DKA risk increased with SGLT2 inhibitor use, but low overall
medwireNews: A large population-based study supports an increased risk for diabetic ketoacidosis (DKA) for users of sodium-glucose cotransporter (SGLT)2 inhibitors compared with dipeptidyl peptidase (DPP)-4 inhibitors, although the absolute risk remains low.
“Because the beneficial effects of SGLT-2 inhibitors in the prevention of cardiovascular and renal disease will probably increase their uptake in the following years, physicians should be aware of DKA as a potential adverse effect,” write the researchers in the Annals of Internal Medicine.
Kristian Filion (McGill University, Montreal, Quebec, Canada) and team used administrative healthcare data from seven Canadian provinces and the UK’s Clinical Practice Research Datalink to identify 208,757 new users of SGLT2 inhibitors and 208,757 new users of DPP-4 inhibitors, matched for factors including age, sex, socioeconomic status, comorbidities, medications, and indicators of general health status.
Overall, the risk for DKA was low, at a rate of just 1.41 hospitalizations for DKA per 1000 person–years. Nevertheless, the risk was significantly increased for people taking SGLT2 inhibitors compared with DPP-4 inhibitors, at 2.03 versus 0.75 events per 1000 person–years, giving a significant hazard ratio of 2.85.
The researchers say that previous studies, being “limited by their modest number of events,” were unable to look at DKA rates for the individual medications.
“This knowledge gap is important, considering the intraclass differences among SGLT-2 inhibitors in pharmacodynamics (SGLT-2 receptor selectivity) and pharmacokinetics (degree of renal elimination),” they write.
In the current study, 42.3% of participants received canagliflozin, 30.7% received dapagliflozin, and 27.0% received empagliflozin.
Filion and team found “some variation in the point estimate” between the three medications, with hazard ratios for DKA of 3.58, 1.86, and 2.52, for canagliflozin, dapagliflozin, and empagliflozin, respectively, versus DPP-4 inhibitor use.
They note that “canagliflozin has a lower SGLT-2/SGLT-1 selectivity compared with empagliflozin and dapagliflozin, and it has been shown to also inhibit SGLT-1, a glucose and galactose transporter mainly expressed in small-intestine enterocytes.”
The latter could potentially contribute to DKA risk, they say, although “additional mechanistic studies are needed to verify this hypothesis.”
Patient characteristics did not influence the SGLT2 inhibitor-associated risk for DKA with the exception of prior insulin use, which was associated with a smaller risk. Specifically, people who had not previously used insulin had a 3.96-fold increased DKA risk with SGLT2 inhibitors versus DPP-4 inhibitors, compared with a 2.24-fold risk increase among those who had previously used insulin.
Insulin is “a potential proxy of more advanced type 2 diabetes,” say the researchers. “Thus, our results suggest that the risk for this adverse drug effect could be higher among patients with less advanced disease.”
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