Rybelsus side effects: A comprehensive guide

Manufactured by Novo Nordisk, Rybelsus is the first and only oral GLP-1 receptor agonist for managing type 2 diabetes. Like Ozempic and Wegovy, Rybelsus contains semaglutide as an active ingredient. The medication has been approved by the FDA (the U.S. Food and Drug Administration) for promoting blood sugar control in patients with type 2 diabetes when used as an adjunct to a balanced and low-calorie diet, daily exercise, and increased physical activity. Rybelsus is not recommended for type 1 diabetes.

In PIONEER phase 3 clinical trials, Rybelsus reduced glycated hemoglobin levels (HbA1c) by 1.3% after 26 weeks compared to 0.9% with Jardiance. Rybelsus demonstrated 44% greater A1c reduction than the placebo. Approximately 67% of patients achieve targeted A1c levels after 26 weeks compared to 40% of patients who used Jardiance. These results reflect that Rybelsus is effective for promoting blood sugar control. However, the medication is associated with a few side effects, especially gastrointestinal side effects.

In 10 different clinical trials, 4% of patients using 7 mg and 8% of patients using 14 mg of Rybelsus experienced gastrointestinal side effects compared to 1% with the placebo. When reading these statistics, you might want to know what the most common Rybelsus side effects are and whether they go away.

This article provides a detailed, easy-to-understand guide to Rybelsus’ common, serious, and long-term side effects, including timelines, and effective strategies for managing these side effects.

How Rybelsus works and why it causes side effects

Rybelsus is a brand-name prescription drug containing the active ingredient semaglutide, a GLP-1 receptor agonist that has 94% structural similarity to the naturally occurring human glucagon-like peptide-1 hormone. The GLP-1 hormone regulates appetite and blood sugar levels in your body after food intake. Rybelsus works in the following ways to promote blood sugar control:

• The medication occupies GLP-1 receptors in the body and mimics the action of human glucagon-like peptide-1 hormone to enhance insulin release from the beta cells of the pancreas.
• Semaglutide affects the lateral hypothalamus of your brain, which is also known as the hunger control center, to promote appetite suppression.
• It slows the rate at which food moves from your stomach to the duodenum (the small intestine) by relaxing the stomach muscles. This is why the food stays longer in your stomach and you experience satiety or a feeling of fullness for a longer time. The medication also reduces the frequency of food cravings.
• The medication reduces glucagon production from the alpha cells of your pancreas. Normally, glucagon elevates blood sugar levels. Reduced glucagon production lowers blood glucose levels.

As Rybelsus delays gastric emptying, food stays longer in the stomach and intestines, leading to an increased incidence of gastrointestinal side effects, such as nausea, vomiting, constipation, heartburn, stomachache, GERD, and excessive belching.

These side effects of Rybelsus are usually dose-dependent. You may experience fewer side effects with a 7 mg daily dosage and more side effects with a 14 mg daily dosage.

Research studies reflect that 30% to 50% of patients experience gastrointestinal adverse effects with oral semaglutide or Rybelsus.

Most common Rybelsus side effects: What to expect and how to manage them

Like other GLP-1 medications, Rybelsus also has common side effects such as nausea, vomiting, diarrhea, constipation, and stomachache. The PIONEER 1-8 clinical studies show that 1.7 to 12% of patients discontinued Rybelsus treatment due to side effects, with gastrointestinal side effects being the most common.

• First 2-4 weeks: During the initial weeks, you experience most side effects as your body is adjusting to the medication. However, these are usually temporary and subside over time.
• After 8 weeks: After 8 weeks, your body starts to have better tolerance, and you typically do not experience severe side effects. However, most patients experience side effects with dose escalation.

In clinical trials, the most frequently reported side effects among patients using a 7 mg daily dose of oral semaglutide were:

• Nausea (11%)
• Abdominal pain (10%)
• Reduced appetite (6%)
• Vomiting (6%)
• Diarrhea (9%)
• Constipation (6%)

Gastrointestinal issues (reported in clinical trials in more than 5% of users)

Nausea (11%)

Nausea is the most common side effect that occurs when you start taking Rybelsus or increase the dosage of the medication. You can try the following tips to manage nausea associated with Rybelsus intake:

• Take the medication on an empty stomach (with ≤4 oz of water).
• Eat bland and low-fat food such as rice, crackers, and toast.
• Avoid greasy, oily, and spicy foods.
• Do not sleep immediately after eating food.
• Try small and more frequent meals.
• Stay adequately hydrated, drink at least one litre of water per day.
• Go for a walk or exercise daily.
• Limit alcohol usage, as alcohol abuse can also worsen nausea.
• You can also try ginger to manage nausea.
• If severe, contact your doctor for over-the-counter medications.

