Rybelsus Cancer Risk Signal Review: What the Evidence Actually Shows

Is there a confirmed cancer risk with Rybelsus?

Not a demonstrated human risk. The label carries a boxed warning about thyroid C-cell tumors because of what happened in rodents, and says outright that human relevance has not been determined [2]. Rybelsus is contraindicated in people with a personal or family history of MTC or with MEN 2 [2].

One observational study did report an association between GLP-1 receptor agonist use and thyroid cancer, including MTC, but it did not show that oral semaglutide caused those cancers and it did not study Rybelsus on its own [1].

What the boxed warning actually says

In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in thyroid C-cell tumors, adenomas and carcinomas, after lifetime exposure at clinically relevant plasma exposures [2]. The label then states that it is unknown whether Rybelsus and Ozempic tablets cause thyroid C-cell tumors, including MTC, in humans, as the human relevance of the rodent tumors has not been determined [2].

The label adds that MTC has been reported in the postmarketing period in patients treated with liraglutide, another GLP-1 receptor agonist, and that those data are insufficient to establish or exclude a causal relationship [2].

The contraindication is narrow and specific: a personal or family history of MTC, or MEN 2 [2]. The label asks that patients be told about symptoms of thyroid tumors: a mass in the neck, dysphagia, dyspnea and persistent hoarseness [2].

The label is also explicit that screening is imperfect. Routine monitoring of serum calcitonin or thyroid ultrasound is of uncertain value for early detection of MTC, and the label says such monitoring may increase the risk of unnecessary procedures given the low specificity of the calcitonin test and the high background incidence of thyroid disease [2]. A significantly elevated calcitonin may indicate MTC, and patients with MTC usually have calcitonin values greater than 50 ng/L. If calcitonin is measured and found elevated, or if a thyroid nodule is noted on physical examination or neck imaging, the label says the patient should be further evaluated [2].

Thyroid cancer: what the human data show

One human observational study was a nested case-control analysis using the French national health insurance database [1]. Bezin and colleagues identified 2,562 people with thyroid cancer among adults with type 2 diabetes treated with second-line diabetes drugs between 2006 and 2018, and matched them with 45,184 controls [1]. Use of a GLP-1 receptor agonist for 1 to 3 years was associated with an adjusted hazard ratio of 1.58 (95% CI 1.27 to 1.95) for all thyroid cancer, and 1.78 (95% CI 1.04 to 3.05) for MTC [1].

Two limits matter when reading that result. The exposure studied was GLP-1 receptor agonist use as a class in people with type 2 diabetes, not oral semaglutide on its own, and cancers were identified from hospital discharge diagnoses and medical procedures [1]. The analysis adjusted for goiter, hypothyroidism, hyperthyroidism, other antidiabetes drugs and social deprivation index [1].

Pancreatic cancer and pancreatitis

Pancreatitis, not pancreatic cancer, is what the Rybelsus label warns about. Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been observed with GLP-1 receptor agonists including semaglutide tablets, and the label says to discontinue Rybelsus and begin appropriate management if pancreatitis is suspected [2]. In the pooled placebo- and active-controlled tablet trials, pancreatitis was reported as a serious adverse event in 6 patients treated with semaglutide tablets [2].

A 2011 analysis of FDA adverse event reports for sitagliptin and exenatide covering 2004 to 2009 found a 6-fold increase in the odds ratio for reported pancreatitis, and pancreatic cancer was reported more commonly than with other therapies [4]. It examined two other drugs, not Rybelsus, and spontaneous reports cannot establish that a drug caused a cancer.

LEADER, a cardiovascular outcomes trial of 9,340 adults with type 2 diabetes and high cardiovascular risk and a median follow-up of 3.8 years, reported that the incidence of pancreatitis was nonsignificantly lower with liraglutide than with placebo [5]. That is a liraglutide trial, not a Rybelsus trial.

What the oral semaglutide trials measured

SOUL randomized 9,650 adults aged 50 or older with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease or both to oral semaglutide up to 14 mg daily or placebo, with a median follow-up of 49.5 months [3]. The primary outcome was major adverse cardiovascular events, which occurred in 12.0% on oral semaglutide versus 13.8% on placebo (hazard ratio 0.86, 95% CI 0.77 to 0.96) [3].

PIONEER 6 randomized 3,183 adults at high cardiovascular risk, with a median of 15.9 months in the trial, and found major adverse cardiovascular events in 3.8% on oral semaglutide versus 4.8% on placebo (hazard ratio 0.79, 95% CI 0.57 to 1.11), which established noninferiority [6].

PIONEER 4 randomized 711 adults with type 2 diabetes to oral semaglutide (escalated to 14 mg), subcutaneous liraglutide (escalated to 1.8 mg) or placebo for 52 weeks, with change in HbA1c at week 26 as the primary endpoint [7].

The primary outcomes of these trials were glycemic control or cardiovascular events rather than cancer incidence [3][6][7].

Reading observational data in people with diabetes

A joint consensus report from the American Diabetes Association and the American Cancer Society notes that cancer incidence is associated with diabetes, with certain diabetes risk factors and with certain diabetes treatments [9]. That is one reason class-level observational findings in people with type 2 diabetes are hard to attribute to a single drug.

What is not known about Rybelsus and cancer

The thyroid question rests on rodent toxicology, a class-level observational study and the label contraindication. The pancreatic question rests on the Rybelsus pancreatitis warning plus an older adverse-event analysis of sitagliptin and exenatide, not Rybelsus [2][4].

Whether the thyroid association reported by Bezin and colleagues applies to oral semaglutide specifically remains unresolved [1].