Rybelsus vs Metformin: Which One Is Better for You?

Rybelsus or metformin: which diabetes drug is better for managing type 2 diabetes? This blog compares the two.

Sarah Zimmer, PT, DPT
— Signos
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Updated by

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Science-based and reviewed

July 19, 2024
November 16, 2023
— Updated:

Table of Contents

Type 2 diabetes is a metabolic disorder characterized by insulin resistance or insufficient insulin production, leading to unnecessary elevations in blood sugar levels. A study performed in 2020 by the Journal of Epidemiology and Global Health reported that “an estimated 462 million individuals are affected by type 2 diabetes, corresponding to 6.28% of the world’s population.”1 

In addition, the authors found “more than 1 million deaths were attributed to this condition in 2017 alone, ranking it as the ninth leading cause of mortality.”1 A disease of this severity warrants quick and effective treatment to control blood sugar levels and prevent complications. 

Pharmaceutical intervention stands as a pivotal cornerstone in the treatment of type 2 diabetes alongside lifestyle modifications such as diet and exercise. Among the arsenal of medications available, metformin and rybelsus come to the forefront, as they possess mechanisms to mitigate the physiological imbalances inherent in type 2 diabetes. They act as powerful allies, working in tandem with lifestyle modifications to maintain blood sugar levels within a healthy range and stave off the potential devastation wrought by uncontrolled diabetes. 

In this article, we'll explore the nuances, differences, and unique contributions of rybelsus and metformin, shedding light on how these pharmaceutical interventions play a crucial role in the intricate tapestry of diabetes management.


What is Rybelsus?

Rybelsus is a groundbreaking medication for managing type 2 diabetes. It belongs to the class of drugs known as GLP-1 receptor agonists. This innovative oral medication contains semaglutide, a synthetic version of a hormone naturally produced in the body. Semaglutide was initially formulated as an injectable medication for diabetes treatment. However, as it continued to show remarkable efficacy in controlling blood sugar levels and promoting weight loss, researchers aimed to create an oral version to improve accessibility for many individuals. 

In 2019, the U.S. Food and Drug Administration (FDA) approved rybelsus (oral semaglutide) for use in adults with type 2 diabetes, marking a pivotal moment in diabetes treatment history. Now, patients struggling with diabetes have a more convenient and effective option for managing their condition by taking an easily ingestible pill instead of an injectable medication. This, along with changes in diet and exercise, is proven to be an effective treatment protocol for managing type 2 diabetes and weight loss.

What is Metformin?

Metformin belongs to the class of drugs called biguanides and has served as a cornerstone in managing type 2 diabetes as well as other chronic diseases over the years.  Over the past 20 to 30 years, metformin has also been utilized in the management of polycystic ovary syndrome (PCOS), a condition marked by hormonal imbalances leading to irregular periods, excess hair growth, and fertility issues.3 Additionally, some studies have explored its potential in mitigating the risk of cardiovascular diseases and certain cancers, although more research is ongoing in these areas.4,5

The history of metformin dates back to the 1920s when the plant Galega officinalis (French lilac or goat's rue) was used in traditional European medicine for its blood sugar-lowering properties. Researchers isolated a compound called guanidine, which led to the development of metformin's precursor, the drug known as phenformin. However, phenformin was associated with severe lactic acidosis, leading to safety concerns and eventual withdrawal from many markets. 

Metformin was thus developed as the safer derivative in the 1950s and gained traction due to its efficacy in lowering blood sugar levels without the significant risk of adverse effects. It received approval for medical use in the United Kingdom in 1957 and later in the United States in 1995, becoming one of the most prescribed medications for type 2 diabetes worldwide.6 

How Does Rybelsus Work?

Rybelsus operates as a GLP-1 receptor agonist designed to manage type 2 diabetes by mimicking the actions of the hormone GLP-1 in the body. When ingested, rybelsus prompts the pancreas to release insulin in response to elevated blood sugar levels after meals, effectively lowering blood glucose levels. Additionally, it suppresses the release of glucagon, a hormone that typically raises blood sugar levels. 

