Research Article|Articles in Press, 110621

Sodium-glucose cotransporter-2 inhibitors and cancer outcomes: A systematic review and meta-analysis of randomized controlled trials


      • Data on malignancy risk with SGLT2 inhibitors is conflicting.
      • The effect of SGLT2 inhibitors on cancer mortality is unknown.
      • Meta-analysis to evaluate cancer outcomes with SGLT2 inhibitor treatment in adults.
      • Pooled data of 116,365 participants showed no increse in risk of cancer outcomes.
      • TSA showed that the sample size was sufficient to avoid missing alternative results.



      Concerns regarding breast and bladder cancer risk with Sodium-glucose cotransporter-2 (SGLT2) inhibitors remain controversial and its effect on cancer mortality is unknown. We aim to evaluate the association between SGLT2 inhibitors and the risk of cancer outcomes.


      We searched PubMed, Embase and CENTRAL up to June 20th, 2022, for randomized controlled trials of SGLT2 inhibitors in adults, with a minimum follow-up of 48 weeks. Researchers extracted study-level data and assessed within-study risk of bias with the RoB 2.0 tool and quality of evidence with GRADE. We performed meta-analyses summarizing the relative risks (RRs) of cancer outcomes.


      Seventy-six trials encompassing 116,375 participants were selected. Overall risk of bias was low. SGLT2 inhibitors did not reduce/increase the overall risk of cancer (RR, 1.03; 95% confidence interval [CI], 0.96–1.10) and cancer mortality (RR, 0.99; 95% CI, 0.85–1.16). SGLT2 inhibitors likely result in little to no difference in the risk of breast (RR, 1.01; 95% CI 0.77–1.32) and bladder cancers (RR, 0.93; 95% CI 0.71–1.21). Trial sequential analysis provided evidence that the sample size was sufficient to avoid missing alternative results.


      SGLT2 inhibitors are not associated with an increased risk of cancer outcomes, providing reassuring data regarding previous safety concerns.



      BMI (body mass index), CI (Confidence interval), DOI (Digital Object Identifier), FDA (Food and Drug Administration), GRADE (Grading of Recommendations, Assessment, Development and Evaluations), NNH (Number needed to harm), PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), RCTs (randomized controlled trials), RD (Risk difference), RoB 2 (Revised Cochrane risk-of-bias tool for randomized trials), robvis (Risk-of-bias VISualization), RR (relative risk), SGLT2 (Sodium-glucose cotransporter-2), TSA (Trial Sequential Analysis)
      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 Diabetes Research and Clinical Practice
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Brown E.
        • Heerspink H.J.L.
        • Cuthbertson D.J.
        • Wilding J.P.H.
        SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications.
        Lancet. 2021; 398: 262-276
        • Braunwald E.
        Gliflozins in the Management of Cardiovascular Disease.
        N Engl J Med. 2022; 386: 2024-2034
        • McGuire D.K.
        • Shih W.J.
        • Cosentino F.
        • Charbonnel B.
        • Cherney D.Z.I.
        • Dagogo-Jack S.
        • et al.
        Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: A Meta-analysis.
        JAMA Cardiol. 2021; 6: 148-158
      1. US Food and Drug Administration. FDA briefing document NDA 202293 Dapagliflozin tablets, 5 and 10 mg 2011 [Available from:

      2. US Food and Drug Administration. Final Risk Evaluation and Mitigation Strategy (REMS) Review 2013 [Available from:

        • Tang H.
        • Dai Q.
        • Shi W.
        • Zhai S.
        • Song Y.
        • Han J.
        SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.
        Diabetologia. 2017; 60: 1862-1872
        • Dicembrini I.
        • Nreu B.
        • Mannucci E.
        • Monami M.
        Sodium-glucose co-transporter-2 (SGLT-2) inhibitors and cancer: A meta-analysis of randomized controlled trials.
        Diabetes Obes Metab. 2019; 21: 1871-1877
        • Rao Kondapally Seshasai S.
        • Kaptoge S.
        • Thompson A.
        • Di Angelantonio E.
        • Gao P.
        • Sarwar N.
        • et al.
        Diabetes mellitus, fasting glucose, and risk of cause-specific death.
        N Engl J Med. 2011; 364: 829-841
        • Tsilidis K.K.
        • Kasimis J.C.
        • Lopez D.S.
        • Ntzani E.E.
        • Ioannidis J.P.
        Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies.
        BMJ. 2015; 350g7607
        • Heerspink H.J.L.
        • Sjöström C.D.
        • Jongs N.
        • Chertow G.M.
        • Kosiborod M.
        • Hou F.F.
        • et al.
        Effects of dapagliflozin on mortality in patients with chronic kidney disease: a pre-specified analysis from the DAPA-CKD randomized controlled trial.
        Eur Heart J. 2021; 42: 1216-1227
        • Page M.J.
        • McKenzie J.E.
        • Bossuyt P.M.
        • Boutron I.
        • Hoffmann T.C.
        • Mulrow C.D.
        • et al.
        The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
        BMJ. 2021; 372n71
        • Santesso N.
        • Glenton C.
        • Dahm P.
        • Garner P.
        • Akl E.A.
        • Alper B.
        • et al.
        GRADE guidelines 26: informative statements to communicate the findings of systematic reviews of interventions.
        J Clin Epidemiol. 2020; 119: 126-135
        • Lenis A.T.
        • Lec P.M.
        • Chamie K.
        • Mshs M.D.
        Bladder Cancer: A Review.
        JAMA. 2020; 324: 1980-1991
        • Sterne J.A.C.
        • Savović J.
        • Page M.J.
        • Elbers R.G.
        • Blencowe N.S.
        • Boutron I.
        • et al.
        RoB 2: a revised tool for assessing risk of bias in randomised trials.
        BMJ. 2019; 366l4898
        • McGuinness L.A.
        • Higgins J.P.T.
        Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments.
        Res Synth Methods. 2021; 12: 55-61
      3. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane; 2022. Available from:

