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Semaglutide vs. Semaglutide in Treatment of Diabetes, Obesity

Dec 2, 2017

Study compares effectiveness of oral GLP-1 medication over injection.

Semaglutide is a glucagon-like peptide (GLP-1) receptor agonist that was developed by Novo Nordisk. Most GLP-1 receptor agonists on the market are injectable; semaglutide will be one of the first oral GLP-1 agonists. GLP-1 receptor agonists decrease glucagon secretion in a glucose-dependent manner, with a low risk of hypoglycemia. They also provide significant weight loss by reducing appetite and energy intake. The drawback to GLP-1 receptor agonists was the injectable formulation, which made it less acceptable to patients.

In this study from JAMA, the objective is to compare effects of oral semaglutide with placebo and open-label subcutaneous semaglutide on glycemic control in type 2 diabetes patients.

This study was in the second phase; it was a randomized, parallel-group, dosage-finding, 26-week trial with a 5–week follow-up at 100-sites in 14 countries for 1 year. There were 1,106 participants with 632 participants who were randomized and had type 2 diabetes and insufficient glycemic control with diet and exercise alone or on a stable dose of metformin. The randomization was stratified by metformin use. For intervention, semaglutide oral had 5 dosages of once-daily oral semaglutide compared with placebo and open-label, once-weekly subcutaneous semaglutide: 2.5 mg (n= 70), 5 mg (n=70), 10 mg (n=70), 20 mg (n=70), 40 mg 4-week dose escalation (n=71), 40 mg 8-week dose escalation (n=70), 40 mg 2-week dose escalation (n=70), oral placebo (n=71) or once-weekly subcutaneous semaglutide of 1.0 mg (n=70) for 26 weeks. The primary endpoint was the change in HbA1c from baseline to week 26.

The secondary endpoints were changes from baseline in body weight and adverse events. The patients were 18 years or older with type 2 diabetes and insufficient glycemic control with HbA1c levels from 7.0%-9.5% on diet and exercise alone or a stable dose of metformin. Other eligibility criteria included BMI of 25 to 40 with HbA1c of 7.0%-9.5%. The baseline characteristics for the patients were a mean age of 57.1 years, mostly men (395), diabetes duration of 6.3 years, body weight of 92.3 kg, BMI of 31.7 and 583 participants completed the trial.

At week 26, the 40 mg oral semaglutide standard and fast escalation groups reduced the mean HbA1c by 1.8% compared with 0.3% with placebo, which achieved the primary endpoint. They found that all dosages of oral semaglutide reduced mean HbA1c significantly compared to placebo.

The mean change in HbA1c from baseline to week 26 decreased with oral semaglutide by -0.7% to -1.9%, subcutaneous semaglutide -1.9% and -0.3% in placebo. Body weight reductions were higher in the oral semaglutide (-2.1 kg- -6.9 kg) group and subcutaneous semaglutide (-6.4 kg) than placebo (-1.2 kg). The common adverse events reported were mild to moderate gastrointestinal events. The adverse events were higher with oral semaglutide (31%-77%) and subcutaneous semaglutide (54%) than with placebo (28%). The overall number of hypoglycemic episodes was low and similar between the groups for oral semaglutide, subcutaneous semaglutide, and placebo.

From HbA1c  level of 7.9% from mean baseline, between 44% (2.5 mg group), and 90% (40 mg standard escalation group) of patients on oral semaglutide achieved the target HbA1c level of less than 7.0%. Clinically relevant weight loss was seen in 71% of patients on oral semaglutide.

Overall, there were improvements in glycemic control and weight with oral semaglutide without hypoglycemia, concluding that in patients with type 2 diabetes, oral semaglutide had better glycemic control than placebo over 26 weeks, which allows phase 3 studies to start and assess for longer-term safety and efficacy.

A limitation of the study was the length of duration. Having a longer study would give more insight to safety and efficacy of the oral semaglutide. These studies show the potential of a new oral GLP-1 agent for patients looking for glycemic control as well as weight loss without the need for injections.

Practice Pearls:

  • Semaglutide is the first oral agent of the GLP-1 receptor agonist class.
  • Semaglutide was found to have better effect on glycemic control and weight loss over placebo in the 26-week phase 2 trial.
  • The most common side effect seen with oral semaglutide was gastrointestinal events.


Davies M, Peiber TR, Hartoft-Nielsen M, et al. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes. JAMA 2017; 318 (15):1460-1470.

Jessica Quach, Doctor of Pharmacy Candidate 2018, GA-PCOM School of Pharmacy