Efficacy and Tolerability of Oral Semaglutide

Glucagon-like peptide-1 receptor (GLP-1) agonists are possible add-on therapies for type 2 diabetics who require

glucose control beyond that of metformin, diet, and exercise. Currently, all of the GLP-1 agonist products available in

the market are only approved to be administered via subcutaneous injection. Of course, this route of administration

serves as a barrier to adherence and optimal therapy for many patients who are not too keen on using needles and

giving themselves daily or weekly injections. Novo Nordisk aims to overcome the current GLP-1 agonists’ adherence

issues with the development of a novel oral GLP-1 agonist, semaglutide.

Recently, Novo Nordisk presented the results of a phase 2 clinical trial, led by Dr. Julio Rosenstock, at the Annual

Meeting of the Endocrine Society in Boston, Massachusetts. The trial included 632 type 2 diabetics with early type 2

diabetes who were on metformin along with diet and exercise regimens. The patient population was largely male

(63%), with a mean HbA1C of 7.9%, a mean duration of diabetes of 6 years, and a mean BMI of 32 kg/m2. Each

patient was randomized to receive oral semaglutide 2.5, 5, 10, 20 or 40 mg once daily or placebo, or open-label

subcutaneous semaglutide 1.0 mg once weekly. The primary endpoint of the trial was to determine the change in

HbA1c from baseline to Week 26. The results of the primary endpoint and other key secondary endpoints are

summarized in the table below:

Treatment Reduction

in HbA1C

Reduction in Fasting

Plasma Glucose

Reduction in

Body Weight

Statistically Significant Reduction

Compared to Placebo?

2.5 mg PO Daily 0.7% Dose dependent

reductions ranging

from 17–51 mg/dL

Dose

dependent

reductions

ranging from 2–

7 kg

No No No

5 mg PO Daily 1.2% Yes Yes No

10 mg PO Daily 1.5% Yes Yes Yes

20 mg PO Daily 1.7% Yes Yes Yes

40 mg PO Daily 1.9% Yes Yes Yes

1 mg SubQ Weekly 1.9% 56 mg/dL 6 kg Yes Yes Yes

Placebo Daily 0.3% 1 mg/dL 1 kg - - -

*Reductions are reported after 26 weeks of treatment

Additionally, 63-86% and 81% of the patients receiving oral and subcutaneous semaglutide, respectively,

experienced dose-dependent adverse events. Only 68% of patients receiving placebo reported adverse events. The

most common adverse events were nausea, vomiting, and diarrhea. Investigators reported three cases of

pancreatitis, two of which occurred in the oral group and one in the subcutaneous group; all three cases were

associated with increases in lipase. Although no serious adverse events occurred, patients receiving any form of

semaglutide discontinued therapy more frequently than patients in the placebo group.

While this oral GLP-1 agonist showed comparable efficacy and tolerability to its subcutaneous counterpart, there are

still some questions left to be answered. The effect of food on the bioavailability of the peptide is of concern given

that the subjects in the oral group were asked to wait at least 30 minutes before eating after taking the medication.

The bioavailability of the oral formulation is also thought to be affected by pH; more research must be done to

determine effects of proton-pump inhibitors and conditions such as delayed gastric emptying. Additionally, because

of the difference in bioavailability, the dosages of the oral formulation are notably larger than that of the

subcutaneous formulation and thus may result in increased costs to patients and payers. While it may seem the oral

semaglutide can help solve the adherence issues associated with the currently available GLP-1 agonists, there are

certainly valid concerns that must be addressed as semaglutide moves in to phase 3 clinical trials.

More info can be found here:

https://endo.confex.com/endo/2016endo/webprogram/Paper25706.html

http://www.firstwordpharma.com/node/1372515#axzz46UIDfSKq