Case: 51 Diagnosis & Conclusions -

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

The normal range for arterial blood pH is 7.35 – 7.45. Looking at the pH will help identify the primary acid/base disturbance:
< 7.35 = acidemia >7.45 = alkalemia

Labs

Looking at both the pCO2 and HCO3 will identify the primary process that led to the pH change. For an acidemia: If the pCO2 is elevated pCO2 (>45) , the primary process is a respiratory acidosis. If the HCO3 is low (<22), the primary process is a metabolic acidosis. For an alkalemia: If the pCO2 is decreased pCO2 (<35) , the primary process is a respiratory alkalosis. If the HCO3 is high (>32), the primary process is a metabolic alkalosis.

Anion gap

Use the bicarbonate from the chemistry panel to calculate the AG, or unmeasured anions (AG = Na – Cl – HCO3). Be sure to estimate the patient’s expected/normal anion gap using the serum albumin.
*The anion gap should be checked even in the absence of an acidemia as a metabolic acidosis may be hiding!

Compensation

Once the primary process has been identified, use the appropriate formulas (follow the link to Acid/Base below) to see if the patient is compensating. If compensation is inadequate, then there may be another process going on!

Other processes

Patients can have up to 3 acid-base disorders – an anion gap metabolic acidosis may coexist with a metabolic alkalosis OR non-gap metabolic acidosis AND 1 respiratory disorder (you can only hyperventilate or hypoventilate).
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.

Early changes in the proximal tubule in diabetes (Diabetic kidney disease: new concepts in pathogenesis and treatment)

Effect of SGLT-2 inhibitors on ketone metabolism

Here’s a Renal Fellow Network post on this topic – and we’ve shared a figure from that post below.

Pathophysiology of eugylcemic DKA in patients on SGLT-2 inhibitors

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!

Case 51 Index
Case 51 Introduction
Case 51 Physical Exam
Case 51 Diagnostic Testing
NephSIM