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The Centers for Disease Control and Prevention (CDC) revealed that 90 to 95% of people with diabetes in the US have type 2 diabetes, while only 5% have type 1 diabetes. Research shows that keeping blood sugar levels stable over time can lower the chances of complications for people with type 2 diabetes.

Fortunately, diabetes management has advanced significantly with the introduction of innovative medications like Rybelsus and Ozempic. Both have demonstrated efficacy in lowering blood sugar levels and reducing the risk of cardiovascular events in patients with type 2 diabetes.

In this article, we’ll explore how effective, safe, and distinctive Rybelsus and Ozempic are in treating diabetes.

What is the Difference Between Rybelsus and Ozempic?

Rybelsus Bottle and Tablets and Ozempic Pen

Parameters Ozempic Rybelsus
Cost (manufacturer’s suggested retail price) $935.77 per month $935.77 per month
Active ingredient Semaglutide Semaglutide
Approved indications Adults with type 2 diabetes, including those with known heart conditions. Adults with type 2 diabetes
Route of administration Subcutaneous (under the skin) Oral
Effectiveness After 30 weeks, participants on 0.5 mg and 1.0 mg lost 8.23 lbs and 9.99 lbs, respectively. At the same time, HbA1c levels decreased significantly by 1.45%. After 26 weeks, participants on 7 mg and 14 mg lost 2.2 lbs and 5.7 lbs, respectively. At the same time, HbA1c level reductions ranged from 0.6% to 1.1%.
Side effects Nausea, vomiting, diarrhea, abdominal pain, and constipation. Nausea, abdominal pain, diarrhea, decreased appetite, vomiting, and constipation.
Dosage and administration Begins with a 0.25 mg weekly injection, which may increase to 0.5 mg weekly, with a maximum of 2 mg weekly. Begins with 3 mg once daily taken orally, which may increase to 7 mg after 30 days, with a maximum of 14 mg daily.
Onset of efficacy 4 to 5 months 4 to 5 months

Efficacy

The effectiveness of once-weekly subcutaneous semaglutide (Ozempic) and once-daily oral semaglutide (Rybelsus) has been studied in the global Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) and Peptide Innovation for Early Diabetes Treatment (PIONEER) phase III clinical trial programs.

The primary endpoint of these trials was the change in mean Hemoglobin A1c (HbA1c), and the confirmatory secondary endpoint was the change in mean body weight.

These trials looked into various clinical situations, including early type 2 diabetes (T2D) managed with diet and exercise, more established T2D cases not controlled with one to three oral antidiabetic drugs, and advanced cases treated with insulin.

Does Ozempic work for weight loss?

Across the SUSTAIN program, once-weekly subcutaneous semaglutide 1.0 mg lowered HbA1c by 1.5–1.8% over 30–56 weeks, which was significantly better than sitagliptin, liraglutide, exenatide extended release, dulaglutide, canagliflozin, or insulin glargine.

For its secondary endpoint, subcutaneous semaglutide led to more significant weight loss than all active comparators. Below are investigations that highlight the efficacy of Ozempic for weight loss:

  • SUSTAIN 1: Over 30 weeks, those on 0.5 mg and 1.0 mg lost 8.23 lbs and 9.99 lbs, respectively, while those on placebo lost 2.16 lbs.
  • SUSTAIN 2: Semaglutide 0.5 mg and 1.0 mg led to reductions of 9.48 lbs and 13.45 lbs, respectively, while sitagliptin users experienced an average reduction of 4.19 lbs.
  • SUSTAIN 3: After 56 weeks, mean body weight (211.2 lbs at baseline) decreased by 12.35 lbs with semaglutide and 4.19 lbs with exenatide ER.
  • SUSTAIN 4: At week 30, semaglutide at doses of 0.5 mg and 1.0 mg resulted in weight reductions of 7.65 lbs and 11.39 lbs, respectively, while patients on insulin glargine experienced a weight gain of 2.54 lbs.
  • SUSTAIN 5: Mean body weight decreased with semaglutide 0.5 and 1.0 mg vs. placebo from baseline to end of treatment by 8.16 lbs, 14.11 lbs, and 3.09 lbs, respectively.

Does Rybelsus cause weight loss?

In the PIONEER program, once-daily oral semaglutide 14 mg reduced HbA1c by 1.0–1.4%, significantly more than sitagliptin or empagliflozin, and comparable to liraglutide after 26 weeks.

