Can pembrolizumab (Keytruda) cause hyperglycemia?

Can Keytruda Cause Hyperglycemia?

Yes, pembrolizumab (Keytruda) can cause hyperglycemia through multiple mechanisms, including checkpoint inhibitor-associated diabetes mellitus (CIADM), steroid-induced hyperglycemia from concurrent corticosteroid use, and worsening of pre-existing diabetes.

Incidence and Risk Profile

The risk of hyperglycemia with pembrolizumab varies significantly by mechanism 1:

• Overall hyperglycemia incidence: 13-27% of all ICI-treated patients
• Drug-attributed hyperglycemia: 2.26% (95% CI 1.28-3.48) in meta-analysis of 52 trials
• Severe (grade 3-4) hyperglycemia: 0.28% (95% CI 0.16-0.42)
• CIADM (autoimmune diabetes): 0.4-1.9% of patients
• Steroid-related hyperglycemia: 68-76% of new-onset hyperglycemia cases are associated with corticosteroid administration 1

The FDA label confirms hyperglycemia as a documented adverse event, with specific data showing 44% all-grade and 4.1% grade 3-4 hyperglycemia in NSCLC patients 2. When combined with enfortumab vedotin, the incidence increases to 66% all-grade and 14% grade 3-4 2.

Clinical Mechanisms

1. Checkpoint Inhibitor-Associated Diabetes Mellitus (CIADM)

This represents autoimmune destruction of pancreatic beta cells 1:

• Median onset: 12 weeks after ICI initiation, but can occur years later
• Presentation: Often fulminant with rapid progression to diabetic ketoacidosis (DKA)
• Diagnostic criteria: New hyperglycemia (≥11.1 mmol/L) + low C-peptide (<0.4 nmol/L) + HbA1c ≥6.5%
• Key feature: Absolute insulin deficiency requiring immediate insulin therapy

Multiple case reports document fulminant type 1 diabetes with DKA following pembrolizumab, including fatal cases 3, 4, 5, 6.

2. Steroid-Induced Hyperglycemia

The most common mechanism, occurring when corticosteroids are used to manage immune-related adverse events 1:

• Diagnosis: Repeated glucose ≥11.1 mmol/L during steroid use
• Typically responds to oral agents (gliclazide, metformin) or intermediate-acting insulin matched to steroid dosing

3. Worsening Pre-Existing Diabetes

Patients with known diabetes experience hyperglycemia in 42-72% of cases 1.

Risk Stratification and Monitoring

The 2025 multidisciplinary consensus guidelines provide a risk-based monitoring algorithm 1:

HIGH RISK (daily self-monitoring required):

• Newly detected hyperglycemia/raised HbA1c
• Pre-existing type 2 diabetes
• Provide glucometer for daily glucose monitoring and ketone testing capability

MODERATE RISK (glucose at clinic visits):

• Commencing corticosteroids
• Raised lipase
• Check 2-hour postprandial or 8-hour post-prednisolone glucose (fasting glucose misses severity)

LOW RISK (routine monitoring):

• Starting ICI without above risk factors
• Serum glucose with each treatment cycle
• HbA1c every 3 months

Duration: Monitor based on risk level for 12 months minimum, then transition to standard type 2 diabetes screening, as CIADM can occur years after initiation 1.

Emergency Recognition Criteria

Immediate hospital referral is required for 1:

• Blood glucose >15 mmol/L (270 mg/dL) with ketones >2 mmol/L (high DKA risk)
• Blood glucose persistently >20 mmol/L (360 mg/dL) or reading "HI" (hyperosmolar hyperglycemic state risk)

Critical Clinical Pitfalls

1. Fulminant presentation: Unlike typical type 1 diabetes, CIADM can progress from normal glucose to DKA within days 3, 4. The median time to onset is only 12 weeks, but vigilance must continue indefinitely.

2. Steroid masking: Corticosteroid use for other immune-related adverse events complicates diagnosis—68-76% of hyperglycemia cases involve concurrent steroids 1.

3. Fasting glucose inadequacy: Fasting blood glucose will not capture the severity of hyperglycemia; 2-hour postprandial or timed post-steroid measurements are superior 1.

4. Combination therapy risk: When pembrolizumab is combined with enfortumab vedotin, hyperglycemia risk increases substantially (66% all-grade, 14% grade 3-4), with 2% requiring hospitalization 2, 7.

Management Algorithm

For new-onset hyperglycemia during pembrolizumab treatment 1:

1. Initial assessment: Bedside capillary glucose and ketones, formal labs including C-peptide with matching glucose, lipase, electrolytes, renal function, and type 1 diabetes autoantibodies

2. If C-peptide <0.4 nmol/L: Diagnose CIADM → immediate insulin therapy required (no role for oral agents)

3. If steroid-associated with preserved C-peptide: Oral agents (gliclazide, metformin) for mild cases; intermediate-acting insulin matched to steroid profile for moderate-severe cases

4. If HbA1c >9% or persistent glucose >15 mmol/L: Urgent endocrinology consultation 1

The association between hyperglycemia and worse cancer outcomes (lower overall survival, increased recurrence risk) underscores the importance of aggressive glucose management 1.