Diabetes medication may increase risk of perioperative ketoacidosis

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 have 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 study, appearing 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 Matthieu Legrand, MD, Ph.D., 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 Roberta Teixeira Tallarico, MD, a critical care physician and UCSF research associate.

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 have 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 study, appearing 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 Matthieu Legrand, MD, Ph.D., 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 Roberta Teixeira Tallarico, MD, a critical care physician and UCSF research associate.