What is the recommended GLP-1 (Glucagon-Like Peptide-1) receptor agonist dosing for a patient on Keytruda (pembrolizumab) with new onset Diabetes Mellitus (DM) and an Hemoglobin A1c (HbA1c) level of 8.9%?

GLP-1 Receptor Agonist Dosing for Patients on Keytruda with New-Onset Diabetes

For patients on Keytruda (pembrolizumab) with new-onset diabetes mellitus and an A1c of 8.9%, insulin therapy should be initiated as the primary treatment, with GLP-1 receptor agonists considered only as adjunctive therapy after insulin is established and autoimmune diabetes has been ruled out.

Understanding Checkpoint Inhibitor-Associated Diabetes (CIADM)

Pembrolizumab (Keytruda) is an immune checkpoint inhibitor (ICI) that can cause immune-related adverse events, including new-onset diabetes mellitus. This condition is specifically classified as checkpoint inhibitor-associated diabetes mellitus (CIADM) and has distinct characteristics:

• Often presents with rapid onset and severe hyperglycemia
• May involve autoimmune destruction of pancreatic beta cells
• Can progress to diabetic ketoacidosis if not promptly treated
• Typically requires insulin therapy due to insulin deficiency

Initial Assessment and Management

1. Laboratory evaluation:

   • Check for ketones (urine or blood)
   • Assess for pancreatic autoantibodies
   • Evaluate C-peptide levels to assess insulin production

2. Initial treatment approach:

   • For A1c of 8.9% with no ketoacidosis: May hold ICI until glucose control is obtained 1
   • Urgent endocrinology consultation is recommended for any patient with new-onset CIADM 1
   • Insulin therapy should be initiated as the primary treatment 1

Insulin Initiation Protocol

• Starting total daily insulin requirement: 0.3-0.4 units/kg/day 1
• Half as basal (long-acting) insulin, half as prandial (rapid-acting) insulin
• Self-monitoring of blood glucose 4+ times daily or continuous glucose monitoring
• Sliding scale insulin can be used to accommodate glucose variability

Role of GLP-1 Receptor Agonists

GLP-1 receptor agonists should not be used as first-line therapy in CIADM for several reasons:

1. CIADM often involves autoimmune destruction of beta cells, limiting the efficacy of incretin-based therapies
2. The American Society of Clinical Oncology (ASCO) guidelines specifically recommend insulin as the appropriate therapy for CIADM 1
3. Evidence suggests that pembrolizumab-associated diabetes may progress with varying speeds, but typically involves declining C-peptide levels indicating loss of beta cell function 2

When to Consider GLP-1 Receptor Agonists

GLP-1 receptor agonists may be considered only after:

1. Stable insulin therapy has been established
2. Autoimmune diabetes has been ruled out (negative pancreatic autoantibodies)
3. C-peptide levels indicate preserved beta cell function
4. The patient has been evaluated by an endocrinologist

If these criteria are met and a GLP-1 receptor agonist is deemed appropriate:

• Start at the lowest available dose and titrate slowly 1
• For liraglutide: Begin at 0.6 mg daily for one week, then increase to 1.2 mg daily for one week, then to 1.8 mg daily (maximum dose) 1
• For other GLP-1 receptor agonists: Follow similar gradual titration schedules

Monitoring and Follow-up

• Monitor glucose levels frequently during treatment
• Assess A1c every 3 months 3
• Watch for signs of diabetic ketoacidosis (even with normal glucose levels)
• Regular endocrinology follow-up is essential

Important Caveats

• CIADM may be permanent and require lifelong insulin therapy
• The "honeymoon period" with temporarily decreased insulin requirements may occur after initial treatment 1
• Pembrolizumab should not be permanently discontinued solely due to diabetes unless clinically indicated for other reasons
• GLP-1 receptor agonists have shown modest A1c reductions (approximately 2.1%) in patients with baseline A1c ≥9% 4, but these studies were not specifically in CIADM patients

Remember that CIADM is a distinct form of diabetes that typically requires insulin therapy. GLP-1 receptor agonists should be considered adjunctive therapy only after insulin is established and autoimmune diabetes has been ruled out.