associated with incident diabetes mellitus among patients in the HIV outpatient study.
        J Acquir Immune Defic Syndr. 2015; 69: 306-311
        • Macedo A.F.
        • Douglas I.
        • Smeeth L.
        • Forbes H.
        • Ebrahim S.
        Statins and the risk of type 2 diabetes mellitus: cohort study using the UK clinical practice pesearch datalink.
        BMC Cardiovasc Disord. 2014; 14: 85
        • Radford N.B.
        • DeFina L.F.
        • Barlow C.E.
        • Kerr A.
        • Chakravorty R.
        • Khera A.
        • et al.
        Effect of fitness on incident diabetes from statin use in primary prevention.
        Atherosclerosis. 2015; 239: 43-49
        • Zaharan N.L.
        • Williams D.
        • Bennett K.
        Statins and risk of treated incident diabetes in a primary care population.
        Br J Clin Pharmacol. 2013; 75: 1118-1124
        • Calza L.
        • Colangeli V.
        • Magistrelli E.
        • Manfredi R.
        • Bon I.
        • Re M.C.
        • et al.
        No correlation between statin exposure and incident diabetes mellitus in HIV-1-infected patients receiving combination antiretroviral therapy.
        HIV Med. 2016 Sep; 17: 631-633
        • Castro M.R.
        • Simon G.
        • Cha S.S.
        • Yawn B.P.
        • Melton 3rd, L.J.
        • Caraballo P.J.
        Statin use, diabetes incidence and overall mortality in normoglycemic and impaired fasting glucose patients.
        J General Intern Med. 2016; 31: 502-508
        • Jick S.S.
        • Bradbury B.D.
        Statins and newly diagnosed diabetes.
        Br J Clin Pharmacol. 2004; 58: 303-309
        • Lin Z.F.
        • Wang C.Y.
        • Shen L.J.
        • Hsiao F.Y.
        • Lin Wu F.L.
        Statin use and the risk for incident diabetes mellitus in patients with acute coronary syndrome after percutaneous coronary intervention: a population-based retrospective cohort study in Taiwan.
        Can J Diabetes. 2016; 40: 264-269
        • Olotu B.S.
        • Shepherd M.D.
        • Novak S.
        • Lawson K.A.
        • Wilson J.P.
        • Richards K.M.
        • et al.
        Use of statins and the risk of incident diabetes: a retrospective cohort study.
        Am J Cardiovasc Drugs Drugs Devices Interv. 2016; 16: 377-390
        • Rha S.W.
        • Choi B.G.
        • Seo H.S.
        • Park S.H.
        • Park J.Y.
        • Chen K.Y.
        • et al.
        Impact of statin use on development of new-onset diabetes mellitus in asian population.
        Am J Cardiol. 2016; 117: 382-387
        • van de Woestijne A.P.
        • van der Graaf Y.
        • Westerink J.
        • Nathoe H.M.
        • Visseren F.L.
        Effect of statin therapy on incident type 2 diabetes mellitus in patients with clinically manifest vascular disease.
        Am J Cardiol. 2015; 115: 441-446
        • Wang K.L.
        • Liu C.J.
        • Chao T.F.
        • Huang C.M.
        • Wu C.H.
        • Chen S.J.
        • et al.
        Statins, risk of diabetes, and implications on outcomes in the general population.
        J Am Coll Cardiol. 2012; 60: 1231-1238
        • Coleman C.I.
        • Reinhart K.
        • Kluger J.
        • White C.M.
        The effect of statins on the development of new-onset type 2 diabetes: a meta-analysis of randomized controlled trials.
        Curr Med Res Opin. 2008; 24: 1359-1362
        • Navarese E.P.
        • Buffon A.
        • Andreotti F.
        • Kozinski M.
        • Welton N.
        • Fabiszak T.
        • et al.
        Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus.
        Am J Cardiol. 2013; 111: 1123-1130
        • Schrom J.R.
        • Caraballo P.J.
        • Castro M.R.
        • Simon G.J.
        Quantifying the effect of statin use in pre-diabetic phenotypes discovered through association rule mining.
        in: AMIA annual symposium proceedings/AMIA symposium. vol. 2013. 2013: 1249-1257
        • Park J.Y.
        • Rha S.W.
        • Choi B.
        • Choi J.W.
        • Ryu S.K.
        • Kim S.
        • et al.
        Impact of low dose atorvastatin on development of new-onset diabetes mellitus in Asian population: three-year clinical outcomes.
        Int J Cardiol. 2015; 184: 502-506
        • Corrao G.
        • Ibrahim B.
        • Nicotra F.
        • Soranna D.
        • Merlino L.
        • Catapano A.L.
        • et al.
        Statins and the risk of diabetes: evidence from a large population-based cohort study.
        Diabetes Care. 2014; 37: 2225-2232
        • Arfe A.
        • Corrao G.
        Tutorial: strategies addressing detection bias were reviewed and implemented for investigating the statins-diabetes association.
        J Clin Epidemiol. 2015; 68: 480-488
        • Swerdlow D.I.
        • Preiss D.
        • Kuchenbaecker K.B.
        • Holmes M.V.
        • Engmann J.E.
        • Shah T.
        • et al.
        HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.
