Rybelsus vs. Metformin - Detailed Comparison

Rybelsus and metformin are FDA-approved prescription medications used to regulate blood sugar levels in adults with type 2 diabetes. Rybelsus is a brand drug, unlike metformin, which is a generic drug, available under names such as Glucophage, Riomet, or Glumetza.

Both medications are administered orally, and both offer great effectiveness in alleviating type 2 diabetes symptoms. Although not officially approved for weight loss, Rybelsus and metformin have shown promising results in this regard as well.

In this article, we will compare these medications, showing the differences between how they work, their side effects, and their cost so you can have a better idea of which medication may suit your needs better. This information will help you prepare for a consultation with your doctor, giving you better clarity in regard to your options.

What Is Rybelsus?

Rybelsus (semaglutide) is a brand-name drug that was approved by the FDA in 2019 as the first GLP-1 receptor agonist available to administer orally.

Rybelsus tablets can be administered in three different strengths: 3 mg, 7 mg, and 14 mg. The drug’s main effect is to lower the blood sugar levels in individuals with type 2 diabetes. The medication increases insulin production, helping patients keep glucose levels within safe parameters.

Rybelsus contains one main active drug – semaglutide, which can also be found in other medications, such as Ozempic and Wegovy.

What Is Metformin?

Metformin is a generic drug that can be found under different names, such as Glucophage, Riomet, or Glumetza. It’s a much older medication than Rybelsus, approved by the FDA in 1995.

Metformin belongs to the class of drugs called biguanides. It has a similar effect to Rybelsus; however, the main difference is that it doesn’t necessarily influence insulin production, more so affecting the way the liver produces glucose, as well as reducing insulin resistance.

It is one of the most commonly prescribed diabetes type 2 medications for adults and children.

You will find generic metformin tablets available in three different strengths: 500 mg, 850 mg, and 1,000 mg.

How Rybelsus Works

The drug works by mimicking the effect of the GLP-1 hormone responsible for managing the glucose levels in the bloodstream, among other things. Rybelsus works by:

  • stimulating insulin production in your body after eating;
  • slowing down the pace at which food leaves your stomach;
  • reducing the amount of glucose produced by the liver.

In broader terms, the drug, through stimulating insulin production, helps transport the sugar you consume from your bloodstream into your cells, where it’s needed. This process lowers your blood sugar level to safe parameters, lowering the risks of experiencing life-threatening hyperglycemia.

Semaglutide, which can be found in other drugs (like Ozempic), is responsible for slowing gastric emptying after eating, which is why patients report feeling fuller for longer periods of time.

How Metformin Works

Metformin lowers blood sugar levels in a few different ways. Mainly, the drug is responsible for:

  • increasing your insulin sensitivity and mitigating insulin resistance;
  • lowering the absorption of sugar in your intestines;
  • lowering the liver’s production of sugar.

One of the more interesting differences between how Rybelsus and metformin work is the fact that the first medication stimulates insulin production, whereas the latter primarily lowers sugar absorption and increases insulin sensitivity.

Insulin resistance can manifest itself in patients who frequently experience high spikes in sugar levels. The condition increases the risk of hyperglycemia, as cells don’t respond to insulin as they should and, therefore, do not receive the sugar that is in the bloodstream. This leads to increased blood sugar levels and a string of related symptoms.

Metformin is effective in stabilizing sugar absorption as well as slowing down the liver’s production of glucose.

Approved and Off-Label Uses - Rybelsus and Metformin

The only FDA-approved use of both Rybelsus and metformin is to treat some of the symptoms (in particular, high blood sugar levels) in patients with type 2 diabetes. It’s also important to mention that each drug is administered in combination with proper diet, exercise, and potentially other medications. 

An important distinction between the two is the fact that metformin is approved for use in the treatment of children above the age of 10. Rybelsus is approved only for adult patients with type 2 diabetes. 

Due to the related properties of Rybelsus, it is currently undergoing studies for its usage in treating type 1 diabetes. Oral semaglutide has not been approved by the FDA for use in type 1 diabetes therapies; however, some doctors prescribe it off-label, as it has shown effectiveness in lowering hemoglobin A1c (HbA1c) levels in patients with this type of diabetes. (Source)  

Rybelsus and metformin can be prescribed by your medical team to support weight loss, as both medications have been shown to be effective in lowering body mass (often in combination with proper diet and physical activity). 

However, you need to be aware that this is considered an off-label use of these drugs. FDA has not approved Rybelsus and metformin to be administered for weight management, so it’s up to your doctor to determine whether any of these medications can be included in your treatment plan with a weight loss goal in mind. 

If you want to learn more about your treatment options for weight loss, talk to your medical team.

