Rybelsus for weight loss and diabetes

Rybelsus is a type 2 diabetes medication that is also being studied as a weight loss drug. It is the only medication that contains semaglutide tablets instead of injections.

The semaglutide in Ribelsus mimics a peptide in the human body that naturally suppresses appetite and lowers blood sugar after meals.

There are currently several products on the market that mimic this peptide, called glucagon-like peptide-1 (GLP-1), as well as other peptides with a similar function:

• Ozempic and Vegavi (semaglutide injections)
• KagriSema (cagrilintide + semaglutide injections)
• Saxenda and Victoza (liraglutide injections)
• Trulicity (dulaglutide injections)
• Munjaro and Zepbound (tirzepatide injections)

In contrast, Rebelsus is semaglutide tablets and is the only product from this group of peptides for weight loss and type 2 diabetes that can be taken orally, not as an injection.

Therapy with Ribelsus is possible only after consultation with qualified and experienced doctor who can issue an electronic prescription and to monitor the treatment.

In this article, you will find the most up-to-date information about Ribelssus, including effectiveness, safety, and how to use it.

What is Ribelsus?

Ribelsus contains semaglutide. This is a peptide from the group of glucagon-like peptide-1 receptor agonists (GLP-1RAs), which mimic the function of the natural hormone GLP-1.

GLP-1 is a hormone produced in the gut after eating that lowers blood sugar (by stimulating insulin release only after eating) and regulates appetite. [1].

Here's what you need to know about the basic structure of the peptide semaglutide:

• Semaglutide and active GLP-1 are peptides of 31 amino acids with 94% identical structure [2]. 
• Semaglutide differs from natural GLP-1 by several modifications, including the replacement of amino acids with others that make it more resistant to degradation. [3]. 
• In addition, a fatty acid is added to the amino acids. This way, it binds to proteins in the blood and its half-life is extended to about 7 days (165 hours). [4]. 
• In other words, the level of semaglutide in the blood and therefore its effectiveness declines quite slowly. Therefore, injectable semaglutide is administered once a week.

But the problem with oral use of GLP-1RAs, including semaglutide tablets, stems from the peptide structure of these medications, which is easily broken down by gastric juices, losing efficacy.

In Ribelssus, this problem has been solved by adding an absorption enhancer called sodium N-(8-[2-hydroxybenzoyl]amino) caprylate or SNAC [5],[6].

SNAC is a synthetic derivative of salicylic acid, classified as an N-acetylated amino acid. With its amphiphilic properties, it improves the solubility of the drug, increases the local pH and protects it from degradation [7].

Additionally, SNAC acts as an absorption enhancer, aiding transport across cell membranes, making enteric coating of the tablet unnecessary. [8].

It is important to note that not every GLP-1RA is suitable for binding to SNAC in tablet form. Semaglutide is suitable due to its low molecular weight (4113.6 Da) and extended half-life.

Tablet semaglutide has a similar half-life (about a week) to the injectable form, but is dosed daily. Ribelsus is approved in doses up to 14 mg/day to reduce variations in semaglutide blood levels, as the risk of fluctuations is higher with oral medications.

What are Ribelssus and other forms of semaglutide approved for?

The development of semaglutide as tablets and the creation of Ribelsus aims to improve convenience, acceptance and adherence to therapy and offer an effective alternative to injections in type 2 diabetes.

Here is a brief timeline of what approvals semaglutide went through, leading up to its approval as semaglutide tablets:

• Semaglutide was discovered and patented by the Danish pharmaceutical company Novo Nordisk in 2012. 
• Semaglutide received its first approval for human use by the U.S. Food and Drug Administration (FDA) in 2017 as an injection under the trade name Ozempic. [9]. 
  You can read all about Ozempic here..
• In 2018, semaglutide (Ozempic) was also approved by European Medicines Agency (EMA) as an injection for second-line therapy in patients with type 2 diabetes. 
• Later, semaglutide (Ozempic) was approved by both the FDA and EMA for reducing cardiovascular risk in type 2 diabetes, as well as for treating diabetes at higher doses (up to 2 mg/week). [5].
• During the period 2021-2023, semaglutide was approved by both the FDA and the EMA in an even higher dose (2.4 mg/week) as an injection for weight loss in BMI>27 under the name Vegovi. Initially, it was approved only for adults, and then for adolescents over 12 years of age with overweight [10].
• Ribelsus was approved by the FDA in 2019 and by the EMA in 2020 as the first-of-its-kind oral GLP-1RA for the treatment of type 2 diabetes [6]. 

