Rybelsus Side Effects: Incidence Rates Across Clinical Trials

What the label's pooled trials show

The incidence figures that matter come from a pool of two placebo-controlled trials in adults with type 2 diabetes: 362 patients took placebo, 356 took semaglutide tablets 7 mg and 356 took 14 mg [1]. Across the pool, 1,071 patients received semaglutide tablets (3 mg, 7 mg or 14 mg) with a mean duration of exposure of 41.8 weeks [1]. The label covers both Rybelsus (3, 7 and 14 mg) and Ozempic tablets (1.5, 4 and 9 mg), and the tablet safety data are drawn from the Rybelsus trials [1].

Common adverse reactions, listed as placebo, 7 mg, 14 mg [1]:

• Nausea: 6%, 11%, 20%
• Abdominal pain: 4%, 10%, 11%
• Diarrhea: 4%, 9%, 10%
• Decreased appetite: 1%, 6%, 9%
• Vomiting: 3%, 6%, 8%
• Constipation: 2%, 6%, 5%

Any gastrointestinal adverse reaction occurred in 21% on placebo, 32% on 7 mg and 41% on 14 mg. Severe gastrointestinal reactions occurred in 0.3%, 0.6% and 2%. Treatment was stopped because of a gastrointestinal reaction in 1%, 4% and 8% [1].

The label states that the majority of reports of nausea, vomiting and/or diarrhea occurred during dose escalation [1]. It says to follow its starting, escalation and maintenance schedule to reduce the risk of gastrointestinal reactions: 3 mg once daily for 30 days (a dose the label says is not effective for glycemic control), 7 mg for days 31 to 60, then 7 mg or 14 mg [1]. The pooled trials also included a 3 mg arm, but the label's table compares only the 7 mg and 14 mg arms with placebo [1].

Does the incidence rise with dose?

For most reactions, yes. Nausea goes from 11% at 7 mg to 20% at 14 mg, vomiting from 6% to 8%, diarrhea from 9% to 10%, abdominal pain from 10% to 11%, and decreased appetite from 6% to 9% [1]. Constipation was the exception, at 6% on 7 mg and 5% on 14 mg [1].

Gastrointestinal reactions reported in under 5% of semaglutide tablet-treated patients, as 14 mg, 7 mg and placebo: abdominal distension 3%, 2%, 1%; dyspepsia 0.6%, 3%, 0.6%; eructation 2%, 0.6%, 0%; flatulence 1%, 2%, 0%; gastroesophageal reflux disease 2%, 2%, 0.3%; gastritis 2%, 2%, 0.8% [1].

Severe GI reactions, gastroparesis and anesthesia

Severe gastrointestinal reactions were reported in 2% of patients on 14 mg, 0.6% on 7 mg and 0.3% on placebo [1]. The label says semaglutide tablets are not recommended in patients with severe gastroparesis, and it does not state that the drug causes gastroparesis [1].

The label also describes pulmonary aspiration during general anesthesia or deep sedation reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures, and says to instruct patients to inform healthcare providers of any planned surgeries or procedures [1].

Diabetic retinopathy

In the label's pooled glycemic-control trials, diabetic retinopathy related adverse reactions were reported during the trial by 4.2% of patients on semaglutide tablets and 3.8% of those on comparator [1]. In a 2-year cardiovascular outcomes trial of semaglutide injection in patients with type 2 diabetes and high cardiovascular risk, retinopathy complications occurred in 3% on semaglutide versus 1.8% on placebo, and 8.2% versus 5.2% among patients who already had retinopathy at baseline [1][3].

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

Hypoglycemia with insulin or sulfonylureas

Semaglutide stimulates insulin release in the presence of elevated blood glucose concentrations [1]. The label warns that patients taking an insulin secretagogue such as a sulfonylurea, or insulin, may have an increased risk of hypoglycemia including severe hypoglycemia, and that lowering the sulfonylurea or insulin dose may be necessary when starting the tablets [1].

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

Pancreatitis, gallbladder and kidney warnings

The label warns that acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been observed with GLP-1 receptor agonists including semaglutide tablets, and says to discontinue if pancreatitis is suspected and start appropriate management [1]. Signs may include persistent or severe abdominal pain, sometimes radiating to the back, with or without nausea or vomiting [1]. In the pooled placebo- and active-controlled trials of semaglutide tablets, pancreatitis was reported as a serious adverse event in 6 patients [1].

The label lists acute gallbladder disease and says gallbladder studies are indicated if cholelithiasis or cholecystitis is suspected [1]. It also describes postmarketing reports of acute kidney injury, some requiring hemodialysis, mostly in patients who had gastrointestinal reactions causing dehydration such as nausea, vomiting or diarrhea, and advises monitoring renal function in patients with reactions that could lead to volume depletion, especially during initiation and dose escalation [1].

Discontinuation in the long cardiovascular trial

The label's 4-year cardiovascular outcomes trial randomized 4,825 patients to semaglutide tablets and 4,825 to placebo, with median follow-up of 49.6 and 49.4 months [1]. Safety data collection in that trial was limited to serious adverse events (including death), adverse events leading to discontinuation and adverse events of special interest; study drug was permanently discontinued because of an adverse event in 15.5% of semaglutide tablet-treated patients and 11.6% of placebo-treated patients [1].

The thyroid C-cell boxed warning

In mice and rats, semaglutide caused dose-dependent and treatment-duration-dependent thyroid C-cell tumors, including adenomas and carcinomas, at clinically relevant plasma exposures; whether it causes thyroid C-cell tumors, including medullary thyroid carcinoma, in humans is unknown [1]. Rybelsus and Ozempic tablets are contraindicated in patients with a personal or family history of MTC or with Multiple Endocrine Neoplasia syndrome type 2 [1].

The label advises counseling patients on symptoms of thyroid tumors, such as a neck mass, difficulty swallowing, shortness of breath and persistent hoarseness. Routine serum calcitonin monitoring or thyroid ultrasound is of uncertain value for early detection, and a significantly elevated calcitonin may indicate MTC and should prompt further evaluation [1].

Suicidal ideation and NAION

The current Rybelsus and Ozempic tablets label carries no warning for suicidal behavior or ideation [1]. It also does not mention non-arteritic anterior ischemic optic neuropathy (NAION) or optic neuropathy; it advises people with diabetes to report vision changes as part of diabetic retinopathy monitoring [1].

In Europe, EMA's safety 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. Large epidemiological studies in adults with type 2 diabetes suggested an approximately two-fold relative increase in risk, or about one extra case per 10,000 person-years, and the committee advised stopping semaglutide if NAION is confirmed [5].