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Newswise — Sodium-glucose cotransporter-2 inhibitors (SGLT2i), or gliflozins, are medications used in the treatment of type 2 diabetes mellitus (T2DM). They are designed to lower high blood glucose levels typical in T2DM, and work by inhibiting the sodium-glucose transport protein 2. SGLT2i have also been shown to improve outcomes among patients with chronic kidney disease, heart failure and coronary artery disease.

These medications are also associated with euglycemic ketoacidosis (eKA), which is characterized by high levels of ketones. In healthy amounts, ketones help the body convert fat cells into energy, but in excess, they can make blood acidic and toxic. One of the underlying reasons for SGLT2i-associated ketoacidosis involves reduced insulin secretion. eKA risk may be increased during the perioperative period given the reduction in oral carbohydrate intake during this time and the effect of surgical stress, which can increase insulin requirements and metabolic demand. This increased risk is also demonstrated by increasing number of case reports and case series of patients with postoperative eKA associated with SGLT2i use. eKA can lead to potentially severe consequences if left untreated.

Interestingly, clinical trials have reported cases of SGLT2i-associated eKA presenting with mildly elevated glucose levels. To explain the association between treatment with SGLT2i and the rate of postoperative eKA, acute kidney injury and mortality after surgery, UCSF researchers conducted a multicenter, retrospective cohort study to evaluate the risk of postoperative eKA and secondary clinical outcomes, including acute kidney injury and mortality, among SGLT2i users compared to matched non-users.

In the , appearing April 30 in JAMA Surgery, patients treated with SGLT2i had a small but significantly higher risk of postoperative euglycemic ketoacidosis but a lower risk of postoperative acute kidney injury (AKI) and mortality at 30 days post-surgery.

“The increased risk of perioperative eKA should be monitored and may necessitate escalated interventions like insulin administration or continuous dextrose infusion, which could be associated with an increased risk of prolonged hospitalization or unplanned admission to an intensive care unit,” said study senior author , MD, PhD, an anesthesiologist and critical care medicine specialist and UCSF professor of Anesthesia.

Using patient data from the Veterans Affairs Healthcare System (VAHCS) National Registry (2014 through 2022), researchers identified adult patients using SGLT2i pre-operatively who underwent inpatient surgical procedures. These patients were compared to a 1-to-5 matched control group using propensity score matching (PSM), including the patient’s demographics, comorbidities and surgical characteristics. After PSM, 7,439 patients were identified as SGLT2i users and were compared to 33,489 controls. In this multicenter retrospective cohort, the risk of perioperative eKA was 11% higher for patients using SGLT2i than their matched counterparts and 18% after emergency surgery, however, there was a 31% reduction in postoperative AKI and a 30% reduction in 30-day mortality.

“The increased risk of eKA was modest, but occurred both after emergency surgery and elective surgery. SGLT2i are usually held before elective surgery but this doesn’t appear to avoid the risk of eKA,” said study first author , MD, a critical care physician and UCSF research associate.

Additional authors: Bocheng Jing, MS, Kaiwei Lu, MS, Shweta Amy Chawla, BS, Yanting Luo, MS, Anusha Badathala, Catherine L. Chen, MD, Arthur w. Wallace, MD, PhD.

Funding: The research was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number T32GM008440, the statistical core of the UCSF Pepper Center (NIH P30AG044281) and UCSF FAST-CaR Seed Research Grant. Dr. Legrand is supported by grants R01-GM151494-01 and R01DK139484-01 from the NIH. Dr. Teixeira Tallarico is supported by a UCSF FAST-CaR Seed Research Grant and the UCSF Anesthesia Research Grant. Dr. Chen is funded by the National Institute on Aging (K23 AG072035), the Patricia Sander Award, and UCSF Anesthesia Research.

About UCSF Health: UCSF Health is recognized worldwide for its innovative patient care, reflecting the latest medical knowledge, advanced technologies and pioneering research. It includes the flagship UCSF Medical Center, which is a , as well as UCSF Benioff Children’s Hospitals, with campuses in San Francisco and Oakland; Langley Porter Psychiatric Hospital and Clinics; UCSF Benioff Children’s Physicians; and the UCSF Faculty Practice. These hospitals serve as the academic medical center of the University of California, San Francisco, which is world-renowned for its graduate-level health sciences education and biomedical research. UCSF Health has affiliations with hospitals and health organizations throughout the Bay Area. Visit . Follow UCSF Health on or on .

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