Currently, Ribesus remains officially approved only for type 2 diabetes, although it has also shown significant effectiveness for weight loss and is sometimes even prescribed off-label for this purpose. [6].

For this reason, Ribelsus is currently being tested in phase 3 weight loss trials in people without diabetes, and these studies could lead to its approval as a weight loss medication as well.

Currently, Ribesus and Ozempic (and soon Vegavi) are available in Bulgaria only by prescription.

How does Ribelsus work?

Thanks to SNAC, Ribelssus is delivered through the digestive system and into the bloodstream, where it exerts effects that have identical mechanisms to those observed after subcutaneous administration. [11].

For this reason, both injectable and oral semaglutide suppress appetite and induce weight loss among patients with T2D.

For example, it activates GLP-1 receptors in the pancreas, which increases insulin secretion (glucose-dependent), suppresses glucagon release, and suppresses hepatic gluconeogenesis. [11]. This leads to a net reduction in blood sugar levels and improved glycemic control.

Furthermore, the weight loss potential of Ribelssus is primarily due to its interaction with GLP-1 receptors in the brain, but also with the digestive system and white adipose tissue. Semaglutide contributes to appetite control by activating neurons in the hypothalamus, an area of the brain responsible for regulating feelings of satiety and hunger. [12].

Ribelsus also interacts with GLP-1 receptors in the gut, significantly reducing gastric emptying with 38% after a meal. [13]. It also stimulates the release of peptide YY 3-36 (PYY) from endocrine cells located in the small intestine. PYY is another appetite suppressant hormone. [14].

Studies have shown that GLP-1RAs, like semaglutide, can counteract the decline in free leptin production by white adipose tissue. This decline in leptin levels often accompanies weight loss efforts. By addressing this issue, semaglutide may help maintain a healthy leptin balance in the body and make it easier to maintain weight loss. [14].

How effective is Ribelsus in type 2 diabetes?

Ribelssus is approved for the treatment of type 2 diabetes thanks to impressive results from phase 3 studies in the PIONEER (Peptide Innovation for Early Diabetes Treatment) program [11].  

This program was initiated by Novo Nordisk and includes fifteen parallel, randomized, controlled trials conducted only in patients with type 2 diabetes (PIONEER 1-12, PIONEER TEENS, PIONEER PLUS and PIONEER REAL) [11],[15],[16].

These studies compared three different doses of Ribelsus (3 mg/day, 7 mg/day, 14 mg/day) with placebo, oral antidiabetic medications, and the EMA-approved injectable GLP-1 receptor agonists liraglutide and dulaglutide. 

According to the data, Ribelsus shows similar or even greater effectiveness in glycemic control compared to these established treatments. Here are some of the most interesting studies:

• The largest trial in the program is PIONEER-3, which included 1,864 participants with type 2 diabetes and followed them for 26 weeks. It compared Ribelsus with a diabetes drug (the DPP-4 inhibitor sitagliptin) and found that Ribelsus was significantly more effective in both lowering HbA1c and weight loss. [17].
• PIONEER-4 showed that the effect of Ribelsus on lowering HbA1c was comparable to that of the approved dose of liraglutide (Victoze) for type 2 diabetes (1.8 mg/day). Specifically, Ribelsus reduced HbA1c by 1.21%, the same as liraglutide, while the placebo group showed little improvement. [18].
• Pooled results from the PIONEER program show that Ribelssus reduced HbA1c by an average of -1.5% and supported weight loss by an average of -5kg. About 70% of participants with diabetes achieved a target HbA1c of less than 7% [19].
• PIONEER PLUS, which included 1,606 participants, investigated the effectiveness of higher doses of Ribelsus (25 mg/day and 50 mg/day). Over 52 weeks, Ribelsus resulted in a reduction in HbA1c of -1.5% at a dose of 14 mg/day, -1.8% at a dose of 25 mg/day, and -2.0% at 50 mg/day. [15].

