Sodium‐glucose co‐transporter‐2 inhibitors and diabetic ketoacidosis: An updated review of the literature

Abstract

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are increasingly used for the treatment of type 2 diabetes (T2D) and can improve glucose control also in type 1 diabetes (T1D). In May 2015, regulatory agencies issued a warning that SGLT2is may cause diabetic ketoacidosis (DKA). We report details on 2 new cases of SGLT2i-associated DKA and review the literature for similar cases within randomized controlled trials (RCTs), cohort studies and single reports. We searched the medical literature for reports of SGLT2i-associated DKA cases. A quantitative analysis of frequency and clinical characteristics is reported. The 2 narrative cases illustrate that SGLT2i-associated DKA can occur in patients with T1D incorrectly diagnosed as T2D, perhaps without the presence of obvious DKA precipitating factors. The incidence of SGLT2i-associated DKA was less than 1/1000 in randomized controlled trials and 1.6/1000 person-years in cohort studies. We retrieved detailed data on 105 SGLT2i-associated DKA case reports, wherein 35% showed glucose levels of less than 200 mg/dL and 22% were not associated with typical triggers. In case reports and in pharmacovigilance databases, duration of SGLT2i treatment before DKA onset was extremely variable. Fatal SGLT2i-associated DKA episodes were found only in pharmacovigilance databases and represented 1.6% of all reported cases. DKA is a rare adverse event during SGLT2i therapy. Predisposing and precipitating factors are still incompletely understood, although a minority of cases lacked typical DKA triggers. More narrative case series and cohort studies are needed to better understand the true risk and the spectrum of this adverse event.

Observational research on sodium glucose co‐transporter‐2 inhibitors: A real breakthrough?

“…A recent literature review analysed RCTs, cohort studies, case reports and pharmacovigilance database studies53: DKA incidence was less than 1/1000 in RCTs (in line with data from an MA54) and 1.6/1000 person‐years in cohort studies. In case reports and in pharmacovigilance databases, duration of SGLT2‐I treatment before DKA onset was extremely variable; overall, DKA is a rare adverse event during SGLT2‐I therapy, with fatal episodes representing 1.6% of all reported cases 55.…”

Sodium–glucose cotransporter 2 inhibitor‐associated diabetic ketoacidosis in patients with type 1 diabetes: Metabolic imbalance as an underlying mechanism

“…Importantly, when DKA does occur in patients taking SGLT2 inhibitors, it often presents with an uncommon feature. Whereas DKA without hyperglycemia, or euglycemic DKA, has long been recognized as a rare condition overall, it occurs not so infrequently in individuals taking SGLT2 inhibitors, with 30–50% of DKA cases taking this form in patients on these drugs. Given the lack of symptoms related to hyperglycemia, it is often difficult to notice the development of euglycemic DKA.…”

“…However, such patients are at a higher risk for DKA than are type 2 diabetes patients. Whereas the incidence of SGLT2 inhibitor‐related DKA was <0.1% in randomized controlled trials with type 2 diabetes patients, the incidence increased to ~4–6% in those with type 1 diabetes. Furthermore, a meta‐analysis showed that the administration of SGLT2 inhibitors significantly increases the incidence of DKA in patients with type 1 diabetes.…”

Sodium‐glucose co‐transporter type‐2 inhibitors: pharmacology and peri‐operative considerations

“…In 2015, the Food and Drug Administration cautioned that SGLT2 inhibitors may increase the risk of ketoacidosis based on 20 cases . The European Medicines Agency subsequently reported 147 cases of ketoacidosis associated with SGLT2 inhibitors . The type‐2 diabetes clinical trials for canagliflozin, dapagliflozin and empagliflozin have accumulated 44,000 patient years of exposure to SGLT2 inhibitors with diabetic ketoacidosis incidence rates varying from 0.16 to 0.76 event per 1000 patient years .…”

“…Treatment consists of stopping the SGLT2 inhibitor, intravenous fluids, insulin and occasionally bicarbonate . Sodium‐glucose co‐transporter type 2 inhibitors compound the hypovolaemia that results from diabetic ketoacidosis and thus large volumes of normal saline may be required. An insulin infusion at a lower‐than‐usual rate of 0.05 units.kg.h ‐1 with an infusion of dextrose‐5% and normal saline is indicated if the patient is euglycaemic .…”