Generic placeholder image

Current Drug Safety

Editor-in-Chief

ISSN (Print): 1574-8863
ISSN (Online): 2212-3911

Research Article

Sodium Glucose Cotransporter-2 Inhibitor Treatment and the Risk of Diabetic Ketoacidosis in Denmark: A Retrospective Cohort Study of Five Years of Use

Author(s): Henrik V.B. Laursen*, Johan B. Røikjer, Jakob Dal and Morten Hasselstrøm Jensen

Volume 16, Issue 1, 2021

Published on: 19 August, 2020

Page: [73 - 81] Pages: 9

DOI: 10.2174/1574886315666200819114629

Price: $65

Abstract

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been associated with increased risk of diabetic ketoacidosis (DKA) in both people with type 1 and type 2 diabetes mellitus. Few studies using data from high-quality registries exist that attempt to determine the real- world impact of the increasing use of this drug.

Objective: The aim of this study was to investigate the incidence and risk of DKA in connection with SGLT2i treatment in Denmark between 2013-2017.

Methods: A nationwide retrospective cohort of people with type 2 diabetes mellitus using SGLT2i or glucagon-like peptide-1 receptor agonists (GLP1-RA) was established and analysed using both Cox-proportional hazard regression and Kaplan-Meier survival analysis.

Results: The 37,058 individuals included in the cohort, were made up of SGLT2i (10,923), GLP1- RA (18,849), SGLT2i+insulin (2,069), and GLP1-RA+insulin (10,178) users. The incidence rate (IR) of DKA was 0.84 (95% CI 0.49-1.44) and 0.53 (95% CI 0.36-0.77) for the SGLT2i and GLP1-RA groups, respectively. There was no statistically significant increase in the risk for DKA with SGLT2i use (HR 1.02, 95% CI, 0.44-2.36). However, for the SGLT2i+insulin and GLP1- RA+insulin groups, IRs were 3.47 (95% CI 1.92-6.27) and 0.97 (95% CI 0.68-1.37) respectively, and the risk was statistically significantly higher (HR 5.42, 95% CI 2.16-13.56).

Conclusion: We observed no significant increase in the risk of DKA for SGLT2i users compared to GLP1-RA. However, a significantly higher IR of DKA was observed with concomitant insulin use, and the risk of DKA was considerably higher for the SGLT2 group using insulin.

Keywords: Sodium-glucose cotransporter 2 inhibitors, retrospective cohort, diabetic ketoacidosis, hyperglycaemia, insulin, Kaplan- Meier.