Moreover, oral semaglutide resulted in more weight loss than sitagliptin and liraglutide, and to a similar extent as empagliflozin. Here are the trials that highlight the efficacy of Rybelsus for weight loss:

  • PIONEER 1: Participants on the 7 mg dose lost 2.0-2.2 lbs, while those on the 14 mg dose experienced weight loss of 5.1-5.7 lbs.
  • PIONEER 2: While there were no significant differences in body weight reduction between oral semaglutide and empagliflozin at week 26 using either estimand, oral semaglutide demonstrated superior efficacy at week 52 when evaluated by the trial product estimand (10.4 lbs vs. 8.4 lbs). Additionally, reductions in waist circumference were consistently greater with oral semaglutide compared to empagliflozin.
  • PIONEER 3: For the treatment policy estimand, the estimated mean changes from baseline in body weight at week 26 for 3 mg, 7 mg, and 14 mg oral semaglutide vs. sitagliptin are 2.6 lbs, 4.9 lbs, and 6.8 lbs vs. 1.3 lbs.
  • PIONEER 4: At week 26 (policy estimand), oral semaglutide resulted in superior weight loss compared to both liraglutide (9.7 lbs vs. 6.8 lbs) and placebo (9.7 lbs vs. 1.1 lbs). When using the trial product estimand, oral semaglutide resulted in about 3.3 lbs greater weight loss than liraglutide and approximately 8.8 lbs greater weight loss than placebo.
  • PIONEER 5: Participants taking oral semaglutide experienced a mean weight loss of 7.5 lbs, whereas those on placebo had 2.0 lbs, based on treatment policy estimand. Under the trial product estimand, participants on oral semaglutide lost 8.2 lbs, while those on placebo had lost 2.4 lbs

Neither form of semaglutide was linked to a higher risk of hypoglycemia, and both improved various aspects of health-related quality of life. Semaglutide is highly effective in both injectable and oral forms.

Definition

  • Treatment Policy Estimand: This estimand focuses on the treatment’s effects as they would occur under real-world conditions, considering factors such as treatment adherence, discontinuation, and switching.
  • Trial Product Estimand: This estimand focuses on the treatment’s effects as they would occur under ideal conditions, without considering factors like treatment discontinuation or non-adherence.

Side Effects

Since Ozempic and Rybelsus contain the same active ingredient, they also share the same side effects. In separate placebo-controlled trials, the adverse reactions that occurred in at least 5% of patients treated with Ozempic and Rybelsus include:

Common Side Effect Ozempic Rybelsus
Nausea 15.8-20.3% 11-20%
Abdominal Pain 5.7-7.3% 10-11%
Diarrhea 8.5-8.8% 9-10%
Decreased appetite Not indicated 6-9%
Vomiting 5-9.2% 6-8%
Constipation 3.1-5% 5-6%

Other gastrointestinal adverse reactions in Ozempic and Rybelsus include dyspepsia, eructation, flatulence, gastroesophageal reflux disease, and gastritis. Both medications have a higher occurrence of such reactions compared to placebo.

Notably, more patients discontinued treatment due to gastrointestinal adverse reactions with Rybelsus 7 mg (4%) and Rybelsus 14 mg (8%) compared to Ozempic 0.5 mg (3.1%) and Ozempic 1 mg (3.8%).

Other side effects that Ozempic and Rybelsus share include:

  • Hypoglycemia: Low blood sugar is more frequent when Ozempic or Rybelsus are combined with insulin secretagogues (e.g., sulfonylureas) or insulin. For instance, severe hypoglycemia occurred in 0.8% and 1.2% of patients when Ozempic 0.5 mg and 1 mg, respectively, were co-administered with sulfonylurea.

Signs and symptoms of low blood sugar may include:

  • dizziness or light-headedness
  • blurred vision
  • anxiety, irritability, or mood changes
  • sweating
  • slurred speech
  • hunger
  • confusion or drowsiness
  • shakiness
  • weakness
  • headache
  • fast heartbeat
  • feeling jittery
  • Increases in amylase and lipase: Ozempic and Rybelsus were found to impact pancreatic enzyme levels. However, the magnitude of the effect differed between them.

In the Ozempic study, patients exposed to the medication showed a mean increase from baseline in amylase of 13% and lipase of 22%, with no such changes observed in the placebo-treated group.