Nausea usually subsides as soon as your body adjusts to the medication. However, if it becomes intolerable or leads to severe vomiting, immediately consult your doctor. They might reduce the dosage of medication and delay dose escalation for at least 4 weeks.

Diarrhea (6%)

Diarrhea is another common side effect of Rybelsus. The same clinical trial reported that 6% of patients taking 7 mg of oral semaglutide experienced diarrhea.

Here are some tips to manage diarrhea:

• Stay hydrated to prevent dehydration that can occur with Rybelsus.
• Take ORS (oral rehydration fluid) to correct the electrolyte imbalance caused by diarrhea.
• Avoid oily, greasy, and spicy foods as they may worsen diarrhea.
• Do not eat unhealthy fast foods or those high in sugar content.
• Consult your doctor for over-the-counter medications.

Remember, staying hydrated is crucial if you have diarrhea. Dehydration caused by diarrhea can lead to acute kidney injury and electrolyte imbalance, which are harmful to your body.

Vomiting (6%)

The same clinical trial reported that 6% of patients experienced vomiting. Diarrhea and vomiting can both lead to dehydration.

Follow these tips to manage vomiting with Rybelsus:

• Avoid high-fat, spicy, and oily foods that trigger nausea.
• Start Rybelsus at a very low dose and increase its dosage gradually to give your body enough time to adjust to the medication.
• Stay hydrated to avoid dehydration and electrolyte imbalance.
• Eat in smaller portions. Large meals can trigger nausea and vomiting.

Abdominal pain/discomfort (10%)

In the same clinical trial, 10% of patients taking 7 mg and 11% of those taking 14 mg of Rybelsus experienced abdominal pain.

Rybelsus delays the rate of gastric emptying. If you eat spicy and unhealthy foods that irritate the lining of your stomach, you may experience abdominal pain, especially stomach aches. Eat healthy foods that soothe your stomach.

Abdominal pain might be due to other underlying problems, such as gastritis, gallstones, and pancreatitis (inflammation of the pancreas). Watch for signs of these medical conditions. Consult your doctor if abdominal pain is persistent.

Decreased appetite (6%)

A reported 6% and 9% of patients who took 7 mg and 14 mg of Rybelsus experienced reduced appetite.

As we have discussed above, Rybelsus works by suppressing appetite and slowing digestion. Food stays in your stomach for a longer time, which gives you a feeling of fullness and reduces hunger cravings.

Although GLP-1 medications suppress appetite, do not skip your meals. Eat in smaller portions and increase your physical activity for optimal digestion. Skipping meals can lead to nutritional deficiencies, fatigue, lethargy, and mood changes.

Constipation (6%)

Rybelsus caused constipation in 6% and 5% of patients using 7 mg and 14 mg daily doses, respectively.

Constipation may be a consequence of dehydration caused by vomiting and diarrhea. Add food rich in dietary fibers (such as green leafy vegetables, fruits, whole grains, and nuts) and drink plenty of water to manage constipation.

Additionally, exercises like walking, jogging, running, swimming, dancing, yoga, and pilates can also relieve constipation by increasing the motility of your intestines.

Bloating and gas 

Some Rybelsus users experience bloating and gas while using the medication. It occurs due to slow digestion and a reduced rate of stomach emptying. In some cases, bloating and gas may indicate gastroparesis (paralysis of the stomach due to ineffective contractions).

To prevent bloating and gas, avoid lying or sleeping immediately after eating, eat in smaller portions, engage in regular exercise, and limit your intake of oily foods.

Burping 

Excessive burping is also a common side effect of Rybelsus due to slow digestion and bloating. You may feel a specific taste or smell after each burp. Avoid drinking sugary beverages and carbonated drinks, and refrain from chewing bubble gum. Properly chew your food, take smaller bites, and eat slowly to avoid burping.

