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BMJ. 2018 Nov 14;363:k4365. doi: 10.1136/bmj.k4365.

Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study.

Author information

1
Clinical Epidemiology Division, Department of Medicine, Solna, Eugeniahemmet, T2, Karolinska University Hospital, 17176 Stockholm, Sweden peter.ueda@ki.se.
2
Clinical Epidemiology Division, Department of Medicine, Solna, Eugeniahemmet, T2, Karolinska University Hospital, 17176 Stockholm, Sweden.
3
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
4
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
5
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
6
Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
7
The Swedish National Diabetes Register, Västra Götalandsregionen, Gothenburg, Sweden.
8
KG Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Science, Norwegian University of Science and Technology, Trondheim, Norway.
9
HUNT Research Center, Faculty of Medicine, Norwegian University of Science and Technology, Levanger, Norway.

Abstract

OBJECTIVE:

To assess the association between the use of sodium glucose cotransporter 2 (SGLT2) inhibitors and seven serious adverse events of current concern.

DESIGN:

Register based cohort study.

SETTING:

Sweden and Denmark from July 2013 to December 2016.

PARTICIPANTS:

A propensity score matched cohort of 17 213 new users of SGLT2 inhibitors (dapagliflozin, 61%; empagliflozin, 38%; canagliflozin, 1%) and 17 213 new users of the active comparator, glucagon-like peptide 1 (GLP1) receptor agonists.

MAIN OUTCOME MEASURES:

The primary outcomes were lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis, as identified from hospital records. Hazard ratios and 95% confidence intervals were estimated by using Cox proportional hazards models.

RESULTS:

Use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation (incidence rate 2.7 v 1.1 events per 1000 person years, hazard ratio 2.32, 95% confidence interval 1.37 to 3.91) and diabetic ketoacidosis (1.3 v 0.6, 2.14, 1.01 to 4.52) but not with bone fracture (15.4 v 13.9, 1.11, 0.93 to 1.33), acute kidney injury (2.3 v 3.2, 0.69, 0.45 to 1.05), serious urinary tract infection (5.4 v 6.0, 0.89, 0.67 to 1.19), venous thromboembolism (4.2 v 4.1, 0.99, 0.71 to 1.38) or acute pancreatitis (1.3 v 1.2, 1.16, 0.64 to 2.12).

CONCLUSIONS:

In this analysis of nationwide registers from two countries, use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation and diabetic ketoacidosis, but not with other serious adverse events of current concern.

Conflict of interest statement

Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and have the following declarations: CJ reports personal fees from Pfizer and Bayer outside the submitted work; BE reports personal fees from Amgen, AstraZeneca, Boerhringer Ingelheim, Eli Lilly, Merck Sharp and Dohme, Mundipharma, Navamedic, Novo Nordisk, and RLS Global outside the submitted work, and grants from Sanofi outside the submitted work; and SG reports personal fees and research grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp and Dohme, Novo Nordisk, and Sanofi outside of the submitted work. The other authors did not have any potential conflicts to report.

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