Novo Nordisk recently presented the latest data from two phase 3a clinical trials of its oral Semaglutide at the annual (ADA) meeting of the American Diabetes Association. Compared with the control drug, in patients with Diabetes mellitus type 2 (T2DM), it can not only reduce blood sugar, but also help lose weight. As an analog of natural human glucagon-like peptide-1 (GLP-1), Semaglutide can stimulate insulin production in a glucose-dependent manner, inhibit glucagon secretion, and reduce appetite and food intake. It has shown good results in a series of clinical trials in the past.

Introduction of Semaglutide

As an analog of natural human glucagon-like peptide-1 (GLP-1), Semaglutide can stimulate insulin production in a glucose-dependent manner, inhibit glucagon secretion, and reduce appetite and food intake. It has shown good results in a series of clinical trials in the past. Compared with Liraglutide, Semaglutide has a longer fat chain and higher hydrophobicity, but Semaglutide is modified by short chain PEG and its hydrophilicity is greatly enhanced. PEG modification can not only bind closely to albumin, cover up the hydrolysis site of DPP-4 enzyme, but also reduce renal excretion, prolong the biological half-life and achieve the effect of long circulation.

The mechanism of action.

Semaglutide is a glucagon-like peptide-1 receptor agonist. It increases insulin production, a hormone that lowers blood sugar levels. It also seems to promote the growth of beta cells in the pancreas, where insulin is produced. On the other hand, it suppresses glucagon, which increases blood sugar. It also reduces food intake by reducing appetite and slows digestion in the stomach. In this way, it plays a role in reducing body fat.

Clinical trials

The data released were from clinical trials of PIONEER 2 and PIONEER 4, respectively. In the first trial, the glycosylated hemoglobin (A1C) level was significantly lower than that of the control drug empagliflozin (25 mg), oral Semaglutide (14 mg) at 26 weeks, with the data of 0.9% and 1.3%, respectively (p < 0.0001). This has also reached its main clinical end point. At the secondary clinical end point A1C levels were also significantly decreased in patients who took Semaglutide orally at 52 weeks. There was no significant difference in weight loss between the two.

In the PIONEER 4 clinical trial, oral Semaglutide (14 mg) achieved non-inferiority in A1C levels compared with Victoza at the 26th week. Compared with placebo, the A1C level decreased significantly. At the secondary clinical end point, the effect of A1C was better than that of Victoza and placebo at 52 weeks. In terms of weight loss, oral Semaglutide was superior to Victoza and placebo at 26 and 52 weeks. At 52 weeks this effect was statistically significant. Specifically, oral Semaglutide lost 4.3kg, which was 3.0kg and 1.0kg in the Victoza and placebo groups, respectively.

Future

“Although its safety and efficacy have been proven, GLP-1 receptor agonists have not been fully used in clinical practice,” said Dr. Ildiko Lingvay, who led the two studies. “As a doctor, I am heartened by these results. Oral Semaglutide has the potential to be the first oral GLP-1 receptor agonist in patients with T2DM. ”

References

  1. Marso, S. P., Bain, S. C., Consoli, A., Eliaschewitz, F. G., Jódar, E., Leiter, L. A., … & Woo, V. (2016). Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine375(19), 1834-1844.
  2. Husain, M., Birkenfeld, A. L., Donsmark, M., Dungan, K., Eliaschewitz, F. G., Franco, D. R., … & Tack, C. J. (2019). Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. The New England journal of medicine.