What is the mechanism behind Euglycemic Diabetic Ketoacidosis (EDKA) in patients with type 2 diabetes taking SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors, such as gliflozins (e.g. canagliflozin, dapagliflozin), and how does it influence insulin production by the pancreas?

Mechanism of Euglycemic Diabetic Ketoacidosis (EDKA) with SGLT2 Inhibitors

SGLT2 inhibitors (gliflozins) cause euglycemic diabetic ketoacidosis through a paradoxical metabolic shift: they promote ketogenesis and lipolysis while simultaneously lowering blood glucose through non-insulin-dependent urinary glucose excretion, creating a dangerous state where severe ketoacidosis develops without the typical warning sign of marked hyperglycemia. 1

Core Pathophysiologic Mechanisms

Primary Metabolic Alterations

• SGLT2 inhibitors block glucose reabsorption in the proximal tubule (S1 and S2 segments), forcing urinary glucose excretion independent of insulin action, which maintains relatively normal or only mildly elevated glucose levels even during states of insulin deficiency 2, 3

• These medications simultaneously increase glucagon secretion and decrease insulin secretion, creating a hormonal milieu that strongly favors ketone production through enhanced lipolysis and hepatic ketogenesis 4, 3

• The drugs reduce renal clearance of ketones while simultaneously promoting their production, leading to rapid accumulation of beta-hydroxybutyrate and acetoacetate 4, 3

The Euglycemic Paradox

• Blood glucose remains deceptively normal (<200 mg/dL, often <250 mg/dL) because SGLT2 inhibitors continue excreting glucose in urine even during ketoacidosis, masking the severity of metabolic decompensation and delaying diagnosis 1, 5, 6

• This absence of marked hyperglycemia removes the primary clinical warning sign that typically prompts patients and providers to suspect diabetic ketoacidosis, leading to dangerous delays in recognition and treatment 5, 3, 6

Impact on Pancreatic Insulin Production

Direct Effects on Beta Cell Function

• SGLT2 inhibitors do NOT directly suppress pancreatic insulin production—rather, they create a metabolic environment where the pancreas appropriately reduces insulin secretion in response to lower circulating glucose levels 2, 3

• The mechanism is indirect: as SGLT2 inhibitors lower blood glucose through urinary excretion, the pancreatic beta cells physiologically decrease insulin secretion because the glucose stimulus is reduced 2

• Simultaneously, pancreatic alpha cells increase glucagon secretion in response to the perceived glucose deficit, further driving ketogenesis despite adequate or near-normal glucose levels 4, 3

Clinical Consequence of Altered Insulin Dynamics

• This creates relative insulinopenia—not absolute insulin deficiency—where insulin levels are insufficient to suppress lipolysis and ketogenesis, but glucose remains controlled through renal excretion 3, 7

• Patients with compromised pancreatic reserve (type 1 diabetes, latent autoimmune diabetes in adults, chronic pancreatitis, or post-pancreatectomy) are at highest risk because they cannot mount adequate insulin responses 1, 4, 8

Critical Risk Factors and Precipitants

High-Risk Patient Populations

• Patients with type 1 diabetes, LADA, pancreatic insufficiency, or history of pancreatitis/pancreatic surgery should NOT receive SGLT2 inhibitors due to extreme EDKA risk 1, 4

• Patients on insulin therapy, particularly those with long-standing type 2 diabetes requiring complex insulin regimens, face substantially elevated risk 1

Specific Precipitating Factors

• Intercurrent illness, reduced food/fluid intake, reduced insulin doses, and alcohol consumption are the most common triggers 1, 5, 8

• Surgical stress, prolonged fasting, very-low-carbohydrate diets, dehydration, and volume depletion from concurrent diuretic use significantly increase risk 1, 7

• Pregnancy represents a special high-risk state where EDKA can develop with glucose <200 mg/dL and mixed acid-base disturbances 1

Incidence and Relative Risk

• The incidence of EDKA in type 2 diabetes patients on SGLT2 inhibitors is 0.6-4.9 events per 1,000 patient-years 1, 4

• The relative risk of DKA is 2.46 (95% CI 1.16-5.21) compared to placebo in randomized controlled trials, and 1.74 (95% CI 1.07-2.83) in observational studies 1, 4

Clinical Recognition and Prevention

Diagnostic Challenges

• EDKA presents with nonspecific symptoms (malaise, nausea, vomiting, abdominal pain, dyspnea, lethargy) and normal or mildly elevated glucose (<200 mg/dL), making diagnosis easily missed in emergency settings 1, 5, 6, 8

• Providers must maintain high suspicion and check ketones (urine or blood beta-hydroxybutyrate) in ANY patient on SGLT2 inhibitors presenting with these symptoms, regardless of glucose level 1, 6

Mandatory Prevention Strategies

• Discontinue SGLT2 inhibitors 3 days before elective surgery (4 days for ertugliflozin) to prevent postoperative EDKA 1, 9

• Stop SGLT2 inhibitors immediately during acute severe illness, vomiting, dehydration, or inability to maintain oral intake 1, 4

• Avoid substantial initial insulin dose reductions (>20%) when initiating SGLT2 inhibitors in insulin-treated patients 1

Patient Education ("Sick Day Rules")

• Patients MUST be counseled to temporarily stop SGLT2 inhibitors during illness, excessive exercise, alcohol intake, or prolonged fasting 4

• Instruct patients to seek immediate medical attention for nausea, vomiting, abdominal pain, or malaise while on these medications 1

• Patients should measure urine or blood ketones when symptomatic or when glucose exceeds 200 mg/dL, even if this seems paradoxical given the euglycemic nature of the condition 1

Management Considerations

• Treatment requires intravenous fluids, insulin infusion, dextrose administration (to prevent hypoglycemia while clearing ketones), and potassium supplementation, with resolution typically occurring over 72-90 hours 5, 6

• SGLT2 inhibitors should be permanently discontinued in patients who develop EDKA, as recurrence risk is unacceptably high 6

• The pharmacologic effects of SGLT2 inhibitors may persist beyond several half-lives of elimination, meaning EDKA can develop days after stopping the medication 7

Common Pitfalls to Avoid

• Never assume normal glucose excludes diabetic ketoacidosis in patients taking SGLT2 inhibitors—this is the most dangerous misconception 5, 3, 6

• Do not continue SGLT2 inhibitors during hospitalization for acute illness or surgical procedures without careful risk assessment 1, 9

• Avoid prescribing SGLT2 inhibitors to patients with any form of insulin-deficient diabetes (type 1, LADA, pancreatic disease) outside of carefully monitored research settings 1, 4, 3