By enhancing insulin secretion and reducing glucagon release,rybelsus aids in regulating blood sugar throughout the day, contributing to improved glycemic control in individuals with type 2 diabetes. This mechanism helps prevent blood sugar spikes after meals, a common concern in diabetes management.7

In addition to its effects on blood sugar control and regulation, rybelsus has shown promise in promoting weight loss in individuals with type 2 diabetes. The medication's influence on appetite control and the delay of gastric emptying contributes to reduced food intake and a feeling of fullness, leading to decreased calorie consumption and subsequent weight loss. 

This dual action of rybelsus in managing blood sugar levels while potentially aiding in weight loss makes it a valuable therapeutic option for individuals seeking both glucose control and weight management benefits in their diabetes treatment plan.8

How Does Metformin Work?

Metformin functions through several mechanisms to effectively manage blood sugar levels. It primarily works by reducing the liver's glucose production while simultaneously enhancing the body's response to insulin, thus increasing glucose uptake by cells. By diminishing excessive glucose release and improving insulin sensitivity, metformin helps maintain stable blood sugar levels in individuals with type 2 diabetes.9

Metformin may modestly contribute to weight loss or mitigate weight gain in some individuals with type 2 diabetes. While its primary function isn't specifically centered on weight loss, its ability to improve insulin sensitivity and regulate blood sugar levels might indirectly support weight management efforts, particularly in those who experience weight gain due to uncontrolled diabetes or insulin resistance. However, individual responses to metformin in terms of weight changes can vary.10

In the context of polycystic ovary syndrome (PCOS), metformin aids in addressing hormonal imbalances and insulin resistance commonly associated with the condition. PCOS often involves insulin resistance, leading to elevated insulin levels, which can contribute to irregular menstrual cycles, excess hair growth, and fertility issues. Metformin helps lower insulin levels, which, in turn, can regulate hormone levels, improve menstrual regularity, and alleviate symptoms associated with PCOS.11

Rybelsus vs. Metformin: Key Differences


Rybelsus and metformin differ in several aspects, from their formulation to usage in specific demographics. Here are the main differences:

  • Use In Children: Rybelsus is not approved for use in children with type 2 diabetes, whereas metformin is often prescribed to pediatric patients under healthcare provider supervision as an off-label use for managing diabetes in children.
  • Dosage: Rybelsus comes in an oral tablet that dissolves under the tongue and is usually taken once a day, while metformin is available in various forms, such as immediate-release or extended-release tablets, and typically requires multiple doses throughout the day.
  • Side Effects: Both medications can cause side effects, but their nature differs. Side effects of rybelsus can include gastrointestinal issues like nausea and diarrhea, while metformin commonly causes digestive disturbances, such as stomach upset and diarrhea, especially when initiating treatment.12,13 

Rybelsus vs. Metformin Efficacy

Both rybelsus and metformin have demonstrated effectiveness in managing type 2 diabetes, albeit through different mechanisms and varying efficacy profiles. Each medication helps to lower HbA1c levels, a key marker of long-term glucose control, by improving insulin sensitivity and reducing glucose levels in the blood. However, depending on your needs and medical history, rybelsus or metformin may offer additional benefits.

For example, rybelsus has exhibited potential in promoting weight loss, making it a favorable choice for individuals aiming to simultaneously manage both blood sugar levels and weight concerns. On the other hand, metformin's benefits extend beyond glycemic control; it has shown some potential in reducing the risk of cardiovascular complications (i.e., heart attacks and heart disease) and has been widely utilized in the management of polycystic ovary syndrome (PCOS), showcasing its versatility in addressing different conditions associated with insulin resistance.

Both medications offer valuable options in the armamentarium against type 2 diabetes, and their effectiveness is often assessed based on individual response and specific treatment goals. Factors such as tolerance, side effects, and patient preferences also play crucial roles in determining the most suitable medication for each individual. 

