Study Outlines Risk of DKA in Patients Taking SGLT2 Inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are associated with an almost 3-fold increased risk of diabetic ketoacidosis (DKA) in some patients with type 2 diabetes (T2D), according to data from a retrospective cohort study published in Annals of Internal Medicine.

SGLT2 inhibitors are a newer class of medications for T2D and have been shown to reduce the risk of heart failure, renal failure, and myocardial infarction, among other cardiovascular complications.

Despite the benefits of SGLT2 inhibitors, the FDA issued a warning in 2015—based on spontaneous reports—that the treatment was associated with an increased risk of DKA.

Using data from electronic healthcare databases from 7 Canadian provinces and the United Kingdom, researchers compared incidence of DKA among patients receiving SGLT2 inhibitors and those receiving dipeptidyl peptidase-4 (DPP-4) inhibitors.

The Canadian Network for Observational Drug Effect Studies (CNODES), funded by the Canadian government, matched 208,757 new users of SGLT2 inhibitors with the same number of DPP-4 inhibitor recipients between January 2013 and June of 2018. All participants were over the age of 18 upon receiving the medication, while any patient with a hospitalization or emergency department visit for DKA in the year prior to study cohort entry was excluded.

Patients were also matched based on level of antidiabetic therapy, use of glucagon-like peptide 1 (GLP-1) receptor agonists in the prior 365 days, calendar time (DPP-4 inhibitor prescription within 120 days of SGLT2 inhibitor initiation), and time-conditional propensity scores (TCPSs).

To calculate TCPSs, researchers performed conditional logistic regression separately for incident and prevalent new users and stratified them by exposure set. “The TCPSs predicted the probability (propensity) of treatment with an SGLT2 inhibitor versus a DPP-4 inhibitor on the basis of prespecified covariates,” authors note. Adjustments for age, sex, duration of diabetes, and TCPSs deciles were taken into account to further control for confounding.

Molecule-specific estimates were determined for the 3 SGLT2 inhibitors that were available in the databases: canagliflozin (n = 88,287), dapagliflozin (n = 64,076), and empagliflozin (n = 56,394). Researchers then stratified recipients by age, sex, and receipt of insulin within the year prior to entry in the cohort study.

Analyses revealed:

• 521 patients were hospitalized with DKA during 370,454 person-years of follow-up (incidence rate per 1000 person-years, 1.40 [95% confidence interval, CI, 1.29 to 1.53])
• Compared with DPP-4 inhibitors, SGLT2 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] per 1000 person-years, respectively; hazard tatio [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 between SGLT2 inhibitors and risk of DKA
• Risk for DKA associated with SGLT2 inhibitors was higher among patients without prior receipt of insulin (HR, 3.96 [CI, 2.74 to 5.72]) than among those with prior receipt of insulin (HR, 2.24 [CI, 1.40 to 3.61])

However, with a crude rate difference of 1.2 per 1000 person-years, the increase in the absolute risk of CDK among those receiving SGLT2 inhibitors was relatively low, researchers note.

In general, insulin users have to more closely monitor their blood sugar, but in this observational study researchers could not determine whether sufficient monitoring was a confounding factor.

Data also showed increased risk of DKA associated with SGLT2 inhibitors appeared to be greater among patients without prior receipt of insulin than in those who did receive insulin—a potential proxy of more advanced T2D. “Our results suggest that the risk for this adverse drug effect could be higher among patients with less advanced disease,” authors point out. This finding may complicate arguments pushing for earlier prescriptions of SGLT2 inhibitors as preventive measures against renal failure and other cardiovascular events.

Greater risks of CKD with canagliflozin may be due to the fact the treatment has a lower SGLT2/SGLT1 selectivity compared with empagliflozin and dapagliflozin, and has been shown to inhibit SGLT1, a glucose and galactose transporter mainly expressed in small-intestine enterocytes. “Intestinal SGLT-1 inhibition could potentially lead to osmotic diarrhea and volume depletion, a predisposing factor for DKA,” authors write.

Because SGLT2 inhibition promotes lipid oxidation and ketogenesis, possibly via volume depletion, this function may provide a pathophysiologic mechanism for SGLT2 inhibitor—related DKA, authors write. However, several observational studies investigating the association have yielded conflicting results.

“The intraclass differences among SGLT-2 inhibitors in pharmacodynamics and pharmacokinetics, the recent emergence of canagliflozin-specific signals for the risk for fractures and lower-extremity amputations, and the methodological limitations of the only study that provided molecule-specific estimates to date,” all contribute to the need for continued research into this field, authors conclude.

Reference

Douros A, Lix LM, Fralick M, et al. Sodium-glucose cotransporter-2 inhibitors and the risk for diabetic ketoacidosis. Ann Intern Med. Published online July 27, 2020. doi:10.7326/M20-0289