What is the mechanism of ketoacidosis associated with Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors?

Mechanism of Ketoacidosis Associated with SGLT2 Inhibitors

SGLT2 inhibitors cause ketoacidosis through multiple mechanisms including increased glucagon secretion, reduced insulin levels, enhanced lipolysis, and decreased renal ketone clearance, creating a perfect metabolic storm for ketone production despite normal or only mildly elevated blood glucose levels. 1

Primary Pathophysiological Mechanisms

• SGLT2 inhibitors promote urinary glucose excretion, effectively removing carbohydrates from the body's available energy pool, which forces a metabolic shift toward fat metabolism as the primary energy source 2
• These medications alter the insulin-to-glucagon ratio by directly stimulating pancreatic alpha cells to increase glucagon secretion while inhibiting beta cells, creating hormonal conditions that favor ketogenesis 1
• The combination of increased glucagon and reduced insulin levels enhances lipolysis (fat breakdown), providing more free fatty acids as substrates for hepatic ketone production 2, 3
• SGLT2 inhibitors may decrease the renal clearance of ketone bodies, further contributing to ketone accumulation in the bloodstream 3
• Volume depletion from the osmotic diuresis caused by glucosuria activates stress hormones (catecholamines and corticosteroids) that further promote lipolysis and ketogenesis 4

Unique Features of SGLT2 Inhibitor-Induced Ketoacidosis

• Unlike typical diabetic ketoacidosis, SGLT2 inhibitor-associated ketoacidosis often presents with normal or only mildly elevated blood glucose levels (<200 mg/dL), termed "euglycemic diabetic ketoacidosis" 1
• This euglycemic presentation can delay diagnosis as healthcare providers may not suspect ketoacidosis in the absence of significant hyperglycemia 1, 5
• The American Diabetes Association acknowledges that SGLT2 inhibitors increase susceptibility to diabetic ketoacidosis through multiple proposed pathways 6

Risk Factors and Precipitating Conditions

• Reduced insulin dosing (>20% reduction) when initiating SGLT2 inhibitors in insulin-dependent patients can precipitate ketoacidosis by removing insulin's suppressive effect on lipolysis 7
• Fasting, very low-carbohydrate diets, or poor oral intake significantly increase the risk of euglycemic ketoacidosis in patients taking SGLT2 inhibitors 1
• Surgical procedures, particularly those requiring fasting periods, are high-risk situations for developing euglycemic ketoacidosis 7, 1
• Acute illness, including infections, can trigger euglycemic ketoacidosis in patients on SGLT2 inhibitors 1
• Dehydration has been identified as both a contributing factor and a necessary condition for SGLT2 inhibitor-induced ketoacidosis in experimental models 4

Molecular and Cellular Mechanisms

• At the cellular level, SGLT2 inhibitors induce a metabolic shift from glucose to fatty acid utilization, increasing lipolysis in white adipose tissue 8
• Increased hepatic acetyl-CoA content from enhanced fatty acid oxidation drives both increased hepatic glucose production and ketogenesis 4
• Animal studies have demonstrated that the combination of insulinopenia and dehydration is both necessary and sufficient to induce euglycemic ketoacidosis with SGLT2 inhibitor treatment 4
• The risk exists on a continuum rather than having a defined threshold, making it important to consider multiple risk factors simultaneously 7

Clinical Implications and Prevention

• The incidence of euglycemic DKA in people with type 2 diabetes treated with SGLT2 inhibitors is relatively rare (0.6–4.9 events per 1,000 patient-years) but represents a serious adverse event 1
• Perioperative risk is higher (1.02 vs. 0.69 per 1000 patients) compared to patients not taking SGLT2 inhibitors, with emergency surgery carrying greater risk (1.1%) than elective procedures (0.17%) 7, 1
• Temporary discontinuation of SGLT2 inhibitors at least 3 days before elective surgery or procedures requiring fasting is recommended to reduce risk 1
• Monitoring ketone levels rather than just glucose is essential for early detection, particularly during high-risk situations 2
• Patient education regarding symptoms of ketoacidosis and preventive strategies is crucial for risk reduction 1

Special Considerations

• The risk of euglycemic ketoacidosis extends to non-diabetic patients taking SGLT2 inhibitors for other indications such as heart failure 9
• Approximately 5-10% of adult-onset diabetes is actually late-onset type 1 diabetes, and these patients have an increased risk of developing ketoacidosis with SGLT2 inhibitor therapy 7
• The combination of SGLT2 inhibitors with loop diuretics may potentially increase the risk of ketoacidosis due to enhanced volume depletion 4