How effective is Ribelsus for weight loss?

Although Ribesus is not yet approved for weight loss, Novo Nordisk is actively conducting a clinical program called OASIS with the aim of demonstrating its effectiveness in this area. 

The first of four studies has already been published, presenting promising results:

• OASIS-1: This study found that in people who were overweight or obese but did not have diabetes, Ribelsus could lead to significant weight loss. The study involved over 600 people. Those taking Ribelsus at a dose of 50 mg/day for 68 weeks achieved an impressive reduction in body weight of 15.11TB3T from baseline, while the placebo group lost only 2.41TB3T. [20].

In addition, studies in diabetics from the PIONEER program also demonstrate the effectiveness of Ribelsus for weight loss:

• PIONEER-4: In this study of diabetics, semaglutide (the active ingredient in Ribelsus) resulted in an average weight loss of 9.7 lb (4.4 kg) after 26 weeks of treatment at 14 mg daily. In comparison, patients treated with liraglutide (1.8 mg daily) lost an average of 6.8 lb (3.1 kg) and those on placebo lost only 1.1 lb (0.5 kg). [18]. 
• PIONEER PLUS: The study shows that in diabetics, higher doses of 25 mg/day and 50 mg/day of semaglutide, which are not yet approved, can lead to even greater weight loss – 14.7 lb (6.7 kg) and 17.6 lb (8 kg), respectively, over a 52-week period. This compares to a reduction of 9.7 lb (4.4 kg) with the standard dose of 14 mg/day. Given that the average weight of the participants was 212.5 lb (96.4 kg), the highest dose of semaglutide resulted in about 8.2% weight loss [15]. 

Ribelsus to reduce cardiovascular risk

Ribelsus may reduce cardiovascular risk in patients with type 2 diabetes, similar to its injectable form, which the FDA and EMA have already approved for this purpose.

This is supported by the results of the PIONEER-6 study, which included patients with type 2 diabetes, 85% of whom had established cardiovascular disease. The study aimed to compare the safety of Ribelssus with placebo. [21].

The results showed that cardiovascular problems occurred in 3.81% of patients receiving Ribelsus (1,591 subjects) and in 4.81% of patients in the placebo group (1,592 subjects).

This suggests that Ribelsus is associated with a lower risk of death from cardiovascular causes (risk was 0.91% CI 3.00-3.00 in the Ribelsus group versus 1.91% CI 3.00-3.00 in the placebo group). Overall mortality was lower in the Ribelsus group compared to the placebo group (1.41% CI 3.00-3.00).

Given these results, scientists decided to launch an even larger study called SOUL (Semaglutide Cardiovascular Outcomes Trial). [22].

SOUL is a study in people with type 2 diabetes and high cardiovascular risk, that is, patients with established atherosclerotic cardiovascular disease, chronic kidney disease, or both.

It included 9,650 people from 33 countries, randomized 1:1 to Ribelssus or placebo, on standard therapy. The dose was escalated from 3 mg to 7 mg, then 14 mg, and the median follow-up was 49.5 months.

SOUL showed that oral semaglutide is not only an antidiabetic drug, but also has proven cardiovascular benefits.

The primary endpoint was the standard 3-point MACE, i.e. a composite endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.

An event occurred in 12.01% of patients on semaglutide versus 13.81% on placebo, representing an approximately 141% relative risk reduction for major cardiovascular events.

How is Ribelsus dosed?

Despite its long half-life, Ribelssus is taken daily. The currently approved dosing regimen is as follows: [23]:

• 3 mg/day for at least 30 days.
• 7 mg/day for at least 30 days or as a maintenance dose.
• If adequate HbA1c control is not achieved after at least 30 days of 7 mg/day, the dose may be increased to 14 mg/day.

