What is the best management approach for a patient with immune checkpoint inhibitor-induced diabetes who is currently being treated with Jardiance (empagliflozin) and metformin?

Management of Immune Checkpoint Inhibitor-Induced Diabetes on Jardiance and Metformin

Discontinue Jardiance immediately and transition to insulin therapy, as checkpoint inhibitor-associated diabetes mellitus (CIADM) represents autoimmune beta-cell destruction requiring insulin, not oral agents designed for type 2 diabetes. 1

Critical Distinction: CIADM vs Type 2 Diabetes

The current regimen of Jardiance (empagliflozin) and metformin is fundamentally inappropriate for CIADM because:

• CIADM results from autoimmune destruction of pancreatic beta cells, presenting similarly to type 1 diabetes with acute insulin deficiency, not the insulin resistance seen in type 2 diabetes 1
• 91.8% of CIADM patients have low or undetectable C-peptide levels, confirming absent pancreatic function 2
• 67.4% of CIADM cases present with diabetic ketoacidosis (DKA), a life-threatening emergency that oral agents cannot prevent or treat 2
• SGLT2 inhibitors like Jardiance increase the risk of diabetic ketoacidosis and are contraindicated when beta-cell function is absent 3

Immediate Actions Required

1. Confirm CIADM Diagnosis

Obtain urgent laboratory evaluation including: 1

• Urine or serum ketones and anion gap to assess for DKA
• C-peptide and insulin levels (typically very low or undetectable in CIADM)
• Anti-GAD, anti-islet cell, or anti-insulin antibodies (positive in many cases, though treatment should not be delayed pending results)
• Basic metabolic panel for electrolytes and renal function

2. Assess Disease Severity and Triage

Grade 1 (fasting glucose >ULN to 160 mg/dL, no ketoacidosis, no evidence of CIADM): 1

• This would represent worsening type 2 diabetes, not CIADM
• Continue checkpoint inhibitor with close monitoring
• Intensify oral therapy or add insulin as needed

Grade 2 (fasting glucose 160-250 mg/dL with evidence of CIADM at any glucose level, no ketoacidosis): 1

• Hold checkpoint inhibitor until glucose control obtained
• Urgent endocrinology consultation mandatory
• Initiate insulin immediately (or as default if any diagnostic uncertainty)
• Consider ED referral or hospital admission if outpatient endocrinology unavailable, developing ketoacidosis, or other concerns

Grade 3-4 (glucose >250 mg/dL or ketoacidosis/metabolic abnormalities): 1

• Hold checkpoint inhibitor
• Immediate hospital admission for DKA management
• Volume and electrolyte resuscitation
• Insulin initiation with endocrine consultation

Insulin Regimen for CIADM

Long-acting insulin alone is insufficient for CIADM due to complete absence of pancreatic beta-cell function. 1

Starting Insulin Protocol:

• Total daily dose: 0.3-0.4 units/kg/day 1
• 50% as basal insulin (once-daily long-acting analog: glargine or detemir)
• 50% as prandial insulin (divided doses with meals using rapid-acting analogs: lispro, aspart, or glulisine)
• Requires self-monitoring 4+ times daily or continuous glucose monitoring 1
• Sliding scale insulin in conjunction with the regimen to accommodate glucose variability 1

Important Considerations:

• "Honeymoon period" with decreased insulin requirements commonly occurs after initial DKA admission 1
• Patient education is critical: hypoglycemia recognition/treatment, exercise anticipation, DKA monitoring, carbohydrate counting, potential transition to insulin pump technology 1

Why Jardiance Must Be Stopped

The FDA label for empagliflozin explicitly warns: 3

• Increases risk of diabetic ketoacidosis, including cases requiring hospitalization
• Causes volume depletion and acute kidney injury, particularly dangerous in DKA
• Efficacy depends on residual beta-cell function, which is absent in CIADM
• Hypoglycemia risk increases when combined with insulin (which this patient will require)

Additionally, research shows empagliflozin has only moderate glucose-lowering action (HbA1c reduction ~0.5%) and even smaller effects in patients with renal impairment, making it inadequate for CIADM management. 4

Metformin Considerations

While metformin can theoretically be continued, practical considerations include: 1

• Limited benefit in absolute insulin deficiency (metformin primarily reduces hepatic glucose production and improves insulin sensitivity)
• Risk of lactic acidosis if DKA develops or in setting of acute illness
• May be discontinued to simplify the regimen during acute management, though not strictly contraindicated

Checkpoint Inhibitor Management

• CIADM is typically irreversible with permanent insulin dependence in all but 2 of 172 reported cases 2
• Immunotherapy rechallenge is feasible once glycemia is well-controlled on insulin (reported in 53 cases without recurrent diabetes) 2
• Corticosteroids are NOT indicated for CIADM, unlike other immune-related adverse events, as no immunosuppressive strategies improve beta-cell recovery 1

Monitoring and Follow-up

• Patients with positive GAD antibodies have earlier onset (median 7 vs 16 weeks) and higher DKA frequency (82.8% vs 62.1%), requiring more vigilant monitoring 2
• Close glucose monitoring essential during any checkpoint inhibitor therapy continuation
• Endocrinology follow-up mandatory for ongoing diabetes management and education 1

Common Pitfalls to Avoid

• Do not treat CIADM like type 2 diabetes with oral agents alone—this delays appropriate insulin therapy and increases DKA risk 1
• Do not use basal insulin monotherapy—prandial coverage is essential due to absent endogenous insulin secretion 1
• Do not continue SGLT2 inhibitors in confirmed or suspected CIADM—they increase ketoacidosis risk 3
• Do not delay insulin initiation pending antibody results if clinical suspicion is high 1