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Cardiovascular outcomes were evaluated in a safety study of RYBELSUS®

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

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PIONEER 6: a cardiovascular outcomes trial (CVOT) for RYBELSUS®1,2

Objective:

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.

event-driven

randomized

double-blind

placebo-controlled

Patients:

3183 with inadequately controlled type 2 diabetes and ASCVD.

Median observation time was 16 months.

Inclusion criteria:

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

Cardiovascular Outcomes Trial For RYBELSUS®
Cardiovascular Outcomes Trial For RYBELSUS®

Primary composite outcome

Time from randomization to first occurrence of MACE:

Primary composite outcome

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
b
Treatment arms included patients taking either RYBELSUS® or placebo who were either treatment-naïve or taking oral antidiabetics (OADs) and/or insulin.2

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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

RYBELSUS® Study Of Cardiovascular Safety

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

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Dose escalation designed to help your patients adjust to therapy1

For your patients to experience the intended efficacy of RYBELSUS®, it’s important to understand proper dosing when you prescribe.

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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; January 2020.
  2. 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.
  3. 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.