What are the side effects of Rybelsus (semaglutide)?

Side Effects of Rybelsus (Semaglutide)

Rybelsus causes predominantly gastrointestinal side effects that are typically mild-to-moderate, transient, and dose-dependent, with nausea being the most common (occurring in up to 44% of patients), but serious adverse events including pancreatitis, gallbladder disease, and acute kidney injury occur 38% more frequently than placebo. 1

Common Gastrointestinal Side Effects

The most frequent adverse effects are gastrointestinal and include:

• Nausea (43.9% vs 16.1% with placebo) - the most common side effect 2
• Diarrhea (29.7% vs 15.9% with placebo) 2
• Vomiting (24.5% vs 6.3% with placebo) 2
• Constipation (24.2% vs 11.1% with placebo) 2
• Abdominal pain and dyspepsia 1
• Esophageal reflux due to delayed gastric emptying 1
• Bloating - can be managed with dose reduction and dietary modifications 3

These gastrointestinal symptoms are typically transient, occurring most frequently during initial treatment or dose escalation, and 99.5% are non-serious with 98.1% being mild-to-moderate in severity 2. Only 4.3% of patients permanently discontinue treatment due to GI side effects 2. Importantly, weight loss with semaglutide is largely independent of GI side effects - less than 1 percentage point of the 7.6-14.4% additional weight loss is mediated by GI symptoms 2.

Serious Adverse Events Requiring Monitoring

Clinical trials demonstrate a 38% higher risk of serious adverse events with semaglutide compared to placebo, including: 1

Gallbladder Disease

• Increased risk of cholelithiasis (gallstones) and cholecystitis requiring regular monitoring 1, 4
• This is a class effect of GLP-1 receptor agonists 5

Pancreatitis

• Acute pancreatitis has been reported, though causality has not been definitively established 1, 4
• Use with caution in patients with history of pancreatitis 1

Acute Kidney Injury

• Risk of acute kidney injury from dehydration, particularly in patients with pre-existing kidney disease 1
• Monitor renal function closely when initiating or escalating doses, especially in patients reporting severe GI reactions 1
• Ensure adequate fluid intake to prevent dehydration-related kidney injury 1

Cardiovascular Events

• Acute myocardial infarction reported in clinical trials 1
• However, major cardiovascular events occurred in 6.5% with semaglutide vs 8% with placebo, demonstrating net cardiovascular benefit 1
• Elevated heart rate is common and requires monitoring 1

Diabetic Retinopathy Complications

• Patients with history of diabetic retinopathy should be monitored closely for progression 1
• Risk appears related to rapid glycemic improvement, particularly when combined with insulin 6

Absolute Contraindications

Rybelsus is absolutely contraindicated in: 1, 4

• Personal or family history of medullary thyroid carcinoma (MTC) - carries FDA Black Box Warning based on rodent studies showing thyroid C-cell tumors 1
• Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 1
• Pregnancy or breastfeeding - safety has not been established 1

Relative Contraindications and Special Cautions

Gastrointestinal Conditions

• Not recommended in patients with clinically meaningful gastroparesis - semaglutide delays gastric emptying and may worsen symptoms 1, 7
• Use caution in patients with prior gastric surgery, including bariatric surgery 1

Renal Impairment

• Can be used with caution in severe renal impairment or ESRD (unlike exenatide which is contraindicated if eGFR <30 mL/min/1.73 m²) 1
• No dose adjustment needed for renal impairment, but careful monitoring required due to increased risk of dehydration from GI side effects 1

Drug Interactions

• Increased risk of hypoglycemia when combined with insulin, sulfonylureas, or glinides - dose reduction of these medications required 1
• Delayed gastric emptying affects absorption of concomitantly administered oral medications, particularly those with narrow therapeutic index like warfarin 1
• For oral hormonal contraceptive users: switch to non-oral contraception or add barrier method for 4 weeks after initiation and each dose escalation 1

Ophthalmologic

• Caution in patients with untreated closed-angle glaucoma 1
• Potential for nonarteritic anterior ischemic optic neuropathy (NAION) 6

Other Notable Side Effects

• Injection site reactions (for subcutaneous formulation) 1
• Insomnia - documented as a common side effect, monitor especially during initial titration 4
• Suicidal ideation reported in clinical trials 1
• Severe allergic reactions possible 1
• Dry mouth (xerostomia) 3

Management Strategies to Minimize Side Effects

Dose Titration

• Slow dose titration is essential to minimize GI side effects 1, 8
• If patient tolerates submaximal dose well with adequate response, continuing that dose long-term is acceptable rather than escalating 1
• If more than 2 consecutive doses missed: resume at same dose if previously tolerated 1
• If 3 or more consecutive doses missed: restart titration schedule 1

Dietary Modifications for Bloating

• Consider low-FODMAP diet under dietitian guidance 3
• Reduce meal size to manage nausea and vomiting 1
• Limit alcohol and carbonated drinks to reduce reflux 1
• Avoid high-fat diets to help with constipation 1
• Smaller, more frequent meals may reduce bloating 3
• Ensure adequate hydration 3

Monitoring Schedule

• Assess efficacy and safety at least monthly for first 3 months, then quarterly thereafter 1
• Monitor renal function, especially with severe GI symptoms 1
• Check for signs of gallbladder disease periodically 1
• Monitor for pancreatitis symptoms 1
• Monitor heart rate 1

Critical Clinical Pearls

The hypoglycemia risk with semaglutide is intrinsically very low due to glucose-dependent insulin secretion - increased risk only occurs when combined with insulin or insulin secretagogues 1. The overall safety profile of oral semaglutide is consistent with the GLP-1 receptor agonist drug class, with cardiovascular safety demonstrated as noninferior to placebo 8, 5. The benefit-risk profile remains favorable for most patients with type 2 diabetes or obesity, given significant metabolic and cardiovascular benefits against a low risk for severe adverse events 5.