Other common side effects

Acid reflux/GERD 

As we have discussed earlier, Rybelsus delays stomach emptying. The food stays for a longer time in your stomach, which can irritate its lining, leading to stomach pain. Additionally, the upper sphincter of your stomach loosens, and the food flushes backwards to the back of your oral cavity. This causes a burning sensation in your chest and stomach.

GERD typically occurs due to the intake of hot, spicy, processed, oily, and fatty foods. Avoid these foods and eat a healthy diet that supports your stomach health.

Headaches

Headaches may occur with Rybelsus due to low blood sugar/glucose levels and low energy. Eat frequently but in smaller portions to keep your blood sugar levels stable. You can also take over-the-counter medications to relieve headaches.

Fatigue

Fatigue is a common side effect of GLP-1 medications. It results from decreased appetite, reduced food intake, low energy levels, and metabolic changes when taking these medications. Moreover, reduced food intake can also lead to nutritional deficiencies, which can cause fatigue.

Take a diet rich in all essential nutrients, such as vitamins and minerals, to avoid these side effects.

Dizziness 

Dizziness usually occurs during the initial stages of the treatment or when your healthcare provider increases the dosage of Rybelsus. It is linked with blood sugar levels. Fluctuations in blood glucose levels cause dizziness. If you experience severe nausea, vomiting, or diarrhea, it can lead to a fluid and electrolyte imbalance. These imbalances can also cause dizziness.

Rybelsus side effects frequency by dosage

Understanding the timeline of Rybelsus side effects

Here is the timeline for when side effects might occur and how long they might last:

Initial phase (first few weeks)

Gastrointestinal side effects are most common during the initial stages of treatment. These include diarrhea, nausea, stomach pain, vomiting, and constipation. They may also occur when your prescriber increases the dosage of Rybelsus.

Dose escalation

These side effects can worsen temporarily with dose escalation as your body tries to adjust to the medication. Over time, they will subside.

Long-term management

When you take medication for long-term management of blood sugar levels, these common side effects tend to disappear over time. It may take days to weeks, depending on how quickly your body adapts to these changes.

Persistent side effects

If the side effects of Rybelsus do not improve over time or become severe, consult your healthcare provider. They will adjust the Rybelsus dosage accordingly. If the side effects do not subside or become intolerable even after lowering the dosage of the medication, they may consider switching to another medication.

If you are pregnant or breastfeeding, the medication is not recommended for you.

Rare and serious Rybelsus side effects: When to seek immediate medical attention

The following are less common but potentially serious side effects. Let’s discuss their warning signs in detail:

Possible thyroid tumors, including cancer (black box warning)

GLP-1 medications, including Rybelsus, have a boxed warning for thyroid tumors. Although no human studies have reported any incidence of thyroid cell carcinoma, animal studies have reported an increased risk of dose-specific thyroid cancer with these medications.

If you feel any lump or swelling in the neck, hoarseness of the voice, difficulty swallowing, or shortness of breath, immediately inform your doctor. They will rule out thyroid cancer first.

Rybelsus is contraindicated for patients with a personal or family history of medullary thyroid carcinoma (MTC) and MEN 2 syndrome (Multiple endocrine neoplasia syndrome type 2).

Pancreatitis (inflammation of the pancreas)

Pancreatitis or inflammation of the pancreas is linked to the usage of GLP-1 receptor agonists. These medications increase the risk of pancreatitis. In a clinical trial of Rybelsus, only one patient reported pancreatitis after using the medication consistently.

If you or your healthcare provider suspect pancreatitis, immediately stop using Rybelsus.

Possible signs of pancreatitis include:

• Severe upper abdominal pain (radiating to the back)
• Nausea
• Vomiting may be present or absent
• Fever

If you are diagnosed with pancreatitis before starting the medication, Rybelsus is not suitable for you. Inform your healthcare professional and discuss other alternative anti-diabetic treatments.

Low blood sugar (hypoglycemia)

Generally, hypoglycemia is rare with Rybelsus. The risk of hypoglycemia increases when you use the medication with other diabetes medications such as sulfonylureas and insulin. Clinical studies show that 1.4% of patients using Rybelsus experienced hypoglycemia, compared to 0.8% with placebo. All patients who experienced lower blood sugar levels were taking insulin or sulfonylureas at the time of the event.

