Rybelsus (semaglutide)
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Rybelsus (semaglutide) is a medication used to improve glycemic control in conjunction with an adequate diet for adults with type 2 diabetes mellitus (T2DM). It is not known if Rybelsus is safe and effective in those under the age of 18. Rybelsus is provided as 3, 7, or 14 milligram (mg) tablets. There are various restrictions to use with Rybelsus, including:

  • Rybelsus should not be used as first-line agent due to potential C-cell tumor effects in rodents
  • Rybelsus has not been researched in patients with pancreatitis
  • Rybelsus should not be used in those with type 1 diabetes mellitus


GLP-1 is a naturally derived hormone that plays a role in glucose regulation through mediation of GLP-1 receptors. Rybelsus, or semaglutide, is a GLP-1 analogue and exerts its action as a GLP-1 receptor agonist. Semaglutide attaches to the GLP-1 receptor and activates it.

Semaglutide has a long half-life because of its extensive albumin binding. This leads to reduced renal clearance and prevents metabolic breakdown. Semaglutide activates the secretion of insulin and decreases the release of glucagon, thus reducing blood glucose. Therefore, when blood glucose levels are high, insulin release is increased, and secretion of glucagon is blocked. This phenomenon can consequently cause a gastric emptying delay during the early postprandial phase.


The most frequent and/or mild adverse effects from Rybelsus include:

  • ??Nausea
  • Stomach (abdominal) pain
  • Diarrhea
  • Decreased appetite
  • Vomiting
  • Constipation
  • Weight loss
  • Heartburn
  • Gastroesophageal reflux disease (GERD)
  • Gas and bloating
  • Burping


Thyroid C-Cell Tumors

In animal models, semaglutide induced dose- and treatment-duration-dependent elevations in thyroid C-cell tumor rates. No human data is available for the incidence of thyroid C-cell tumors. Medullary thyroid carcinoma (MTC) has been reported in other GLP-1 receptor agonists, though a causal relationship cannot be determined. Therefore, Rybelsus is not recommended in patients that have an individual or family history of MTC or for those that have Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Patients should be made aware of the signs and symptoms of thyroid tumors, including neck masses, dyspnea, dysphagia, hoarseness.


In studies with Rybelsus, 6 patients on Rybelsus experienced pancreatitis compared to 1 patient on placebo. Patients should be monitored closely for pancreatitis symptoms such as serious abdominal pain. If pancreatitis is suspected, stop Rybelsus right away and initiate proper management. If pancreatitis is the case, do not initiate Rybelsus again.

Diabetic Retinopathy Complications

Patients treated with Rybelsus have been reported to develop diabetic retinopathy.  Specifically, with quick glucose control improvements, transient worsening of diabetic retinopathy has occurred. Patients who have a diabetic retinopathy history should be observed for potential worsening.

Hypoglycemia with Simultaneous Use of Insulin Product

Patients on an insulin product concomitantly with Rybelsus have an elevated risk of developing hypoglycemia. Patients should be counseled on hypoglycemia symptoms such as shakiness, dizziness, sweating, increased heartbeat, or hunger. Lowering the dose of a sulfonylurea may decrease the risk of hypoglycemia.

Acute Kidney Injury

Patients on GLP-1 receptor agonists have reported acute kidney injury (AKI) and worsening chronic renal failure. Patients should be monitored for worsening renal function when starting or increasing doses of Rybelsus in those who experience GI symptoms.


Rybelsus has caused serious hypersensitivity reactions, including anaphylaxis and angioedema. If a patient experiences hypersensitivity, they should stop Rybelsus immediately and receive appropriate supportive care. Use Rybelsus with caution in those who have a history of anaphylaxis or angioedema with other GLP-1 receptor agonists should use caution.


Simultaneous Use with Insulin Products

Other insulin products, such as sulfonylureas, can increase hypoglycemia risk when used concomitantly with Rybelsus. Consider decreasing the dose of insulin products if given together with Rybelsus.

Oral Medication

Rybelsus can cause gastric emptying delays which can affect how other medications are absorbed. For example, levothyroxine exposure increased by 33% while being taken with Rybelsus. If taking other oral medications, ensure compliance with proper Rybelsus administration instructions. For drugs with narrow therapeutic windows, consider more frequent monitoring.



