Medications to Hold in DKA
In diabetic ketoacidosis, SGLT2 inhibitors must be discontinued immediately, metformin should be held, and all other oral antihyperglycemic agents should be stopped. 1
Critical Medications to Discontinue
SGLT2 Inhibitors (Highest Priority)
SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin, etc.) must be stopped immediately in DKA. These agents directly increase ketogenesis risk and can cause or perpetuate euglycemic DKA, where glucose may be normal or only mildly elevated despite severe ketoacidosis 2, 3. The mechanism involves:
- Enhanced renal glucose excretion leading to relative insulin deficiency
- Increased glucagon secretion promoting ketone production
- Continued ketogenesis even after DKA treatment begins if not discontinued 4, 5
Critical pitfall: Patients on SGLT2 inhibitors can present with severe DKA despite blood glucose <200 mg/dL (euglycemic DKA), making diagnosis easy to miss 6, 7, 8. Always check ketones and acid-base status in any patient on SGLT2 inhibitors presenting with metabolic symptoms, regardless of glucose level.
The KDIGO guidelines explicitly state it is reasonable to withhold SGLT2 inhibitors during critical medical illness when patients are at greater risk for ketosis 2. Multiple case reports demonstrate rebound ketoacidosis when SGLT2 inhibitors are continued during DKA management 5, 7.
Metformin
Metformin should be held during DKA. 1 While metformin doesn't directly cause DKA, it should be discontinued because:
- Risk of lactic acidosis in the setting of severe dehydration and tissue hypoperfusion common in DKA
- Gastrointestinal side effects can worsen dehydration
- Renal function is often compromised in DKA, increasing metformin accumulation risk
The KDIGO guidelines recommend stopping metformin when eGFR <30 ml/min per 1.73 m² 2, 9, a threshold often met during acute DKA due to prerenal azotemia.
All Other Oral Antihyperglycemic Agents
Discontinue all other oral diabetes medications during DKA:
- Sulfonylureas - increase hypoglycemia risk during DKA treatment
- DPP-4 inhibitors - ineffective in insulin-deficient state
- Thiazolidinediones - no role in acute management
- GLP-1 receptor agonists - oral formulations should be held; injectable forms have limited data but generally held during critical illness 1
Management Algorithm
Step 1: Immediately discontinue SGLT2 inhibitors upon DKA diagnosis or suspicion
Step 2: Hold metformin, especially if eGFR <30 or significant dehydration present
Step 3: Stop all other oral antihyperglycemic medications
Step 4: Initiate intravenous insulin infusion as primary treatment 1
Step 5: Provide adequate dextrose-containing fluids once glucose <200-250 mg/dL to prevent hypoglycemia while continuing insulin to suppress ketogenesis 1, 4
Transition Considerations
When transitioning from IV to subcutaneous insulin after DKA resolution:
- Administer basal insulin 2-4 hours before stopping IV insulin to prevent rebound ketoacidosis 1
- Do not restart SGLT2 inhibitors until metabolically stable and precipitating factors resolved 3
- Metformin can be restarted once eGFR >30 ml/min per 1.73 m² and patient is eating/drinking normally 9
- Other oral agents can be resumed based on clinical stability and individualized glycemic targets
Prevention of Recurrence
For patients previously on SGLT2 inhibitors who developed DKA:
- Consider permanent discontinuation, especially if precipitant was minor (e.g., routine illness, fasting) 3
- If restarting is considered, provide explicit "sick day rules": stop SGLT2 inhibitor during illness, fasting, dehydration, or reduced oral intake 6, 3
- Ensure patient understands early warning signs and has access to ketone testing 3
Common pitfall: The combination of metformin-induced gastrointestinal symptoms (nausea, vomiting) with continued SGLT2 inhibitor use can precipitate severe euglycemic DKA within days in treatment-naive patients 6. This underscores the importance of stepwise medication initiation and early follow-up.