Euglycaemic diabetic ketoacidosis as a complication of SGLT-2 inhibitors: epidemiology, pathophysiology, and treatment

ABSTRACT

Introduction

Sodium-glucose co-transporters 2 (SGLT-2) inhibitors are a relatively novel class of oral medications for the treatment of Type 2 Diabetes Mellitus, which lower plasma glucose by inhibiting glucose reabsorption in the proximal renal tubule. Apart from their hypoglycemic action, recent data suggest these agents have additional major cardioprotective and nephroprotective properties.

Areas covered

This review summarizes the existing data on epidemiology, pathophysiology, and treatment of euglycaemic ketoacidosis (euDKA) as a complication of SGLT-2 inhibitor use.

Expert opinion

Although SGLT-2 inhibitors have a relatively good adverse event profile, they have been associated with the serious and potentially life-threatening metabolic complication of euDKA. Data from major outcome trials suggest that the rate of DKA is quite low. However, the rate of DKA could be generally underestimated in clinical trials due to the atypical presentation of ketoacidosis, and even more so in real-life conditions. Management of this serious metabolic complication requires a proper understanding of its pathophysiology as well as increased awareness and early recognition of the potential risk factors involved. Following this, the institution of an array of simple supportive measures, could safely restore normal acid–base balance in most patients.

KEYWORDS:

• SGLT-2 inhibitors
• Type 2 Diabetes Mellitus
• diabetic ketoacidosis
• euglycaemic diabetic ketoacidosis
• adverse effects
• metabolic acidosis

Article highlights

• SGLT2 inhibitors are a relatively novel class of oral medications for the treatment of Type 2 Diabetes Mellitus. Apart from their hypoglycemic action, recent data suggest these agents possess cardioprotective and nephroprotective properties

• EuDKA is a rare but serious metabolic complication associated with SGLT2 inhibitor therapy. Patients with euDKA often present with serious high anion gap metabolic acidosis but only mild to moderate glucose elevation [<250 mg/dl (13.9 mmol/L)].

• The rate of DKA in major trials was quite low, but there are suggestions that the incidence of DKA in everyday practice could be underestimated due to its atypical presentation.

• Understanding of the pathophysiology of euDKA, employment of simple preventive measures in high-risk patients, increased awareness and prompt diagnosis of this complication is of major importance.

• Early institution of simple therapeutic measures will safely restore normal acid–base balance in most patients.

This box summarizes the key points contained in the article.

Author contributions

ES and PA conceived the idea of the paper and drafted the manuscript. AP critically revised the manuscript for intellectual content.

Declaration of interest

PA Sarafidis has received research support for an Investigator-Initiated Study from Astra Zeneca and is an advisor/speaker to Astra Zeneca and Boehringer Ingelheim. E Sampani and A Papagianni have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.