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.

Keywords: acute complications; case reports; clinical trials; glucose-lowering drugs; pharmacovigilance.