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Now Approved: RYBELSUS®

The world’s first and only oral GLP-1 RA1

Once-daily RYBELSUS® is an oral GLP-1 RA indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

Once-daily RYBELSUS® is an oral GLP-1 RA indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

See Prescribing Information »

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Learn more about this new oral GLP-1 RA

Learn more about this new oral GLP-1 RA

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RYBELSUS® demonstrated statistically significant A1C reductions vs Januvia® and Jardiance®1-3,a

RYBELSUS® has been studied in 10 PIONEER clinical trials, which enrolled 9543 participants with type 2 diabetes and included head-to-head studies of RYBELSUS® vs sitagliptin, empagliflozin, and liraglutide 1.8 mg.4

PIONEER 3: RYBELSUS® vs Januvia®, a DPP-4i1,2

Study design:

Phase 3a trial to compare the safety and efficacy of RYBELSUS® vs Januvia®

  • double-blind
  • double-dummy

Patients:

1864

Inclusion criteria:

Adults with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea

Study design for RYBELSUS® vs Januvia® head-to-head trial

Primary endpoint: Mean change in A1C at week 26

Study design for RYBELSUS® vs Januvia® head-to-head trial

aEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication, and region.
bThe ITT population includes all randomized patients. At Week 26, the primary A1C endpoint was missing for 5.8%, 6.2%, and 4.5% of patients randomized to RYBELSUS® 7 mg, RYBELSUS® 14 mg, and Januvia® 100 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at Week 26. During the trial, additional antidiabetic medication was initiated as an add on to randomized treatment by 2.4%, 1.1%, and 2.8% of patients randomized to RYBELSUS® 7 mg, RYBELSUS® 14 mg, and Januvia® 100 mg, respectively.
cP<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.

Confirmatory secondary endpoint: Mean change in body weight at week 26

RYBELSUS® is not indicated for weight loss. 

The mean baseline body weight was 201 lb, 201 lb, and 200 lb in the RYBELSUS® 7 mg, RYBELSUS® 14 mg, and sitagliptin 100 mg arms, respectively. The mean changes from baseline to Week 26 were –4.8 lb, –6.8 lb and –1.3 lb in the RYBELSUS® 7 mg, RYBELSUS® 14 mg, and sitagliptin 100 mg arms, respectively. The difference from sitagliptin (95% CI) for RYBELSUS® 7 mg was –3.5 lb (–4.4, –2.4) and RYBELSUS® 14 mg was –5.5 lb (–6.6, –4.4).

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PIONEER 2: RYBELSUS® vs Jardiance®, an SGLT-2i1,3

Study design:

Phase 3a trial to compare the safety and efficacy of RYBELSUS® vs Jardiance®

  • open-label

Patients:

822

Inclusion criteria:

Adults with type 2 diabetes inadequately controlled with metformin

Study design for RYBELSUS® vs Jardiance® head-to-head trial

Primary endpoint: Mean change in A1C at week 26

Study design for RYBELSUS® vs Januvia® head-to-head trial

aEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value and region.
cP<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.
dThe ITT population includes all randomized patients. At Week 26, the primary A1C endpoint was missing for 4.6% and 3.7% of patients randomized to RYBELSUS® 14 mg and Jardiance® 25 mg, respectively. Missing data were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at Week 26. During the trial, additional antidiabetic medication was initiated as an add on to randomized treatment by 1.9% and 1.2% of patients randomized to RYBELSUS® 14 mg and Jardiance® 25 mg, respectively.

Confirmatory secondary endpoint: Mean change in body weight at week 26

RYBELSUS® is not indicated for weight loss. 

The mean baseline body weight was 202 lb and 201 lb in the RYBELSUS® 14 mg and empagliflozin 25 mg arms, respectively. The mean changes from baseline to Week 26 were –8.4 lb and –8.1 lb in the RYBELSUS® 14 mg and empagliflozin 25 mg arms, respectively. The difference from empagliflozin (95% CI) for RYBELSUS® 14 mg was –0.2 lb (–1.5, 1.1).

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PIONEER 4: RYBELSUS® vs liraglutide 1.8 mg, a GLP-1 RA1,5

Study design:

Phase 3a trial to compare the safety and efficacy of RYBELSUS® vs liraglutide 1.8 mg

  • double-blind
  • double-dummy

Patients:

711

Inclusion criteria:

Adults with type 2 diabetes inadequately controlled with metformin with or without an SGLT-2 inhibitor

Study design for RYBELSUS® vs liraglutide head-to-head trial

Primary endpoint: Mean change in A1C at week 26

Study design for RYBELSUS® vs Januvia® head-to-head trial

aEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication and region.
cP<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.
eThe ITT population includes all randomized patients. At Week 26, the primary A1C endpoint was missing for 5.6%, 4.2%, and 2.5% of patients randomized to placebo, liraglutide 1.8 mg, and RYBELSUS® 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at Week 26. During the trial, additional antidiabetic medication was initiated as an add on to randomized treatment by 7.7%, 3.2%, and 3.5% of patients randomized to placebo, liraglutide 1.8 mg, and RYBELSUS® 14 mg, respectively.

