How do Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors cause Diabetic Ketoacidosis (DKA)?

Mechanism of SGLT2 Inhibitor-Induced Diabetic Ketoacidosis

SGLT2 inhibitors cause diabetic ketoacidosis through a metabolic shift toward fat breakdown by promoting urinary glucose excretion (removing carbohydrates from the body's energy pool), increasing glucagon secretion, and reducing insulin levels—all of which drive lipolysis and ketone production, while simultaneously decreasing renal clearance of ketones. 1, 2, 3

Core Pathophysiological Mechanisms

The development of DKA with SGLT2 inhibitors involves three interconnected metabolic processes:

1. Altered Insulin-to-Glucagon Ratio

• SGLT2 inhibitors lower blood glucose by forcing urinary glucose excretion, which fundamentally changes the insulin-to-glucagon ratio and predisposes patients to ketosis 4, 2
• SGLT2 receptors are expressed on pancreatic α-cells, and SGLT2 inhibitors directly promote glucagon secretion, further driving ketogenesis 5
• When SGLT2 inhibitors are combined with insulin therapy, insulin doses are often reduced to prevent hypoglycemia, which decreases suppression of lipolysis and promotes fat breakdown 1, 5

2. Metabolic Shift to Fat Metabolism

• By removing glucose through urinary excretion, SGLT2 inhibitors effectively eliminate carbohydrates from the body's available energy pool 1
• This forces a metabolic shift toward fat as the primary energy source, promoting lipolysis and ketone production 1
• The combination of increased glucagon levels and reduced carbohydrate utilization creates a pro-ketogenic state 1

3. Reduced Renal Ketone Clearance

• Phlorizin (a nonselective SGLT inhibitor) decreases urinary excretion of ketone bodies, and SGLT2 inhibitors may have similar effects 5
• Decreased renal clearance of ketones contributes to rising plasma ketone levels 5

Euglycemic DKA: The Diagnostic Challenge

The most dangerous aspect of SGLT2 inhibitor-induced DKA is that it presents with normal or only mildly elevated glucose levels (often <250 mg/dL or <14 mmol/L), which delays recognition and treatment. 2, 3, 6

• Blood glucose levels at presentation may be below those typically expected for DKA (less than 250 mg/dL), with the average being 265.6 ± 140.7 mg/dl in case series 7, 8
• The FDA labels for both dapagliflozin and empagliflozin specifically warn that ketoacidosis may be present even if blood glucose levels are less than 250 mg/dL 3, 6
• Patients present with metabolic acidosis (pH <7.3), elevated ketones (>3.0 mmol/L), and symptoms of dehydration and severe metabolic acidosis including nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath 4, 2, 6

High-Risk Clinical Scenarios

Precipitating Factors

The following situations dramatically increase DKA risk and require heightened vigilance:

• Surgery and prolonged fasting: Emergency surgery carries 1.1% risk versus 0.17% for elective surgery 2
• Insulin dose reduction or omission: Particularly in patients with insulin deficiency or pancreatic disorders 2, 3, 6
• Reduced caloric intake: Very low-carbohydrate or ketogenic diets are particularly dangerous—cases have occurred after just 1 week on a ketogenic diet 2, 9
• Acute illness: Intercurrent infections or febrile illness increase counterregulatory hormones that drive ketogenesis 4, 2, 6
• Volume depletion: Physiological stress from dehydration increases counterregulatory hormone production 4
• Excessive alcohol consumption 2, 6

High-Risk Patient Populations

• Type 1 diabetes patients (though SGLT2 inhibitors are not indicated for this population) 3, 6
• Type 2 diabetes patients with latent autoimmune diabetes of adulthood (LADA) or pancreatic disorders (history of pancreatitis or pancreatic surgery) 2, 3, 6, 8
• Pregnant individuals and those with autoimmune conditions 2

Critical Clinical Caveat: Persistent Risk After Discontinuation

Ketoacidosis can occur even when SGLT2 inhibitors have been withheld for >72 hours, with postmarketing reports documenting ketoacidosis lasting up to 2 weeks after discontinuation. 4, 3

• Urinary glucose excretion persists for 3 days after discontinuing SGLT2 inhibitors, but ketoacidosis and glucosuria may persist much longer than typically expected 4, 3
• This emphasizes that withholding the medication does not immediately eliminate risk, particularly in the perioperative setting 4

Prevention Strategies

Perioperative Management

• Withhold SGLT2 inhibitors at least 3 days (preferably 3-4 days) before elective surgery or procedures requiring prolonged fasting 4, 10, 2, 3
• The FDA label for dapagliflozin specifically states to withhold for at least 3 days prior to major surgery 3
• Omitting the drug the day before surgery provides a minimum 48-52 hour gap for morning procedures, or 36 hours for evening dosing 4
• Resume only when the patient is clinically stable, eating and drinking normally (usually 24-48 hours post-surgery), and ketones are <0.6 mmol/L 10, 2, 3

Patient Education and Monitoring

• The American Association of Clinical Endocrinologists recommends monitoring ketone bodies (not just glucose) to prevent euglycemic ketoacidosis 1
• Educate patients on DKA symptoms and instruct them to discontinue SGLT2 inhibitors and seek immediate medical attention if symptoms occur 3, 6
• Provide detailed instructions on medication adjustments during illness and advise monitoring of urine or blood ketones during high-risk situations 2
• Patients must be explicitly warned to avoid ketogenic or very low-carbohydrate diets while on SGLT2 inhibitors 2, 9

Insulin Management

• Maintain basal insulin even when not eating—never omit insulin entirely 2
• Avoid inappropriate insulin dose reductions that could precipitate ketosis 2, 7

Incidence and Risk Quantification

• Overall incidence in type 2 diabetes is relatively rare: 0.6-4.9 events per 1,000 patient-years 2
• Meta-analyses show relative risk of 2.46 (95% CI 1.16-5.21) in randomized controlled trials 2
• Perioperative risk is higher: 1.02 vs. 0.69 per 1,000 patients (OR 1.48,95% CI 1.02-2.15) 4, 2
• Risk in patients with diabetes is substantially higher than those without: 1 in 339 vs. 1 in 15,592 4
• However, recent case reports document euglycemic ketoacidosis even in patients without diabetes mellitus, challenging the assumption that sufficient endogenous insulin prevents ketosis 4