Rybelsus Side Effects

Despite its efficacy in managing type 2 diabetes, rybelsus may pose certain side effects. It's important to be aware of these potential adverse reactions, as understanding them can aid in timely recognition and management, ensuring a safer and more informed treatment experience. Most clinical trials performed on the efficacy and safety of rybelsus have found the following side effects to be the most common:14 

  • Diarrhea
  • Nausea
  • Vomiting
  • Abdominal discomfort
  • Reduced appetite
  • Constipation

As with any medication, more serious side effects can occur with the use of rybelsus.  Some animal studies have indicated an increased risk of thyroid tumors with GLP-1 receptor agonists like rybelsus. However, this risk's relevance to humans is still under investigation. In addition, there have been reports of pancreatitis in individuals using rybelsus. Symptoms may include severe abdominal pain that might radiate to the back, nausea, and vomiting. Immediate medical attention is crucial if these symptoms occur.15,16

Metformin Side Effects

Metformin may elicit several side effects, although many individuals tolerate it well if given the appropriate dosage by a healthcare professional. Again, awareness of these potential adverse reactions is essential for informed treatment, timely management, and obtaining optimal results. Here is a list of potential adverse reactions to metformin:17 

  • Diarrhea
  • Nausea and upset stomach
  • Vomiting
  • Abdominal discomfort
  • Gas
  • Weakness

Similarly to rybelsus, research studies have found a few more serious adverse reactions while taking metformin, including lactic acidosis, cardiac failure, and liver failure, especially in patients who have a pre-existing condition (i.e., COPD, CKD, etc.).17

Can You Take Rybelsus and Metformin Together?


In some cases, patients do not see sufficient blood sugar reductions by just taking metformin; thus, combining it with another blood sugar-lowering medication can be a safe option to see optimum results.14 However, consulting a healthcare professional is paramount before considering the concurrent use of rybelsus and metformin. These medications operate through different mechanisms to manage type 2 diabetes, potentially offering complementary benefits, but their interaction can influence treatment outcomes or increase the risk of adverse reactions.18

A healthcare provider's expertise is crucial in determining the most appropriate treatment plan tailored to an individual's needs. They can evaluate the patient's current health status, medications, and underlying conditions to determine the compatibility and safety of combining rybelsus and metformin. Additionally, a healthcare professional can monitor potential side effects, drug interactions, and the overall efficacy of the combined therapy, ensuring optimal diabetes management while minimizing risks.

Learn More About How to Improve Blood Sugar Health with Signos’ Expert Advice

If you have more questions about incorporating medications and addressing lifestyle habits to improve your blood sugar levels and overall health, seek the expert advice of the Signos continuous glucose monitor (CGM) and the Signos team. A CGM can give you the insights to make smarter nutrition and exercise choices, highly complementary to any prescription medication your physician provides. 

Signos offers a variety of plans to help you get started on your wellness journey while maintaining quality of care without breaking your bank account. The time to invest in your health is now! Check out more articles and information about CGMs, weight-loss strategies, and exercise tips for a well-rounded, healthy lifestyle approach. Or start now by taking this quiz to see if using Signos could help you on your weight loss and healthy lifestyle journey.

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Topics discussed in this article:


  1. Khan, M. A. B., Hashim, M. J., King, J. K., Govender, R. D., Mustafa, H., & Al Kaabi, J. (2020). Epidemiology of Type 2 Diabetes - Global Burden of Disease and Forecasted Trends. Journal of epidemiology and global health, 10(1), 107–111. https://doi.org/10.2991/jegh.k.191028.001
  2. Bando, H. (2022). Effective oral formulation of semaglutide (Rybelsus) for diabetes and obesity due to absorption enhancer development. Int J Endocrinol Diabetes, 5(1), 130.
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  12. Siavash, M., Tabbakhian, M., Sabzghabaee, A. M., & Razavi, N. (2017). Severity of gastrointestinal side effects of metformin tablet compared to metformin capsule in type 2 diabetes mellitus patients. Journal of research in pharmacy practice, 6(2), 73.
  13. Quinn, D. H. New option for the treatment of Type 2 Diabetes: Rybelsus®(oral semaglutide). Retrieved from:  https://www.pshp.org/news/486332/New-option-for-the-treatment-of-Type-2-Diabetes-Rybelsus-oral-semaglutide.htm
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About the author

Sarah is a Doctor of Physical Therapy, graduating from the University of Wisconsin Madison in 2017.

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