        • Guyatt G.H.
        • Oxman A.D.
        • Vist G.E.
        • Kunz R.
        • Falck-Ytter Y.
        • Alonso-Coello P.
        • et al.
        GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
        BMJ. 2008; 336: 924-926
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • Cahn A.
        • Raz I.
        • Bonaca M.
        • Mosenzon O.
        • Murphy S.A.
        • Yanuv I.
        • et al.
        Safety of dapagliflozin in a broad population of patients with type 2 diabetes: Analyses from the DECLARE-TIMI 58 study.
        Diabetes Obes Metab. 2020; 22: 1357-1368
        • Cefalu W.T.
        • Leiter L.A.
        • de Bruin T.W.
        • Gause-Nilsson I.
        • Sugg J.
        • Parikh S.J.
        Dapagliflozin's Effects on Glycemia and Cardiovascular Risk Factors in High-Risk Patients With Type 2 Diabetes: A 24-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study With a 28-Week Extension.
        Diabetes Care. 2015; 38: 1218-1227
        • Singh J.S.S.
        • Mordi I.R.
        • Vickneson K.
        • Fathi A.
        • Donnan P.T.
        • Mohan M.
        • et al.
        Dapagliflozin Versus Placebo on Left Ventricular Remodeling in Patients With Diabetes and Heart Failure: The REFORM Trial.
        Diabetes Care. 2020; 43: 1356-1359
        • Brown A.J.M.
        • Gandy S.
        • McCrimmon R.
        • Houston J.G.
        • Struthers A.D.
        • Lang C.C.
        A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes: the DAPA-LVH trial.
        Eur Heart J. 2020; 41: 3421-3432
      4. GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1736–88.

        • Gregg E.W.
        • Cheng Y.J.
        • Srinivasan M.
        • Lin J.
        • Geiss L.S.
        • Albright A.L.
        • et al.
        Trends in cause-specific mortality among adults with and without diagnosed diabetes in the USA: an epidemiological analysis of linked national survey and vital statistics data.
        Lancet. 2018; 391: 2430-2440
        • Pearson-Stuttard J.
        • Bennett J.
        • Cheng Y.J.
        • Vamos E.P.
        • Cross A.J.
        • Ezzati M.
        • et al.
        Trends in predominant causes of death in individuals with and without diabetes in England from 2001 to 2018: an epidemiological analysis of linked primary care records.
        Lancet Diabetes Endocrinol. 2021; 9: 165-173
      5. U.S. Department of Health and Human Services: Food and Drug Administration Center for Drug Evaluation and Research. Guidance for Industry Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes 2008 [Available from:

      6. European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus 2012 [Available from:

        • Bassler D.
        • Briel M.
        • Montori V.M.
        • Lane M.
        • Glasziou P.
        • Zhou Q.
        • et al.
        Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis.
        JAMA. 2010; 303: 1180-1187
        • Ueda P.
        • Svanström H.
        • Hviid A.
        • Eliasson B.
        • Svensson A.M.
        • Franzén S.
        • et al.
        Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Bladder and Renal Cancer: Scandinavian Cohort Study.
        Diabetes Care. 2022; 45 (e93-e6)
        • Chung M.C.
        • Hsu H.T.
        • Chang C.H.
        • Hung P.H.
        • Hsiao P.J.
        • Wu L.Y.
        • et al.
        Association of SGLT2 inhibitors with lower incidence of death in type 2 diabetes mellitus and causes of death analysis.
        Sci Rep. 2022; 12: 10147
        • Scafoglio C.R.
        • Villegas B.
        • Abdelhady G.
        • Bailey S.T.
        • Liu J.
        • Shirali A.S.
        • et al.
        Sodium-glucose transporter 2 is a diagnostic and therapeutic target for early-stage lung adenocarcinoma.
        Sci Transl Med. 2018; 10