Dr. Ahmed Glipizide Vs Rybelsus is a comparison of the two oral diabetes medications. Glipizide belongs to the class of drugs called sulfonylureas. It is a 2nd generation sulfonylurea and is very effective in lowering A1C.
Rybelsus, on the other hand, is one of the latest FDA-approved oral diabetes medications. It belongs to the class of drugs called GLP-1 analogs.
Like the other GLP-1 analogs, Ozempic, Victoza, and Trulicity, it is very effective in lowering A1C and body weight.
However, unlike other GLP-1 analogs, it is available as an oral tablet that is taken once daily.
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Glipizide Vs Rybelsus: Basic Differences:
Glipizide is one of the time-tested medicine. It is one of the cheapest and most potent diabetes medicines. In addition, apart from hypoglycemia, it is less likely to be associated with significant side effects.
Rybelsus is a newly approved diabetes medicine. It is the only GLP-1 analog that is available in a tablet formulation.
However, it costs around $30 per tablet which is almost the monthly cost of Glipizide. Here are some basic differences between Glipizide and Rybelsus:
Glipizide | Rybelsus | |
| Medication class | 2nd Generation Sulfonylurea | Glucagon-like peptide-1 receptor agonist |
| Mechanism of action | Stimulates insulin release | ⇑ insulin secretion, ⇓ glucagon secretion, and slows gastric emptying |
| Formulation | Oral tablet (immediate-release and extended-release) | Oral tablet |
| Indication | Type 2 diabetes | Type 2 diabetes |
| Dosage frequency | Once or twice daily before meals | Once daily |
| Onset of action | Rapid | Slow |
| Time to peak effect | 1- 3 | 8-12 hours |
| Duration of action | 12-24 hours | 24 hours |
| Side effects | Hypoglycemia, weight gain | Nausea, diarrhea, vomiting, decreased appetite |
| Important precautions/ contraindications | Allergy to sulfonylureas, type 1 diabetes, diabetic ketoacidosis | Medullary thyroid carcinoma or MEN-2, gastroparesis |
| Interactions | Alcohol, beta-blockers, certain antibiotics, anticoagulants | other GLP-1, twincretins, DPP-IV, and drugs affecting GI motility |
| Pregnancy category | C | C |
| Availability | Generic available | Rybelsus is the only brand available |
| Cost per tablet (USD) | $0.5 to $1 | $30 |
Glipizide is available under different brand names. It is also available as an immediate-release tablet as well as an extended-release tablet. It is not recommended with insulin or other sulfonylureas.
Rybelsus is not recommended with DPP-IV inhibitors like Januvia and Galvus, GLP-1 analogs like Ozempic and Trulicity, and Twincretin (Tirzepatide).
Glipizide Vs Rybelsus: Comparing Efficacies in Diabetes:
Glipizide is a potent and time-tested drug. Glipizide has not been compared in a head-to-head trial. It is associated with an A1C reduction of about -0.6% in various studies [Ref: 1, 2]
Rybelsus is one of the most potent oral medicine for treating Diabetes Type 2. Its A1C lowering effect is dose-dependent. However, even when given in the lowest dose (the priming dose), it is as effective as Glipizide.
The maximum A1C lowering effect has been around -1.3% as observed in clinical trials and per the manufacturer’s site [Ref].
Here is a table of comparison of the A1C lowering effect of Glipizide Vs Rybelsus:
Glipizide/ Rybelsus | A1C reduction |
| Glipizide | -0.6% [Ref: 1 and 2] |
| Rybelsus 3 mg | -0.7% |
| Rybelsus 7 mg | -1.2% |
| Rybelsus 14 mg | -1.4% |
Very few drugs lower the A1C beyond -1% and Rybelsus is one of them. Even Jardiance lowers A1C by only -0.8 to -1%.
Rybelsus lowers the A1C by about -0.8% greater than Glipizide (based on the indirect comparisons).
A higher dose Rybelsus formulation is being studied for greater A1C lowering effect as well as weight loss effects.
The Pioneer-PLus study published in The Lancet demonstrated significant improvements in A1C at higher doses. A summary of the A1C-lowering effect of higher doses of Rybelsus is tabulated below:
Rybelsus | A1C reduction |
| Rybelsus 14 mg | -1.5% |
| Rybelsus 25 mg | -1.8% |
| Rybelsus 50 mg | -2.0% |
Glipizide Vs Rybelsus: Comparing Weight Loss Effects:
Glipizide stimulates insulin release. Like all sulfonylureas and insulin, it is associated with weight gain. Rybelsus, on the other hand, is associated with weight loss.
In fact, the high-dose formulation of Semaglutide (Wegovy) has already been approved for the treatment of obesity.
Here is a comparison of the effect of Glipizide Vs Rybelsus on body weight:
Glipizide/ Rybelsus | Weight change (kg) | Weight change (lb) |
| Glipizide | +0.14 [Ref] to +1.2 [Ref] | + 0.3 to + 2.64 |
| Rybelsus 3 mg | -0.2 | -0.44 |
| Rybelsus 7 mg | -2.3 | -5.06 |
| Rybelsus 14 mg | -3.7 | -8.14 |
Recently, there are studies going on evaluating the use of higher doses of Rybelsus (up to 50 mg per day) for the treatment of obesity and diabetes.
The Oasis-1 Trial evaluated Rybelsus in a dose of 50 mg for the treatment of obesity in individuals who had a BMI of 30 kg/m² or 27 kg/m² plus at least one obesity-associated medical condition.
The results of the study are summarized in the table below:
Treatment | Mean Change in Body Weight |
| Oral Semaglutide | -15.1% |
| Placebo | -2.4% |
High-dose Rybelsus 50 mg resulted in a weight loss of about -15% which is equivalent to the weight loss associated with Wegovy. It is important to note that Wegovy is a weight loss drug while Rybelsus is approved only for the treatment of diabetes.
The weight loss associated with high dose Rybelsus 50 mg orally once daily and Wegovy 2.4 mg weekly are equivalent.
In addition, high-dose Ryeblsus resulted in a weight loss of more than 15% in half of the patients. The percent weight loss is summarized in the table below:
Weight Reduction | Rybelsus 50 mg | Placebo |
| ≥5% | 269 (85%) | 76 (26%) |
| ≥10% | 220 (69%) | 35 (12%) |
| ≥15% | 170 (54%) | 17 (6%) |
| ≥20% | 107 (34%) | 8 (3%) |
Above data is taken from the Oasis-1 Trial.
In contrast, Glipizide causes weight gain. Not everybody wants to lose weight. Glipizide may be a better option for lean diabetic patients who are underweight and have a low risk of hypoglycemia.
In Summary:
Glipizide and Rybelsus are two oral medications approved for treating Diabetes Type 2. Rybelsus is more effective than GLipizide in lowering A1C even when used in the lowest dose.
In addition, Rybelsus use is associated with weight loss while Glipizide is associated with weight gain.
However, Rybelsus is costlier. It is almost 30 times costlier than Glipizide. In addition, people with stomach issues may not be able to tolerate Rybelsus as it causes stomach fullness, bloating, constipation/ diarrhea, and abdominal pain.
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