SGLT2 Inhibitors Must Be Discontinued During Acute Illness
SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin) should be temporarily discontinued during any acute illness, including infections, gastrointestinal illness, dehydration, or conditions causing reduced oral intake. This recommendation is based on the risk of euglycemic diabetic ketoacidosis (DKA) and acute kidney injury, both of which can be life-threatening complications 1, 2.
Primary Medications to Discontinue
SGLT2 Inhibitors (Empagliflozin, Canagliflozin, Dapagliflozin)
Immediate discontinuation is required when:
- Any acute illness develops (pneumonia, gastroenteritis, urinary tract infections) 3, 4
- Reduced oral intake occurs (nausea, vomiting, anorexia) 2
- Fluid losses are present (diarrhea, excessive sweating, fever) 2
- Dehydration or volume depletion is suspected 1
- Surgery or prolonged fasting is planned 1
The KDIGO 2020 guidelines explicitly state it is reasonable to withhold SGLT2 inhibitors during times of prolonged fasting, surgery, or critical medical illness when patients may be at greater risk for ketosis 1. The FDA labeling for empagliflozin (Jardiance) specifically instructs clinicians to "consider temporarily discontinuing JARDIANCE in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure)" 2.
Critical Timing for Discontinuation
Stop SGLT2 inhibitors 3-4 days before elective procedures:
- Empagliflozin, canagliflozin, dapagliflozin: at least 3 days before 1, 4
- Ertugliflozin: at least 4 days before 1
The glycosuric effects of SGLT2 inhibitors persist for 3-4 days after discontinuation, meaning the risk of ketoacidosis continues even after stopping the medication 4, 5. One case report documented recurrent euglycemic DKA occurring 8 days after the last dose of dapagliflozin 5.
Why Acute Illness Requires Discontinuation
Risk of Euglycemic Diabetic Ketoacidosis
The combination of acute illness and SGLT2 inhibitors creates a perfect storm for ketoacidosis:
- Acute illness triggers counter-regulatory hormones that promote lipolysis and ketogenesis 4
- Reduced food intake during illness creates a state of "starvation ketosis" 4
- SGLT2 inhibitors continue forcing glucose excretion, mimicking fasting even when eating 4
- Blood glucose may remain normal (<250 mg/dL) while dangerous ketoacidosis develops 3, 4, 6
The American Diabetes Association and European Association for the Study of Diabetes jointly recommend that SGLT2 inhibitors should be omitted in the setting of severe illness, vomiting, or dehydration 4. Patients with signs or symptoms of ketoacidosis (dyspnea, nausea, vomiting, abdominal pain) should discontinue SGLT2 inhibitors and seek immediate medical attention 1.
Risk of Acute Kidney Injury
Volume depletion during acute illness is compounded by SGLT2 inhibitors' osmotic diuretic effects:
- Acute illness commonly causes volume depletion through fever, tachypnea, and reduced oral intake 4
- SGLT2 inhibitors have osmotic diuretic effects that can precipitate acute kidney injury 4
- Acute kidney injury further impairs ketone clearance, creating a vicious cycle 4
The FDA labeling warns that postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, have occurred in patients receiving SGLT2 inhibitors 2.
Specific Clinical Scenarios
Community-Acquired Pneumonia
Stop SGLT2 inhibitors immediately upon diagnosis of pneumonia 4. Pneumonia causes decreased oral intake and dehydration while SGLT2 inhibitors continue forcing glucose excretion 4. The combination is particularly dangerous due to hypoxia, shock risk, and volume depletion 4.
Gastrointestinal Illness
Discontinue immediately with any vomiting, diarrhea, or reduced oral intake 2. The FDA labeling specifically identifies gastrointestinal illness as a setting requiring temporary discontinuation 2.
Urinary Tract Infections
Consider temporary discontinuation in severe or recurrent UTIs 7. While mild to moderate genital mycotic infections can be treated without stopping SGLT2 inhibitors, severe infections or urosepsis require immediate discontinuation 7, 2.
When to Restart SGLT2 Inhibitors
All of the following criteria must be met before restarting:
- Patient eating and drinking normally for at least 24-48 hours 4
- Capillary ketones <0.6 mmol/L (always check ketones, not just glucose) 4
- Acute illness clinically improving with stable vital signs 4
- Renal function stable and adequate (eGFR considerations per baseline) 4
- No ongoing volume depletion or dehydration 4
Additional Medications to Consider Adjusting
Diuretics (Thiazides, Loop Diuretics)
Consider decreasing diuretic dosages before or during acute illness 1. SGLT2 inhibitors have diuretic effects, and the combination with prescribed diuretics increases risk for volume depletion and hypotension 1.
Insulin and Sulfonylureas
Reduce doses to prevent hypoglycemia, but do NOT stop insulin entirely 3, 2. The American College of Cardiology recommends maintaining at least low-dose insulin in insulin-requiring individuals to prevent ketoacidosis 3. Avoid substantial insulin dose reductions (>20%) when managing SGLT2 inhibitor therapy 3.
Metformin
Continue metformin unless contraindicated by renal function or severe illness 1. The KDIGO guidelines recommend continuing metformin during SGLT2 inhibitor therapy and do not suggest routine discontinuation during mild acute illness 1.
Critical Pitfalls to Avoid
Do not assume normal glucose means no ketoacidosis: Always check ketones during acute illness in patients on SGLT2 inhibitors 4, 6. Euglycemic DKA presents with blood glucose <250 mg/dL despite metabolic acidosis 4.
Do not continue SGLT2 inhibitors "for cardioprotection" during acute illness: The immediate risk of ketoacidosis and acute kidney injury outweighs theoretical cardiovascular benefits during acute illness 4. The cardiovascular benefits are long-term and do not apply to acute management 4.
Do not restart SGLT2 inhibitors before confirming ketone clearance: Check capillary ketones before restarting, with target <0.6 mmol/L 4. The glycosuric effects persist for days after discontinuation 4, 5.
Do not forget to provide sick-day rules at discharge: Educate patients to discontinue SGLT2 inhibitors during intercurrent illness (nausea, vomiting, diarrhea) and implement "STOP DKA" protocol: Stop SGLT2 inhibitor, Test for ketones, maintain fluid and carbohydrate intake 3, 4.
Monitoring During Acute Illness
Check both glucose AND ketone levels at presentation and serially 4. Blood glucose monitoring alone is insufficient to detect euglycemic DKA 4, 6.
Monitor for signs and symptoms of acute kidney injury: The FDA labeling instructs clinicians to monitor patients for signs and symptoms of acute kidney injury, and if it occurs, discontinue SGLT2 inhibitors promptly and institute treatment 2.
Maintain adequate hydration with intravenous fluids if oral intake is compromised 4. Avoid prolonged fasting periods during acute illness 4.
Controversial Evidence
While the KDIGO 2020 guidelines and FDA labeling clearly recommend withholding SGLT2 inhibitors during acute illness 1, 2, one recent 2022 research article suggests re-examining this widespread policy, noting low rates of DKA in cardiovascular outcome trials and potential benefits in COVID-19 hospitalizations 8. However, this single research opinion does not override the consensus of multiple international guidelines and FDA labeling. The established guidelines prioritize patient safety by preventing rare but potentially fatal complications 1, 3, 4. Until high-quality randomized trials demonstrate safety of continuation during acute illness, the standard of care remains temporary discontinuation 8, 9.