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A once-daily oral form of semaglutide, an investigational drug being developed for type 2 diabetes, worked just as well as the once-weekly injected form for glycemic control and weight loss, a phase II dose-finding trial found.

In patients with poorly controlled diabetes, mean glycated hemoglobin (HbA1c) fell by 0.7% to 1.9% after 26 weeks on oral semaglutide, depending on the dose, versus 1.9% for injected semaglutide and 0.3% for placebo (P<0.001 for both drugs versus placebo), reported Melanie Davies, MD, of the University of Leicester Diabetes Research Center in England, and colleagues.

Compared with placebo, the estimated treatment difference was identical for the highest (40 mg) dose of oral semaglutide (-1.6%; 95% CI -1.9 to -1.3; P<0.001) and the injected form (-1.6%; 95% CI -1.8 to -1.3; P<0.001), the authors wrote in the .

They also reported that 90% of patients on the 40-mg dose of oral semaglutide achieved a target HbA1c of less than 7.0%, versus 93% of patients on injectable semaglutide and 28% of those on placebo (P<0.001 for both drugs versus placebo).

Patients on 40-mg oral semaglutide lost a mean 6.9 kg (about 15 lbs) of body weight, and patients on the injected form lost 6.4 kg, compared with 1.2 kg for patients on placebo (P<0.001).

Adverse events were reported by 86% of patients on 40-mg oral semaglutide, 81% of those on injected semaglutide, and 68% of those in the placebo group. The most common adverse events were gastrointestinal and mild to moderate in severity, the authors said.

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. This class of drugs reduces hyperglycemia by increasing insulin and decreasing glucagon secretion in a glucose-dependent manner, they explained. Several injected formulations have been approved. "The oral formulation of semaglutide may improve acceptance and adherence for some patients compared with the injectable formulation of GLP-1 receptor agonists," they noted.

Robert Eckel, MD, of the University of Colorado Denver Anschutz Medical Campus, told 番茄社区 via email that, "These are impressive and encouraging findings. The dose dependent effect of oral semaglutide on HbA1c and weight was impressive, equaling the effect of 1 mg injectable semaglutide."

However, dose escalation continues to be important for both modes of administration to avoid upper gastrointestinal side effects," said Eckel, who was not involved in the study. "For many patients, avoiding injections is important and oral semaglutide appears to be an effective option."

The randomized, parallel-group, dose-finding trial included 632 patients with poorly controlled type 2 diabetes (HbA1c range 7%-9.5%) on diet and exercise or with a stable dose of metformin. More than half (63%) were men, their mean age was 57, mean BMI was 32, and the mean duration of their diabetes was 6 years.

Participants were randomized to one of five doses of oral semaglutide (2.5 mg, 5 mg, 10 mg, 20 mg, or 40 mg); oral placebo; or 1 mg once-weekly injected semaglutide given open-label. For patients receiving 40-mg oral semaglutide, there was a 4-week standard dose escalation group, in which the initial 5-mg dose was doubled every 4 weeks until the trial maintenance dose was achieved. There was also an 8-week slow dose escalation group and a 2-week fast dose escalation group.

The 26-week treatment period was followed by a 5-week follow-up period and a clinical visit at week 31. The primary efficacy endpoint was change in HbA1c at 26 weeks from baseline. Secondary endpoints included the proportion of patients achieving a target HbA1c of less than 7.0%, change from baseline in body weight, and the proportion of patients achieving weight loss of 5% or more.

In the 40-mg oral standard dose escalation group, the proportion of patients achieving 5% or more of body weight loss was 71%, and the proportion in the injected group was 66%, compared with 13% in the placebo group (P<0.001 for both comparisons).

The proportion of patients discontinuing treatment because of adverse events, mostly gastrointestinal, was 23% in the 40-mg oral semaglutide standard escalation group, 14% in the injected semaglutide group, and 1% with placebo. Discontinuation rates were higher in the fast escalation group (26%) and lower in the slow escalation group (14%), the authors reported.

Heart rate increased by a mean of 3 beats/minute in the oral semaglutide group and 2.6 beats/minute with injected semaglutide, versus a decrease of 4 beats/minute with placebo. The investigators confirmed three cases of acute pancreatitis in patients taking semaglutide, one in the injected group, one in the 20-mg oral group, and one in the 40-mg standard escalation group. Two episodes of severe hypoglycemia occurred, one in the 40-mg fast escalation group and one in the injected semaglutide group, the investigators said.

The study's main limitation was its short duration. "Longer-term data will provide more information about the safety and efficacy durability of oral semaglutide. A longer study duration may have demonstrated the maximum HbA1c level and weight reductions in the groups administered the higher doses of the medication," they authors wrote.

"Future trials should assess the efficacy of oral semaglutide in patients with a high baseline HbA1c level to explore its potential in patients who are less well controlled, and in combination with other glucose-lowering agents," they concluded.

Neither the once-weekly injectable nor the daily oral formulations of semaglutide are yet FDA approved. The injectable form will be .

Click for the American Association of Clinical Endocrinologists and the American College of Endocrinology Comprehensive Type 2 Diabetes Management Algorithm 2017 – Executive Summary.

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