Conversely, in the Rybelsus study, patients receiving 7 mg and 14 mg showed a mean increase from baseline in amylase of 10% and 13%, respectively, and lipase of 30% and 34%, respectively. Again, no significant changes were observed in the placebo-treated group.

  • Cholelithiasis (Gallstones): In the Ozempic study, cholelithiasis was reported in 1.5% and 0.4% of patients treated with Ozempic 0.5 mg and 1 mg, respectively, while it was not reported in placebo-treated patients.

Meanwhile, in the Rybelsus study, cholelithiasis was reported in 1% of patients treated with Rybelsus 7 mg, with no occurrences reported in those treated with Rybelsus 14 mg or placebo.

  • Increased heart rate: Both Ozempic 0.5 mg and 1 mg resulted in a mean increase in heart rate of 2 to 3 beats per minute, whereas placebo-treated patients experienced a mean decrease in heart rate of 0.3 beats per minute.

At the same time, both Rybelsus 7 mg and 14 mg led to a mean increase in heart rate of 1 to 3 beats per minute, with no change observed in placebo-treated patients.

Side effects that were experienced only by Ozempic-treated individuals are:

  • Injection site reactions: Adverse reactions at the injection site, such as discomfort or redness, were documented in 0.2% of individuals treated with Ozempic.
  • Fatigue, dysgeusia, and dizziness: Ozempic also elicited these side effects, occurring at rates greater than 0.4%.

Ozempic and Rybelsus may also have potential risks or safety concerns that users need to be aware of, such as:

  • Pancreatitis
  • Diabetic Retinopathy
  • Acute Kidney Injury
  • Risk of Thyroid C-Cell Tumors
  • Hypersensitivity

Active Ingredient and Mechanism of Action

Ozempic and Rybelsus both contain semaglutide, a medication belonging to the class of glucagon-like peptide-1 receptor agonists (GLP-1 RAs). These drugs mimic the hormone GLP-1’s action within the body, which is naturally produced in response to food intake.

GLP-1 helps regulate blood sugar levels by stimulating insulin release, reducing glucagon secretion (which lowers blood sugar), slowing gastric emptying, and promoting a feeling of fullness or satiety.

Acting as GLP-1 receptor agonists, both Ozempic and Rybelsus enhance these effects, leading to improved blood sugar control, reduced appetite, and potential weight loss.

Approved Indications

Doctor Writing Prescription for Senior patient

Semaglutide is the only GLP-1RA available in both injectable and oral forms. The US Food and Drug Administration (FDA) approved once-weekly subcutaneous semaglutide in December 2017, followed by the European Medicines Agency in February 2018.

Meanwhile, once-daily oral semaglutide gained approval in the US in September 2019 and in Europe in April 2020. It was believed that an oral version might make using GLP-1RA therapy easier and more acceptable, potentially helping more patients reach their blood sugar goals, especially those hesitant to start injectable medications.

Is Ozempic/Rybelsus approved for weight loss?

No. The FDA approved Ozempic and Rybelsus as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Moreover, Ozempic has an additional indication.

In January 2020, The FDA approved Ozempic to reduce the risk of major adverse cardiovascular events (MACE) such as heart attack, stroke, or death in adults with type 2 diabetes and known heart disease.

The approval was based on findings from the SUSTAIN 6 trial. Over the 2-year trial, Ozempic significantly decreased the risk of experiencing cardiovascular death, non-fatal heart attack, or non-fatal stroke by 26% compared to placebo.

In contrast, oral semaglutide (Rybelsus) was found to show only a trend towards MACE reduction. The PIONEER 6 trial, which focused on the cardiovascular safety of oral semaglutide, successfully demonstrated that semaglutide was noninferior to placebo in terms of cardiovascular safety. However, it lacked the statistical power to prove superiority definitively.

Additional research is underway to determine if oral semaglutide treatment can achieve positive outcomes on MACE similar to its injectable form.

Dosage and Administration

The primary difference between Ozempic and Rybelsus is their dosage and administration.

Ozempic

Injecting Ozempic into Arm

Patients typically start with a 0.25 mg injection once weekly for four weeks to begin treatment, followed by an increase to 0.5 mg once weekly.

If further regulation of blood sugar is necessary following a minimum of four weeks on the 0.5 mg dosage, the dose may be increased to 1 mg administered once weekly. The maximum recommended weekly dose is 2 mg.

Rybelsus

Woman in white t-shirt holding white pills in cupped hand and water glass in hand closeup

To begin Rybelsus treatment, patients are instructed to start with a 3 mg dose once daily for the first 30 days. This initial dose of 3 mg is specifically designed for treatment initiation and is not sufficient for glycemic control.

After 30 days on the 3 mg dose, the dosage should be increased to 7 mg once daily. If further improvement in glycemic control is necessary after at least 30 days on the 7 mg dose, the dose may be increased to 14 mg once daily.

Taking two 7 mg Rybelsus tablets to achieve the 14 mg dose is not recommended.

Comparing the dosing schedule of Ozempic and Rybelsus:

Medication Starting Dose Titration Dose Maximum Dose
Month 1 Month 2 Month 3 Month 4 Month 5+
Ozempic (subcutaneous semaglutide) 0.25 mg once weekly 0.25 mg per week 0.5 mg per week 0.5-1.0 mg per week 1.0-2.0 mg per week 1.0-2.0 mg per week 2.0 mg once weekly
Rybelsus (oral semaglutide) 3 mg once daily 3 mg once daily 7 mg once daily 7-14 mg once daily 14 mg once daily

Fun Fact

A survey of 600 patients compared preferences for once-daily oral semaglutide and once-weekly injectable GLP-1RA. Initially, more patients favored the oral treatment (77% vs 24%), but preference shifted after receiving detailed dosing information.

Preferences may vary by region. For instance, a survey of Japanese patients showed that about 90% preferred once-daily oral semaglutide over once-weekly injectable dulaglutide.

Cost

Ozempic and Rybelsus share the same price point. In the US, they’re both priced at $935.77 per package. Due to their high costs, getting these medications can be financially challenging without insurance. Many individuals in the US seek more affordable options, often turning to Canadian pharmacies like Pharma Giant.

At Pharma Giant, customers can save up to 90% on prescription medications such as Ozempic and Rybelsus. Customers can also enjoy additional discounts and offers when ordering larger quantities. New customers can use the coupon code PGSAVE10 for a 10% discount on their first order.

Pharma Giant promises expedited delivery, with medications typically arriving within 3-5 business days. Strict measures are taken to package temperature-sensitive medications securely.

For reference, here’s a price comparison of common weight loss drugs available on Pharma Giant with those found in online pharmacies in the US:

Brand Name Pharma Giant Walgreens CVS Pharmacy Rite Aid
Ozempic $419 $1,141 $1,131 $1,250
Rybelsus $297 $1,127.47 $1,003 $1,058.41
Victoza $250 $969 $656 $737
Trulicity $282 $1,106 $1,167 $1,263

Data Source: GoodRx and SingleCare

Onset of Efficacy

Individual factors such as physical activity, diet, and overall health can influence the effectiveness of Rybelsus or Ozempic and impact how quickly the medications begin to take effect.

Since Ozempic and Rybelsus have the same active ingredient, they both take 4 to 5 weeks to reach a steady level in the system.

Researchers conducted population pharmacokinetic and exposure-response analyses to explore whether administering semaglutide orally instead of subcutaneously affected its effectiveness and tolerability.

Their findings revealed that higher levels of semaglutide in the body were associated with greater reductions in HbA1c and body weight, regardless of the administration route. However, it was observed that the oral intake of semaglutide resulted in reduced bioavailability, meaning that the body absorbed less of the medication compared to when it was administered subcutaneously.

Since the drug level in the bloodstream may fluctuate more with oral administration than with subcutaneous injection, this might influence how quickly and consistently the medication begins to work. However, further research is needed to fully understand the impact of these differences on the onset of efficacy.

According to the Mayo Clinic, the effects of semaglutide, including changes in appetite and weight loss, can begin within the first week of use, with most weight loss typically occurring within the initial 4 to 5 months.

Rybelsus vs. Ozempic: Which One Should You Take?

Both forms of the semaglutide work similarly well, but there are different factors to consider when choosing between Ozempic and Rybelsus. Some patients, for instance, are hesitant to start injectable treatments due to concerns about injection pain.

Likewise, doctors may have reservations about prescribing injectable treatments, fearing that patients won’t adhere to the treatment plan.

For patients who are hesitant about injections like Ozempic, oral semaglutide might be a better option. However, patients must follow specific instructions for oral semaglutide (Rybelsus) to work effectively. These instructions include taking the tablet as soon as waking up, on an empty stomach, with a small sip of water. Neglecting these instructions may compromise the medication’s efficacy.

