Why are SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors contraindicated in diabetic ketoacidosis (DKA)?

SGLT2 Inhibitors and Diabetic Ketoacidosis: Mechanism and Risk

SGLT2 inhibitors are contraindicated in diabetic ketoacidosis (DKA) because they can both precipitate and mask DKA by promoting ketogenesis while maintaining normal or only slightly elevated blood glucose levels, creating potentially life-threatening euglycemic DKA. 1

Pathophysiological Mechanism

SGLT2 inhibitors contribute to DKA risk through several mechanisms:

1. Altered insulin/glucagon ratio: SGLT2 inhibitors lower glucose concentrations, which changes the insulin/glucagon ratio, predisposing patients to ketosis 1

2. Enhanced ketogenesis: They stimulate glucagon release and promote ketone body production 2

3. Reduced ketone clearance: SGLT2 inhibitors increase ketone reabsorption in the renal tubules, elevating ketone body concentrations 2

4. Euglycemic presentation: They can cause DKA with normal or only mildly elevated blood glucose (<200 mg/dL), masking a key diagnostic feature of traditional DKA 3

Risk Factors for SGLT2 Inhibitor-Associated DKA

The risk of DKA is significantly higher in certain populations:

• Type 1 diabetes: ~4% incidence (5-17 times higher than non-SGLT2 users) 1, 3
• Type 2 diabetes: 0.6-4.9 events per 1,000 patient-years 1
• Insulin deficiency states: Including late-onset type 1 diabetes (LADA) 3
• History of previous DKA 3, 4
• Reduced beta cell function reserve 3

Precipitating Factors

Several conditions can trigger SGLT2 inhibitor-associated DKA:

• Very low-carbohydrate or ketogenic diets 3, 5
• Prolonged fasting or reduced food intake 1, 3
• Dehydration 1, 3
• Acute illness 3, 4
• Surgery (even when discontinued 48 hours prior) 6
• Excessive alcohol intake 1, 3
• Substantial reduction in insulin dose (>20%) 3
• Pregnancy 3
• Liver failure 3
• Chronic pancreatitis 4

Clinical Presentation and Diagnostic Challenges

The euglycemic presentation creates significant diagnostic challenges:

• Normal or minimally elevated blood glucose (<200 mg/dL) 1, 3
• Metabolic acidosis with elevated anion gap 3, 6
• Positive serum or urine ketones 3
• Classic DKA symptoms may be present: nausea, vomiting, abdominal pain, weakness 3
• Absence of hallmark hyperglycemia often leads to delayed diagnosis 4

Prevention and Management

For patients on SGLT2 inhibitors:

1. Education: Inform patients about euDKA risk, symptoms, and when to seek medical attention 3

2. Monitoring: Measure urine or blood ketones during illness or when symptoms develop, particularly when glucose exceeds 200 mg/dL 1, 3

3. Temporary discontinuation: Stop SGLT2 inhibitors during:

   • Acute illness 3
   • Fasting or reduced food intake 3
   • Before surgery (at least 48-72 hours prior) 1, 6

4. Avoid in high-risk patients: Do not use in type 1 diabetes or those with previous DKA 1, 3

Treatment of SGLT2 Inhibitor-Associated DKA

When euglycemic DKA occurs:

• Immediate discontinuation of the SGLT2 inhibitor 3
• Intravenous insulin and dextrose infusions (unlike traditional DKA, dextrose is needed earlier) 3
• Aggressive fluid resuscitation 3
• Electrolyte monitoring and replacement 3
• Close monitoring of acid-base status 3

Common Pitfalls to Avoid

1. Delayed diagnosis: Don't rule out DKA based on normal glucose levels in patients taking SGLT2 inhibitors 4

2. Insufficient pre-operative discontinuation: Consider stopping SGLT2 inhibitors >48 hours before major surgery, as pharmacokinetic effects may persist longer than previously thought 6

3. Failure to recognize risk factors: Always perform thorough medication reconciliation and assess for concurrent risk factors 4

4. Inadequate patient education: Patients must understand the risks of combining SGLT2 inhibitors with ketogenic diets 5

5. Overlooking euglycemic DKA: Consider checking ketones in any patient on SGLT2 inhibitors presenting with unexplained illness, even with normal glucose 3