Animal models show the possible risk of Rybelsus to fetuses during pregnancy. Providers and patients should weigh the risks and benefits of Rybelsus including the potential birth defect, miscarriage, or maternal/fetal outcome risk and the benefits of controlled diabetes.


No data exists on the concentration of Rybelsus in human milk, exposure to a breastfed infant, or influence on milk production. Because little data is available, breastfeeding is not recommended when taking Rybelsus. There are other semaglutide formulations that may be more suitable for lactating patients.


Rybelsus has an extensive washout period after discontinuation. Therefore, Rybelsus should be stopped a minimum of 2 months before an expected pregnancy.


Rybelsus has not been studied in patients younger than 18 years of age. Therefore, safety and efficacy has not been determined in this patient population.


Rybelsus has been studied in older adults, and no major differences in efficacy and safety were seen. However, there is still the chance that geriatric patients are more sensitive to drugs such as Rybelsus.

Renal Impairment

Rybelsus doses should not be adjusted for those with renal impairment.

Hepatic Impairment

Rybelsus doses should not be adjusted for those with hepatic impairment.


Take Rybelsus 30 minutes with less than 4 ounces of plain water prior to having your first food, beverage, or medications of the day. Waiting for less than 30 minutes can decrease absorption and decrease the effectiveness of Rybelsus. Waiting more than 30 minutes can elevate the absorption of Rybelsus. This is why it is important to establish a routine with Rybelsus when you wake up. It is recommended that you keep Rybelsus on your nightstand with a glass of water. Make sure you swallow tablets whole and do not chew, crush, or split tablets.

Rybelsus is provided in a child-proof blister pack. With your thumb, push down on the tab that say “#1”. While pushing on #1, also grab tab #2 with the other thumb and pointer finger. From there, you should be able to take out the blister pack. Only push the tablet out of the blister. Do not cut the tablet out from the packaging.

If you miss a dose, skip the missed dose. Resume your normal medication schedule.

Before starting any medication, you should let your doctor know what medications you take. This includes prescription medications, over-the-counter medications, and herbal products. Rybelsus can influence how other medications work. Additionally, let your provider know if you:

  • Have had problems with your kidneys or pancreas
  • Have had problems with vision because of your diabetes
  • Are pregnant or plan to become pregnant
  • Breastfeed or plan to breastfeed

A serious side effect of Rybelsus includes potential thyroid tumors. Look out for symptoms including neck swelling or lumps, hoarseness, difficulty swallowing, or shortness of breath. These could indicate signs of thyroid cancer. Rybelsus should therefore not be used if you have a history of a thyroid cancer called MTC or MEN 2.

Rybelsus can also cause other serious side effects. Alert your doctor if you demonstrate signs of:

  • Pancreatitis: Severe upper stomach pain that radiates to your back, nausea and/or vomiting, increased heart rate
  • Low blood sugar: Sweating, weakness, confusion, hunger, dizziness, increased heart rate, irritability, feeling jittery
  • Kidney problems: Decreased or lack of urination, foot or ankle swelling, fatigue, shortness of breath

Rybelsus can still be present in your body for up to 5 weeks after your last dose. This is why it is important to stop Rybelsus at least 2 months before planning to become pregnant.

If you overdose on Rybelsus, contact your healthcare provider immediately or visit your nearest emergency room. Appropriate supportive treatment should be initiated, and you should be monitored for an extended period due to the long half-life of Rybelsus.

There are a few drugs that may react with Rybelsus. These drugs include:

  • Carbamazepine
  • Cyclosporine
  • Digoxin
  • Levothyroxine
  • Phenytoin
  • Tacrolimus
  • Theophylline
  • Warfarin

Other drugs might mask symptoms of hypoglycemia. Rybelsus, in combination with other medications, can increase your risk of hypoglycemia. Use caution in drugs that may hide hypoglycemia symptoms, such as:

  • Beta blockers
  • Clonidine
  • Reserpine

If you take any of the drugs above, be sure to let your provider know along with any other medications that you take.

Keep Rybelsus at room temperature and in a dry place. Do not open the container until you are ready to take Rybelsus. Keep all medications, including Rybelsus, out of reach from children.

More common side effects include:

  • Nausea
  • Vomiting
  • Diarrhea
  • Constipation
  • Decreased appetite
  • Abdominal pain

More serious side effects include:

  • Pancreatitis
  • Vision changes
  • Low blood sugar
  • Kidney problems
  • Severe allergic reactions