SGLT2 inhibitors triple DKA risk compared with DPP-IV inhibitors
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SGLT2 inhibitor use is associated with an almost threefold increased risk for diabetic ketoacidosis compared with use of DPP-IV inhibitors, according to findings published in Annals of Internal Medicine.
“With more than 350,000 patients and more than 500 DKA events, the results of our study corroborate existing concerns about DKA as an adverse effect of SGLT2 inhibitors, showing an almost threefold increase in the relative risk,” Antonios Douros, MD, PhD, an assistant professor in the department of medicine at McGill University in Montreal, told Healio. “With a crude rate difference of 1.2 per 1,000 person-years, the increase in the absolute risk at the level of the individual patient was relatively low. However, type 2 diabetes has a prevalence of approximately 10% and SGLT2 inhibitors are increasingly being used in the treatment of type 2 diabetes. Consequently, the risk for DKA at the population level is non-negligible. That being said, it is important to weigh this risk against the established cardiovascular and renal benefits of SGLT2 inhibitors.”
In a population-based cohort study using electronic health care databases, Douros and colleagues analyzed data from 208,757 new users of SGLT2 inhibitors (between 2013-2018), matched using time-conditional propensity scores with 208,757 recipients of DPP-IV inhibitors. Researchers used Cox proportional hazards models to estimate site-specific HRs for DKA risk, comparing receipt of SGLT2 inhibitors with receipt of DPP-IV inhibitors.
Within the cohort, 521 patients were diagnosed with DKA during 370,454 person-years of follow-up, for an incidence rate of 1.4 per 1,000 person-years (95% CI, 1.29-1.53). Compared with DPP-IV inhibitors, SGLT2 inhibitors were associated with an increased risk for DKA, with incidence rates of 0.75 (95% CI, 0.63-0.89) and 2.03 (95% CI, 1.83-2.25), respectively, for an HR of 2.85 (95% CI, 1.99-4.08).
Molecule-specific analyses suggest a possible class effect. HRs for DKA were 1.86 for dapagliflozin (Farxiga, AstraZeneca; 95% CI, 1.11-3.1), 2.52 for empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly; 95% CI, 1.23-5.14), and 3.58 for canagliflozin (Invokana, Janssen; 95% CI, 2.13-6.03). Results persisted after adjustment for age and sex; however, prior receipt of insulin appeared to decrease the risk, according to researchers.
“Given that the mean follow-up of our study was relatively short — 0.9 years — further studies are needed to assess the longer-term safety of SGLT2 inhibitors regarding the risk for DKA,” Douros said.
For more information:
Antonios Douros MD, PhD, can be reached at the Centre for Clinical Epidemiology, Lady Davis Institute, 3755 Cote-Ste Catherine Road, Suite 492, Montreal, Quebec, Canada H3T 1E2; email: antonois.douros@mcgill.ca.
Perspective
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Zachary T. Bloomgarden, MD, MACE, FASPC
These data are not surprising. We have known for many years about the potential of SGLT2 inhibitors to increase ketones, and it appears that the ketone production of SGLT2 inhibitors may be intrinsic to their cardioprotective properties — so, not a bad thing at all.
The issue is that these drugs appear to act in a very complicated fashion. They are not just “water pills for sugar.” Furthermore, many people with type 2 diabetes are treated inappropriately and are not given insulin when they need it, and so have poor diabetes control. If such a patient with HbA1c well over 8% is treated with an SGLT2 inhibitor, their insulin deficiency is likely to lead the ketone production associated with the treatment to cause adverse effect.
These are, then, wonderful medicines when used appropriately; however, medicine is not without side effects. It is a matter of knowing the characteristics of the medicine, understanding the illness and treating it appropriately. Among people with insulin-requiring, poorly controlled type 2 diabetes, these are drugs that should never be given. For type 1 diabetes, there is controversy, but for many the risk for ketoacidosis outweighs the potential for benefits. Yet, SGLT2 inhibitors are marvelous drugs that reduce hospitalization for heart failure and progression of kidney disease among susceptible people with type 2 diabetes — and, perhaps, among people without diabetes as well. They simply must be prescribed correctly.
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