Case Published: December 2020
Case Submitted By: David Kearney
Diagnosis: Diabetic ketoacidosis (euglycemic) in the setting of SGLT-2 inhibitor use
Case Summary: Well done! Let’s take a closer look at this case. We have a 39 year-old woman with non-insulin dependent diabetes who recently started treatment with an sodium-glucose transporter-2 (SGLT-2) inhibitor, empagliflozin. She presents with nausea, poor oral intake, polyuria and polydipsia – and was found to have a severe metabolic acidosis with an elevated anion gap. She has a minimally elevated serum glucose and she has developed ketonemia. Her intact mental status suggests against a toxic ingestion and serum lactate is within normal limits. Let’s review an approach to acid/base disorders first:
A trick to solving every acid/base problem: pLACO
< 7.35 = acidemia >7.45 = alkalemia
*The anion gap should be checked even in the absence of an acidemia as a metabolic acidosis may be hiding!
Calculate the delta gap, Δ/Δ = (Anion gap – normal anion gap) / (Pt’s HCO3 – normal HCO3)
If the ratio above is > 2, then there is a concomitant metabolic alkalosis. If it is < 1, then there is a concomitant metabolic alkalosis.
For more on pLACO, check out our Acid/Base tutorial.
A useful mnemonic for the differential diagnosis of a high anion gap metabolic acidosis is GOLDMARK
Euglycemic diabetic ketoacidosis (euDKA) is an increasingly recognized complication of SGLT-2 inhibitors, though the frequency of this complication seems to be rare. It was seen in 0.1% of patients with empagliflozin in the EMPA-REG Trial, 0.6 events per 1000 patient years with canagliflozin in the CANVAS Trial, and 0.3% event rate with dapagliflozin in the DECLARE-TIMI trial. Of note, the Federal Drug Administration (FDA) has issued a warning risk of euglycemic DKA in patients on SGLT-2 inhibitors. It can be precipitated by acute illness, volume depletion, major surgery, low carbohydrate diet (e.g. “keto diet”), and high alcohol intake. Thus, it is suggested that patients prescribed SGLT-2 inhibitors follow “sick day rules,” or to hold the medication if they experience these scenarios.
SGLT-2 inhibitors precipitate ketosis through a variety of pathways. This class of drugs inhibits the SGLT-2 co-transporter at the proximal tubule, thereby inducing glycosuria. The hypoglycemic effects inhibit further release of insulin from pancreatic (β cells), while stimulating release of glucagon (aα cells). This increased glucagon:insulin ratio favors mobilization of adipose tissue as an energy source, leading to release of free fatty acids which are then metabolized to ketone bodies by the liver. Furthermore, the reabsorption of ketones in the proximal tubule is mediated by the sodium-dependent monocarboxylate transporters, dependent upon the sodium gradient. When the proximal tubule is already under the influence of natriuresis (as occurs with SGLT-2 inhibitor use), reabsorption of ketones may be enhanced. Of note, SGLT-2 inhibitors should be used with caution in patients with type 1 diabetes mellitus as DKA may be more likely to occur.
Here’s a Renal Fellow Network post on this topic – and we’ve shared a figure from that post below.
Once euglycemic DKA has developed, treatment entails discontinuing the medication and inhibiting further ketone production by giving insulin. Since patients are euglycemic, they will require dextrose-containing IV fluids to prevent hypoglycemia.
Check out this summary of additional potential adverse events of SGLT-2 inhibitors.
Take a look at these references for more!
- Zinman B, et al. “Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes”. The New England Journal of Medicine. 2015. 373(22):2117-28.
- Neal B, et al. “Canagliflozin and cardiovascular and renal events in type 2 diabetes”. The New England Journal of Medicine. 2017. 377(7):644-657.
- Wiviott SP, et al. “Dapagliflozin and cardiovascular outcomes in type 2 diabetes”. The New England Journal of Medicine. 2019. 380(4):347-357.
- Qiu, Hongyu et al. “Ketosis and diabetic ketoacidosis in response to SGLT2 inhibitors: Basic mechanisms and therapeutic perspectives.” Diabetes/metabolism research and reviews vol. 33,5 (2017)
- Goldenberg, Ronald M et al. “SGLT2 Inhibitor-associated Diabetic Ketoacidosis: Clinical Review and Recommendations for Prevention and Diagnosis.” Clinical therapeutics vol. 38,12 (2016): 2654-2664.e1.