Finally, there’s a GLP-1 RA in a once-daily pill1
Explore the efficacy of the first type 2 diabetes pill in its class (GLP-1 RA).1,2 See how RYBELSUS® measured up in phase 3 clinical trials.
Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.
See 2 GLP-1 RAs
head-to-head1,3
Head-to-head vs the most prescribed DPP-4i1,4,5
Head-to-head vs the most prescribed SGLT-2i1,4,6
CVOT study design
See 2 GLP-1 RAs head-to-head1,3
Head-to-head vs the most prescribed DPP-4i1,4,5
Head-to-head vs the most prescribed SGLT-2i1,4,6
Cardiovascular outcomes trial
CVOT study design
Comparable A1C reductions with RYBELSUS® 14 mg vs liraglutide 1.8 mg1,3
PIONEER 4 study design1,3
In a double-blind, double-dummy trial with a primary endpoint of mean change in A1C from baseline to 26 weeks, 711 adult patients with type 2 diabetes on metformin alone or metformin with an SGLT-2i were randomized to RYBELSUS® 14 mg (n=285), liraglutide 1.8 mg subcutaneous injection (n=284), or placebo (n=142), all once daily.
- Confirmatory secondary endpoint: Mean change in body weight from baseline to 26 weeks
- Select secondary endpoint: Proportion of patients achieving A1C <7% at Week 26
Comparable A1C control with RYBELSUS® 14 mg vs liraglutide 1.8 mg1,3
PIONEER 4 study design1,3
In a double-blind, double-dummy trial with a primary endpoint of mean change in A1C from baseline to 26 weeks, 711 adult patients with type 2 diabetes on metformin alone or metformin with an SGLT-2i were randomized to RYBELSUS® 14 mg (n=285), liraglutide 1.8 mg subcutaneous injection (n=284), or placebo (n=142), all once daily.
- Confirmatory secondary endpoint: Mean change in body weight from baseline to 26 weeks
- Select secondary endpoint: Proportion of patients achieving A1C <7% at Week 26
Superior weight reduction with RYBELSUS® 14 mg vs liraglutide 1.8 mg1,3
RYBELSUS® is not indicated for weight loss.
PIONEER 4 study design1,3
In a double-blind, double-dummy trial with a primary endpoint of mean change in A1C from baseline to 26 weeks, 711 adult patients with type 2 diabetes on metformin alone or metformin with an SGLT-2i were randomized to RYBELSUS® 14 mg (n=285), liraglutide 1.8 mg subcutaneous injection (n=284), or placebo (n=142), all once daily.
- Confirmatory secondary endpoint: Mean change in body weight from baseline to 26 weeks
- Select secondary endpoint: Proportion of patients achieving A1C <7% at Week 26
ETD=estimated treatment difference.
Superior A1C reductions with RYBELSUS® 7 mg and 14 mg vs Januvia®1,5
PIONEER 3 study design1,5
In a double-blind, double-dummy trial with a primary endpoint of mean change in A1C from baseline to 26 weeks, 1864 adult patients with type 2 diabetes on metformin alone or metformin with a sulfonylurea were randomized to RYBELSUS® 3 mg (n=466), RYBELSUS® 7 mg (n=465), RYBELSUS® 14 mg (n=465), or Januvia® 100 mg (n=467), all once daily.
- Confirmatory secondary endpoint: Mean change in body weight from baseline to 26 weeks
- Select secondary endpoint: Proportion of patients achieving A1C <7% at Week 26
Superior A1C control with RYBELSUS® 14 mg and 7 mg vs Januvia®1,5
PIONEER 3 study design1,5
In a double-blind, double-dummy trial with a primary endpoint of mean change in A1C from baseline to 26 weeks, 1864 adult patients with type 2 diabetes on metformin alone or metformin with a sulfonylurea were randomized to RYBELSUS® 3 mg (n=466), RYBELSUS® 7 mg (n=465), RYBELSUS® 14 mg (n=465), or Januvia® 100 mg (n=467), all once daily.
- Confirmatory secondary endpoint: Mean change in body weight from baseline to 26 weeks
- Select secondary endpoint: Proportion of patients achieving A1C <7% at Week 26
Superior weight reductions with RYBELSUS® 14 mg and 7 mg vs Januvia®1,5
RYBELSUS® is not indicated for weight loss.
PIONEER 3 study design1,5
In a double-blind, double-dummy trial with a primary endpoint of mean change in A1C from baseline to 26 weeks, 1864 adult patients with type 2 diabetes on metformin alone or metformin with a sulfonylurea were randomized to RYBELSUS® 14 mg (n=465), 7 mg (n=465), 3 mg (n=466), or Januvia® 100 mg (n=467), all once daily.