Rybelsus Effectiveness in Type 2 Diabetes Treatment

The high effectiveness of Rybelsus in treating type 2 diabetes symptoms, in particular, high blood sugar levels, has been backed up by studies and clinical trials. 

Studies found that Rybelsus:

  • Showed a significant reduction in HbA1c in patients with type 2 diabetes versus a placebo (decrease level of 0.7% to 1.9% compared to 0.3% for placebo) (Source);
  • Was superior in reducing HbA1c than other medications, such as empagliflozin or sitagliptin, in patients with type 2 diabetes uncontrolled on metformin (Source 1, Source 2);
  • Reduced HbA1c more efficiently than placebo in patients with type 2 diabetes uncontrolled on metformin (Source); 
  • Offered significantly better results in lowering HbA1c in patients with moderate renal impairment than placebo (Source); 
  • Is well tolerated even by patients with severe hepatic impairment (Source);
  • Significantly improved fasting and post-prandial glucose metabolism, as well as delayed gastric emptying (Source).

In clinical trials, Rybelsus was proven to be effective in treating high blood sugar levels, was well tolerated by patients with a history of liver impairment and moderate renal impairment, and has shown effectiveness in supporting fasting. 

Oral semaglutide offered more effective glycemic management than other common oral glucose-lowering therapies.

Metformin Effectiveness in Type 2 Diabetes Treatment

Metformin is a known and commonly prescribed medication to treat high glucose levels in patients with type 2 diabetes. In trials, it presented a high effectiveness in the treatment, prevention, or delay of type 2 diabetes for people at high risk of developing the disease. 

We know that metformin is effective in:

  • Reducing the progression of diabetes by 31% compared to placebo in people at risk of type 2 diabetes (Source);
  • Reducing HbA1c. In clinical trials, it decreased HbA1c by up to 0.9%, compared to an increase in HbA1c by 1.2% in patients administering a placebo (Source);  
  • Increasing insulin sensitivity and suppressing the glucose production by the liver (Source);
  • Providing better glycaemic outcomes for patients who administer sulfonylurea and metformin than those who take sulfonylurea with glibenclamide (HbA1c 7.1% vs 8.7%) (Source).

Metformin is considered a safe and proven medication, and its other uses (for example, the prevention of frailty in older, prediabetic patients) are being researched.

Rybelsus vs. Metformin for Weight Loss

What about Rybelsus vs metformin for weight loss? Which of these medications presents better outcomes for the patients? 

Both Rybelsus and metformin have been shown to cause a delay in gastric emptying and a decrease in appetite. 

In clinical trials, oral semaglutide caused a reduction in energy intake, improved control of eating, promoted weight loss, and fewer food cravings (Source). The OASIS 1 trials have shown that a 50 mg dose of Rybelsus administered once a day for 68 weeks can lead to a body weight reduction of 15.1% compared to 2.4% with a placebo (Source). The trial was done on a group of adults diagnosed with obesity without type 2 diabetes. 

When it comes to metformin, researchers have found that the drug caused a body weight reduction of 2.06%- 5.65% compared to the placebo (0.02%-5.52%) in the double-blind clinical trial that was followed by a 7–8-year period of analysis of change in weight. This study also suggests that weight loss can be maintained for at least 10 years of treatment (Source). 

Another long-term study, conducted with a sample of over 3,000 people, noted an average body weight loss of 5.5 pounds in participants who were administering metformin. One-third of those on medication lost at least 5% of their body mass during the first year of the treatment. The longer the medication was administered, the better the results, with an average loss of 6.2% of body weight for long-term metformin use (Source). 

In the comparison between metformin vs Rybelsus for weight loss, the latter offers greater outcomes, both for short-term and long-term use.

Rybelsus Dosage and Administration

Rybelsus is typically administered once a day and can be taken in the form of 3 mg, 7 mg, and 14 mg pills.

The most common course of treatment starts with a 3 mg pill once a day. This dose is sustained for at least 30 days. After this time of initiation, the dose is typically increased to 7 mg a day. If further glycemic control is required, the dose can be increased to 14 mg daily.

When taking Rybelsus, it’s imperative to follow your doctor’s dosage recommendations and discuss with them any changes in the course of treatment.

Rybelsus pills should not be crushed, split, or chewed when you’re taking them. The best practice is to swallow them whole.

Metformin Dosage and Administration

Metformin dosage and administration will differ between adult and pediatric patients.

The tablets are available in strengths such as 500 mg, 750 mg, 850 mg, 1000 mg, 500 mg/5 mL, and 625 mg.

Metformin can be administered for immediate or extended-release.



Typically you start with a dose of 500 mg orally twice a day or 850 mg once a day. The dosage can be increased weekly for the lower dose of 500 mg and biweekly for 850 mg until you reach the maintenance dose of 2000 mg a day (administered in a few divided doses, taken with meals).


