Cardiovascular outcomes were evaluated in a safety study of RYBELSUS® (semaglutide)
Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.
PIONEER 6: a cardiovascular outcomes trial (CVOT) for RYBELSUS®1,2
Confirm treatment with RYBELSUS® does not result in an unacceptable increase in CV risk compared to placebo (rule out 80% excess risk) in subjects with type 2 diabetes at high risk of CV events.
3183 with inadequately controlled type 2 diabetes and ASCVD.
Median observation time was 16 months.
Diagnosed with type 2 diabetes and ≥50 years of age and established CVD or CKD OR ≥60 years of age with at least 1 CV risk factora
Primary composite outcome
Time from randomization to first occurrence of MACE:
ASCVD=atherosclerotic cardiovascular disease; CKD=chronic kidney disease; CV=cardiovascular; CVD=cardiovascular disease; MACE=major adverse cardiovascular event; MI=myocardial infarction.
aCV risk factors included microalbuminuria or proteinuria, hypertension and left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction, or ankle-brachial index of <0.9.2
bTreatment arms included patients taking either RYBELSUS® or placebo who were either treatment naïve or taking oral antidiabetics (OADs) and/or insulin.2
RYBELSUS® demonstrated CV safety with no increased risk of MACE1
Noninferiority of RYBELSUS® vs placebo—both in addition to standard of care—was confirmed1,3,a
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with RYBELSUS®
Patients were at high CV risk and followed for a relatively short duration (16 months median observation time).1
21% fewer MACE events with RYBELSUS® vs placebo—both in addition to standard of care—
which helped establish no increased risk of MACE (P=0.17, NS)3
aTreatment arms included patients taking either RYBELSUS® or placebo who were either treatment naïve or taking oral antidiabetics (OADs) and/or insulin.2
Important Safety Information for RYBELSUS® (semaglutide) tablets 7 mg or 14 mg
WARNING: RISK OF THYROID C-CELL TUMORS
- In rodents, semaglutide causes dose-dependent and treatment-duration dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether RYBELSUS® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined
- RYBELSUS® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of RYBELSUS® and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with RYBELSUS®
Indication and Usage
RYBELSUS® (semaglutide) tablets 7 mg or 14 mg is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.
Limitations of Use
- RYBELSUS® has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis
- RYBELSUS® is not indicated for use in patients with type 1 diabetes
Important Safety Information
- RYBELSUS® is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), and in patients with a prior serious hypersensitivity reaction to semaglutide or to any of the excipients in RYBELSUS®. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with RYBELSUS®
Warnings and Precautions
- Risk of Thyroid C-Cell Tumors: Patients should be further evaluated if serum calcitonin is measured and found to be elevated or thyroid nodules are noted on physical examination or neck imaging
- Pancreatitis: Has been reported in clinical trials. Observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue RYBELSUS® and initiate appropriate management; if confirmed, do not restart RYBELSUS®
- Diabetic Retinopathy Complications: In a pooled analysis of glycemic control trials with RYBELSUS®, patients reported diabetic retinopathy related adverse reactions during the trial (4.2% with RYBELSUS® and 3.8% with comparator). In a 2-year trial with semaglutide injection involving patients with type 2 diabetes and high cardiovascular risk, more events of diabetic retinopathy complications occurred in patients treated with semaglutide injection (3.0%) compared to placebo (1.8%). The absolute risk increase for diabetic retinopathy complications was larger among patients with a history of diabetic retinopathy at baseline than among patients without a known history of diabetic retinopathy.
Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy
- Hypoglycemia: Patients receiving RYBELSUS® in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia
- Acute Kidney Injury: There have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis, in patients treated with GLP-1 receptor agonists, including semaglutide. Some of these events have been reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function when initiating or escalating doses of RYBELSUS® in patients reporting severe adverse gastrointestinal reactions
- Hypersensitivity: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported in patients treated with RYBELSUS®. If hypersensitivity reactions occur, discontinue use of RYBELSUS®, treat promptly per standard of care, and monitor until signs and symptoms resolve. Use caution in a patient with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist
- Acute Gallbladder Disease: Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In placebo-controlled trials, cholelithiasis was reported in 1% of patients treated with RYBELSUS® 7 mg. Cholelithiasis was not reported in RYBELSUS® 14 mg or placebo-treated patients. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated
- Most common adverse reactions (incidence ≥5%) are nausea, abdominal pain, diarrhea, decreased appetite, vomiting and constipation
- RYBELSUS® stimulates insulin release in the presence of elevated blood glucose concentrations. When initiating RYBELSUS®, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia
- RYBELSUS® delays gastric emptying and has the potential to impact the absorption of other oral medications. Closely follow RYBELSUS® administration instructions when coadministering with other oral medications and consider increased monitoring for medications with a narrow therapeutic index, such as levothyroxine
Use in Specific Populations
- Pregnancy: Available data with RYBELSUS® are not sufficient to determine a drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Based on animal reproduction studies, there may be risks to the fetus from exposure to RYBELSUS®. Use only if the potential benefit justifies the potential risk to the fetus
- Lactation: There are no data on the presence of semaglutide in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the unknown potential for serious adverse reactions in the breastfed infant due to the possible accumulation of salcaprozate sodium (SNAC), an absorption enhancer in RYBELSUS®, from breastfeeding and because there are alternative formulations of semaglutide that can be used during lactation, advise patients that breastfeeding is not recommended during treatment with RYBELSUS®
- Discontinue RYBELSUS® in women at least 2 months before a planned pregnancy due to the long washout period for semaglutide
- Pediatric Use: Safety and effectiveness of RYBELSUS® have not been established in pediatric patients
Please click here for Prescribing Information, including Boxed Warning.
- RYBELSUS® [package insert]. Plainsboro, NJ: Novo Nordisk Inc; January 2023.
- Bain SC, Mosenzon O, Arechavaleta R, et al. Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial. Diabetes Obes Metab. 2019;21(3):499-508.
- Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381(9):841-851.