Can Keytruda (pembrolizumab) and GLP-1 (Glucagon-like peptide-1) receptor agonists be used together in patients with cancer and type 2 diabetes or obesity?

Can Keytruda and GLP-1 Receptor Agonists Be Used Together?

Yes, Keytruda (pembrolizumab) and GLP-1 receptor agonists can be used together safely in patients with cancer and concurrent type 2 diabetes or obesity, with no documented drug interactions or contraindications between these medication classes. 1, 2

Evidence Supporting Concurrent Use

No Direct Drug Interactions

• GLP-1 receptor agonists work through glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying, and central appetite suppression—mechanisms that do not interfere with immune checkpoint inhibitor function 2
• The primary drug interaction concern with GLP-1 receptor agonists involves delayed gastric emptying affecting oral medication absorption, which is irrelevant for intravenous pembrolizumab 2

Cancer Risk Profile of GLP-1 Receptor Agonists

• Recent meta-analyses of 48 trials involving 94,245 participants demonstrate that GLP-1 receptor agonists probably have little or no effect on thyroid cancer risk (OR 1.37,95% CI 0.82-2.31), pancreatic cancer (OR 0.84,95% CI 0.53-1.35), breast cancer (OR 0.95% CI 0.60-1.49), or kidney cancer (OR 1.12,95% CI 0.78-1.60) with moderate certainty of evidence 3
• GLP-1 receptor agonists were associated with reduced pancreatic cancer incidence in patients with type 2 diabetes, with hazard ratios ranging from 0.42 to 0.82 compared to other antidiabetes medications 4
• In patients with type 2 diabetes, GLP-1 receptor agonists were associated with lower hepatocellular carcinoma risk (HR 0.20 compared to insulin, HR 0.39 compared to sulfonylureas) 5

Cardiovascular and Metabolic Benefits During Cancer Treatment

• The European Society of Cardiology recommends GLP-1 receptor agonists with proven cardiovascular benefit for patients with type 2 diabetes and chronic coronary syndromes to reduce cardiovascular events, independent of baseline HbA1c 1
• For overweight patients (BMI >27 kg/m²) with established cardiovascular disease, semaglutide should be considered to reduce cardiovascular mortality, myocardial infarction, or stroke even without diabetes 1
• GLP-1 receptor agonists reduce albuminuria and slow eGFR decline, providing renal protection that may be particularly valuable during nephrotoxic cancer treatments 2

Practical Management Considerations

Medication Selection

• For patients with type 2 diabetes and established cardiovascular disease: Prioritize semaglutide 2.4mg weekly due to proven 20% reduction in cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.80) 6
• For maximum weight loss and glycemic control: Consider tirzepatide 15mg weekly, which achieves 20.9% weight loss and superior HbA1c reduction compared to semaglutide 6
• For patients with chronic kidney disease: Dulaglutide, liraglutide, or semaglutide require no dose adjustment across all CKD stages, including eGFR <30 mL/min/1.73m² 2

Monitoring Requirements

• Assess patients every 3 months for weight, blood pressure, cardiovascular risk factors, and medication adherence 6
• Monitor for gastrointestinal side effects (nausea, vomiting, diarrhea) which occur in 17-44% of patients but are typically mild-to-moderate and transient 6
• Watch for signs of pancreatitis (persistent severe abdominal pain) and gallbladder disease, though causality with GLP-1 receptor agonists has not been definitively established 6

Peri-Operative Considerations for Cancer Surgery

• For non-diabetic patients on GLP-1 receptor agonists: Discontinue semaglutide or tirzepatide for 3 weeks (three half-lives) before elective surgery to minimize delayed gastric emptying and aspiration risk 1, 6
• For diabetic patients: Consult endocrinology to weigh risks and benefits of holding medication, as prolonged cessation may have detrimental effects on peri-operative glycemic control 1
• Consider gastric ultrasound pre-operatively to assess residual gastric contents, as 24.2% of semaglutide users show increased residual gastric content versus 5.1% of controls despite extended fasting 6

Absolute Contraindications

• Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 is an absolute contraindication for all GLP-1 receptor agonists 6, 2
• Type 1 diabetes is an absolute contraindication 2

Common Pitfalls to Avoid

• Do not unnecessarily withhold GLP-1 receptor agonists based on unfounded cancer concerns—the evidence shows neutral to protective effects across most cancer types 3, 5, 4
• Do not ignore hypoglycemia risk when combining GLP-1 receptor agonists with insulin or sulfonylureas during cancer treatment—reduce doses of these agents by 20% when initiating GLP-1 therapy 2
• Do not forget to adjust antihypertensive medications as weight loss progresses, since blood pressure reduction may necessitate medication adjustment 1, 6
• Do not combine GLP-1 receptor agonists with DPP-4 inhibitors, as concurrent use provides no additional benefit and is not recommended 1, 2