The world of type 2 diabetes has been buzzing with anticipation over the first oral GLP-1 agonist to become approved and available. Oral semaglutide (Rybelsus) got the official nod from the FDA in September 2019 and is now available on pharmacy shelves.

What does this mean for the diabetes community? How similar is Rybelsus to Ozempic, injectable semaglutide? Should I expect my doctor to prescribe this for me?

Let’s go over what we have learned about this new drug from clinical trials and NovoNordisk, the drug’s manufacturer.

Rybelsus bottles lined up with a spoon and pills

How does Rybelsus work?

GLP-1 is a hormone that is released when we eat. Its job is to stimulate insulin secretion and inhibit glucagon, the hormone that notifies the liver to produce glucose. GLP-1 agonists are able to copy the action of the hormone and lower blood sugar. In addition, GLP-1 agonists slow the rate that food moves through the digestive tract, leading to a feeling of fullness. All of these actions occur when glucose is present, so the risk of hypoglycemia is low with all GLP-1 agonists. Click here for a review of injectable GLP-1 drugs.

How much will it lower A1C?

A1C is still the gold standard for measuring a diabetes drug’s effectiveness. Rybelsus was tested against multiple classes of medications for treating type 2 diabetes. The comparisons and A1C outcomes are as follows:

Rybelsus 7 mg, Rybelsus 14 mg vs placebo (diet/exercise)

When the two therapeutic doses were tested against diet and exercise alone (placebo group) over a six-month period, the 7 mg dose lowered A1C 1.2% while the 14 mg dose achieved 1.4% decrease. Interestingly, the placebo group decreased A1C 0.3%.

Rybelsus 14mg vs Empagliflozin (Jardiance) 25 mg

All patients in this trial were taking metformin and took one of the two drugs studied. Rybelsus + metformin lowered A1C 1.4% while Jardiance + metformin lowered it 0.9% during the 6-month timeframe. The fasting glucose levels decreased similarly between the two drugs, about 36 points from the start of the study.

Rybelsus 7 mg, Rybelsus 14 mg vs Sitagliptin (Januvia) 100 mg

In this trial of patients taking either metformin or metformin + sulfonylurea, either Rybelsus 7 mg, Rybelsus 14 mg or the DDP-4 inhibitor Sitagliptin 100 mg was added. The decreases in A1C were 1%, 1.3% and 0.8%, respectively.

Rybelsus 14 mg vs Liraglutide (Victoza) 1.8 mg

In this trial, patients could be on metformin plus or minus an SGLT-2 inhibitor. Rybelsus 14 mg decreased A1C 1.2% while the daily injectable liraglutide decreased A1C 1.1%.


GLP-1 hormone is known to be inactivate in the stomach, so Rybelsus is specially formulated to prevent this breakdown from happening. For maximum results, it must be taken every morning with a sip to no more than 4 ounces of water. There must then be at least a 30-minute wait before eating or drinking anything else, including other medications.  If these directions are not followed, Rybelsus will not work as well at decreasing blood sugar.

The first month of Rybelsus is dosed at 3 mg once a day. This is considered a “warm-up” dose and is not expected to lower blood sugar very much. In month two, the 7 mg tablet is used.  If the drug is well tolerated at this point and further blood sugar control is needed, 14 mg can be prescribed in month three and beyond.

Side effects and risks

The most common side effects are GI-related, such as nausea, vomiting, abdominal pain, diarrhea, and decreased appetite. In clinical trials, most of these occurred around the time doses were increased. Many people developed a tolerance to these effects and were able to continue taking Rybelsus as directed.

All GLP-1 agonists carry the risk of thyroid cell tumors, so Rybelsus also contains this Black Box Warning – “You should not use Rybelsus if you have a personal or family history of thyroid cancer.”

Pancreatitis and worsening of retinopathy were seen in a small number of study participants, so make sure your doctor is aware of these conditions if they affect you.

woman standing on a scale taking her weight

Weight loss

Determining how much a drug will cause weight loss in real-world use is never exact. In clinical trials, a decrease of 4-9 lbs. was seen over a six-month period, which is similar to the studies using injectable GLP-1 agonists.  SGLT-2 inhibitors (flozins) and metformin to a small degree, can both cause weight loss. Other diabetes drugs such as sulfonylureas, (glipizide, glyburide), pioglitazone and insulin can cause weight gain, while DPP4-inhibitors (gliptins) are weight-neutral.

In some cases, more weight loss is seen in actual use than in clinical trials because the combined effects of diet and exercise changes add up.

Cardiovascular disease

Several diabetes drugs in the GLP-1 agonist class (including Ozempic) and SGLT-2 inhibitor class of medications have proven to have cardiovascular protection in type 2 diabetes patients with established cardiovascular risk. So far, Rybelsus has shown cardiovascular safety, but the evidence isn’t strong enough yet to label it cardioprotective. The FDA is reviewing additional data from trials and is expected to revisit the topic in 2020.

Rybelsus vs. Ozempic

There are more similarities than differences between the two versions of semaglutide. Ozempic is injected subcutaneously once weekly while Rybelsus is a once-daily oral medication. The two drugs are similar in terms of A1C decrease and weight loss.  Rates of nausea and vomiting are slightly higher with Rybelsus. Ozempic has been shown to reduce cardiovascular events in people with diabetes and heart disease while Rybelsus is considered neutral in this regard.

Switching between Ozempic and Rybelsus

If you have been taking Ozempic 0.5 mg once weekly injection and want to switch to oral Rybelsus, wait seven days after your last Ozempic injection, then start either Rybelsus 7 mg or 14 mg as prescribed. There is no dose equivalent for Ozempic 1 mg, but the same switching strategy is recommended.

When switching from Rybelsus 7 mg or 14 mg to Ozempic, the 0.5 mg injection can be given the day after the last Rybelsus dose, and weekly injections should follow.

How much does Rybelsus cost?

The greatest limitation to the widespread use of Rybelsus will be the monthly cost of approximately $770. Injectable GLP-1 agonists range from $620-$920. Expect these to be in the top tier of insurance formularies; however, commercial insurance co-pay cards could bring down the monthly cost for some plans.

Place in therapy

Behind the cornerstones of lifestyle changes and metformin, type 2 diabetes treatment is individualized based on a variety of factors. The effect on weight, level of A1C reduction, cardiovascular profile, cost, hypoglycemia risk, and each drug’s unique side effect profile are all considered when choosing what’s after metformin for any particular person.

It is likely that the weight loss benefit and meaningful A1C reduction will be major factors when considering the next step in therapy. However, the high cost of another new, brand-name only diabetes drug remains a significant barrier for many people. If further cardiovascular studies prove that Rybelsus is indeed protective against heart disease, this additional advantage will position it higher in the medication selection algorithm.

Since most people prefer oral medications over injectables, all eyes will be on how well Rybelsus is tolerated and received by the diabetes community.

Let us know your experience! Have you been prescribed oral Rybelsus? What results have you seen?  If you’re interested in a comprehensive overview of type 2 diabetes, including all of the medication classes used, find one here.

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