How do SGLT (Sodium-Glucose Linked Transporter) inhibitors contribute to the development of euglycemic diabetic ketoacidosis (EDKA) in patients with diabetes?

Mechanism of SGLT Inhibitor-Induced Euglycemic Diabetic Ketoacidosis

SGLT inhibitors cause euglycemic diabetic ketoacidosis through three primary mechanisms: reduction in insulin levels (either from dose reduction or altered insulin-to-glucagon ratio), increased glucagon secretion leading to enhanced lipolysis and ketone production, and decreased renal clearance of ketones—all occurring despite normal or only mildly elevated blood glucose levels. 1

Primary Pathophysiological Mechanisms

The development of EDKA with SGLT inhibitors involves multiple interconnected pathways that fundamentally alter metabolic homeostasis:

1. Altered Insulin-to-Glucagon Ratio

• SGLT inhibitors promote urinary glucose excretion independent of insulin, which lowers blood glucose and changes the insulin-to-glucagon ratio, creating a metabolic environment that favors ketogenesis even when glucose levels appear normal 1, 2
• When glucose is lowered through non-insulin-dependent mechanisms, patients or clinicians often reduce insulin doses to avoid hypoglycemia, but this reduction may be insufficient to suppress lipolysis and ketone production 1, 3

2. Direct Glucagon Stimulation

• SGLT2 receptors are expressed on pancreatic α-cells, and SGLT2 inhibitors directly promote glucagon secretion 3
• Elevated glucagon levels drive increased lipolysis and hepatic ketone production, creating a pro-ketogenic state 1

3. Decreased Renal Ketone Clearance

• SGLT inhibitors, particularly through effects similar to phlorizin (a nonselective SGLT inhibitor), decrease urinary excretion of ketone bodies, allowing ketones to accumulate more rapidly in the bloodstream 1, 3
• This reduced clearance compounds the increased production, accelerating the development of ketoacidosis 1

4. Volume Depletion and Stress Response

• The osmotic diuresis induced by SGLT inhibitors causes volume depletion, which triggers counterregulatory hormone release (catecholamines, cortisol) that further promotes lipolysis and ketogenesis 1, 4
• During physiological stress (surgery, infection, fasting), the speed of ketone accumulation increases dramatically, and the body's inability to compensate for the resulting acidemia leads to rapid progression where ketones can rise to >3.0 mmol/L and pH can drop to <7.3 1

The "Euglycemic" Paradox

The defining feature of EDKA is that blood glucose remains normal (<200 mg/dL or <11.0 mmol/L) or only mildly elevated, which creates a dangerous diagnostic delay 1, 2:

• Traditional DKA presents with marked hyperglycemia (typically >250 mg/dL), but SGLT inhibitors continuously excrete glucose in urine, preventing the expected glucose elevation 4, 5
• This normal glucose misleads both patients and clinicians into dismissing the possibility of DKA, delaying recognition of the emergent metabolic crisis 6, 4
• Metabolic acidosis with pH <7.3 and elevated ketones (β-hydroxybutyrate >3.0 mmol/L) develop despite reassuring glucose levels 1, 2

High-Risk Clinical Scenarios

The susceptibility to EDKA increases dramatically in specific situations where additional metabolic stressors compound the baseline pro-ketogenic effects:

Perioperative Risk

• Surgical stress triggers massive release of counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone), inducing peripheral insulin resistance and increasing hepatic ketone production 1
• Perioperative DKA risk is significantly elevated in SGLT inhibitor users (1.02 vs 0.69 per 1000 patients; OR 1.48,95% CI 1.02-2.15) 1, 2
• Emergency surgery carries 6.5-fold higher risk than elective surgery (1.1% vs 0.17% incidence) 1, 2

Reduced Caloric Intake

• Fasting, very low-carbohydrate diets, poor oral intake, or prolonged starvation periods dramatically increase EDKA risk by reducing insulin secretion while maintaining glucagon-driven ketogenesis 2, 6
• The combination of SGLT inhibitor-induced glucose loss and inadequate caloric intake creates a perfect storm for ketoacidosis 5

Acute Illness

• Intercurrent infections (UTI, pneumonia, sepsis), acute pancreatitis, or other acute medical conditions are the most common precipitating factors, reported in 37.9% of EDKA cases 2, 5
• Illness-related stress hormones compound the baseline pro-ketogenic effects of SGLT inhibitors 6

Alcohol Consumption

• Excessive alcohol intake suppresses gluconeogenesis while promoting ketogenesis, synergizing with SGLT inhibitor effects 2

Critical Timing Considerations

EDKA risk persists even after SGLT inhibitor discontinuation, which is a crucial clinical pitfall:

• Cases of postoperative ketoacidosis have been documented even when patients withheld SGLT inhibitors for >72 hours, emphasizing that risk reduction is a continuum rather than an absolute threshold 1, 2
• One case report documented EDKA occurring 5 days after discontinuation of an SGLT2 inhibitor before cardiac surgery, with persistence of ketonemia and urinary glucose excretion postoperatively 7
• The pharmacodynamic effects on ketone metabolism may outlast the drug's presence in the circulation 7

Population-Specific Vulnerabilities

Type 1 Diabetes and LADA

• Patients with type 1 diabetes, latent autoimmune diabetes in adults (LADA), or pancreatic insufficiency have baseline insulin deficiency, making them particularly susceptible to EDKA 2
• These populations were excluded from major cardiovascular and heart failure outcomes trials, which explains the low ketoacidosis rates in those studies 1

Non-Diabetic Patients

• Recent evidence challenges the assumption that non-diabetic patients have sufficient endogenous insulin to prevent ketosis 1, 2
• EDKA has been documented in patients without diabetes taking SGLT2 inhibitors for heart failure or chronic kidney disease, particularly in perioperative settings 1

Clinical Presentation and Diagnostic Challenges

The absence of hallmark hyperglycemia, polyuria, and polydipsia leads to delayed diagnosis in the majority of cases 6, 4:

• Presenting symptoms are nonspecific: nausea/vomiting (65.1%), abdominal pain (37.3%), breathlessness (30.8%), and malaise 5
• Laboratory findings show metabolic acidosis (pH <7.3), elevated anion gap, elevated β-hydroxybutyrate (>3.0 mmol/L), but normal or minimally elevated glucose 1, 2
• Clinicians must check ketones and pH rather than relying solely on glucose levels when SGLT inhibitor use is identified 2

Incidence and Relative Risk

While EDKA remains relatively rare, the risk is clinically significant:

• Overall incidence in type 2 diabetes: 0.6-4.9 events per 1,000 patient-years 2
• Meta-analysis relative risk: 2.46 (95% CI 1.16-5.21) in randomized controlled trials and 1.74 (95% CI 1.07-2.83) in observational studies 2
• Despite low absolute rates in cardiovascular trials, these studies systematically excluded high-risk populations (type 1 diabetes, recent DKA history) 1

Common Clinical Pitfalls

Healthcare providers must avoid these critical errors:

• Failing to recognize EDKA because glucose levels appear reassuring—always check ketones when patients on SGLT inhibitors present with acidosis or nonspecific symptoms 2, 6
• Discontinuing insulin therapy prematurely when glucose normalizes—ketosis may persist despite normal glucose, requiring continued insulin to suppress ketogenesis 2
• Inadequate medication reconciliation on hospital admission—SGLT inhibitor use may not be immediately apparent, delaying diagnosis 6
• Assuming adequate preoperative discontinuation eliminates risk—EDKA can occur even with appropriate timing of drug cessation 1, 7