What are the potential long-term side effects of semaglutide (glucagon-like peptide-1 receptor agonist) therapy?

Long-Term Side Effects of Semaglutide

Semaglutide carries several established long-term safety concerns that require ongoing monitoring, including increased risks of gallbladder disease, diabetic retinopathy complications in susceptible patients, and a black box warning for thyroid C-cell tumors observed in rodents, though the clinical significance of gastrointestinal side effects typically diminishes over time. 1, 2

Established Long-Term Safety Concerns

Gallbladder and Biliary Disease

• Cholelithiasis (gallstones) and cholecystitis represent one of the most clinically significant long-term risks, with increased incidence documented across multiple trials 1, 3
• This is a GLP-1 receptor agonist class effect, not specific to semaglutide alone 1, 3
• Monitor patients for right upper quadrant pain, particularly those with rapid weight loss 1

Thyroid C-Cell Tumor Risk

• Black box warning exists for risk of thyroid C-cell tumors (adenomas and carcinomas) based on rodent studies with lifetime exposure 1, 2
• Human relevance remains undetermined, but semaglutide is absolutely contraindicated in patients with personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 1, 2
• Cases of MTC have been reported with liraglutide in post-marketing surveillance, though causality is not established 2
• Routine serum calcitonin monitoring is of uncertain value and may lead to unnecessary procedures due to low test specificity 2

Diabetic Retinopathy Complications

• In the SUSTAIN-6 trial, diabetic retinopathy complications occurred in 3.0% of semaglutide-treated patients versus 1.8% on placebo over 2 years 2
• The absolute risk increase was substantially higher among patients with pre-existing diabetic retinopathy (8.2% vs 5.2%) compared to those without known retinopathy (0.7% vs 0.4%) 2
• This effect is hypothesized to result from rapid and sustained glucose reductions rather than a direct drug effect 1
• Patients with proliferative retinopathy require careful risk-benefit assessment and recent ophthalmologic examination before initiating semaglutide 1

Pancreatitis

• Acute pancreatitis has been reported in clinical trials at rates of approximately 0.3 cases per 100 patient-years with semaglutide versus 0.2 with comparators 2
• A 2024 case report documented fatal pancreatitis after 4 years of semaglutide use, occurring 4 weeks after dose escalation from 0.25 mg to 0.5 mg weekly 4
• Semaglutide should be permanently discontinued if pancreatitis is confirmed and not restarted 2
• Consider alternative therapies in patients with prior pancreatitis history 2

Gastrointestinal Effects Over Time

Transient Nature of Common GI Side Effects

• Nausea, vomiting, diarrhea, constipation, and abdominal pain are the most common adverse reactions but are typically dose-dependent and more pronounced during initial treatment 1, 5
• These effects are usually self-limited with longer-acting GLP-1 receptor agonists 1
• Gradual dose titration minimizes these effects 1

Delayed Gastric Emptying

• Semaglutide may delay gastric emptying, which persists with chronic use 1, 6
• This creates anesthetic risks including pulmonary aspiration and residual gastric content 6
• Use caution in patients with clinically significant gastroparesis 1

Cardiovascular and Renal Considerations

Cardiovascular Effects

• Elevated heart rate (approximately 5 beats per minute increase) is a consistent finding 1, 7
• Despite this, semaglutide demonstrated cardiovascular benefit in SUSTAIN-6, reducing the composite outcome of cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.74,95% CI 0.58-0.95) 1

Renal Function

• Acute kidney injury has been reported, particularly when dehydration occurs from gastrointestinal side effects 1, 3, 6
• Use with caution in patients with severe renal impairment or end-stage renal disease 1
• Monitor renal function when initiating therapy, especially in patients with baseline kidney disease 1

Monitoring Requirements for Long-Term Use

Essential Monitoring Parameters

• Assess for signs and symptoms of pancreatitis (persistent severe abdominal pain, potentially radiating to back) 2
• Monitor for gallbladder symptoms (right upper quadrant pain, particularly after meals) 1
• Evaluate for diabetic retinopathy progression in patients with pre-existing retinopathy 1, 2
• Monitor renal function, particularly in first several weeks and in patients with baseline impairment 1
• Assess for thyroid nodules on physical examination; if serum calcitonin is measured and >50 ng/L, further evaluation is warranted 2

Hypoglycemia Risk Management

• Hypoglycemia risk increases when combined with insulin or insulin secretagogues (sulfonylureas) 1
• Reduce doses of concomitant insulin or sulfonylureas when initiating semaglutide 1, 7

Critical Pitfalls to Avoid

• Do not dismiss new abdominal pain as typical GI side effects without evaluating for pancreatitis or gallbladder disease, as these represent serious complications requiring intervention 1, 2, 4
• Do not initiate semaglutide without screening for personal or family history of MTC or MEN 2 2, 8
• Do not rapidly escalate doses in patients with pre-existing diabetic retinopathy without recent ophthalmologic evaluation 1
• Current pretreatment assessment in clinical practice is inadequate, with one study showing only 1.8% of patients had appropriate disease history screening despite 98.6% having relevant conditions 8