Graphical Abstract
[1]
Henriksen OM, Prahl JB, Røder ME, Svendsen OL. Treatment of diabetic ketoacidosis in adults in Denmark: A national survey. Diabetes Res Clin Pract 2007; 77(1): 113-9.
[http://dx.doi.org/10.1016/j.diabres.2006.10.013] [PMID: 17126447]
[2]
Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019; 393(10166): 31-9.
[http://dx.doi.org/10.1016/S0140-6736(18)32590-X] [PMID: 30424892]
[3]
Lee PC, Ganguly S, Goh S-Y. Weight loss associated with sodium-glucose cotransporter-2 inhibition: a review of evidence and underlying mechanisms. Obes Rev 2018; 19(12): 1630-41.
[http://dx.doi.org/10.1111/obr.12755] [PMID: 30253050]
[4]
Scheen AJ. An update on the safety of SGLT2 inhibitors. Expert Opin Drug Saf 2019; 18(4): 295-311.
[http://dx.doi.org/10.1080/14740338.2019.1602116] [PMID: 30933547]
[5]
European Medicines Agency. EMA confirms recommendations to minimise ketoacidosis risk with SGLT2 inhibitors for diabetes 2018.https://www.ema.europa.eu/en/news/ema-confirms-recommendations-minimise-ketoacidosis-risk-sglt2-inhibitors-diabetes
[6]
Wiviott SD, Raz I, Bonaca MP, et al. Declare–TIMI 58 investigators. dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019; 380(4): 347-57.
[http://dx.doi.org/10.1056/NEJMoa1812389] [PMID: 30415602]
[7]
Zinman B, Wanner C, Lachin JM, et al. EMPA-REG outcome investigators. empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373(22): 2117-28.
[http://dx.doi.org/10.1056/NEJMoa1504720] [PMID: 26378978]
[8]
Neal B, Perkovic V, Mahaffey KW, et al. CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377(7): 644-57.
[http://dx.doi.org/10.1056/NEJMoa1611925] [PMID: 28605608]
[9]
Ueda P, Svanström H, Melbye M, et al. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: Nationwide register based cohort study. BMJ 2018; 363: k4365.
[http://dx.doi.org/10.1136/bmj.k4365] [PMID: 30429124]
[10]
Hamblin PS, Wong R, Ekinci EI, et al. SGLT2 inhibitors increase the risk of diabetic ketoacidosis developing in the community and during hospital admission. J Clin Endocrinol Metab 2019; 104(8): 3077-87.
[http://dx.doi.org/10.1210/jc.2019-00139] [PMID: 30835263]
[11]
Kildemoes HW, Sørensen HT, Hallas J. The Danish National Prescription Registry. Scand J Public Health 2011; 39(7)(Suppl.): 38-41.
[http://dx.doi.org/10.1177/1403494810394717] [PMID: 21775349]
[12]
Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. Scand J Public Health 2011; 39(7)(Suppl.): 30-3.
[http://dx.doi.org/10.1177/1403494811401482] [PMID: 21775347]
[13]
Helweg-Larsen K. The Danish Register of Causes of Death. Scand J Public Health 2011; 39(7)(Suppl.): 26-9.
[http://dx.doi.org/10.1177/1403494811399958] [PMID: 21775346]
[14]
Schmidt M, Pedersen L, Sørensen HT. The Danish Civil Registration System as a tool in epidemiology. Eur J Epidemiol 2014; 29(8): 541-9.
[http://dx.doi.org/10.1007/s10654-014-9930-3] [PMID: 24965263]
[15]
Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018; 61(12): 2461-98.
[http://dx.doi.org/10.1007/s00125-018-4729-5] [PMID: 30288571]
[16]
Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: A predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 2015; 38(9): 1638-42.
[http://dx.doi.org/10.2337/dc15-1380] [PMID: 26294774]
[17]
Jensen ML, Persson F, Andersen GS, et al. Incidence of ketoacidosis in the danish type 2 diabetes population before and after introduction of sodium-glucose cotransporter 2 inhibitors-A nationwide, retrospective cohort study, 1995-2014. Diabetes Care 2017; 40(5): e57-8.
[http://dx.doi.org/10.2337/dc16-2793] [PMID: 28283564]
[18]
Fadini GP, Bonora BM, Avogaro A. SGLT2 inhibitors and diabetic ketoacidosis: Data from the FDA Adverse Event Reporting System. Diabetologia 2017; 60(8): 1385-9.
[http://dx.doi.org/10.1007/s00125-017-4301-8] [PMID: 28500396]
[19]
Blau JE, Tella SH, Taylor SI, Rother KI. Ketoacidosis associated with SGLT2 inhibitor treatment: Analysis of FAERS data. Diabetes Metab Res Rev 2017; 33(8)e2924
[http://dx.doi.org/10.1002/dmrr.2924] [PMID: 28736981]
[20]
Fralick M, Schneeweiss S, Patorno E. Risk of Diabetic Ketoacidosis after Initiation of an SGLT2 Inhibitor. N Engl J Med 2017; 376(23): 2300-2.
[http://dx.doi.org/10.1056/NEJMc1701990] [PMID: 28591538]
[21]
Erondu N, Desai M, Ways K, Meininger G. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care 2015; 38(9): 1680-6.
[http://dx.doi.org/10.2337/dc15-1251] [PMID: 26203064]
[22]
Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic diabetic ketoacidosis: A potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care 2015; 38(9): 1687-93.
[http://dx.doi.org/10.2337/dc15-0843] [PMID: 26078479]
[23]
Waylen AL, Riedel B. Sodium-glucose co-transporter 2 inhibitors in the peri-operative period: A warning to all clinicians. BJU Int 2019; 123(Suppl. 5): 6-7.
[http://dx.doi.org/10.1111/bju.14766] [PMID: 31116003]
[24]
Krass I, Schieback P, Dhippayom T. Adherence to diabetes medication: A systematic review. Diabet Med 2015; 32(6): 725-37.
[http://dx.doi.org/10.1111/dme.12651] [PMID: 25440507]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy