Which antidiabetic drug classes are associated with an increased risk of aspiration and which are linked to euglycemic diabetic ketoacidosis?

Antidiabetic Drugs Associated with Aspiration and Euglycemic Ketoacidosis

SGLT2 Inhibitors and Euglycemic Diabetic Ketoacidosis

SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) are the primary antidiabetic drug class associated with euglycemic diabetic ketoacidosis, with a relative risk of 2.46 compared to placebo. 1

Mechanism and Pathophysiology

• SGLT2 inhibitors predispose to ketoacidosis through multiple pathways: increased ketone production from reduced insulin doses, elevated glucagon levels leading to increased lipolysis, and decreased renal clearance of ketones 2, 1
• The incidence of euglycemic DKA in type 2 diabetes patients on SGLT2 inhibitors ranges from 0.6 to 4.9 events per 1,000 patient-years 1
• This complication can occur even when blood glucose levels are normal or only minimally elevated (150-250 mg/dL), which delays recognition by both patients and providers 2, 3, 4

High-Risk Populations

• Type 1 diabetes patients (SGLT2 inhibitors should be avoided or stopped) 1
• Latent autoimmune diabetes in adults (LADA) 1
• Patients with pancreatic insufficiency or history of pancreatitis/pancreatic surgery 1
• Patients on complex insulin regimens or with "brittle" diabetes 2, 3
• Recent history of diabetic ketoacidosis 2

Critical Precipitating Factors

• Acute severe illness, vomiting, or dehydration (requires immediate SGLT2 inhibitor discontinuation) 1, 3
• Substantial insulin dose reductions greater than 20% after SGLT2 inhibitor initiation 2, 3
• Prolonged fasting or severe carbohydrate restriction 2
• Major surgery or procedures requiring extended NPO status 5, 6
• Insulin pump malfunctions 2

Clinical Presentation

• Symptoms include nausea, vomiting, abdominal pain, generalized weakness, and dyspnea 2, 3
• Blood glucose may be normal or only mildly elevated (<250 mg/dL), creating diagnostic confusion 2, 3, 4
• Anion gap metabolic acidosis with elevated serum or urine ketones 4, 7
• The absence of significant hyperglycemia delays recognition of the emergent nature of the problem 4

Management Algorithm During Acute Illness

1. Immediately discontinue the SGLT2 inhibitor when acute illness, reduced oral intake, fever, vomiting, or diarrhea occurs 1, 3
2. Check blood glucose and ketones (serum β-hydroxybutyrate or urine ketones) 1
3. Maintain adequate hydration and avoid prolonged fasting 1
4. Never stop insulin completely in insulin-requiring patients, even when holding the SGLT2 inhibitor 3
5. Seek immediate medical attention if symptoms of ketoacidosis develop 2

Perioperative Management

• Stop SGLT2 inhibitors at least 3 days (preferably 1 week) before major surgery or procedures requiring prolonged fasting 3, 5, 6
• Provide low-dose basal insulin during the perioperative period to inhibit ketogenesis 6
• Monitor for euglycemic DKA in the postoperative period, as cases have been reported 48 hours after the last SGLT2 inhibitor dose 6

Criteria for Restarting SGLT2 Inhibitors

• Patient eating and drinking normally 1
• Capillary ketones <0.6 mmol/L 1
• Clinical improvement of acute illness 1
• Stable renal function 1

Duration of Risk

• Clinical effects of SGLT2 inhibitors persist much longer than the reported half-life would predict (dapagliflozin half-life is 12.9 hours, but ketosis can persist for days) 5
• Ketonemia and glucosuria may continue well beyond the expected pharmacokinetic effect 5

Aspiration Risk

No antidiabetic drug class has been specifically associated with increased aspiration risk in the provided evidence. However, GLP-1 receptor agonists cause delayed gastric emptying, which theoretically could increase aspiration risk during procedures requiring sedation or anesthesia, though this was not directly addressed in the guidelines reviewed.

Other Antidiabetic Drug Safety Concerns (Not Related to Aspiration or Euglycemic DKA)

DPP-4 Inhibitors

• Saxagliptin and alogliptin may increase heart failure risk, especially in patients with preexisting heart failure or renal impairment 2
• These agents are well-tolerated in the hospital with low hypoglycemia risk 2

Sulfonylureas

• Associated with sustained hypoglycemia risk, particularly in elderly patients, those with renal impairment, and when combined with insulin 2
• Professional societies recommend against routine hospital use 2

Metformin

• Risk of lactic acidosis in patients with sepsis, hypoxia, significant renal impairment (eGFR <30 mL/min/1.73 m²), or liver failure 2
• Should be discontinued before iodinated contrast procedures in at-risk patients 2