What medications most frequently cause normal glycemic diabetic ketoacidosis (DKA)?

Medications Most Frequently Causing Euglycemic Diabetic Ketoacidosis

SGLT2 inhibitors are the primary class of medications responsible for euglycemic diabetic ketoacidosis (euDKA), a potentially life-threatening condition characterized by metabolic acidosis with ketosis despite normal or only mildly elevated blood glucose levels (<200 mg/dL). 1

Understanding Euglycemic DKA

Euglycemic DKA is a unique presentation of diabetic ketoacidosis where patients develop significant ketosis and metabolic acidosis despite having blood glucose levels that are normal or only minimally elevated (typically <200 mg/dL). This makes diagnosis challenging as traditional DKA screening often relies on detecting hyperglycemia.

Key Characteristics:

• Metabolic acidosis with ketosis
• Normal or mildly elevated blood glucose (<200 mg/dL)
• Similar symptoms to traditional DKA (nausea, vomiting, abdominal pain, weakness)

SGLT2 Inhibitors and euDKA Risk

SGLT2 inhibitors work by preventing glucose reabsorption in the kidneys, leading to increased urinary glucose excretion. This mechanism creates several metabolic changes that can predispose to euDKA:

1. Reduced insulin secretion due to lower blood glucose levels
2. Increased glucagon secretion
3. Enhanced lipolysis and ketogenesis
4. Increased renal reabsorption of ketones

Specific SGLT2 Inhibitors Associated with euDKA:

• Dapagliflozin 2
• Canagliflozin 3, 4
• Empagliflozin 5
• Sotagliflozin 6

Incidence and Risk Factors

The incidence of DKA in type 2 diabetes patients treated with SGLT2 inhibitors ranges from 0.6-4.9 events per 1,000 patient-years 1. In type 1 diabetes (off-label use), the risk is significantly higher at approximately 4% of patients, which is 5-17 times higher than in those not treated with SGLT2 inhibitors 7.

Patient-Related Risk Factors:

• Type 1 diabetes (including latent autoimmune diabetes in adults/LADA)
• Insulin deficiency states
• History of previous DKA
• Reduced beta cell function reserve

Precipitating Factors:

• Reduced food intake or fasting 1
• Acute illness 1
• Alcohol consumption 1
• Substantial reduction in insulin dose (>20%) 1
• Very low-carbohydrate diets 7, 1
• Dehydration 7, 1
• Pregnancy 1
• Liver failure 1

Clinical Presentation

Patients with euDKA typically present with:

• Normal or minimally elevated blood glucose (<200 mg/dL) 1
• Nausea, vomiting, abdominal pain
• Generalized weakness
• Metabolic acidosis with elevated anion gap
• Positive serum or urine ketones

Prolonged Duration of Ketosis

A particularly concerning feature of SGLT2 inhibitor-associated euDKA is that ketosis may persist much longer than expected based on the medication's half-life:

• Clinical effects of dapagliflozin have been reported to persist much longer than its reported half-life of 12.9 hours 2
• Cases of ketonemia persisting for up to 12 days after discontinuation have been reported 4
• Standard DKA treatment protocols may need modification for these cases

Prevention and Management

Prevention:

• Avoid SGLT2 inhibitors in type 1 diabetes (not FDA approved for this use) 7
• Educate patients about euDKA risk and symptoms
• Advise patients to discontinue SGLT2 inhibitors during illness, fasting, or reduced food intake
• Recommend ketone monitoring during illness, especially when glucose exceeds 200 mg/dL
• Avoid substantial insulin dose reductions (>20%) when initiating SGLT2 inhibitors
• Discontinue SGLT2 inhibitors at least 1 week prior to elective procedures 2

Treatment:

• Immediate discontinuation of the SGLT2 inhibitor
• Intravenous insulin and dextrose infusions (may need to be continued longer than in typical DKA)
• Aggressive fluid resuscitation
• Electrolyte monitoring and replacement
• Close monitoring of acid-base status
• Consider earlier initiation of basal insulin to prevent recurrence of ketosis

Conclusion

SGLT2 inhibitors are by far the most common cause of euglycemic diabetic ketoacidosis. The risk is highest in patients with type 1 diabetes but exists for all patients taking these medications, especially during periods of physiologic stress or reduced carbohydrate intake. Clinicians should maintain a high index of suspicion for euDKA in any patient taking an SGLT2 inhibitor who presents with symptoms of DKA, even if blood glucose levels are not significantly elevated.