Rybelsus Side Effects: Rare But Serious Adverse Events Explained

Which serious side effects does the Rybelsus label list?

Rybelsus is the oral tablet form of semaglutide, a GLP-1 receptor agonist approved for adults with type 2 diabetes [1]. The label carries one boxed warning and eight warnings and precautions:

• Thyroid C-cell tumors (boxed warning) [1]
• Acute pancreatitis [1]
• Diabetic retinopathy complications [1]
• Hypoglycemia when used with insulin or an insulin secretagogue [1]
• Acute kidney injury from volume depletion [1]
• Severe gastrointestinal reactions [1]
• Hypersensitivity reactions [1]
• Acute gallbladder disease [1]
• Pulmonary aspiration during general anesthesia or deep sedation [1]

In tablet trials, severe gastrointestinal reactions occurred in 2.0% of patients on 14 mg, 0.6% on 7 mg and 0.3% on placebo [1]. In these trials, 1% of patients on placebo, 4% on Rybelsus 7 mg and 8% on Rybelsus 14 mg stopped treatment because of GI reactions [1].

The boxed warning: thyroid C-cell tumors

In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in thyroid C-cell adenomas and carcinomas after lifetime exposure at clinically relevant plasma exposures [1]. The label states that it is unknown whether Rybelsus causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, because the human relevance of the rodent findings has not been determined [1].

Rybelsus is contraindicated in anyone with a personal or family history of MTC or multiple endocrine neoplasia syndrome type 2 (MEN 2) [1]. The label asks prescribers to counsel patients on the symptoms of thyroid tumors, such as a mass in the neck, dysphagia, dyspnea and persistent hoarseness, and says routine serum calcitonin monitoring or thyroid ultrasound is of uncertain value for early detection [1]. A significantly elevated calcitonin may indicate MTC; the label notes that patients with MTC usually have values above 50 ng/L, and that an elevated value or a thyroid nodule found on examination or imaging should be further evaluated [1].

Acute pancreatitis

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists including semaglutide tablets [1]. The label asks for careful observation for persistent or severe abdominal pain, sometimes radiating to the back and sometimes with nausea or vomiting, and says to discontinue Rybelsus if pancreatitis is suspected and start appropriate management [1]. In the pooled placebo- and active-controlled tablet trials, pancreatitis was reported as a serious adverse event in 6 semaglutide-tablet patients [1].

A meta-analysis of 113 randomized GLP-1 receptor agonist trials in type 2 diabetes, published in Diabetes, Obesity and Metabolism in 2017, found no significant difference in pancreatitis versus comparator arms (OR 0.93, 95% CI 0.65 to 1.34) [4].

Diabetic retinopathy complications

In the pooled glycemic-control tablet trials, diabetic retinopathy-related adverse reactions were reported in 4.2% of patients on semaglutide tablets versus 3.8% on comparator [1]. The larger retinopathy numbers come from a different product: a 2-year cardiovascular outcomes trial of semaglutide injection, where the four-part retinopathy endpoint occurred in 3% versus 1.8% on placebo (hazard ratio 1.76, 95% CI 1.11 to 2.78) [1][5]. The gap was widest in people who already had retinopathy at baseline (8.2% versus 5.2%) and small in those who did not (0.7% versus 0.4%) [1].

The label notes that rapid improvement in glucose control has been associated with temporary worsening of diabetic retinopathy, and that the effect of long-term glycemic control with Rybelsus on retinopathy complications has not been studied [1]. The label says patients with a history of diabetic retinopathy should be monitored for progression [1].

Acute kidney injury

Acute kidney injury has been reported in people treated with semaglutide, some cases requiring hemodialysis. Most reported cases followed nausea, vomiting or diarrhea that led to dehydration [1]. The label says to monitor renal function in patients reporting reactions that could lead to volume depletion, especially during dose initiation and escalation [1].

Severe GI reactions and gastroparesis

In pooled placebo-controlled trials, 8% of patients on 14 mg, 4% on 7 mg and 1% on placebo stopped treatment because of GI reactions [1]. GI adverse reactions occurred in 41% on 14 mg, 32% on 7 mg and 21% on placebo, including severe reactions in 2.0%, 0.6% and 0.3% [1]. Most of the nausea, vomiting and diarrhea reported in the trials occurred during dose escalation [1].

Rybelsus is not recommended in patients with severe gastroparesis [1]. The label does not say semaglutide causes gastroparesis; it says semaglutide delays gastric emptying and is associated with GI adverse reactions, sometimes severe [1].

Low blood sugar with insulin or a sulfonylurea

Semaglutide stimulates insulin release in the presence of elevated blood glucose, and the label's hypoglycemia warning is specifically about combining Rybelsus with insulin or an insulin secretagogue such as a sulfonylurea [1]. That combination may raise the risk of hypoglycemia, including severe hypoglycemia, and reducing the dose of the sulfonylurea or insulin may lower the risk [1].

In a 52-week study of Rybelsus added to insulin, glucose below 54 mg/dL was reported in 32% of placebo patients, 26% of those on 7 mg and 30% of those on 14 mg [1].

Serious allergic reactions

Anaphylaxis and angioedema have been reported with semaglutide tablets [1]. The label says to discontinue Rybelsus if a hypersensitivity reaction occurs and to monitor until signs and symptoms resolve [1]. A prior serious hypersensitivity reaction to semaglutide or to any excipient in the tablet is a contraindication [1].

Gallbladder disease

Acute gallbladder disease is a labeled warning: if cholelithiasis or cholecystitis is suspected, the label says gallbladder studies are indicated [1]. In the 2017 meta-analysis of 113 randomized GLP-1 receptor agonist trials, cholelithiasis was significantly more common than in comparator arms (OR 1.30, 95% CI 1.01 to 1.68) [4].

NAION: a very rare eye risk recognized in Europe

Non-arteritic anterior ischemic optic neuropathy (NAION) is not mentioned in the current US Rybelsus label [1]. Europe's Pharmacovigilance Risk Assessment Committee concluded on 6 June 2025 that NAION is a very rare side effect of semaglutide medicines, meaning it may affect up to 1 in 10,000 people [2]. Large epidemiological studies in adults with type 2 diabetes suggested roughly a two-fold increase in risk, or about one extra case per 10,000 person-years of treatment [2]. The committee recommended adding NAION to the product information as a very rare side effect and advised stopping semaglutide if NAION is confirmed [2].

Before surgery: pulmonary aspiration

The label lists pulmonary aspiration during general anesthesia or deep sedation, reported in patients receiving GLP-1 receptor agonists who had elective procedures, and instructs patients to inform healthcare providers of any planned surgery or procedure [1].