Predisposing factors for the development of diabetic ketoacidosis with lower than anticipated glucose levels in type 2 diabetes patients on SGLT2-inhibitors: a review

Eur J Clin Pharmacol. 2021 May;77(5):651-657. doi: 10.1007/s00228-020-03051-3. Epub 2020 Nov 26.


Purpose: SGLT2-inhibitors (SGLT-2i) have been linked to the risk of potential life-threatening diabetic ketoacidosis (DKA). The U.S. Food and Drug Administration and the European Medicines Agency issued warnings in 2015 and 2016 respectively on the predisposing factors to the development of DKA in individuals on an SGLT2i. New predisposing factors to DKA are still being discovered with the use of SGLT-2i. The list by FDA and EMA is yet to be updated. This article aims to provide a holistic list that includes the newer factors that have been implicated in the development of DKA. The overall aim is to guide physicians in prescribing this class of drugs for type 2 diabetes mellitus (T2D).

Method: A search was done using PUBMED, Google Scholar, and Directory of Open Access Journals with the following words: SGLT-2 Inhibitors AND Ketoacidosis were entered. We included articles from 2000 to 2020, those in English, those involving any of the approved SGLT2i medications in T2D patients, and studies that focused on DKA linked to SGLT-2i. These articles were reviewed, and relevant data extracted and compiled.

Results and conclusion: The review has revealed that predisposing factors include (excess) alcohol consumption, female gender, starvation due to illness or fasting, withholding the use of SGLT2i for less than 48 h peri-operatively, and the existence of a variations in the expression of SGLT2 receptors. Patients should be advised on "sick day rules," and if a patient becomes unwell while on an SGLT2i, they should be advised to withhold the medication for the duration of the intercurrent illness.

Keywords: Euglycemic diabetic ketoacidosis; Predisposing; SGLT2-inhibitors; Type 2 diabetes.

Publication types

  • Review

MeSH terms

  • Alcohol Drinking / epidemiology
  • Blood Glucose / metabolism*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetic Ketoacidosis / chemically induced*
  • Fasting / physiology
  • Genetic Predisposition to Disease
  • Health Status
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Hypoglycemic Agents / therapeutic use
  • Insulin / administration & dosage
  • Risk Factors
  • Sex Factors
  • Sodium-Glucose Transporter 2 Inhibitors / adverse effects*
  • Sodium-Glucose Transporter 2 Inhibitors / therapeutic use
  • Surgical Procedures, Operative / statistics & numerical data


  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Sodium-Glucose Transporter 2 Inhibitors