For extended-release, you might start with 500 to 1000 mg once a day and increase the dose by 500 mg in weekly intervals. The maximum dose is 2000 mg a day. The dosage is taken with the evening meal or divided into two doses throughout the day.



For children above the age of 10, the initial dose is 500 mg orally twice a day. It can be increased by 500 mg on a weekly basis. The maximum dose is 2000 mg a day. The daily dose should be split into smaller doses and administered with meals 2 to 3 times throughout the day.


The initial dose is 500 mg, which is taken orally once a day with the evening meal. It can be increased in increments of 500 mg on a weekly basis. The maximum dose is 2000 mg a day.

Rybelsus Side Effects

Common side effects with Rybelsus include:

  • nausea and vomiting
  • lack of or decreased appetite
  • weight loss
  • diarrhea
  • abdominal pain
  • constipation
  • indigestion
  • mild allergic reaction

There’s also a risk of experiencing more severe Rybelsus side effects, such as:

  • pancreatitis
  • kidney impairment
  • severe allergic reaction 
  • hypoglycemia
  • risk of thyroid cancer
  • vision impairment, detached retina

If you experience any of the above symptoms, it’s imperative to stop the Rybelsus treatment immediately and seek medical help. 

Metformin Side Effects

On the list of metformin side effects, we can find:

  • nausea and vomiting
  • lack of or decreased appetite
  • fever
  • diarrhea
  • abdominal pain
  • indigestion
  • gas
  • headache
  • weakness
  • mild allergic reaction

More serious metformin side effects can include:

  • low vitamin B12 levels
  • lactic acidosis
  • serious allergic reaction
  • hypoglycemia

Rybelsus and Metformin Costs Compared

In the cost comparison between metformin vs Rybelsus, the first drug is much more affordable, especially if you’re covering the costs of the medications out of pocket.

Without insurance, you can be expected to pay close to $1,300 for 30 7 mg Rybelsus tablets. However, these costs may be lower, depending on your insurance plan. Rybelsus is covered by Medicare Part D.

The average price for 30 500 mg tablets of metformin is $11 (the price without insurance). It’s partially due to the fact that metformin is often the drug of first choice for patients with type 2 diabetes.

Rybelsus vs Metformin - Final Thoughts

While having similar effects, Rybelsus and metformin are two different medications with varied mechanisms of action, different age limitations, side effects, and weight loss outcomes.    Both drugs are safe and effective in lowering blood sugar levels in type 2 diabetes patients and can support weight loss. It’s up to you and your doctor to determine which of the two can and should be included in your treatment plan. Are you looking for a way to order Rybelsus at much more affordable rates? Learn about the advantages of ordering Rybelsus from Canada, Mexico and the UK.

Comparative Analysis Table

Category Rybelsus Metformin
Generic Name Semaglutide Metformin
Drug Type GLP-1 receptor agonist Biguanide
FDA Approval Year 2019 1995
Indications and Usage Type 2 diabetes; off-label for weight loss Type 2 diabetes; off-label for weight loss
Mechanism of Action Mimics GLP-1, enhancing insulin secretion, inhibiting glucagon release, slowing gastric emptying Increasing insulin sensitivity, mitigating insulin resistance, lowers the absorption of sugar in the intestines, as well as lowers the liver’s production of sugar.
Dosage and Administration Oral tablet: starting dose typically 3 mg once daily, may increase to 7 mg and then max 14 mg Oral tablet: starting dose typically 500 mg twice a day, usually increasing to the maximum dose of 2000 mg a day.
Efficacy Effective in lowering blood sugar levels, potential weight loss benefits Effective in lowering blood sugar levels, increasing insulin sensitivity, potential weight loss benefits
Side Effects Nausea, abdominal pain, diarrhea, decreased appetite Nausea, abdominal pain, diarrhea, gas, decreased appetite
Costs Varies; can be expensive without insurance coverage Low


Does Rybelsus work better than metformin?

Both Rybelsus and metformin are effective at treating type 2 diabetes. Although they work in different ways, each has been shown to lower blood sugar levels and promote weight loss.

When it comes to Rybelsus vs metformin for weight loss, on average, better results can be achieved with Rybelsus. However, it’s important to note that both drugs can lower your body mass. Sustainable body weight loss is usually the result of administering a medication combined with lifestyle changes.

Yes, Rybelsus and metformin can be administered together. Usually, type 2 diabetes patients will be put on metformin in the first place, and other drugs, like Rybelsus, can be added to the treatment plan in instances when more extensive glucose management is required.