While taking any GLP-1 medication, watch for the following symptoms of hypoglycemia:

• Dizziness
• Lightheadedness
• Confusion
• Sweating
• Tremors
• fast heartbeat
• Anxiety.
• Weakness
• Blurred vision
• Slurred speech
• Hunger
• Drowsiness
• Feeling jittery

In case of hypoglycemia, immediately take fast-acting carbohydrates such as glucose tablets, honey, candy, juice, or sugar. If your friend or family member becomes unconscious due to hypoglycemia, immediately rush to a nearby healthcare facility, as it is a life-threatening medical emergency that needs urgent care to prevent brain damage.

If you experience any episode of hypoglycemia, immediately inform your doctor. They may reduce the dosage of Rybelsus.

Kidney problems (kidney failure/damage)

Vomiting and dehydration are the most common side effects of Rybelsus. Persistent vomiting or diarrhea can lead to acute kidney injury or kidney damage. If not treated promptly, acute kidney injury may result in kidney disease or kidney failure.

If you already have diarrhea or vomiting, look for signs of dehydration such as dry mouth, sunken eyes, dizziness, and difficulty concentrating. You can also do a skin pinch test to check the severity of dehydration. Stay well hydrated to reduce the risk of dehydration and its consequences, like acute kidney injury.

Symptoms of acute kidney injury (AKI) are:

• Decreased urination/ less urine output
• Swollen legs/ankles
• Fatigue
• Nausea
• Shortness of breath
• Confusion
• Bloody or foamy urine
• Drowsiness

If you have severe dehydration, visit your doctor. They will give intravenous or oral rehydration solutions to combat dehydration.

Serious allergic reactions

An allergic or hypersensitivity reaction may occur if your body is allergic to any active or inactive ingredient of the medication. Mild allergic reactions are usually transient. They may cause itching, skin rash and redness, formation of reddish papules, and sneezing. However, severe allergic reactions need emergency care. Symptoms of severe hypersensitivity reaction are:

• Skin rash
• Hives
• Swelling of the face, lips, tongue, throat, and eyelids
• Difficulty swallowing
• Difficulty breathing
• Increased heart rate
• Dizziness
• Fever
• Nausea or vomiting

In case of a severe allergic reaction, immediately visit the emergency department of a nearby hospital to receive emergency care. Do not take the medication again. Inform your healthcare provider, and they may switch the medication.

Gallbladder problems (gallstones, cholecystitis)

Gallbladder stones and inflammation of the gallbladder (cholecystitis) have been reported in different clinical trials of semaglutide. A meta-analysis that evaluated the results of 76 clinical trials suggests that GLP-1 medications, including Rybelsus, are linked to an increased risk of biliary and gallbladder diseases, inflammation of the gallbladder, and gallstones.

GLP-1 medications induce weight loss and lower blood glucose levels. These changes increase the release of extra cholesterol into the bile, which contributes to the formation of gallstones.

Watch for the following symptoms of gallbladder problems:

• Severe abdominal pain (in the upper right abdomen
• Nausea
• Yellowing of eyes and skin
• Jaundice
• Clay colored stools
• Vomiting

If you have any of these signs, contact your healthcare provider for further evaluation and laboratory investigation.

Diabetic retinopathy complications

Complication in diabetic retinopathy is a possible side effect of Rybelsus. Improvement in blood sugar levels with Rybelsus is associated with a temporary worsening of vision, particularly when starting the treatment or increasing the dosage of your medication. It can worsen diabetic retinopathy in patients with type 2 diabetes.

If you notice any changes in vision when taking Rybelsus, inform your healthcare provider and consult an ophthalmologist for a detailed evaluation. This complication needs immediate treatment to prevent vision loss.

Severe stomach problems (including gastroparesis/ileus)

Rybelsus reduces the rate of stomach emptying. Slowed gastric emptying can cause or worsen pre-existing gastroparesis or, rarely, contribute to severe constipation and bowel obstruction. Bowel obstruction is a surgical emergency that needs prompt medical attention.

Although gastroparesis or paralysis of stomach muscles is a rare complication of Rybelsus, clinical studies reflect that semaglutide has a greater risk of gastroparesis than other weight loss medications, such as bupropion/naltrexone.

