Rybelsus vs Metformin: Which Medication Is Better?

Ten different classes of medications are currently being used to treat type 2 diabetes. 

Within each drug class, there are usually several different medications available.

Some of the medications are older and might be more familiar to you, while the ever-growing list of newer diabetes medications can be overwhelming to try to sort out.

We’ll compare metformin, one of the older “tried and true” medications, vs Rybelsus, a newer medication that has only been on the market since 2019.

What is metformin?

Metformin is one of the most frequently prescribed first-line medications for type 2 diabetes. Metformin is the generic name that is most commonly prescribed, and the brand name for metformin is Glucophage. You take metformin orally as tablets with a dosage range of 500-2,550 milligrams daily.

Metformin is in a drug class called biguanides. Biguanides help reduce the amount of sugar your liver makes while improving insulin sensitivity, which helps reduce high blood sugar. 

There are two types of metformin – regular and extended-release (XR). You only take extended-release metformin once daily instead of 2-3 times a day.

Metformin doesn’t cause low blood sugar (hypoglycemia), which is one of its major benefits. Because it doesn’t cause low blood sugar, people with type 2 diabetes can take metformin with other medications like sulfonylureas and injectable insulin.

While metformin is most commonly used for type 2 diabetes, it’s also used to help treat polycystic ovary syndrome (PCOS) (1). Polycystic ovarian syndrome is a hormonal disorder in women, often stemming from insulin resistance. 

What is Rybelsus?

Rybelsus is an oral form of the drug semaglutide, a type of GLP-1 receptor agonist (2). The United States Food and Drug Administration (FDA) approved Rybelsus in 2019 to treat type 2 diabetes.

GLP-1 receptor agonists like Rybelsus help increase your natural insulin secretion while reducing glucagon secretion, a hormone that raises blood sugar levels. 

GLP-1 receptor agonists slow the rate of digestion, which can make you feel fuller longer after you eat. 

Delayed stomach emptying can cause weight loss. This is a potential benefit for patients with type 2 diabetes who are also overweight or obese.

Rybelsus comes in 3-, 7-, and 14-milligram tablets. The 3-milligram dosing is only used to initiate treatment and isn’t typically a therapeutic dose.

The dosing for Rybelsus is usually as follows:

• Start taking Rybelsus at a dose of 3 milligrams daily for 30 days.
• After taking the 3-milligram dose for 30 days, increase your amount to 7 milligrams daily.
• If you’re not meeting your blood sugar targets after 30 days on the 7-milligram dose, increase your Rybelsus dose to 14 milligrams daily, which is the maximum dose.

Are Rybelsus and metformin the same thing?

Rybelsus and metformin aren’t the same drugs. While they are both oral medications used to treat type 2 diabetes, they are in different classes of medications. Rybelsus is a GLP-1 receptor agonist and metformin is a biguanide. 

Metformin vs Rybelsus effectiveness for diabetes

Rybelsus

Rybelsus is unique as a GLP-1 receptor agonist because it’s the only oral medication in its drug class. The rest of the GLP-1 receptor agonists are injectable medications. 

One study noted that Rybelsus is just as effective as injectable forms of semaglutide (3). 

Metformin

According to studies, metformin effectively lowers fasting blood sugar and hemoglobin A1c levels. The reduction in blood sugar levels appears to be dose-dependent, meaning the more metformin you take, the more it can lower your blood sugar (4).

Metformin lowers blood sugar levels in both obese and non-obese patients with type 2 diabetes. One study found that hemoglobin A1c levels dropped by slightly over 1% in obese and non-obese patients after 12 months of taking metformin (5).

At maximum doses, metformin might be able to lower your A1c by as much as 1.5%.

According to a meta-analysis of 35 studies lasting at least 12 weeks, metformin tends to lower A1c levels by around 1%, whether alone or in conjunction with other diabetes medications (6).

Benefits of metformin vs Rybelsus

6 benefits of metformin

• Less expensive
• Has been successfully used to treat diabetes longer than Rybelsus
• Can be used to treat PCOS symptoms 
• Can be taken while breastfeeding
• It is considered safer than Rybelsus during pregnancy
• Has fewer rare but serious side effects compared to Rybelsus

3 benefits of Rybelsus

• Rybelsus has once-a-day dosing vs multiple daily doses of metformin (non-XR version)
• Might lower blood sugar slightly more than metformin
• Can provide similar results as injectable GLP-1 receptor agonists in an oral form

What are the side effects of each medication?

Metformin side effects

The most common side effects of metformin include:

• Heartburn
• Stomach pain
• Nausea or vomiting
• Bloating
• Gas
• Diarrhea
• Constipation
• Weight loss
• Headache
• Metallic taste in your mouth

Rarely, metformin may cause lactic acidosis if you take too much (more than prescribed). Lactic acidosis is rare, but it is very dangerous.

Rybelsus side effects

The more commonly reported side effects of Rybelsus include:

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

While rare, there is a risk of developing thyroid tumors, as well as gallbladder or kidney problems, when taking Rybelsus. You shouldn’t take Rybelsus if you have a history of thyroid cancer, pancreatitis, or kidney problems.

Which medication is cheaper?

Metformin is significantly cheaper than Rybelsus. According to GoodRx, a 30-day supply of 7-milligram tablets of Rybelsus will be $800-$900 out of pocket. A bottle of 60 pills (500 milligrams each) of metformin is under $15 out of pocket at most pharmacies, according to GoodRx.

Your cost for metformin or Rybelsus will vary if you have medical or prescription coverage, which can make your cost of medications less expensive than their out-of-pocket cost.