- Confirmatory secondary endpoint: Mean change in body weight from baseline to 26 weeks
- Select secondary endpoint: Proportion of patients achieving A1C <7% at Week 26
ETD=estimated treatment difference.
Superior A1C reduction vs Jardiance®1,6
PIONEER 2 study design1,6
In an open-label trial with a primary endpoint of mean change in A1C from baseline to 26 weeks, 822 adult patients with type 2 diabetes on metformin were randomized to RYBELSUS® 14 mg (n=411) or Jardiance® 25 mg (n=410), both once daily.
- Confirmatory secondary endpoint: Mean change in body weight from baseline to 26 weeks
- Select secondary endpoint: Proportion of patients achieving A1C <7% at Week 26
Superior A1C control with RYBELSUS® 14 mg vs Jardiance®1,6
PIONEER 2 study design1,6
In an open-label trial with a primary endpoint of mean change in A1C from baseline to 26 weeks, 822 adult patients with type 2 diabetes on metformin were randomized to RYBELSUS® 14 mg (n=411) or Jardiance® 25 mg (n=410), both once daily.
- Confirmatory secondary endpoint: Mean change in body weight from baseline to 26 weeks
- Select secondary endpoint: Proportion of patients achieving A1C <7% at Week 26
Comparable weight reduction with RYBELSUS® 14 mg vs Jardiance®1,6
RYBELSUS® is not indicated for weight loss.
PIONEER 2 study design1,6
In an open-label trial with a primary endpoint of mean change in A1C from baseline to 26 weeks, 822 adult patients with type 2 diabetes on metformin were randomized to RYBELSUS® 14 mg (n=411) or Jardiance® 25 mg (n=410), both once daily.
- Confirmatory secondary endpoint: Mean change in body weight from baseline to 26 weeks
- Select secondary endpoint: Proportion of patients achieving A1C <7% at Week 26
ETD=estimated treatment difference.
A1C=glycated hemoglobin; CVOT=cardiovascular outcomes trial; DPP-4i=dipeptidyl peptidase-4 inhibitor; GLP-1 RA=glucagon-like peptide-1 receptor agonist; MET=metformin; SGLT-2i=sodium-glucose cotransporter-2 inhibitor.
Explore the CVOT study for RYBELSUS®
PIONEER 6: cardiovascular safety7,8
Study design: In a double-blind trial, 3183 adult patients with inadequately controlled type 2 diabetes at high CV risk (≥50 years of age with CVD or CKD, or ≥60 with at least 1 CV risk factor) were randomized to RYBELSUS® 14 mg (n=1591) or placebo (n=1592), both once daily and in addition to standard of care for a median observation time of 16 months. Background antidiabetic therapy included OADs and/or insulin. Patients could also be treatment naïve. Most patients were also on antihypertensive therapies, lipid-lowering therapies, and antiplatelet or antithrombotic therapy.
The primary endpoint was the time to first occurrence of MACE, which included CV death, nonfatal myocardial infarction, or nonfatal stroke.
Secondary endpoints included time from randomization to the first occurrence of an expanded composite outcome consisting of the primary outcome plus unstable angina resulting in hospitalization or heart failure resulting in hospitalization or a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke.
CKD=chronic kidney disease; CV=cardiovascular; CVOT=cardiovascular outcomes trial; MACE=major adverse cardiovascular event; OADs=oral antidiabetic drugs.
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® is not recommended as a first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans
- 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 (cont'd)
Contraindications
- 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
Adverse Reactions
- The most common adverse reactions, reported in ≥5% of patients treated with RYBELSUS® are nausea, abdominal pain, diarrhea, decreased appetite, vomiting and constipation
Drug Interactions
- 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 efficacy of RYBELSUS® have not been established in pediatric patients (younger than 18 years)
Please click here for Prescribing Information, including Boxed Warning.
References:
- RYBELSUS® [package insert]. Plainsboro, NJ: Novo Nordisk Inc; June 2022.
- Rodbard HW, Dougherty T, Taddei-Allen P. Efficacy of oral semaglutide: overview of the PIONEER clinical trial program and implications for managed care. Am J Manag Care. 2020;26(suppl 16):S335-S343.
- Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet. 2019;394(10192):39-50.
- IQVIA weekly NPA (TRx count), latest 52 weeks ending 8/2/21.
- Rosenstock J, Allison D, Birkenfeld AL, et al. Effect of additional oral semaglutide vs sitagliptin on glycated hemoglobin in adults with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea: the PIONEER 3 randomized clinical trial. JAMA. 2019;321(15):1466-1480.
- Rodbard HW, Rosenstock J, Canani LH, et al. Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial. Diabetes Care. 2019;42(12):2272-2281.
- 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.