Symptoms of gastroparesis are:

• Severe abdominal pain
• Constipation
• Inability to pass gas
• Bloating
• Persistent nausea/vomiting
• Feeling full quickly

If you have a history of gastroparesis, inform your doctor. They will most likely not start your treatment with Rybelsus and will look for other alternatives.

Pulmonary aspiration during anesthesia/sedation

Generally, doctors recommend that you stop eating food 6-8 hours before any surgical procedures to give your stomach enough time to move the gastric content into the intestines completely. Your stomach should be empty during surgery to avoid the risk of aspiration. When you are on Rybelsus treatment, the gastric emptying is delayed, despite staying nil per os (NPO), your stomach might not be completely empty. This is how Rybelsus increases the risk of pulmonary aspiration (food entering the airway) during sedation and surgical procedures.

When you are on Rybelsus treatment, always inform your medical professional before any procedure requiring anesthesia or sedation.

Rybelsus adverse events frequency by dosage

Long-term considerations and potential effects

Let’s get into the details of long-term considerations and the potential effects of Rybelsus.

Weight loss and maintenance

Although Rybelsus is FDA-approved for type 2 diabetes management, its blood sugar-lowering and appetite-suppressing effects contribute to weight reduction. The medication is also used off-label for weight management in obese and overweight patients, but at higher doses.

The OASIS 1 clinical trial shows that patients using a 50 mg daily dose of Rybelsus lost approximately 15% of their body weight after 16 months. In the OASIS 4 clinical trial, patients lost around 14% of their body weight with a 25 mg daily dose of Rybelsus after 15 months.

You can expect similar results with Rybelsus, provided you follow healthy lifestyle modifications. These include taking a low-fat, healthy, and balanced diet, daily exercise, and staying physically active.

Cardiovascular effects

In a PIONEER 6 cardiovascular outcomes trial (CVOT), patients with type 2 diabetes and established cardiovascular diseases used oral semaglutide (Rybelsus). As a result, the incidence of MACE (major adverse cardiovascular event) was reduced by 21% as compared to placebo.

There was a reduced incidence of cardiovascular death, nonfatal myocardial infarction (MI), and stroke. These results suggest that Rybelsus has cardiovascular benefits.

Impact on other medications

As Rybelsus slows gastric emptying, it can affect the absorption of other oral medications and supplements. They might not get absorbed quickly, increasing exposure time. The medication increases the exposure of Levothyroxine by 33%.

Inform your doctor about all medications you are taking before starting your treatment with Rybelsus. Certain medications, such as oral contraceptives, should not be taken along with Rybelsus.

Potential for nutrient absorption issues (related to persistent GI side effects)

Persistent gastrointestinal side effects of Rybelsus, especially vomiting and diarrhea, can cause nutritional deficiencies. Frequent vomiting and diarrhea do not give your body enough time to absorb essential nutrients, as the food moves out of the body before nutrients are absorbed.

Take a balanced diet and stay in contact with your doctor to manage these effects in order to prevent further complications.

Managing and reducing Rybelsus side effects

Here are a few tips to manage common side effects of Rybelsus:

Take Rybelsus correctly

Take the medication on an empty stomach with a small sip of water 30 minutes before eating food or other medications. Always take the medication as prescribed by your doctor.

Start with a low dose and titrate slowly

Do not start the medication at higher doses. Start at a low dose of 3 mg daily and increase the dosage after 4 weeks or 30 days, as prescribed by your healthcare provider. Follow your prescribed dosing schedule strictly. In case of serious side effects, consult your doctor before taking your next dosage.

Avoid alcohol

Limit alcohol consumption when taking GLP-1 medications for diabetes or weight loss. Alcohol consumption worsens nausea and vomiting and leads to dehydration. Alcohol also counteracts the blood glucose-lowering effect of Rybelsus.

Dietary adjustments

Take foods that complement the effect of Rybelsus instead of worsening its side effects. Eat smaller and more frequent meals. Avoid high-fat, oily, greasy, and processed food, carbonated drinks, and sugary beverages. Eat slowly and chew your food properly.

Hydration

Vomiting and diarrhea associated with GLP-1 medications can cause dehydration. In some patients, dehydration can lead to severe consequences such as acute kidney injury. Stay well hydrated to prevent these problems.

