Mechanisms of SGLT2 Inhibitor-Induced Euglycemic DKA in Patients with Normal Insulin Levels
SGLT2 inhibitors can cause euglycemic diabetic ketoacidosis (euDKA) in patients with normal insulin levels and sensitivity through multiple mechanisms, including altered insulin-to-glucagon ratio, increased lipolysis, and reduced renal ketone clearance. 1, 2
Primary Pathophysiological Mechanisms
- SGLT2 inhibitors promote urinary glucose excretion by inhibiting glucose reabsorption in the proximal renal tubules, which changes the insulin-to-glucagon ratio even in patients with normal baseline insulin levels 1, 3
- These medications stimulate glucagon secretion directly, as SGLT2 is expressed in pancreatic α-cells, leading to increased hepatic glucose production and ketogenesis despite normal insulin levels 1, 4
- The resulting urinary glucose excretion leads to volume depletion and metabolic changes that further promote ketosis 2, 5
Contributing Factors in Patients with Normal Insulin
- SGLT2 inhibitors cause a shift in substrate utilization from carbohydrates to lipids, increasing lipolysis and free fatty acid availability for ketogenesis 1, 4
- The combination of increased glucagon and reduced insulin action (even when insulin levels are normal) creates a hormonal environment that favors ketone body production 1, 2
- Volume depletion from osmotic diuresis increases counterregulatory hormone secretion (catecholamines, cortisol, growth hormone), which further promotes ketogenesis 6, 5
Unique Aspects of Euglycemic DKA
- Unlike typical DKA, glucose levels remain normal or only mildly elevated (<200 mg/dL) because SGLT2 inhibitors continue to promote urinary glucose excretion 1, 7
- This euglycemic presentation often delays diagnosis, as traditional DKA screening relies on significant hyperglycemia 1, 8
- SGLT2 inhibitors may decrease urinary excretion of ketone bodies, potentially increasing plasma ketone levels even further 4, 5
Risk Factors That Amplify These Mechanisms
- Reduced caloric intake or low-carbohydrate/ketogenic diets significantly increase the risk of euDKA by further promoting ketosis 1, 9
- Acute illness, surgery, or excessive alcohol consumption increase counterregulatory hormones and reduce carbohydrate intake 1, 2
- Insulin dose reduction (even in patients who normally have adequate insulin) can tip the balance toward ketosis when combined with SGLT2 inhibition 1, 5
Clinical Implications
- The incidence of euDKA in patients with type 2 diabetes on SGLT2 inhibitors is relatively rare (0.6–4.9 events per 1,000 patient-years) but represents a significant clinical concern 1
- Perioperative risk is higher (1.02 vs. 0.69 per 1000 patients), with emergency surgery carrying greater risk than elective procedures (1.1% vs. 0.17%) 2
- Even patients with normal insulin sensitivity can develop euDKA when multiple risk factors converge with SGLT2 inhibitor use 2, 7
The pathophysiology of SGLT2 inhibitor-induced euDKA represents a perfect storm of metabolic alterations that can occur even in patients with normal baseline insulin levels and sensitivity, particularly when combined with precipitating factors that further promote ketogenesis.