How should I manage hyperglycemia in a patient with chronic kidney disease (eGFR ~47 mL/min) on metformin who requires steroid therapy for a chimeric antigen receptor T‑cell (CAR‑T) therapy reaction?

Management of Hyperglycemia in a Patient with CKD on Metformin Requiring Steroid Therapy for CAR-T Reaction

Immediate Metformin Management

With an eGFR of 47 mL/min/1.73 m², you should continue metformin at the current dose but increase monitoring frequency to every 3–6 months, and temporarily hold metformin if the patient develops acute illness, volume depletion, or requires hospitalization during CAR-T toxicity management. 1, 2

• At eGFR 45–59 mL/min/1.73 m², metformin can be safely continued without mandatory dose reduction, though the benefit-risk balance should be reassessed given the patient's clinical complexity 1
• Metformin does not require dose reduction until eGFR falls to 30–44 mL/min/1.73 m² (at which point reduce to maximum 1000 mg daily) 1, 2
• Hold metformin immediately if the patient develops cytokine release syndrome (CRS) grade ≥2, requires vasopressors, develops fever with volume depletion, or is admitted to the ICU, as these acute illnesses impair metformin clearance and increase lactic acidosis risk 2, 1

Steroid-Induced Hyperglycemia Management Algorithm

For steroid-induced hyperglycemia during CAR-T toxicity treatment, initiate intermediate-acting insulin (NPH) or rapid-acting insulin to match the steroid's peak hyperglycemic effect, which occurs 7–9 hours after dosing. 1

Steroid Dosing and Corresponding Insulin Strategy

• For dexamethasone 10 mg IV every 6–12 hours (CRS grade 3): Expect peak hyperglycemia 7–9 hours post-dose; use rapid-acting insulin (e.g., insulin aspart) with meals plus correction doses, or NPH insulin dosed to cover the afternoon/evening hyperglycemic peak 1
• For high-dose methylprednisolone 500–1000 mg IV every 12 hours (CRS grade 4): Initiate basal-bolus insulin at 0.3–0.5 units/kg/day, split 50/50 between long-acting basal (glargine) and rapid-acting prandial insulin (aspart), with aggressive correction scales 1
• Prednisone (if used orally) causes peak hyperglycemia approximately 8 hours after morning dosing, requiring afternoon/evening insulin coverage 1

Specific Insulin Regimens

Option 1 (Preferred for hospitalized patients):

• Basal-bolus regimen: Insulin glargine once daily plus insulin aspart before each meal 1
• Start at 0.3–0.5 units/kg/day total, divided 50% basal and 50% prandial 1
• Adjust doses daily based on glucose patterns

Option 2 (For patients managing at home):

• NPH insulin twice daily (morning and evening) to cover steroid-induced afternoon/evening hyperglycemia 1
• Add rapid-acting insulin with meals if needed for prandial control 1

Option 3 (Simplified regimen):

• Mixed insulin (e.g., Novomix 30) twice daily for patients who cannot manage four injections daily 1

Metformin Continuation vs. Temporary Hold Decision Tree

Continue Metformin If:

• CRS grade 1 (fever only, no hypotension or hypoxia) 1
• Patient remains hemodynamically stable without vasopressor requirement 1
• No acute volume depletion or dehydration 2
• eGFR remains stable at 47 mL/min/1.73 m² 1

Temporarily Discontinue Metformin If:

• CRS grade ≥2 (requiring tocilizumab, oxygen, or fluid boluses) 1, 2
• Any vasopressor requirement (even low-dose) 1
• ICU admission for CAR-T toxicity management 1
• Fever with volume depletion or inability to maintain oral intake 2
• Acute kidney injury (rising creatinine or declining eGFR) 2

Additional Glucose-Lowering Agents During Steroid Therapy

If metformin must be held or if glycemic control is inadequate with insulin alone, add a DPP-4 inhibitor with renal dose adjustment as the safest option during acute illness. 1, 3

• Sitagliptin 50 mg daily (standard dose for eGFR 45–59 mL/min/1.73 m²; reduce to 25 mg daily if eGFR falls below 45) 3
• Linagliptin 5 mg daily requires no dose adjustment at any eGFR level and is preferred if renal function is fluctuating 3
• Avoid sulfonylureas during acute illness due to high hypoglycemia risk, especially with unpredictable oral intake during CAR-T toxicity 1
• GLP-1 receptor agonists (dulaglutide, liraglutide, semaglutide) can be continued if already prescribed but should not be initiated during acute illness due to gastrointestinal side effects 1

Monitoring Requirements During Steroid Therapy

• Check blood glucose 4 times daily (fasting, pre-lunch, pre-dinner, bedtime) to capture steroid-induced hyperglycemic peaks 1
• Monitor eGFR every 3–6 months while on metformin at this level of renal function 1, 2
• Check eGFR within 48 hours if metformin was held during acute illness before restarting 2
• Assess for hypoglycemia risk as steroids are tapered, requiring proportional insulin dose reductions 1

Steroid Taper and Insulin Adjustment

As steroids are tapered following CRS resolution, reduce insulin doses proportionally (typically 25–50% reduction for each 50% steroid dose reduction) to prevent hypoglycemia. 1, 4

• When dexamethasone is reduced from 10 mg to 5 mg every 12 hours, reduce total daily insulin by approximately 25–30% 1
• When transitioning from IV to oral steroids, expect less pronounced hyperglycemia and adjust insulin accordingly 1
• Monitor for hypoglycemia closely during steroid taper, as insulin requirements may drop precipitously 4

Restarting Metformin After CAR-T Toxicity Resolution

Restart metformin only after all of the following criteria are met: 2

• CRS resolved to grade 0–1 1
• Patient hemodynamically stable without vasopressor support for ≥48 hours 1
• eGFR stable or improved to baseline (≥45 mL/min/1.73 m²) 2
• Patient tolerating oral intake without nausea/vomiting 2
• No ongoing acute illness or infection 2

Common Pitfalls to Avoid

• Do not discontinue metformin prematurely at eGFR 47 mL/min/1.73 m²—this level is well above the threshold requiring cessation (eGFR <30) 1, 2
• Do not use serum creatinine alone to guide metformin decisions; always calculate eGFR, especially in elderly or small-stature patients 2
• Do not forget to reduce insulin doses as steroids are tapered—failure to do so causes severe hypoglycemia 1, 4
• Do not restart metformin immediately after acute illness without confirming stable eGFR and adequate oral intake 2
• Do not use GM-CSF for CRS management, as it is not recommended and may worsen cytokine storm 1

Antifungal Prophylaxis Consideration

• Strongly consider antifungal prophylaxis (e.g., fluconazole) in patients receiving steroids for CRS or ICANS management, as prolonged steroid use increases fungal infection risk 1