What are the risks and potential cancer links associated with Wygovy (semaglutide)?

Wegovy (Semaglutide) Risks and Cancer Links

Based on the highest quality evidence, Wegovy (semaglutide) does not increase overall cancer risk and may actually reduce certain cancer risks, though thyroid C-cell tumor warnings remain in the FDA label due to rodent studies—the human relevance of which has not been established. 1

Key Safety Concerns

Thyroid C-Cell Tumors (Black Box Warning)

• Semaglutide caused thyroid C-cell tumors (adenomas and carcinomas) in rodents at clinically relevant exposures, but human relevance remains undetermined. 1
• The medication is contraindicated in patients with personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). 1
• Counsel patients about potential MTC symptoms including neck mass, dysphagia, dyspnea, and persistent hoarseness. 1
• Routine serum calcitonin monitoring is of uncertain value and may lead to unnecessary procedures due to low test specificity. 1

Cancer Risk Evidence from Clinical Trials and Real-World Data

Most recent high-quality evidence shows protective effects:

• A 2024 analysis of 1.1 million patients demonstrated significant cancer risk reductions with semaglutide across multiple cancer types: gastrointestinal cancers (HR 0.45), skin cancers, breast cancer, and others. 2
• A 2023 systematic review and meta-analysis of 37 RCTs found no increased risk of pancreatic cancer (OR 0.25), thyroid cancer (OR 2.04, not statistically significant), or all neoplasms (OR 0.95) compared to placebo. 3
• The FDA and European Medicines Agency have not identified a causal link between GLP-1 receptor agonists and either pancreatitis or pancreatic cancer. 4

Important nuance: A 2022 FAERS database analysis detected signals for thyroid cancers (medullary thyroid cancer PRR 27.43, papillary thyroid cancer PRR 8.68) and pancreatic neoplasms (PRR 9.86), but these represent reporting ratios, not causation. 5

Common and Serious Adverse Effects

Gastrointestinal Effects (Most Common)

• Nausea, vomiting, and diarrhea are the most frequently reported side effects, typically transient and self-limited with longer-acting formulations. 4
• Minimize by starting at the lowest dose (0.25 mg weekly for 4 weeks), up-titrating gradually, and eating smaller portions. 4, 1
• Increased risk of gallbladder disease including cholelithiasis and acute cholecystitis. 4
• Risk of gastrointestinal disorders including severe constipation and small bowel obstruction/ileus. 4

Pancreatitis

• Pancreatitis has been reported in clinical trials, but causality has not been established. 4, 6
• The LEADER trial did not demonstrate increased pancreatitis risk. 4
• Discontinue immediately if pancreatitis is suspected (persistent severe abdominal pain, sometimes radiating to back, with or without vomiting). 1
• Do not restart if pancreatitis is confirmed. 1
• Wegovy has not been studied in patients with a history of pancreatitis; consider alternative therapies in these patients. 1

Diabetic Retinopathy Complications

• In the SUSTAIN-6 trial, semaglutide was associated with increased diabetic retinopathy complications (3.0% vs 1.8% placebo), particularly in patients with pre-existing proliferative retinopathy. 4, 1
• The absolute risk increase was larger among patients with baseline diabetic retinopathy (8.2% vs 5.2%) compared to those without (0.7% vs 0.4%). 1
• This effect is hypothesized to result from rapid and sustained blood glucose reductions. 4
• Patients should undergo appropriate eye examination before starting therapy if not completed within the last 12 months. 4
• Close monitoring is warranted in high-risk individuals (older patients, diabetes duration ≥10 years). 4

Cardiovascular and Metabolic Effects

• Semaglutide can cause modest elevations in heart rate. 4
• Blood pressure typically decreases by 1-6 mm Hg. 4
• In the SELECT trial, Wegovy reduced major cardiovascular events (6.5% vs 8% placebo) in adults with obesity/overweight and established cardiovascular disease. 4

Renal Considerations

• Use caution in patients with severe renal impairment or end-stage renal disease when initiating or increasing dose due to potential risk of acute kidney injury. 4
• No dose adjustment required for semaglutide based on kidney function. 4

Hypoglycemia Risk

• Semaglutide is unlikely to cause hypoglycemia on its own but may do so when combined with insulin or insulin secretagogues (especially sulfonylureas). 4
• Lower doses of these concomitant medications may be required. 4

Contraindications and Drug Interactions

Absolute contraindications: 4, 1

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

Important cautions: 4

• Do not coadminister with DPP-4 inhibitors (both work through GLP-1 signaling)
• Use caution in patients with clinically significant gastroparesis
• Care should be taken in patients with prior gastric surgery

Monitoring Recommendations

At initiation: 4

• Recent eye examination (within 12 months) if patient has diabetes, especially with history of retinopathy
• Assess for contraindications including personal/family history of MTC or MEN 2

Ongoing monitoring: 4

• Assess efficacy and safety at least monthly for first 3 months, then at least quarterly
• Monitor for signs/symptoms of pancreatitis, gallbladder disease, and thyroid tumors
• Monitor for potential consequences of delayed absorption of oral medications with narrow therapeutic index

Clinical Context

The overall risk-benefit profile of semaglutide is favorable for patients with type 2 diabetes and obesity. 6 The cardiovascular benefits demonstrated in outcome trials, combined with the lack of confirmed increased cancer risk in high-quality human studies, support its use when appropriately indicated. The thyroid C-cell tumor warning, while mandated by FDA based on rodent data, has not been substantiated in human clinical trials or large real-world analyses. 4, 6, 3