Preoperative SGLT2 inhibitors increase metabolic acidosis with euglycemia, study finds

Japan: According to a retrospective matched cohort study, using sodium-glucose cotransporter 2 (SGLT2) inhibitor preoperatively is associated with increased metabolic acidosis with euglycemia. This necessitates close monitoring of patients before invasive surgical procedures to measure the risk of developing euglycemic diabetic ketoacidosis.

These findings were published by Iwasaki et al., Department of Anesthesiology and Critical Care, Japan, in BMC Endocrine Disorders. SGLT2 inhibitors are the second-line drugs in managing diabetes mellitus, as mentioned in the Canadian guidelines. Their use is increasing worldwide, including in Japan.

SGLT2 inhibitors have side effects like dry mouth, urinary tract infections, dehydration, and euglycemic diabetic ketoacidosis. These drugs increase glucagon, thereby promoting ketogenesis and lipolysis in the liver. However, there is less evidence in literature mentioning SGLT2 inhibitors as a direct cause of perioperative ketoacidosis.

Iwasaki et al. and the team hypothesized that SGLT2 inhibitors are associated with an increased risk of metabolic acidosis. The study included 155 patients analyzed for primary and secondary outcomes.

The study was conducted in the intensive care unit (ICU) of Saitama Medical center of Jichi Medical University, Japan. The inclusion criteria included patients aged 20 years or older with a history of Type 1 or Type 2 diabetes mellitus. The characteristic data collected were age, sex, surgery year (2014-2019), surgical types (cardiovascular, respiratory, urological, neurosurgery, orthopedic, abdominal), hemoglobin A1c level (HbA1c < 6%, ≥ 6% and < 7%, ≥ 7 % and < 8 %, ≥ 8 % and < 9 % and ≥ 9 %) and prescription of SGLT2 inhibitors and antidiabetic drugs. The exclusion criteria included emergency surgeries and cardiopulmonary bypass.

Eligible patients were divided into the case (SGLT2-inhibitor group) and control groups. Four patients with similar characteristics were randomly selected from the control group and compared for each patient in the case group.The statistical analysis included comparing continuous variables using the t-test and Man-Whitney U test. Categorical variables were compared using Fisher's exact test. A two-sided p-value of < 0.05 was statistically significant.

The key points from the study include:

• Empagliflozin was used in 24 patients in the study group and was withdrawn on the day of surgery.

• The primary outcome was defined as pH < 7.3, anion gap of > 12 mmol/L, PaCO2 < 45 mmHg and glucose level of < 252 mg/DL. The outcome measured the incidence of metabolic acidosis with an elevated anion gap and euglycemia during the ICU stay.

• The secondary outcome measured the proportion of metabolic acidosis, ICU stay, the lowest pH value, and the blood gas analysis.

• The extracted characteristics were reviewed for matched patients were weight, height, body mass index, Acute Physiology and Chronic Health Evaluation II (APACHE) scores, type of SGLT2 inhibitor, other antidiabetic, serum creatinine, estimated glomerular filtration rate, and medical history.

• 22.6 % of patients on SGLT2 inhibitors had metabolic acidosis with euglycemia.

• A total of 10 out of 124 patients (8.1 %) in the control group had metabolic acidosis.

• P value for metabolic acidosis was 0.047.

• P values for bicarbonate, base excess and anion gap were < 0.001, 0.002, 0.004 respectively.

• SGLT2 inhibitors affect pH, and their perioperative usage is associated with metabolic ketoacidosis, one of the major causes of mortality in diabetic patients.

Previous studies have shown that food deprivation and dehydration perioperatively develop metabolic ketoacidosis. But the results of this study highlight the most significant information of monitoring blood gas analysis and drug withdrawal time of SGLT2 inhibitors to assess the risk of metabolic acidosis.

References:

• Iwasaki, Y., Sasabuchi, Y., Horikita, S. et al. The effect of preoperative sodium-glucose cotransporter 2 inhibitors on the incidence of perioperative metabolic acidosis: A retrospective cohort study. BMC Endocr Disord 22, 209 (2022). https://doi.org/10.1186/s12902-022-01126-z