Sodium–Glucose Cotransporter-2 Inhibitors and the Risk for Diabetic Ketoacidosis: A Multicenter Cohort Study
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Visual Abstract. SGLT-2 Inhibitors and the Risk for DKA
This large, population-based cohort study compares the risk for diabetic ketoacidosis between diabetic patients using sodium–glucose cotransporter-2 inhibitors and those using dipeptidyl peptidase-4 inhibitors.
Abstract
Background:
Sodium–glucose cotransporter-2 (SGLT-2) inhibitors could increase the risk for diabetic ketoacidosis (DKA).
Objective:
To assess whether SGLT-2 inhibitors, compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, are associated with an increased risk for DKA in patients with type 2 diabetes.
Design:
Population-based cohort study; prevalent new-user design between 2013 and 2018. (ClinicalTrials.gov: NCT04017221)
Setting:
Electronic health care databases from 7 Canadian provinces and the United Kingdom.
Patients:
208 757 new users of SGLT-2 inhibitors were matched by using time-conditional propensity scores to 208 757 recipients of DPP-4 inhibitors.
Measurements:
Cox proportional hazards models estimated site-specific hazard ratios (HRs) with 95% CIs of DKA comparing receipt of SGLT-2 inhibitors with receipt of DPP-4 inhibitors, which were pooled by using random-effects models. Secondary analyses were stratified by molecule, age, sex, and prior receipt of insulin.
Results:
Overall, 521 patients were diagnosed with DKA during 370 454 person-years of follow-up (incidence rate per 1000 person-years, 1.40 [95% CI, 1.29 to 1.53]). Compared with DPP-4 inhibitors, SGLT-2 inhibitors were associated with an increased risk for DKA (incidence rate, 2.03 [CI, 1.83 to 2.25] versus 0.75 [CI, 0.63 to 0.89], respectively; HR, 2.85 [CI, 1.99 to 4.08]). Molecule-specific HRs were 1.86 (CI, 1.11 to 3.10) for dapagliflozin, 2.52 (CI, 1.23 to 5.14) for empagliflozin, and 3.58 (CI, 2.13 to 6.03) for canagliflozin. Age and sex did not modify the association; prior receipt of insulin appeared to decrease the risk.
Limitations:
There was unmeasured confounding and no laboratory data were available for the majority of patients, and molecule-specific analyses were conducted at a limited number of sites.
Conclusion:
SGLT-2 inhibitors were associated with an almost 3-fold increased risk for DKA, with molecule-specific analyses suggesting a class effect.
Primary Funding Source:
Canadian Institutes of Health Research.
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Published In
Annals of Internal Medicine
Volume 173 • Number 6 • 15 September 2020
Pages: 417 - 425
History
Published online: 28 July 2020
Published in issue: 15 September 2020
Keywords
Copyright
© 2020 American College of Physicians.
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Sodium–Glucose Cotransporter-2 Inhibitors and the Risk for Diabetic Ketoacidosis: A Multicenter Cohort Study. Ann Intern Med.2020;173:417-425. [Epub 28 July 2020]. doi:10.7326/M20-0289
Sodium–Glucose Cotransporter-2 Inhibitors and the Risk for Diabetic Ketoacidosis: A Multicenter Cohort Study. Ann Intern Med.2020;173:417-425. [Epub 28 July 2020]. doi:10.7326/M20-0289
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The cardiovascular beneficial effects of SGLT2i are minimized Metformin coadministration.
We read with interest Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i) and the Risk for Diabetic Ketoacidosis. A Multicenter Cohort Study by Douros A. and coworkers. It is worth noting that SGLT2i typically produces euglycemic diabetic ketoacidosis, unlike typical hyperglycemic diabetic ketoacidosis. (1)
SGLT2i are increasingly used in view of their documented cardiovascular benefits, and fixed-dose combination (FDC) pill containing metformin and SGLT2i, is also approved by the US FDA. It is important to note that the cardiovascular protective effects of SGLT2i (canagliflozin) are minimized when combined with metformin. The risk of CV death and hospitalization reduced by 36% in metformin nonusers versus 12% in metformin users. (p= 0.03). (2) A similar trend is observed with empagliflozin as well. (3)
References:
Disclosures:
The authors have nothing to disclose.
Response to “The cardiovascular beneficial effects of SGLT2i are minimized with metformin coadministration.”
We thank Dr. Gupta et al. for their interest in our study (1). We agree that the diabetic ketoacidosis (DKA) associated with sodium-glucose co-transporter 2 (SGLT2) inhibitors is often euglycemic. However, we were unable to differentiate between euglycemic and hyperglycemic DKA in our study, because this information is not documented in administrative data.
We also agree that there is some evidence of effect modification in the efficacy of SGLT2 inhibitors, with potentially greater benefits reported among patients not using metformin at baseline than among those using metformin (2, 3). This evidence underscores the importance of considering demographic and clinical characteristics when choosing the most appropriate treatment option for patients with type 2 diabetes. Our study adds to the available knowledge base, allowing clinicians and patients to make more informed decisions regarding the benefits and risks of SGLT2 inhibitors.
References
Disclosures:
The authors have no conflicts to disclose.