Ketoacidosis and SGLT2 Inhibitors: A Narrative Review

Abstract

An acute metabolic complication of diabetes mellitus, especially type 1, is diabetic ketoacidosis (DKA), which is due to an increase in blood ketone concentrations. Sodium/glucose co-transporter-2 inhibitor (SGLT2-i) drugs have been associated with the occurrence of a particular type of DKA defined as euglycemic (euDKA), characterized by glycemic levels below 300 mg/dL. A fair number of euDKA cases in SGLT2-i-treated patients have been described, especially in the last few years when there has been a significant increased use of these drugs. This form of euDKA is particularly insidious because of its latent onset, associated with unspecific symptomatology, until it evolves (progressing) to severe systemic forms. In addition, its atypical presentation can delay diagnosis and treatment. However, the risk of euDKA associated with SGLT2-i drugs remains relatively low, but it is essential to promptly diagnose and manage it to prevent its serious life-threatening complications. In this narrative review, we intended to gather current research evidence on SGLT2i-associated euDKA from randomized controlled trials and real-world evidence studies, its diagnostic criteria and precipitating factors.

Keywords: SGLT2-i; adverse drug reaction; diabetic ketoacidosis.

Figure 1

Mechanism of glucose and Na⁺ renal reabsorption mediated by sodium/glucose co-transporters.

Figure 2

Possible etiopathogenetic mechanism of EuDKA in patients taking SGLT2-i. SMCT-2: sodium-coupled monocarboxylate transporter-2. URAT-1: urate anion transporter 1. ACC: acetyl-CoA carboxylase. CPT-I: carnitine palmitoyltransferase-I. FFA: free fatty acid.