Why should Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors be held or discontinued during community-acquired pneumonia?

Why SGLT2 Inhibitors Should Be Held During Community-Acquired Pneumonia

SGLT2 inhibitors must be discontinued during community-acquired pneumonia because acute illness, reduced oral intake, and volume depletion create a perfect storm for euglycemic diabetic ketoacidosis (DKA), a life-threatening complication that can occur even with normal blood glucose levels. 1, 2

Primary Risk: Euglycemic Diabetic Ketoacidosis

Mechanism of Risk During Acute Illness

• Acute illness triggers multiple ketogenic pathways: reduced food intake, increased counter-regulatory hormones, and volume depletion all promote lipolysis and ketogenesis 1, 2
• SGLT2 inhibitors independently promote ketone production by lowering insulin requirements, stimulating pancreatic α-cell glucagon secretion, and potentially reducing renal clearance of ketone bodies 3
• The combination is particularly dangerous: pneumonia causes decreased oral intake and dehydration while SGLT2 inhibitors continue forcing glucose excretion, creating a state of "starvation ketosis" despite adequate glycemic control 1, 2

Clinical Presentation Challenges

• Euglycemic DKA presents with blood glucose <250 mg/dL (often <200 mg/dL), making it easily missed if clinicians only check glucose without ketones 2
• Symptoms are nonspecific: nausea, vomiting, abdominal pain, dyspnea, and generalized weakness can be attributed to pneumonia itself rather than metabolic decompensation 2
• The metabolic acidosis can be severe (pH <7.3, bicarbonate <18 mEq/L, elevated anion gap) despite reassuring glucose readings 2

Evidence-Based Discontinuation Guidelines

Timing of Discontinuation

• Stop SGLT2 inhibitors immediately upon diagnosis of pneumonia or any severe illness 1
• The glycosuric effects persist for 3-4 days after discontinuation, meaning the risk window extends well beyond the last dose 2
• For elective procedures, guidelines recommend stopping 3 days before surgery (4 days for ertugliflozin), but acute illness requires immediate cessation 1

Supporting Guideline Consensus

• 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 1
• The Lancet Diabetes & Endocrinology guidelines specifically state SGLT2 inhibitors should be discontinued in patients at risk for ketoacidosis, including those with acute illness, hypoxia, or shock 1
• COVID-19 pneumonia guidelines reinforced this principle, recommending discontinuation in patients with severe symptoms to reduce risk of acute metabolic decompensation 1

Additional Risk Factors During Pneumonia

Volume Depletion and Renal Function

• Pneumonia commonly causes volume depletion through fever, tachypnea, and reduced oral intake 1
• SGLT2 inhibitors have osmotic diuretic effects that compound volume depletion, potentially leading to acute kidney injury 1
• Acute kidney injury further impairs ketone clearance, creating a vicious cycle that accelerates ketoacidosis 3

Insulin Dose Reduction

• When patients become ill and eat less, insulin doses are often reduced to prevent hypoglycemia 1
• Lower insulin doses may be insufficient to suppress lipolysis and ketogenesis, especially when combined with SGLT2 inhibitor effects 3
• This is particularly problematic in patients with type 1 diabetes or latent autoimmune diabetes (5-10% of adult-onset diabetes), who have minimal endogenous insulin reserves 2

Management Algorithm During Pneumonia

Immediate Actions

1. Discontinue SGLT2 inhibitor immediately upon pneumonia diagnosis 1
2. Check both glucose AND ketone levels (blood or urine) at presentation and serially 2
3. Maintain adequate hydration with intravenous fluids if oral intake is compromised 1, 2
4. Avoid prolonged fasting periods and consider glucose-containing IV fluids if NPO 1

Alternative Glycemic Management

• Transition to insulin therapy (basal-bolus regimen) for glycemic control during acute illness 4
• Continue metformin if eGFR ≥30 mL/min/1.73 m² and no contraindications (though metformin should also be held if severe illness with risk of lactic acidosis) 1, 4
• Consider DPP-4 inhibitors as a safer alternative during hospitalization, as they have low hypoglycemia risk and no ketoacidosis risk 1

Monitoring Requirements

• Monitor blood glucose AND ketones every 4-6 hours during acute illness 2
• Check renal function (creatinine, eGFR) as acute kidney injury increases ketoacidosis risk 1
• Assess volume status and maintain adequate hydration 1, 2
• Monitor for DKA symptoms: nausea, vomiting, abdominal pain, dyspnea, altered mental status 2

When to Restart SGLT2 Inhibitors

Criteria for Safe Reinitiation

• Patient must be eating and drinking normally for at least 24-48 hours 1
• Capillary ketones must be <0.6 mmol/L before restarting 1
• Pneumonia should be clinically improving with stable vital signs and oxygen requirements 1
• Renal function should be stable and adequate for SGLT2 inhibitor use 1

Post-Discharge Considerations

• Provide written sick-day rules at discharge emphasizing when to stop SGLT2 inhibitors 1
• Educate patients to check ketones during any future illness, not just glucose 2
• Consider permanent discontinuation if patient experienced DKA during pneumonia 5

Counterpoint: Emerging Evidence on Continuation

Recent Observational Data

• Some recent research suggests SGLT2 inhibitors may reduce pneumonia risk compared to DPP-4 inhibitors (HR 0.63-0.71) 6, 7
• One perspective article argues that routine sick-day guidance should be re-examined given low DKA rates in cardiovascular outcome trials 8
• The DARE-19 trial in COVID-19 pneumonia showed no excess adverse events with dapagliflozin, though the study was underpowered 1

Why Guidelines Still Recommend Discontinuation

• The absolute risk of DKA may be low, but the consequences are severe with potential mortality 1, 2
• Case reports document prolonged glucosuria and ketonuria lasting 8-11 days after SGLT2 inhibitor cessation, with DKA relapse occurring even after initial treatment 9
• The risk-benefit calculation changes during acute illness: the immediate cardiovascular benefits are less relevant than preventing life-threatening ketoacidosis 1
• Current consensus guidelines from multiple societies (ADA, EASD, ACC, multidisciplinary UK consensus) all recommend discontinuation during severe 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 2
• Do not restart SGLT2 inhibitors before confirming ketone clearance: persistent ketonuria can lead to DKA relapse even days after discontinuation 9
• Do not continue SGLT2 inhibitors "for cardioprotection" during acute pneumonia: the immediate risk outweighs theoretical benefits 1
• Do not forget to provide sick-day rules at discharge: patient education is essential for preventing future episodes 1, 2