Confirmatory secondary endpoint: Mean change in body weight at week 26

RYBELSUS® is not indicated for weight loss. 

The mean baseline body weight was 205 lb, 210 lb, and 204 lb in the placebo, liraglutide 1.8 mg, and RYBELSUS® 14 mg arms, respectively. The mean changes from baseline to Week 26 were –1.1 lb, –6.8 lb and –9.7 lb in the placebo, liraglutide 1.8 mg, and RYBELSUS® 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS® 14 mg was –8.4 lb (–10.3, –6.6). The difference from liraglutide 1.8 mg for RYBELSUS® 14 mg was –2.6 lb (–4.2, –1.3).

quaternary_msg

Explore abstract »

See Prescribing Information »

RYBELSUS® demonstrated statistically significant A1C reductions vs Januvia® and Jardiance®1-3,a

RYBELSUS® has been studied in 10 PIONEER clinical trials, which enrolled 9543 participants with type 2 diabetes and included head-to-head studies of RYBELSUS® vs sitagliptin, empagliflozin, and liraglutide 1.8 mg.4

PIONEER 3: RYBELSUS® vs Januvia®, a DPP-4i1,2

Study design:

78-week, phase 3a trial to compare the safety and efficacy of RYBELSUS® vs Januvia®

  • double-blind
  • double-dummy

Patients:

1864

Inclusion criteria:

Adults with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea

Study design for RYBELSUS® vs Januvia® head-to-head trial

Primary endpoint: Mean change in A1C at week 26

Study design for RYBELSUS® vs Januvia® head-to-head trial

aEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication, and region.
bThe ITT population includes all randomized patients. At Week 26, the primary A1C endpoint was missing for 5.8%, 6.2%, and 4.5% of patients randomized to RYBELSUS® 7 mg, RYBELSUS® 14 mg, and Januvia® 100 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at Week 26. During the trial, additional antidiabetic medication was initiated as an add on to randomized treatment by 2.4%, 1.1%, and 2.8% of patients randomized to RYBELSUS® 7 mg, RYBELSUS® 14 mg, and Januvia® 100 mg, respectively.
cP<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.

Confirmatory secondary endpoint: Mean change in body weight at week 26

RYBELSUS® is not indicated for weight loss. 

The mean baseline body weight was 201 lb, 201 lb, and 200 lb in the RYBELSUS® 7 mg, RYBELSUS® 14 mg, and sitagliptin 100 mg arms, respectively. The mean changes from baseline to Week 26 were –4.8 lb, –6.8 lb and –1.3 lb in the RYBELSUS® 7 mg, RYBELSUS® 14 mg, and sitagliptin 100 mg arms, respectively. The difference from sitagliptin (95% CI) for RYBELSUS® 7 mg was –3.5 lb (–4.4, –2.4) and RYBELSUS® 14 mg was –5.5 lb (–6.6, –4.4).

secondary_msg

Explore abstract »

See Prescribing Information »

PIONEER 2: RYBELSUS® vs Jardiance®, an SGLT-2i1,3

Study design:

Phase 3a trial to compare the safety and efficacy of RYBELSUS® vs Jardiance®

  • open-label

Patients:

822

Inclusion criteria:

Adults with type 2 diabetes inadequately controlled with metformin

Study design for RYBELSUS® vs Jardiance® head-to-head trial

Primary endpoint: Mean change in A1C at week 26

Study design for RYBELSUS® vs Januvia® head-to-head trial

aEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value and region.
cP<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.
dThe ITT population includes all randomized patients. At Week 26, the primary A1C endpoint was missing for 4.6% and 3.7% of patients randomized to RYBELSUS® 14 mg and Jardiance® 25 mg, respectively. Missing data were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at Week 26. During the trial, additional antidiabetic medication was initiated as an add on to randomized treatment by 1.9% and 1.2% of patients randomized to RYBELSUS® 14 mg and Jardiance® 25 mg, respectively.

Confirmatory secondary endpoint: Mean change in body weight at week 26

RYBELSUS® is not indicated for weight loss. 

The mean baseline body weight was 202 lb and 201 lb in the RYBELSUS® 14 mg and empagliflozin 25 mg arms, respectively. The mean changes from baseline to Week 26 were –8.4 lb and –8.1 lb in the RYBELSUS® 14 mg and empagliflozin 25 mg arms, respectively. The difference from empagliflozin (95% CI) for RYBELSUS® 14 mg was –0.2 lb (–1.5, 1.1).

tertiary_msg

See Prescribing Information »

PIONEER 4: RYBELSUS® vs liraglutide 1.8 mg, a GLP-1 RA1,5

Study design:

Phase 3a trial to compare the safety and efficacy of RYBELSUS® vs liraglutide 1.8 mg

  • double-blind
  • double-dummy

Patients:

711

Inclusion criteria:

Adults with type 2 diabetes inadequately controlled with metformin with or without an SGLT-2 inhibitor

Study design for RYBELSUS® vs liraglutide head-to-head trial

Primary endpoint: Mean change in A1C at week 26

Study design for RYBELSUS® vs Januvia® head-to-head trial

aEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication, and region.
cP<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.
eThe ITT population includes all randomized patients. At Week 26, the primary A1C endpoint was missing for 5.6%, 4.2%, and 2.5% of patients randomized to placebo, liraglutide 1.8 mg, and RYBELSUS® 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at Week 26. During the trial, additional antidiabetic medication was initiated as an add on to randomized treatment by 7.7%, 3.2%, and 3.5% of patients randomized to placebo, liraglutide 1.8 mg, and RYBELSUS® 14 mg, respectively.

Confirmatory secondary endpoint: Mean change in body weight at week 26

RYBELSUS® is not indicated for weight loss. 

The mean baseline body weight was 205 lb, 210 lb, and 204 lb in the placebo, liraglutide 1.8 mg, and RYBELSUS® 14 mg arms, respectively. The mean changes from baseline to Week 26 were –1.1 lb, –6.8 lb and –9.7 lb in the placebo, liraglutide 1.8 mg, and RYBELSUS® 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS® 14 mg was –8.4 lb (–10.3, –6.6). The difference from liraglutide 1.8 mg for RYBELSUS® 14 mg was –2.6 lb (–4.2, –1.3).

quaternary_msg

Explore abstract »

See Prescribing Information »

Most common adverse reactions1

Adverse reactions were evaluated across multiple placebo- and active-controlled trials:

2 placebo-controlled trials in patients with type 2 diabetes. These data reflect exposure of 1071 patients to RYBELSUS® and a mean duration of exposure to RYBELSUS® of up to 41.8 weeks

9 placebo- and active-controlled glycemic control trials. In addition to monotherapy and add-on therapy to oral medications, RYBELSUS® has been studied in combination with insulins. In this pool, a total of 4116 patients with type 2 diabetes were treated with RYBELSUS® for a mean duration of 59.8 weeks

Adverse reactions in placebo-controlled trials reported in ≥5% of RYBELSUS®-treated patientsf

fExcluding hypoglycemia.

Most common adverse reactions1

Adverse reactions were evaluated across multiple placebo- and active-controlled trials:

2 placebo-controlled trials in patients with type 2 diabetes. These data reflect exposure of 1071 patients to RYBELSUS® and a mean duration of exposure to RYBELSUS® of up to 41.8 weeks

9 placebo- and active-controlled glycemic control trials. In addition to monotherapy and add-on therapy to oral medications, RYBELSUS® has been studied in combination with insulins. In this pool, a total of 4116 patients with type 2 diabetes were treated with RYBELSUS® for a mean duration of 59.8 weeks

Adverse reactions in placebo-controlled trials reported in ≥5% of RYBELSUS®-treated patientsf

fExcluding hypoglycemia.

gFor commercially insured patients only. Additional eligibility and restrictions apply.

Two ways for your patients to get savings and support

TEXT READY TO 21848h

Patients will receive co-pay savings and text messages to help them start and stay on RYBELSUS®.

VISIT SAVEONR.COM

Patients can download a savings card at SaveOnR.com and receive personalized email support.

gFor commercially insured patients only. Additional eligibility and restrictions apply.
hMessage and data rates may apply. Tell patients to check with their mobile service provider. See Terms of Use & Conditions at RYBELSUS.com.

hMessage and data rates may apply. Tell patients to check with their mobile service provider. See Terms of Use & Conditions at RYBELSUS.com.

Pharmacists: Have questions about processing the RYBELSUS® savings offer?

Call Pharmacy Connect at 1-888-401-0112 or email RpharmacyConnect@connectiverx.com if you need assistance processing the RYBELSUS® Savings Card.

Available Monday to Friday, 8:00 am – 8:00 pm ET, except holidays.

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Selected Important Safety Information

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®

Indications 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 or for the treatment of patients with diabetic ketoacidosis

Important Safety Information

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®

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 known hypersensitivity to semaglutide or to any of the components in RYBELSUS®

Warnings & 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: The risk of hypoglycemia is increased when RYBELSUS® is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Patients may require a lower dose of the secretagogue or insulin to reduce the risk of hypoglycemia in this setting
  • 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 with GLP-1 receptor agonists, including semaglutide. 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

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

  • The risk of hypoglycemia may be lowered by a reduction in the dose of concomitantly administered secretagogues or insulin
  • 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:

  1. RYBELSUS® [package insert]. Plainsboro, NJ: Novo Nordisk Inc; September 2019.
  2. 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.
  3. 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. doi:10.2337/dc19-0883.
  4. Data on file. Novo Nordisk Inc., Plainsboro, NJ.
  5. Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomized, double-blind, phase 3a trial. Lancet. 2019;394(10192):39-50.

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