Ease of use for metformin vs Rybelsus

Both medications are pretty similar in terms of their ease of use. If you’re taking regular metformin and not the once-daily extended-release tablets, Rybelsus might be easier to use because of its once-daily dosing.

Metformin

• Metformin is considered safe to use while breastfeeding. It is also one of the safer medications for use during pregnancy (category B risk).
• Ideally, you should take metformin with food to reduce side effects.
• If you need to have imaging done with contrast dye, your doctor might advise you to stop taking metformin before the imaging and for 48 hours afterward. There is a small risk of developing lactic acidosis from taking metformin while receiving IV contrast, especially if you have decreased kidney function.

Rybelsus

• It’s not recommended to breastfeed while taking Rybelsus, nor is it considered a safe drug during pregnancy as it may cause fetal harm.
• Rybelsus is a good choice for people who fear needles or prefer oral medications over injections. Other GLP-1 receptor agonists like Trulicity, Ozempic, and Victoza are all injectables.
• You should take Rybelsus on an empty stomach at least 30 minutes before you eat or drink anything. This isn’t an ideal option if you prefer to eat something immediately upon waking.

Rybelsus vs metformin for weight loss

Metformin

According to a study, people taking metformin for six months lost around 13 pounds (a little over 5% of their starting body weight). Patients who were more insulin resistant lost more weight (8).

A review of over 30 clinical trials on metformin weight loss summarized that taking metformin significantly reduced both weight and BMI (9). 

Researchers determined that doses of 1,000 milligrams or 3,000 milligrams daily (the maximum typical dose is 2,550 milligrams) were the most effective doses to promote weight loss.

Rybelsus

Rybelsus is associated with weight loss, likely due to its delaying stomach emptying and boosting satiety. Some side effects, like nausea, might also promote weight loss by reducing your normal caloric intake.

 In a 52-week study, the average weight loss while taking Rybelsus (up to 14 milligrams) was around 4.4 kilograms (almost 10 pounds). Patients in that study had already been taking metformin with a stable dose (7). 

Rybelsus vs metformin for PCOS

Metformin

Metformin is commonly prescribed to treat polycystic ovary syndrome (PCOS) symptoms. While metformin isn’t FDA-approved to treat PCOS, many healthcare providers use metformin for PCOS off-label.

Polycystic ovary syndrome is one of the leading causes of infertility in women. High levels of androgens (male sex hormones) can disrupt ovulation, the process when an egg is released to be fertilized. PCOS patients typically have long, irregular menstrual cycles since they don’t ovulate very often.

Metformin helps treat the most common root cause of PCOS, which is insulin resistance. This medication helps sensitize cells to insulin which helps lower blood sugar levels. Metformin may help improve hormonal imbalances and regulate irregular menstrual cycles.

Using metformin for fertility might help increase ovulation rates in women with polycystic ovary syndrome. This could help achieve pregnancy in women who experienced infertility due to PCOS (10).

Metformin treatment has been shown to inhibit androgen production, which can help lessen some of the unwanted side effects of PCOS, like unwanted hair growth and hair loss (11).

Rybelsus

Rybelsus isn’t used to treat PCOS like metformin is. However, a small clinical trial is underway to assess Rybelsus’ potential ability to treat PCOS (12). The estimated completion of the study is in 2024.

Anecdotally, Rybelsus might help improve PCOS symptoms if the patient also has insulin resistance. However, routine treatment of women with PCOS with Rybelsus isn’t a common trend in the medical field.

Can you take metformin with Rybelsus?

You can take metformin and Rybelsus at the same time. Neither medications are high-risk of causing low blood sugar. Therefore, they can safely be used together under the supervision of the prescribing healthcare provider.

Metformin is often used along with other diabetes medications because it’s generally well-tolerated and more affordable than many newer diabetes drugs.

Natural alternatives to metformin and Rybelsus

Berberine

Berberine is a compound found in some plants and is used as a natural alternative for treating insulin resistance and high blood sugar.

According to a small study on people with metabolic syndrome (a condition that can lead to type 2 diabetes), berberine improved insulin sensitivity and reduced participants’ waist circumference (13). 

A pilot study directly compared berberine and metformin for their ability to help treat symptoms of type 2 diabetes (14). 

The researchers found that berberine produced identical results as metformin in improving blood glucose metabolism. 

Berberine can improve insulin resistance, making weight loss more achievable in some people.

Magnesium

Type 2 diabetes stems from insulin resistance, which is when your body doesn’t use insulin effectively. Both metformin and Rybelsus aim to treat insulin resistance by increasing natural insulin secretion and reducing how much sugar your body releases.

People with diabetes tend to have lower levels of magnesium in their blood compared to people without diabetes, which suggests that magnesium may play a role in the development of diabetes.

According to a study, magnesium helps improve insulin sensitivity and boosts insulin secretion, making it a good option as a natural alternative to metformin and Rybelsus (17).

Aloe vera

Aloe vera acts as an insulin secretagogue, which means it helps your body release insulin. According to animal studies on rodents, aloe vera helped stimulate insulin secretion in diabetic rats (15).

A review of nine studies concluded that oral aloe vera can significantly lower fasting blood sugar and A1c levels in humans. The average reduction in A1c levels was just over 1%, which is similar to metformin and Rybelsus. (16)

Conclusion

Rybelsus and metformin are both FDA-approved for the treatment of type 2 diabetes. Neither is meant to treat type 1 diabetes.

Some of the benefits of Rybelsus are its once-daily dosing and its slight potential advantage in blood sugar-lowering ability over metformin.

Metformin’s benefits include its affordability, effectiveness in treating PCOS symptoms, and better safety during pregnancy and lactation. Metformin is also associated with fewer rare but serious complications compared to Rybelsus.

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