Sodium-Glucose Cotransporter-2 Inhibitors and Risk of Diabetic Ketoacidosis Among Adults With Type 2 Diabetes: A Systematic Review and Meta-Analysis

  • Michael Colacci
    Address for correspondence: Michael Colacci MD, St. Michael’s Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada.
    Department of Medicine, Sinai Health System and the University of Toronto, Toronto, Ontario, Canada

    Department of Medicine, General Internal Medicine, University of Toronto, Toronto, Ontario, Canada
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  • John Fralick
    Applied Health Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Department of Medicine and Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
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  • Ayodele Odutayo
    Department of Medicine, General Internal Medicine, University of Toronto, Toronto, Ontario, Canada

    Department of Medicine, General Internal Medicine, University of Calgary, Calgary, Alberta, Canada
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  • Michael Fralick
    Department of Medicine, Sinai Health System and the University of Toronto, Toronto, Ontario, Canada

    Department of Medicine, General Internal Medicine, University of Toronto, Toronto, Ontario, Canada
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Published:April 27, 2021DOI:



      The magnitude and precision regarding the risk of diabetic ketoacidosis (DKA) with sodium-glucose cotransporter-2 (SGLT2) inhibitors is unclear. Thus, we examined the risk of DKA with SGLT2 inhibitors in both observational studies and large clinical trials.


      Searches were performed in PubMed, Embase, CENTRAL and Google Scholar (from inception to April 15, 2019) without language restrictions, including conference proceedings and reference lists. Study selection consisted of randomized controlled trials and observational studies that quantified the rate of DKA with an SGLT2 inhibitor in comparison to other diabetes medications or placebo. Two independent investigators abstracted the study data and assessed the quality of evidence. Data were pooled using random effects models with the Hartung–Knapp–Sidik–Jonkman method. Absolute event rates and hazard ratios for DKA were extracted from each study.


      Seven randomized trials encompassing 42,375 participants and 5 cohort studies encompassing 318,636 participants were selected. Among the 7 randomized controlled trials, the absolute rate of DKA among patients randomized to an SGLT2 inhibitor ranged from 0.6 to 2.2 events per 1,000 person years. Four randomized trials were included in the meta-analysis and, compared with placebo or comparator medication, SGLT2 inhibitors had a 2.5-fold higher risk of DKA (relative risk [RR], 2.46; 95% confidence interval [CI], 1.16 to 5.21]; I2=0%; p=0.54). Among the 5 observational studies, the absolute rate of DKA associated with SGLT2 inhibitor use ranged from 0.6 to 4.9 per 1,000 person years and a 1.7-fold higher rate of DKA compared with another diabetes medication (RR, 1.74; 95% CI, 1.07 to 2.83; I2=45%; p=0.12).


      In adults with type 2 diabetes, SGLT2 inhibitors were found to increase the risk of DKA in both observational studies and large randomized clinical trials.



      On ignore l’ampleur et l’exactitude du risque d’acidocétose diabétique (ACD) associée aux inhibiteurs du cotransporteur sodium-glucose de type 2 (SGLT2). Par conséquent, nous avons consulté des études observationnelles et des essais cliniques d’envergure pour examiner le risque d’ACD associée aux inhibiteurs du SGLT2.


      Nous avons effectué des recherches dans PubMed, Embase, PubMed Central et Google Scholar (du début au 15 avril 2019) sans restriction de langue, comprenant des comptes rendus de conférences et des listes de références. La sélection des études regroupait des essais cliniques à répartition aléatoire et des études observationnelles qui portaient sur la quantification du taux d’ACD associée aux inhibiteurs du SGLT2 par rapport aux autres médicaments contre le diabète ou au placébo. Deux examinateurs indépendants ont extrait les données des études et évalué la qualité des données probantes. Les données ont été groupées à l’aide de modèles à effets aléatoires selon la méthode Hartung–Knapp–Sidik–Jonkman. Les taux absolus d’événements et les rapports de risque d’ACD ont été extraits de chacune des études.


      Nous avons sélectionné 7 essais à répartition aléatoire qui regroupaient 42 375 participants et 5 études de cohortes qui regroupaient 318 636 participants. Parmi les 7 études cliniques à répartition aléatoire, le taux absolu d’ACD chez les patients répartis de façon aléatoire à un inhibiteur du SGLT2 allait de 0,6 à 2,2 événements par 1000 personnes-années. Nous avons inclus 4 essais à répartition aléatoire à la méta-analyse et, par rapport au placébo ou aux médicaments, les inhibiteurs du SGLT2 avaient un risque d’ACD 2,5 fois plus élevé (risque relatif [RR], 2,46; intervalle de confiance [IC] à 95 %, 1,16 à 5,21]; I2 =0 %; p = 0,54). Parmi les 5 études observationnelles, le taux absolu d’ACD associée à l’utilisation des inhibiteurs du SGLT2 allait de 0,6 à 4,9 par 1000 personnes-années et avait un risque d’ACD 1,7 fois plus élevé qu’un autre médicament contre le diabète (RR, 1,74; IC à 95 %, 1,07 à 2,83; I2 = 45 %; p = 0,12).


      Nous avons observé dans les études observationnelles et les essais cliniques à répartition aléatoire d’envergure que chez les adultes atteints du diabète de type 2 les inhibiteurs du SGLT2 augmentent le risque d’ACD.


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