SGLT2 Inhibitors Increase the Risk of Diabetic Ketoacidosis Developing in the Community and During Hospital Admission

Peter S. Hamblin; Rosemary Wong; Elif I. Ekinci; Spiros Fourlanos; Sonali Shah; Alicia R. Jones; Matthew J. L. Hare; Genevieve L. Calder; Dilan Seneviratne Epa; Elizabeth M. George; Rinky Giri; Mark A. Kotowicz; Mervyn Kyi; Nicole Lafontaine; Richard J. MacIsaac; Brendan J. Nolan; David N. O'Neal; Debra Renouf; Suresh Varadarajan; Jennifer Wong; Sylvia Xu; Leon A. Bach

Disclosures

J Clin Endocrinol Metab. 2019;104(8):3077-3087. 

In This Article

Abstract and Introduction

Abstract

Context: Diabetic ketoacidosis (DKA) has been associated with the use of sodium glucose cotransporter 2 inhibitors (SGLT2is).

Objective: To determine the incidence, characteristics, and outcomes of DKA in SGLT2i users vs nonusers with type 2 diabetes.

Design: Retrospective, multicenter, controlled cohort study.

Setting: All public hospitals in Melbourne and Geelong (combined population of 5 million), Australia, from 1 September 2015 to 31 October 2017.

Patients: Consecutive cases of DKA that developed in the community, or during the course of hospital admission, in patients with type 2 diabetes

Main Outcome Measures: In SGLT2i users vs nonusers: (i) OR of DKA developing during hospital admission, and (ii) incidence of DKA.

Results; There were 162 cases of DKA (37 SGLT2i users and 125 non-SGLT2i users) with a physician-adjudicated diagnosis of type 2 diabetes. Of these, DKA developed during the course of inpatient admission in 14 (38%) SGLT2i users vs 2 (2%) non-SGLT2i users (OR, 37.4; 95% CI, 8.0 to 175.9; P < 0.0001). The incidence of DKA was 1.02 per 1000 (95% CI, 0.74 to 1.41 per 1000) in SGLT2i users vs 0.69 per 1000 (95% CI, 0.58 to 0.82 per 1000) in non-SGLT2i users (OR, 1.48; 95% CI, 1.02 to 2.15; P = 0.037). Fifteen SGLT2i users (41%) had peak blood glucose <250 mg/dL (14 mmol/L) compared with one (0.8%) non-SGLT2i user (P < 0.001).

Conclusions: SGLT2i users were more likely to develop DKA as an inpatient compared with non-SGLT2i users. SGLT2i use was associated with a small but significant increased risk of DKA.

Introduction

Sodium glucose cotransporter 2 inhibitors (SGLT2is) have changed the management of type 2 diabetes, especially for those with established cardiovascular disease. The potential risk of diabetic ketoacidosis (DKA), first highlighted in 2015 with a Food and Drug Administration safety warning,[1] remains a concern. The pathophysiology of SGLT2i-associated DKA is not fully understood but relates in part to an elevated glucagon/insulin ratio favoring lipolysis.[2,3] SGLT2is decrease insulin requirements by decreasing blood glucose concentrations as they promote glycosuria. Moreover, insulin concentrations may be further decreased by acute reductions in carbohydrate intake such as occur during fasting.[4] Additionally, it has been suggested that SGLT2is may reduce renal excretion of ketones[5] and increase ketone production.[6]

Whereas several studies found no increased risk of DKA with SGLT2i use,[7–9] others have reported an increase.[10–15] The totality of the peer-reviewed literature, as well as data analyses by regulatory agencies, supports the conclusion that there is some degree of increased risk of DKA in SGLT2i users with type 2 diabetes.

The incidence, presentation, and detailed risk factors of SGLT2i-associated DKA have not been compared with patients with type 2 diabetes who developed DKA, but were not using SGLT2is. Additionally, the OR of developing DKA during the course of hospital admission in SGLT2i users compared with nonusers has not been reported.

To address these issues, we undertook a large retrospective multicenter, controlled, physician-adjudicated cohort study across all public hospitals in the cities of Melbourne and Geelong, with a combined population of 5 million, in the state of Victoria, Australia.

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