Sodium glucose cotransporter-2 inhibitor use associated with increased risk of diabetic ketoacidosis

1. The use of sodium-glucose cotransporter-2 (SGLT-2i) increased study participants’ risk of diabetic ketoacidosis (DKA) hospital presentations when compared to dipeptidyl peptidase 4 inhibitors

2. Amongst all the sodium-glucose cotransporter-2 inhibitors included in the study, canagliflozin demonstrated the highest risk of DKA hospital presentations

Evidence Rating Level: 2 (Good)

Study Rundown: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are diabetes medications that work on the proximal tubule of the nephron to prevent the renal reabsorption of glucose and promote its excretion in the urine. There is mounting evidence for their utility in congestive heart failure patients as well. However, there has also been concern for increased risk of DKA in patients taking SGLT-2 inhibitors. Over a 5-year period, a cohort of more than a quarter million Canadian patients’ health records were used for a clinic study exploring the relationship between SGLT-2 inhibitors and DKA hospital presentation. During this time, patients on SGLT-2 inhibitors were matched with patients on dipeptidyl peptidase 4 (DPP4) inhibitors and their rates of DKA hospital presentations were noted.  The risk of DKA was almost three-fold higher for patient taking SGLT-2 inhibitors. This relationship persisted across all the individual SGLT-2 inhibitors. However, canagliflozin had the highest risk which was attributed to its relative non-selectivity between SGLT-2 and SGLT-1 receptors which, in synchronicity, can promote both diuresis and diarrhea leading to increased risk of DKA.  The study was limited by its inability to track individual patients’ Hemoglobin A1c, and its inability to control for regional variations in prescribing practices of individual SGLT-2 inhibitors. Results were strengthened by the study’s relatively high number of DKA hospital presentation cases and the size of the study cohort, both of which increased its generalizability.

Click to read the study, published today Annals of Internal Medicine

Relevant Reading: SGLT2 Inhibitors: A Systematic Review of Diabetic Ketoacidosis and Related Risk Factors in the Primary Literature

In-Depth [retrospective cohort]: This retrospective cohort study was conducted using health administrative data from 7 Canadian providers and a UK health care database.  The base cohort was assembled amongst patients receiving care between Jan 2013 and June 2018.  Patients on either SGLT-2 inhibitors or DPP4 inhibitors were matched and time conditional propensity scores were calculated. Included patients had to be older than 18 years old, have health care coverage for greater than 1-year health care coverage prior to the study period, and had no prior history of DKA.  The primary outcome of DKA was based on primary diagnosis given during a hospital admission.  A total of 903,016 receive either drug during the study period and 208,757 patients on SGLT-2 inhibitors were matched to the patients on DPP4 inhibitors.  Amongst the study participants on SGLT-2 inhibitors,  42.3% were on canagliflozin, 30.7% were on dapagliflozin, 27% were on empagliflozin.  There were 521 cases of DKA hospital presentation amongst the study cohort and patients on SGLT-2 inhibitors had an almost three-fold increased risks of DKA presentation. Being insulin naïve carried a higher risk of DKA presentation.  Amongst the individual SGLT-2 inhibitors the individual hazard ratio was 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.

Image: PD

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