        Lancet. 2015; 385: 351-361
        • Andersson C.
        • Lyass A.
        • Larson M.G.
        • Robins S.J.
        • Vasan R.S.
        Low-density-lipoprotein cholesterol concentrations and risk of incident diabetes: epidemiological and genetic insights from the Framingham Heart Study.
        Diabetologia. 2015; 58: 2774-2780
        • Li N.
        • van der Sijde M.R.
        • LifeLines Cohort Study G
        • Bakker S.J.
        • Dullaart R.P.
        • van der Harst P.
        • et al.
        Pleiotropic effects of lipid genes on plasma glucose, HbA1c, and HOMA-IR levels.
        Diabetes. 2014; 63: 3149-3158
        • Fall T.
        • Xie W.
        • Poon W.
        • Yaghootkar H.
        • Magi R.
        • Consortium G.
        • et al.
        Using genetic variants to assess the relationship between circulating lipids and type 2 diabetes.
        Diabetes. 2015; 64: 2676-2684
        • Besseling J.
        • Kastelein J.J.
        • Defesche J.C.
        • Hutten B.A.
        • Hovingh G.K.
        Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus.
        Jama. 2015; 313: 1029-1036
        • Brault M.
        • Ray J.
        • Gomez Y.H.
        • Mantzoros C.S.
        • Daskalopoulou S.S.
        Statin treatment and new-onset diabetes: a review of proposed mechanisms.
        Metab Clin Exp. 2014; 63: 735-745
        • Zhao W.
        • Zhao S.P.
        Different effects of statins on induction of diabetes mellitus: an experimental study.
        Drug Des Dev Ther. 2015; 9: 6211-6223
        • Nakata M.
        • Nagasaka S.
        • Kusaka I.
        • Matsuoka H.
        • Ishibashi S.
        • Yada T.
        Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control.
        Diabetologia. 2006; 49: 1881-1892
        • Khan T.
        • Hamilton M.P.
        • Mundy D.I.
        • Chua S.C.
        • Scherer P.E.
        Impact of simvastatin on adipose tissue: pleiotropic effects in vivo.
        Endocrinology. 2009; 150: 5262-5272
        • McGuire T.F.
        • Xu X.Q.
        • Corey S.J.
        • Romero G.G.
        • Sebti S.M.
        Lovastatin disrupts early events in insulin signaling: a potential mechanism of lovastatin's anti-mitogenic activity.
        Biochem Biophys Res Commun. 1994; 204: 399-406
        • Takaguri A.
        • Satoh K.
        • Itagaki M.
        • Tokumitsu Y.
        • Ichihara K.
        Effects of atorvastatin and pravastatin on signal transduction related to glucose uptake in 3T3L1 adipocytes.
        J Pharmacol Sci. 2008; 107: 80-89
        • Brunham L.R.
        • Kruit J.K.
        • Hayden M.R.
        • Verchere C.B.
        Cholesterol in beta-cell dysfunction: the emerging connection between HDL cholesterol and type 2 diabetes.
        Curr Diabetes Rep. 2010; 10: 55-60
        • Brunham L.R.
        • Kruit J.K.
        • Pape T.D.
        • Timmins J.M.
        • Reuwer A.Q.
        • Vasanji Z.
        • et al.
        Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment.
        Nat Med. 2007; 13: 340-347
        • Kruit J.K.
        • Kremer P.H.
        • Dai L.
        • Tang R.
        • Ruddle P.
        • de Haan W.
        • et al.
        Cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1) and cholesterol uptake via the LDL receptor influences cholesterol-induced impairment of beta cell function in mice.
        Diabetologia. 2010; 53: 1110-1119
        • Vallejo-Vaz A.J.
        • Kondapally Seshasai S.R.
        • Kurogi K.
        • Michishita I.
        • Nozue T.
        • Sugiyama S.
        • et al.
        Effect of pitavastatin on glucose, HbA1c and incident diabetes: a meta-analysis of randomized controlled clinical trials in individuals without diabetes.
        Atherosclerosis. 2015; 241: 409-418
        • Chapman M.J.
        • Orsoni A.
        • Robillard P.
        • Hounslow N.
        • Sponseller C.A.
        • Giral P.
        Effect of high-dose pitavastatin on glucose homeostasis in patients at elevated risk of new-onset diabetes: insights from the CAPITAIN and PREVAIL-US studies.
        Curr Med Res Opin. 2014; 30: 775-784
        • Teramoto T.
        • Shimano H.
        • Yokote K.
        • Urashima M.
        New evidence on pitavastatin: efficacy and safety in clinical studies.
        Expert Opin Pharmacother. 2010; 11: 817-828
        • Odawara M.
        • Yamazaki T.
        • Kishimoto J.
        • Ito C.
        • Noda M.
        • Terauchi Y.
        • et al.
        Effect of pitavastatin on the incidence of diabetes in Japanese individuals with impaired glucose tolerance.
        Diabetologia. 2013; 56: S59
        • Collins R.
        • Reith C.
        • Emberson J.
        • Armitage J.
        • Baigent C.
        • Blackwell L.
        • et al.
        Interpretation of the evidence for the efficacy and safety of statin therapy.
        Lancet. 2016; 388: 2532-2561