Eventually, the decision regarding which formulation to use depends on the patient’s preferences and requirements.

Frequently Asked Questions

It’s difficult to definitively say whether Rybelsus is better than Ozempic as no head-to-head studies have compared these medications. While Rybelsus showed numerically greater reductions in HbA1c compared to Ozempic 0.5 mg in a network meta-analysis, there was no statistical difference between Rybelsus 14 mg and Ozempic 1.0 mg. Additionally, weight loss with Rybelsus was not significant compared to Ozempic 0.5 mg and 1.0 mg.

Rybelsus and Ozempic are priced similarly. However, the cost of Rybelsus and Ozempic may vary depending on factors such as insurance coverage, pharmacy discounts, and dosage.

Patients currently taking Rybelsus 14 mg daily can switch to Ozempic subcutaneous injection at a dosage of 0.5 mg once weekly. They can start Ozempic the day after their last Rybelsus dose. Conversely, patients on once-weekly Ozempic 0.5 mg subcutaneous injection can transition to Rybelsus at dosages of 7 mg or 14 mg. They can start Rybelsus up to 7 days after their last Ozempic injection. Note that there is no equivalent Rybelsus dose available for Ozempic 1 mg.

Aetna’s policy on Ozempic coverage does not specifically mention prediabetes as a qualifying condition for coverage. The criteria outlined in the policy focus on patients with type 2 diabetes mellitus who have either demonstrated a reduction in A1c with GLP-1 Agonist therapy, experienced an inadequate response to metformin, or require combination therapy with an A1c of 7.5% or greater. Therefore, Aetna’s coverage for Ozempic may not extend to individuals solely diagnosed with prediabetes. It’s recommended to consult directly with Aetna or review your plan documents for precise coverage details related to prediabetes.

Rybelsus and Ozempic are both medications containing the active ingredient semaglutide, albeit in different formulations. Rybelsus is an oral tablet, while Ozempic is administered via subcutaneous injection. Consequently, their side effects, mechanism of action, and treatment outcomes closely resemble each other.

Insurance coverage is commonly provided when Ozempic is prescribed to manage type 2 diabetes and associated cardiovascular risks. However, if Ozempic is prescribed specifically for weight loss purposes, insurance coverage is often not extended.

According to the prescribing information of both drugs, listed under the limitations of use, neither Ozempic nor Rybelsus is indicated for patients with type 1 diabetes.

Medications like Ozempic can lead to a weight loss plateau, where further weight reduction slows or halts. Similar to other methods of healthy weight loss, the body eventually stabilizes at a suitable weight, which may align with the individual’s weight loss objectives or not.

While Ozempic lacks FDA approval for weight loss treatment, Wegovy, containing higher semaglutide levels, holds FDA approval for chronic weight management. Eligible individuals include those with a body mass index (BMI) of 30 or higher, or 27 or higher in the presence of a weight-related health condition.

While Ozempic is generally associated with weight loss due to its mechanism of action, some individuals have reported weight gain while taking this medication. Although weight gain is not a common side effect of Ozempic, it can occur in certain patients. Various factors beyond the medication itself, such as lifestyle choices, dietary habits, and levels of physical activity, may contribute to weight gain while on Ozempic. While it might appear that Ozempic directly causes weight gain, it could be indirectly influencing these other factors, leading to changes in weight. Monitor any changes in your weight while taking Ozempic and discuss them with your healthcare provider. This will help identify any underlying causes and develop an appropriate management plan.

Rybelsus is specifically indicated for the treatment of type 2 diabetes and is not approved for use in individuals who do not have diabetes.

Taking Rybelsus and Ozempic together is not recommended as they both belong to the same class of medications. Using them together may increase the risk of side effects and may not provide additional benefits beyond what each medication offers.

While it’s not specifically indicated for weight loss, many people may experience weight loss as a side effect of taking Ozempic. The weight loss effect is believed to occur due to the medication’s action on the appetite control center in the brain, leading to reduced feelings of hunger and increased feelings of fullness. Additionally, Ozempic can help regulate blood sugar levels, which may indirectly contribute to weight loss in some individuals with type 2 diabetes. However, individual responses to the medication can vary, and not everyone will experience weight loss while taking Ozempic.

Although not officially endorsed for weight management, it has demonstrated efficacy in promoting weight loss when combined with diet and consistent physical activity.

Related Articles

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