What are the potential side effects and risks of GLP-1 (Glucagon-like peptide-1) receptor agonist therapy, such as tirzepatide, in patients with a history of pancreatitis or thyroid cancer?

GLP-1 Receptor Agonist Side Effects

GLP-1 receptor agonists, including tirzepatide, are contraindicated in patients with personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), and should be used with extreme caution in patients with history of pancreatitis. 1

Absolute Contraindications

Thyroid C-Cell Tumor Risk:

• Personal or family history of medullary thyroid carcinoma (MTC) or MEN 2 is an absolute contraindication to all GLP-1 receptor agonists including tirzepatide 2, 1
• Tirzepatide causes dose-dependent thyroid C-cell tumors (adenomas and carcinomas) in rats at clinically relevant exposures, though human relevance remains undetermined 1
• Counsel patients on symptoms of thyroid tumors: neck mass, dysphagia, dyspnea, persistent hoarseness 1
• Routine serum calcitonin monitoring is of uncertain value and may lead to unnecessary procedures; however, if measured and elevated (>50 ng/L suggests MTC), further evaluation is warranted 1

Hypersensitivity:

• History of serious hypersensitivity reaction (anaphylaxis, angioedema) to tirzepatide or any excipient is an absolute contraindication 1

Gastrointestinal Side Effects (Most Common)

Frequency and Severity:

• Nausea, diarrhea, vomiting, constipation, and abdominal pain occur in 15-20% of patients and are the most common adverse effects 3
• GI side effects are dose-dependent: 39% at 5 mg, 46% at 10 mg, and 49% at 15 mg doses 4
• Symptoms typically abate over several weeks to months with dose titration 3
• Dyspepsia, gastroesophageal reflux, abdominal distension, and eructation also occur 3, 5

Management Strategy:

• Start at 2.5 mg subcutaneously weekly (initiation dose, not for glycemic control) 1
• Increase to 5 mg after 4 weeks, then escalate by 2.5 mg increments every 4 weeks as needed, up to maximum 15 mg weekly 1
• Reduce meal size, limit alcohol and carbonated drinks, avoid high-fat diets 5
• Drug discontinuation due to GI adverse events is highest at 15 mg dose (10%) 4

Delayed Gastric Emptying Complications:

• GLP-1 receptor activation delays gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone 5
• Risk of ileus, delayed absorption of oral medications (particularly those with narrow therapeutic indices like warfarin), and increased risk of pulmonary aspiration during general anesthesia or deep sedation 5, 1
• Instruct patients to inform healthcare providers of any planned surgeries or procedures requiring anesthesia 1
• Avoid use in patients with gastroparesis or prior gastric surgery 2

Pancreatitis Risk

Clinical Evidence:

• Acute pancreatitis (including fatal hemorrhagic or necrotizing pancreatitis) has been observed with GLP-1 receptor agonists 1
• In tirzepatide trials: 14 confirmed events in 13 treated patients (0.23 per 100 patient-years) versus 3 events in comparator groups (0.11 per 100 patient-years) 1
• Overall incidence remains rare (≤1% across all doses) 4
• Use with extreme caution in patients with history of acute pancreatitis and monitor closely 2
• Tirzepatide has not been studied in patients with prior pancreatitis history 1

Clinical Action:

• Observe for persistent severe abdominal pain (sometimes radiating to back), with or without vomiting 1
• If pancreatitis is suspected, discontinue tirzepatide immediately and initiate appropriate management 1
• Recent case reports demonstrate temporal association between tirzepatide initiation and acute pancreatitis, with clinical resolution upon discontinuation 6, 7

Hypoglycemia Risk

When Combined with Other Agents:

• GLP-1 receptor agonists do not cause hypoglycemia per se, but concomitant use with insulin secretagogues (sulfonylureas) or insulin increases risk of severe hypoglycemia 3, 1
• Incidence of mild hypoglycemia (blood glucose <70 mg/dL) highest with 10 mg dose: 22.6% 4
• Reduce dose of sulfonylurea or insulin when initiating tirzepatide to prevent hypoglycemia 3, 2
• In moderate-to-severe CKD (stages G3-G4), hypoglycemia rates are reduced by half even with concurrent insulin therapy 3

Cardiovascular Effects

Heart Rate:

• Heart rate typically increases by approximately 5 bpm 3, 5
• Not associated with higher blood pressure or other adverse cardiovascular events 3
• If cardiac arrhythmia or tachycardia becomes symptomatic, monitor and consider beta blockers 5

Hepatobiliary Effects

Gallbladder Disease:

• Acute gallbladder disease (cholelithiasis, cholecystitis) can occur but is usually asymptomatic 3, 5
• Incidence ≤1% across all doses 5
• If cholelithiasis is suspected, obtain gallbladder studies and clinical follow-up 1
• Use caution in patients with history of cholelithiasis 3

Renal Considerations

Acute Kidney Injury:

• Monitor renal function in patients with renal impairment who report severe gastrointestinal reactions (due to volume depletion from vomiting/diarrhea) 1
• Use with caution in severe renal impairment or end-stage renal disease 2
• GLP-1 receptor agonists have been studied with eGFR as low as 15 mL/min/1.73 m² and retain glucose-lowering potency across the range of eGFR 3
• Contraindicated in patients on dialysis 2

Diabetic Retinopathy

Monitoring Required:

• Tirzepatide has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema 1
• Monitor patients with history of diabetic retinopathy for progression 2, 1

Other Notable Side Effects

Less Common Effects:

• Injection site reactions: rare (<1%) 3, 5
• Alopecia (hair loss) 5
• Headache, fatigue, dizziness 3, 5
• Suicidal ideation and behavior (monitor for) 3

Pancreatic Cancer Concerns

Long-term Safety Data:

• A large population-based cohort study over 9 years found no support for increased pancreatic cancer incidence over 7 years following GLP-1RA initiation (HR 0.50,95% CI 0.15-1.71 comparing GLP-1RA to basal insulin) 8
• However, monitoring beyond 7 years following therapy initiation is still required 8
• GLP-1 receptor agonist treatment is not recommended in patients at risk for pancreatic cancer based on theoretical risks from preclinical models 3

Special Populations

Females of Reproductive Potential:

• Advise females using oral contraceptives to switch to non-oral contraceptive method or add barrier method for 4 weeks after initiation and 4 weeks after each dose escalation (due to delayed gastric emptying affecting oral medication absorption) 1

Pregnancy and Breastfeeding:

• Contraindicated in pregnancy and breastfeeding based on animal studies showing potential fetal harm 3, 1