  1. American Diabetes Association . “Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2020.” Diabetes Care, vol. 43, no. Supplement 1, 20 Dec. 2020, pp. S98–S110, https://doi.org/10.2337/dc20-s009.
  2. Davies, Melanie, et al. “Effect of Oral Semaglutide Compared with Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients with Type 2 Diabetes.” JAMA, vol. 318, no. 15, 17 Oct. 2017, p. 1460, jamanetwork.com/journals/jama/article-abstract/2657376, https://doi.org/10.1001/jama.2017.14752.
  3. Rodbard, Helena W., et al. “Oral Semaglutide versus Empagliflozin in Patients with Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial.” Diabetes Care, 17 Sept. 2019, p. dc190883, https://doi.org/10.2337/dc19-0883.
  4. Rosenstock, Julio, 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.” JAMA, vol. 321, no. 15, 16 Apr. 2019, p. 1466, jamanetwork.com/journals/jama/fullarticle/2729339, https://doi.org/10.1001/jama.2019.2942.
  5. Pratley, Richard, et al. “Oral Semaglutide versus Subcutaneous Liraglutide and Placebo in Type 2 Diabetes (PIONEER 4): A Randomised, Double-Blind, Phase 3a Trial.” The Lancet, vol. 394, no. 10192, July 2019, pp. 39–50, https://doi.org/10.1016/s0140-6736(19)31271-1.
  6. Mosenzon, Ofri, et al. “Efficacy and Safety of Oral Semaglutide in Patients with Type 2 Diabetes and Moderate Renal Impairment (PIONEER 5): A Placebo-Controlled, Randomised, Phase 3a Trial.” The Lancet Diabetes & Endocrinology, vol. 7, no. 7, July 2019, pp. 515–527, https://doi.org/10.1016/s2213-8587(19)30192-5.
  7. Baekdal, Tine A., et al. “Pharmacokinetics, Safety, and Tolerability of Oral Semaglutide in Subjects with Hepatic Impairment.” The Journal of Clinical Pharmacology, vol. 58, no. 10, 25 Apr. 2018, pp. 1314–1323, https://doi.org/10.1002/jcph.1131. Accessed 15 Apr. 2021.
  8. Hjerpsted, Julie B., et al. “Semaglutide Improves Postprandial Glucose and Lipid Metabolism, and Delays First-Hour Gastric Emptying in Subjects with Obesity.” Diabetes, Obesity and Metabolism, vol. 20, no. 3, 27 Oct. 2017, pp. 610–619, https://doi.org/10.1111/dom.13120.
  9. Aroda, Vanita R., and Robert E. Ratner. “Metformin and Type 2 Diabetes Prevention.” Diabetes Spectrum, vol. 31, no. 4, Nov. 2018, pp. 336–342, spectrum.diabetesjournals.org/content/31/4/336, https://doi.org/10.2337/ds18-0020.
  10. Garber, Alan J., et al. “Efficacy of Metformin in Type II Diabetes.” The American Journal of Medicine, vol. 103, no. 6, Dec. 1997, pp. 491–497, www.sciencedirect.com/science/article/pii/S0002934397002544, https://doi.org/10.1016/s0002-9343(97)00254-4.
  11. Nasri, Hamid, and Mahmoud Rafieian-Kopaei. “Metformin: Current Knowledge.” Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences, vol. 19, no. 7, July 2014, pp. 658–64, www.ncbi.nlm.nih.gov/pmc/articles/PMC4214027/.
  12. Sanchez-Rangel, Elizabeth, and Silvio E. Inzucchi. “Metformin: Clinical Use in Type 2 Diabetes.” Diabetologia, vol. 60, no. 9, 2 Aug. 2017, pp. 1586–1593, link.springer.com/article/10.1007/s00125-017-4336-x, https://doi.org/10.1007/s00125-017-4336-x.
  13. Blundell, John, et al. “Effects of Once‐Weekly Semaglutide on Appetite, Energy Intake, Control of Eating, Food Preference and Body Weight in Subjects with Obesity.” Diabetes, Obesity and Metabolism, vol. 19, no. 9, 5 May 2017, pp. 1242–1251, https://doi.org/10.1111/dom.12932.
  14. Knop, Filip K, et al. Oral Semaglutide 50 Mg Taken Once per Day in Adults with Overweight or Obesity (OASIS 1): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial. 1 June 2023, https://doi.org/10.1016/s0140-6736(23)01185-6.
  15. The Diabetes Prevention Program Research Group. “Long-Term Safety, Tolerability, and Weight Loss Associated with Metformin in the Diabetes Prevention Program Outcomes Study.” Diabetes Care, vol. 35, no. 4, 22 Mar. 2012, pp. 731–737, https://doi.org/10.2337/dc11-1299.