Rybelsus Side Effects: Potentially Permanent Adverse Events Explained

Does Rybelsus cause lasting damage?

Most Rybelsus reactions are digestive and cluster around dose increases. In the label's pooled placebo-controlled trials, any gastrointestinal reaction occurred in 41% of people on 14 mg, 32% on 7 mg and 21% on placebo, and the label says most reports of nausea, vomiting and diarrhea came during dose escalation [1]. Treatment was stopped for gastrointestinal reasons in 8% on 14 mg, 4% on 7 mg and 1% on placebo [1].

The more serious events are listed in the label's warnings section, and European regulators have classified one eye condition, NAION, that the current US label does not name [1][2].

Thyroid C-cell tumors: what the boxed warning says

Rybelsus and Ozempic tablets carry the same boxed warning. In mice and rats, semaglutide caused dose-dependent and treatment-duration-dependent thyroid C-cell tumors, adenomas and carcinomas, after lifetime exposure at clinically relevant plasma exposures. It is unknown whether the tablets cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, because the human relevance of the rodent findings has not been determined [1]. The label also notes that MTC cases reported with liraglutide, another GLP-1 receptor agonist, were insufficient to establish or exclude a causal relationship [1].

Rybelsus is contraindicated in people with a personal or family history of MTC or with Multiple Endocrine Neoplasia syndrome type 2 [1]. The label directs prescribers to counsel patients about the symptoms of thyroid tumors, such as a mass in the neck, difficulty swallowing, shortness of breath and persistent hoarseness, and states that routine serum calcitonin monitoring or thyroid ultrasound is of uncertain value for early detection, partly because calcitonin has low specificity and thyroid disease is common [1]. A calcitonin value above 50 ng/L may indicate MTC, and an elevated value or a thyroid nodule found on examination or imaging calls for further evaluation [1].

An observational signal comes from a nested case-control study using the French national health insurance database, published in Diabetes Care in 2023. It compared 2,562 people with thyroid cancer against 45,184 matched controls and found that 1 to 3 years of GLP-1 receptor agonist use was associated with a higher risk of all thyroid cancer (adjusted hazard ratio 1.58, 95% CI 1.27 to 1.95) and of medullary thyroid cancer (adjusted hazard ratio 1.78, 95% CI 1.04 to 3.05) [4]. That analysis covered the GLP-1 class, not Rybelsus alone, and an association of this kind cannot show cause.

Acute pancreatitis

The label warns that acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed with GLP-1 receptor agonists including semaglutide tablets. It describes the signs as persistent or severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by nausea or vomiting, and says to discontinue Rybelsus if pancreatitis is suspected [1]. In the pooled placebo- and active-controlled trials behind the label, pancreatitis was reported as a serious adverse event in 6 patients treated with semaglutide tablets [1].

Diabetic retinopathy complications

The label gives two sets of numbers. In a pooled analysis of glycemic control trials, patients reported diabetic retinopathy-related adverse reactions during the trial in 4.2% on semaglutide tablets versus 3.8% on comparator [1]. In a 2-year cardiovascular outcomes trial of semaglutide injection in people with type 2 diabetes and high cardiovascular risk, adjudicated retinopathy complications occurred in 3% on semaglutide versus 1.8% on placebo, and the absolute increase was larger in those with retinopathy at baseline (8.2% versus 5.2%) than in those without a known history (0.7% versus 0.4%) [1].

That injection trial, SUSTAIN 6, enrolled 3,297 adults with type 2 diabetes; retinopathy complications there had a hazard ratio of 1.76 (95% CI 1.11 to 2.78) [5]. The Rybelsus label carries the same retinopathy warning, and states that rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy and that the effect of long-term glycemic control with the tablets on retinopathy complications has not been studied [1]. The label's advice is that patients with a history of diabetic retinopathy should be monitored for progression [1].

Acute kidney injury

Postmarketing reports describe acute kidney injury in some patients treated with semaglutide, in some cases requiring hemodialysis. The majority of the reported events occurred in patients who had gastrointestinal reactions leading to dehydration, such as nausea, vomiting or diarrhea, and the label directs monitoring of renal function in patients reporting reactions that could lead to volume depletion, especially during dose initiation and escalation [1].

Severe GI reactions and gastroparesis

Severe gastrointestinal reactions were reported more often on semaglutide tablets than placebo: 2% on 14 mg, 0.6% on 7 mg and 0.3% on placebo [1]. The same warning states that Rybelsus is not recommended in patients with severe gastroparesis, and the label notes separately that semaglutide delays gastric emptying [1]. The label does not state that semaglutide causes gastroparesis; it describes the drug as one to avoid in people who already have the severe form [1].

Vision loss from NAION

Non-arteritic anterior ischemic optic neuropathy is a separate condition from diabetic retinopathy. In June 2025 the European Medicines Agency's safety committee concluded that NAION is a very rare side effect of semaglutide medicines, including Rybelsus, 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, corresponding to about one additional case per 10,000 person-years, and the committee advised that semaglutide be stopped if NAION is confirmed [2]. NAION is not named in the current US Rybelsus tablet label [1].

A retrospective matched cohort study at one academic institution, using a registry of patients evaluated by neuro-ophthalmologists, included 710 patients with type 2 diabetes: 194 prescribed semaglutide and 516 prescribed other diabetes medicines. NAION occurred in 17 of those prescribed semaglutide and 6 of those prescribed the comparison drugs, and the 36-month cumulative incidence was 8.9% versus 1.8% [6]. Because the patients came from a specialist referral registry, these figures should not be read as the risk for all Rybelsus users [6].

Other labeled risks

The label also warns about acute gallbladder disease, serious hypersensitivity reactions including anaphylaxis and angioedema (with instruction to discontinue if they occur), hypoglycemia when Rybelsus is combined with insulin or a sulfonylurea, and pulmonary aspiration during general anesthesia or deep sedation [1]. In a 52-week add-on study to insulin, glucose below 54 mg/dL occurred in 32% on placebo, 26% on 7 mg and 30% on 14 mg, and the label suggests considering a reduction in the insulin or secretagogue dose when starting [1].