Over-the-counter remedies

You can use over-the-counter remedies to relieve common side effects of Rybelsus, such as ginger tea for nausea and vomiting, psyllium husk for constipation, and a homemade oral rehydration solution (ORS) for dehydration and diarrhea. Always ask your healthcare provider before trying any remedy, if it is safe for you.

Prescription medications

Your healthcare professional may prescribe medications like ondansetron to help manage persistent nausea or vomiting and laxatives to relieve constipation. They may prescribe proton pump inhibitors (PPIs) for stomach pain.

Lifestyle modifications

Lifestyle modifications play a critical role in the management of Rybelsus side effects. Regular light exercise, such as light cardio, strength training, yoga, meditation, cycling, jogging, and swimming, can help manage most gastrointestinal side effects. Stress can worsen these side effects; practicing stress management techniques and healthy sleep habits can improve them.

Rybelsus vs. other GLP-1 side effects comparison

Oral vs. injectable

Rybelsus has both pros and cons when compared to other GLP-1 medications. The medication may cause more nausea during early treatment due to direct contact with the stomach compared to injectable medications such as Ozempic and Wegovy.

Rybelsus is taken orally, which means the medication does not cause any injection site reactions. Oral tablets are also convenient to take compared to injectables.

Weight loss drugs

Wegovy at higher doses has similar side effects, but they are stronger than those of Rybelsus.

FAQs about Rybelsus side effects

Does Rybelsus cause weight loss?

Yes, Rybelsus can cause weight loss, like other GLP-1 medications of the same class. The medication is primarily used to manage blood sugar levels, but the same mechanism that lowers blood sugar levels also aids in weight reduction. A phase 3 clinical trial suggests that patients who used a 50 mg dose of oral semaglutide (Rybelsus) showed 15.5% weight reduction after 68 weeks.

How long does Rybelsus nausea last?

Rybelsus nausea is usually transient and subsides over time. You may feel nauseous at the beginning of treatment or during dose escalation. It will vanish over time as your body adjusts to Rybelsus. However, some patients may have persistent nausea, and they may need over-the-counter or prescription medication to treat it.

Can Rybelsus cause hair loss?

Rybelsus may cause hair loss, but it is reported rarely. Most patients do not experience hair loss with the medication.

What foods make Rybelsus side effects worse?

Oily, fatty, greasy, processed, and fried foods, carbonated drinks, alcohol, and sugary beverages make Rybelsus side effects worse.

When to speak with a doctor about side effects

It is crucial to contact your doctor to seek medical advice when you have:

• Severe or persistent side effects that do not subside over time or with over-the-counter remedies
• Symptoms of any of the serious side effects listed above.
• Any side effects that significantly impact your quality of life or are intolerable.
• When you have missed a dose of Rybelsus.
• Before stopping the medication.

Conclusion

Rybelsus can be an effective medication for blood sugar control in type 2 diabetes, but the medication is associated with certain side effects. Understanding these potential side effects is essential to managing them effectively.

Always start with a low dose, increase the dosage gradually, and maintain a balanced diet that complements the effect of Rybelsus to minimize the risk of side effects. The benefits of Rybelsus in managing type 2 diabetes may outweigh the risks of side effects for many individuals, especially with proper management and adherence to the prescribed regimen.

If you cannot tolerate the side effects of Rybelsus, you experience severe GI problems, or you have a history of pancreatitis, contact your healthcare provider to discuss other alternatives.

Always have open communication with your doctor to manage side effects effectively and ensure safe and successful treatment. Most side effects of Rybelsus are temporary and subside within a few weeks.

Trusted source

New England Journal of Medicine

• A prestigious weekly medical journal published by the Massachusetts Medical Society

Go to source

Trusted source

New England Journal of Medicine

• A prestigious weekly medical journal published by the Massachusetts Medical Society

Go to source

Trusted source

JAMA Network

• Established in 2018, JAMA Network Open is a monthly open-access medical journal published by the American Medical Association covering all aspects of the biomedical sciences.

Go to source

Trusted source

The Lancet

• One of the world's highest impact and oldest general medical journals

Go to source

Trusted source

JAMA Network

• Established in 2018, JAMA Network Open is a monthly open-access medical journal published by the American Medical Association covering all aspects of the biomedical sciences.

Go to source