Dose increases may be made more slowly than once every 30 days. The currently approved maximum dose is 14 mg/day, but clinical trials are actively investigating the safety and effectiveness of doses of 25 mg/day and 50 mg/day.

It is extremely important to take Ribelsus early in the morning on an empty stomach, as otherwise its absorption is significantly reduced. After taking the medicine, food should not be consumed for at least 30 minutes.

If you miss taking your dose in the morning before eating, do not make up for it; just take the next dose the next morning.

What are the side effects of Ribelsus?

Ribelsus has similar side effects to those of injectable GLP-1 receptor agonists, including Ozempic and Victoza. Both drugs cause typical side effects, mainly related to gastrointestinal disturbances. [24].

According to data from the PIONEER-4 study, the incidence of adverse reactions with Ribelsus is similar to that of injectable GLP-1 receptor agonists such as Victoza (liraglutide 1.8 mg/day). The adverse reactions observed in more than 51% of subjects taking 14 mg/day of Ribelsus are as follows: [18]:

• Nausea: 20%
• Diarrhea: 15%
• Vomiting: 9%
• Headache: 9%
• Constipation: 8%
• Abdominal pain: 6%
• Digestive problems: 6%

Both Ribelsus and Victoza resulted in more serious adverse events in 81% of participants. The researchers also found that 111% of participants in the Ribelsus group, 91% in the liraglutide group, and 41% in the placebo group discontinued treatment prematurely due to adverse events, most of which were related to gastrointestinal disturbances. [18].

Is Ribelsus safe?

Contraindications for Ribelssus are the same as for injectable GLP-1 receptor agonists. The use of the drug should be avoided in certain situations, such as pregnancy, breastfeeding, or in individuals with a history of certain types of cancer. [24].

In particular, Ribelsus should not be used in individuals with a history of thyroid cancer or multiple endocrine neoplasia type 2 (MEN 2) syndrome. These contraindications are based on studies in rats that have shown an increased risk of thyroid C-cell carcinoma. It is important to note that this increased risk has not yet been confirmed in humans. [24].

Ribelsus or Ozempic for weight loss?

Ribesus and Ozempic are two versions of the same active ingredient used to treat type 2 diabetes and aid weight loss. While Ribesus is not yet specifically approved for weight loss, ongoing clinical trials such as the OASIS program are showing promising results in this area.

Weight loss effectiveness:

• Ribelsus: In the OASIS-1 study, in overweight or obese people without diabetes, taking Ribelsus at a dose of 50 mg/day, combined with lifestyle changes, resulted in an average weight loss of 15.1% after 68 weeks. [20]. However, currently Ribelssus is only available on the market in doses up to 14 mg/day, which results in about 4–5 kg loss in 26 weeks in diabetics. [18].
• Ozempic: In studies with semaglutide at doses of 1 mg/week and 2 mg/week, without lifestyle changes, an average weight loss of about 6.7 kg was reported in patients with type 2 diabetes. [25]. Doses of 2.4 mg/week (Vegovi), combined with lifestyle changes, result in 14.9% weight loss over the same period [26].

Effectiveness in diabetes:

• Ribelsus: In the PIONEER PLUS study, diabetic patients taking 50 mg/day of Ribelsus lost an average of 8 kg over 52 weeks and achieved a reduction in HbA1c to 2% [15].
• Ozempic: In patients with diabetes, the drug demonstrated a reduction in HbA1c to 2.2% at a dose of 2 mg/week for 68 weeks [25].

Safety and side effects:

• Ribels: In some studies, adverse reactions were reported in about 70–80% of participants [18].
• Ozempic: Overall incidence of adverse reactions is below 60% according to most studies [25]. 

Both Ribesus and Ozempic are effective in improving glycemic control and aiding weight loss. 

Ozempic may offer slightly better results in lowering HbA1c and weight loss, especially when compared to the lower 14 mg/day dose of Ribesus. In addition, Ozempic has a lower incidence of adverse reactions. 

For patients who prefer oral administration or avoid injections, Ribelsus provides a convenient and effective alternative. The choice between the two preparations should be made in conjunction with a healthcare professional, taking into account the patient's individual needs and preferences.

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