Not Out of the Woods yet-a Case of Recurrent Euglycemic Diabetic Ketoacidosis Secondary to Empagliflozin and Pancreatitis

While Sodium Glucose Co-Transporter 2 (SGLT2) inhibitors have demonstrated impressive clinical benefits, we should maintain vigilant when prescribing. I report a patient with euglycemic diabetic ketoacidosis (eDKA) precipitated by empagliflozin and pancreatitis, which recurred following initial resolution. This case demonstrates several points of practical relevance to clinicians.

The patient is a 43 year old male with Diabetes Mellitus diagnosed at age 36, for which he was initially treated with glipizide. The patient developed an episode of acute necrotizing pancreatitis in 2015, for which investigations revealed Common Bile Duct (CBD) dilatation with no calculi. Due to worsening glycaemic control following this episode of pancreatitis, he was subsequently switched to twice-daily biphasic insulin aspart (Novomix) with metformin in June 2015, and was on follow up with his General Practitioner (GP). Although HbA1c and glucose readings were not available, the patient’s GP had informed him that his glycaemic control was suboptimal, prompting the addition of empagliflozin 10 mg daily to his regime in December 2020. He had no known cardiac or renal disease, retinopathy or neuropathy. 

One month later, the patient was admitted to our institution with epigastric pain radiating to the back and vomiting of 2 days duration. There was no fever, diarrhea or other symptoms of infection, and the patient had abstained from alcohol. On initial assessment, he was afebrile (temperature 36.3 degrees Celsius), blood pressure was 153/90 mm Hg, heart rate was 91 beats per minute and oxygen saturation was 98% on room air. Clinical examination revealed epigastric tenderness with no rebound or guarding. Examination of the cardiovascular, respiratory and neurological systems was unremarkable. Biochemical investigations showed elevated amylase and lipase with ketonemia, high anion gap metabolic acidosis and normoglycemia, while CT of the abdomen revealed peripancreatic inflammatory stranding with a 5 mm pancreatic duct calculus (Table 1). The clinical presentation and investigations were consistent with eDKA and acute pancreatitis secondary to pancreatic duct calculus. As the patient was haemodynamically stable with no local complications, systemic complications or organ failure, the modified Marshall score was 0, consistent with mild acute interstitial edematous pancreatitis. 

Table 1: Investigations for diagnosis of euglycemic diabetic ketoacidosis and acute pancreatitis, as well as related investigations. 

The patient was started on intravenous insulin infusion and fluids with close monitoring of serum electrolytes. Empagliflozin was stopped. Following close to 2 days of IV insulin infusion, acidosis had resolved but there was persistent ketonemia. This was attributed to nil oral in take, and the patient was switched to subcutaneous insulin and allowed diet. However, severe abdominal pain occurred the following day. Investigations confirmed the recurrence of ketoacidosis for which IV insulin infusion was resumed and IV Dextrose 10% fluid was started (Table 2).The patient remained haemodynamically stable. The increase in risk of procedure-related pancreatitis notwithstanding, the decision was made to proceed with Endoscopic Retrograde Cholangiopancreatography (ERCP), which was performed uneventfully. No calculi were found on ERCP despite initial CT findings of a pancreatic duct calculus, which could be explained by spontaneous passage of the calculus (Table 2). Subsequently, the patient remained well with no ketonemia or acidosis and was converted to subcutaneous insulin. empagliflozin continued to be held off on discharge. 

Table 2: Trend of capillary glucose, ketones, pH and HC03 with corresponding IV fluid and IV insulin infusion rate.

SGLT2 inhibitors and acute pancreatitis have both been associated with eDKA [5,6]. To the best of my knowledge, this is the first reported case of eDKA simultaneously due to empagliflozin and acute pancreatitis. SGLT2 inhibitors lead to increased glycosuria and reduction of the insulin-to-glucagon ratio, which stimulates lipolysis and ketogenesis [5,6]. With worsening insulin deficiency or restriction of carbohydrate intake, ketosis may deteriorate into ketoacidosis [5], both factors, particularly the latter, were relevant in this patient. Although resuming oral intake initially led to resolution of persistent ketosis, the ensuing pancreatic exocrine activity likely led to recurrent pancreatic inflammation and ketoacidosis despite ongoing therapy with subcutaneous insulin. This was supported by the observed resolution of recurrent ketoacidosis following the switch to parenteral carbohydrate administration. 

There is currently no consensus regarding the optimal timing of resumption of oral feeding in acute pancreatitis. While enteral nutrition is believed to stimulate release of pancreatic exocrine enzymes and possibly prolong recovery, it might also help maintain the gut protective barrier and reduce bacterial translocation and sepsis [7,8], In patients with eDKA secondary to both SGLT2 inhibitor and acute pancreatitis, due to the possible risk of recurrent pancreatic inflammation and ketoacidosis, the clinician might wish to opt for a more judicious approach to resuming oral feeding. 

Another important reason for recurrent ketoacidosis is the prolonged effect of SGLT2 inhibitors, which have been described to lead to prolonged glycosuria and ketonemia [9,10]. Suggested mechanisms include active drug secretion into the renal proximal tubule, drug binding to plasma proteins in an acidic environment and dissociation following resolution of acidosis, and receptor down-regulation [11-13]. Thus, prolonged treatment and increased vigilance for recurrence following resolution of SGLT2 inhibitor-associated eDKA may be required. 

Should empagliflozin have been started? As with Type 1 Diabetes but perhaps less well-known, SGLT2 inhibitors should be prescribed with caution in patients with pancreatic disease including previous pancreatitis [5,14,15]. Prior to initiation, a detailed risk-benefit analysis and explanation of the necessary precautions should be undertaken beforehand.

In conclusion, this case highlights the following clinical pearls in the management of eDKA secondary to SGLT2 inhibitor and acute pancreatitis: 

• • The author declares that there is no funding source.
• • The author declares that there is no conflict of interest.
• • The author declares that there is no acknowledgement.
• • Informed consent was obtained from the patient for publication of this manuscript.