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FDA Approves First Oral GLP-1 Treatment for Type 2 Diabetes, But Wait!

Oct 26, 2019
 
Editor: David L. Joffe, BSPharm, CDE, FACA

Author:  Alessa Grieff, PharmD Candidate, University of South Florida College of Pharmacy

Unique directions for taking first oral GLP-1 may cause a compliance issue; it’s not as simple as just taking a pill once a day.

The following are the results of several studies showing the effectiveness of oral semaglutide.  The studies have shown a significant reduction in A1c, a reduction in cardiovascular disease, and a reduction in weight, without the risk of hypoglycemia.  The main difference between this drug and the other GLP-1 drugs is that it is an oral dosage and not an injection. But there are some issues with this oral dosage, as you will learn.

The new oral GLP-1 receptor agonist, semaglutide, was just recently approved for the treatment of type 2 diabetes. Because type 2 diabetes management is multifactorial, it is important to understand the role of this new medication. This article will summarize trials investigating oral semaglutide’s part in diabetic therapy management.

Oral semaglutide is formulated with the absorption enhancer SNAC and works by increasing pH in the stomach, yielding higher solubility and protection against proteolytic degradation. GLP-1 receptor agonists are particularly advantageous because of their low risk of hypoglycemia and ability to reduce hyperglycemia by increasing insulin and decreasing glucagon secretion, and can also provide significant weight loss. Other GLP-1 RAs are also known to improve cardiovascular outcomes, making this class even more appealing for this patient population. With this new formulation, it is imperative to investigate if these benefits are retained.

One 26-week randomized, parallel-group, phase 2, dosage finding trial compared 5 dosages of once-daily oral semaglutide with placebo in a double-blind design and had an open-label component comparing the oral form with its once-weekly subcutaneous injection form. The patients in this trial had uncontrolled type 2 diabetes and were either taking metformin or no other medications for glycemic control. The primary efficacy endpoint of this study was changed from baseline in HbA1C level at week 26. Secondary efficacy endpoints included the proportion of patients achieving HbA1C of less than 7.0%, change from baseline in fasting blood glucose and body weight, the proportion of patients achieving weight loss of at least 5% and at least 10%, change from baseline in fasting insulin and fasting glucagon, fasting C-peptide, insulin resistance, and beta-cell function, fasting lipid profile and some patient-reported outcomes. 583 patients completed this trial, with 492 (78%) completing treatment with a mean baseline HbA1C of 7.9%. All dosages of oral semaglutide reduced mean HbA1C levels significantly more than placebo by week 26, in a dosage-dependent manner. Between 44% (2.5mg oral semaglutide group) and 90% (40mg oral semaglutide group) achieved target HbA1c of less than 7%. Weight loss of at least 5% was seen in 71% of patients receiving oral semaglutide. There were no unexpected safety findings in the study and GI adverse events were more common in the semaglutide group. The adverse event profile of the oral form was like the subcutaneous form, and 20mg and 40mg oral groups had the most similar degree of improvements to the subcutaneous form.

The PIONEER 3 trial was a randomized, double-blind, double-dummy, parallel-group phase 3a trial that was conducted over 78 weeks and included 1864 patients. Patients were at least 18 years old with type 2 diabetes uncontrolled with metformin with or without a sulfonylurea. The trial compared oral semaglutide vs sitagliptin. The main primary endpoint was changed in glycated hemoglobin, and the main secondary endpoint was the change in body weight from baseline to week 26. Semaglutide was dosed at 3mg/d, 7mg/d, and 14mg/d. The 7 and 14mg/d groups, compared with sitagliptin, showed a significant difference in HbA1C respectively; P < .001 for both) and body weight differences -1.6kg and -2.5 kg, respectively; P < .001 for both) from baseline to week 26. The dose of semaglutide 3mg/d did not show noninferiority vs sitagliptin.

The PIONEER 4 trial compared subcutaneous liraglutide and placebo to oral semaglutide. The trial was also a randomized, double-blind, double-dummy, phase 3a trial. Patients had type 2 diabetes and were recruited from 100 sites and 12 countries. Patients were at least 18 years old, had an HbA1C of 7-9.5%, were taking metformin with or without an SGLT2 inhibitor. The primary endpoint was change from baseline to week 26 in HbA1C and the secondary endpoint was change from baseline to week 26 in body weight. Oral semaglutide was dose escalated to 14mg/d and liraglutide to 1.8mg/d. The trial included 711 patients that were randomized.  Mean change from baseline in HbA1C at week 26 was -1.2% with oral semaglutide, -1.1% with subcutaneous liraglutide, and -0.2% with placebo. Oral semaglutide was non-inferior to subcutaneous liraglutide in decreasing HbA1c  and superior to placebo. Regarding the secondary endpoint, semaglutide was superior compared with both placebo and liraglutide at week 26. The safety and tolerability of the oral semaglutide was like subcutaneous liraglutide. 

Another key question is if this oral form has cardiovascular benefits. The PIONEER 6 trial assessed this. In this trial, they found that the CV risk profile of oral semaglutide was not inferior to that of a placebo, but they did not find superiority over placebo as its injectable form had.

Because compliance is always a major issue in taking a daily pill, this tablet presents even greater issues that may make it difficult for patients to understand and follow the specific directions. These issues include taking the tablet by mouth on an empty stomach when first waking up.  It needs to be taken with a sip of water, not more than 4 ounces. It cannot be chewed or crushed and swallowed whole, and you must wait 30 – 60 minutes before you can eat or drink. And finally, it cannot be taken with any other medications. The cash price is over $800 a month without insurance.

The results of these studies show that oral semaglutide is a safe and efficacious treatment option for type 2 diabetes. Because of its oral form, it may lead to earlier initiation of GLP-1 receptor agonist therapy. Only doses of 20mg and 40mg of oral semaglutide were comparable to its injectable form, so the 14mg recommended dose may not include all the same benefits. More studies are needed to assess potential CV benefits of this form.

Practice Pearls:

  • Oral semaglutide, brand name Rybelsus, is the first GLP-1 agonist that does not require injection.
  • Oral semaglutide reduces the risk of heart attacks, stroke, and heart-related deaths; reduces A1c, and allows for weight reduction without causing hypoglycemia
  • Oral semaglutide must be taken under specific conditions to ensure efficacy

 

Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on  Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial. JAMA. 2017 Oct 17;318(15):1460-1470. doi: 10.1001/jama.2017.14752.

 

Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The  PIONEER 3 Randomized Clinical Trial. JAMA. 2019 Apr 16;321(15):1466-1480. doi: 10.1001/jama.2019.2942.

 

 Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomized, double-blind, phase 3a trial. Lancet. 2019 Jul 6;394(10192):39-50.

Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019 Aug 29;381(9):841-851. doi: 10.1056/NEJMoa1901118.]

 Alessa Grieff, PharmD Candidate, University of South Florida College of Pharmacy

 

For more on oral semaglutide, visit our GLP-1 Agonist therapy center.