What are the adverse effects of Glucagon-Like Peptide (GLP), Glucose-Dependent Insulinotropic Polypeptide (GIP), and tirzepatide in an adult patient with a history of metabolic disorders, such as type 2 diabetes or obesity?

Adverse Effects of Tirzepatide (GLP-1/GIP Dual Agonist)

Most Common Adverse Effects: Gastrointestinal

Gastrointestinal side effects are the most frequently reported adverse effects of tirzepatide, occurring in a dose-dependent manner and typically being mild-to-moderate in severity. 1, 2

Specific Gastrointestinal Effects and Incidence:

• Nausea occurs in 17-22% of patients taking tirzepatide, with higher rates at the 15mg dose 2
• Diarrhea affects 13-16% of patients 2
• Vomiting occurs in 6-10% of patients 2
• Constipation is also commonly reported 1, 2
• Dyspepsia and gastroesophageal reflux can occur 1
• These effects are most pronounced during dose escalation and typically decrease over time with continued exposure 1, 2, 3

Management Strategies for GI Effects:

• Start at low dose (2.5mg) and titrate slowly every 4 weeks to minimize gastrointestinal symptoms 1, 2, 4
• Reduce meal size to help manage symptoms 1
• Limit alcohol and carbonated drinks to reduce reflux 1
• Avoid high-fat diet to minimize constipation 1
• Reassure patients that symptoms are usually temporary and improve with continued use 2

Serious but Rare Adverse Effects

Pancreatitis:

• Acute pancreatitis has been reported in clinical trials, though causality has not been definitively established 1, 2, 4
• Discontinue tirzepatide immediately if pancreatitis is suspected (persistent severe abdominal pain) 4
• Use with caution in patients with a history of pancreatitis 1, 2

Gallbladder Disease:

• Acute gallbladder disease, including cholelithiasis and cholecystitis, has occurred in clinical trials 1, 2, 4
• Monitor for symptoms of gallbladder disease and obtain gallbladder studies if suspected 4

Thyroid C-Cell Tumors:

• Tirzepatide causes thyroid C-cell tumors in rats, though human relevance remains unknown 4
• Absolute contraindication in patients with personal or family history of medullary thyroid cancer or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 2, 4
• Counsel patients regarding potential risk and symptoms of thyroid tumors 4

Hypoglycemia Risk

• Tirzepatide has minimal risk for hypoglycemia when used as monotherapy due to its glucose-dependent mechanism of action 2, 4
• Risk increases significantly when combined with insulin secretagogues (sulfonylureas) or insulin 2, 4
• Reduce insulin dose by 20% and consider discontinuing or reducing sulfonylurea doses by 50% when initiating tirzepatide 2

Renal and Metabolic Effects

Acute Kidney Injury:

• Monitor renal function in patients with renal impairment who report severe gastrointestinal reactions, as dehydration from GI effects can precipitate acute kidney injury 4
• No dose adjustment required for any degree of renal impairment, including end-stage renal disease 4

Diabetic Retinopathy:

• Monitor patients with a history of diabetic retinopathy for progression 4
• Has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema 4

Perioperative Risks

Pulmonary Aspiration:

• Tirzepatide delays gastric emptying, with the delay being largest after the first dose 4
• Retained gastric contents are documented even after extended fasting periods, creating aspiration risk during anesthesia 1, 2
• 24.2% of semaglutide users (similar GLP-1 agonist) showed increased residual gastric content versus 5.1% of controls, despite 10-14 day discontinuation and 12-hour fasting 2
• Discontinue tirzepatide at least 3 weeks (three half-lives) before elective surgery requiring general anesthesia or deep sedation 2, 4

Cardiovascular Safety Profile

• Tirzepatide shows favorable cardiovascular safety, with MACE-4 events having hazard ratios <1.0 and upper confidence bounds <1.3 2, 5
• Does not increase all-cause mortality compared to usual care 2
• May cause cardiac arrhythmia/tachycardia in some patients; if symptomatic, monitor and consider beta blockers 1

Treatment Discontinuation

• Tirzepatide 15mg leads to higher discontinuation rates due to adverse events regardless of comparator 2, 6
• Discontinuation rates are 34 more per 1000 patients compared to placebo, primarily from gastrointestinal effects 2
• Serious adverse events and mortality rates are similar to comparators 6

Special Populations

Elderly Patients:

• No overall differences in safety detected between elderly (≥65 years) and younger patients, though greater sensitivity in some older individuals cannot be ruled out 4
• Elderly patients require more vigilant monitoring for adverse effects, including dehydration risk from GI side effects 2

Hepatic Impairment:

• No dose adjustment required for any degree of hepatic impairment 4

Critical Contraindications

Absolute contraindications include: 4

• Personal or family history of medullary thyroid carcinoma
• Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
• Known serious hypersensitivity to tirzepatide or excipients

Drug Interactions

• Tirzepatide delays gastric emptying and may impact absorption of concomitantly administered oral medications 4
• Women using oral contraceptives should switch to non-oral methods or add barrier contraception for 4 weeks after initiation and each dose escalation 2
• Low potential to inhibit or induce CYP enzymes or drug transporters 4

Comparison to GLP-1 Receptor Agonists

• Adverse effect profile is similar to GLP-1 receptor agonists (like semaglutide), with gastrointestinal effects predominating 2, 3
• Gastrointestinal effects occur at similar rates between tirzepatide and semaglutide, except for diarrhea with tirzepatide 10mg (slightly higher) 6
• Both share identical serious but rare risks including pancreatitis, gallbladder disease, and thyroid cancer contraindications 2