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SGLT-2 Inhibitors Tied to Nearly Three-Fold Higher Risk of Diabetic Ketoacidosis

By Marilynn Larkin, Reuters Health
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Sodium-glucose transporter-2 (SGLT-2) inhibitors were associated with an almost three-fold increased risk for diabetic ketoacidosis (DKA) compared with dipeptidyl peptidase-4 (DPP-4) inhibitors in a large cohort study.

The increased risk "was observed for all three SGLT-2 inhibitors (canagliflozin, dapagliflozin, empagliflozin) included in the study," Dr. Kristian Filion of McGill University told Reuters Health by email. "Our study provides important confirmatory evidence using real-world data and more precise estimates than previous studies of this issue, decreasing uncertainty surrounding this adverse drug effect."

"Patients should be made aware of this risk and educated regarding the early signs and symptoms of DKA, a rare but potentially life-threatening complication of diabetes," he said.

As reported in Annals of Internal Medicine, Dr. Filion and colleagues used electronic health data from seven Canadian provinces and the UK to compare 208,757 new users of SGLT-2 inhibitors with matched recipients of DPP-4 inhibitors.

Overall, 521 patients were hospitalized with DKA during more than 370,000 person-years of follow-up (incidence rate per 1,000 person-years, 1.40).

Compared with DPP-4 inhibitors, SGLT-2 inhibitors were associated with an almost three-fold increased risk for DKA (incidence rate, 2.03 versus 0.75, respectively; hazard ratio, 2.85).

Molecule-specific HRs were 1.86 for dapagliflozin, 2.52 for empagliflozin, and 3.58 for canagliflozin. Results were consistent regardless of sex or age, although previous use of insulin seemed to decrease the risk.

Limitations included unmeasured confounding and lack of laboratory data for the majority of patients. Further, molecule-specific analyses were conducted at a limited number of sites; however, those analyses suggested a class effect.

An additional limitation, noted Dr. Filion, "was that the average follow-up was slightly less than one year. There remains a need to examine the risk of DKA with long-term use. However, we need time for the administrative databases to accrue a sufficient number of observations with long durations of follow-up to be able to do so."

Dr. Jason Ng, Clinical Unit Leader, Diabetes Multidisciplinary Unit at the University of Pittsburgh Medical Center, commented in an email to Reuters Health, "There is mild concern about the increased DKA risk, but this was a known potential side effect so not a totally surprising finding. The absolute risk increase is fairly low, given how much SGLT2 inhibitors are used."

"The benefits of SGLT-2 inhibitors are still numerous and I would not hesitate prescribing after a comprehensive discussion with patients about risks/benefits, and if they are agreeable," he said.

He added that the study did not mention that the comparison drug, DPP-4 inhibitors, "also have increased risk of pancreatitis and a theoretical increased risk of medullary thyroid cancer (found to be increased in animal models) ,so there is a trade off between the two medications in terms of risk."

SOURCE: https://bit.ly/2El1a70 Annals of Internal Medicine, online July 27, 2020.