In adults with type 2 diabetes inadequately controlled with metformin (alone or with sulfonylurea), oral semaglutide (7 mg and 14 mg) significantly reduced HbA1c and body weight compared to sitagliptin over 26 weeks, while the 3 mg dose showed no significant benefit.
PICO Summary
Population:
1864 adults with type 2 diabetes, HbA1c levels between 7.0%–10.5%, on stable metformin therapy alone or with sulfonylurea.
Intervention:
Once-daily oral semaglutide at 3 mg, 7 mg, or 14 mg, administered for 78 weeks with dose escalation.
Comparison:
Sitagliptin, 100 mg daily.
Outcome:
- Efficacy: Semaglutide at 7 mg and 14 mg resulted in HbA1c reductions of −1.0% and −1.3% versus −0.8% with sitagliptin and weight reductions of −1.6 kg and −2.5 kg versus −0.6 kg with sitagliptin.
- Safety and Tolerability: Gastrointestinal side effects were more common with semaglutide, particularly at the 14 mg dose, leading to a higher discontinuation rate in this group.
Clinical Summary
Main Finding:
The PIONEER 3 trial found that oral semaglutide at 7 mg and 14 mg doses, added to metformin with or without sulfonylurea, achieved significant improvements in glycaemic control and body weight compared to sitagliptin over a 26-week period. At the 14 mg dose, semaglutide reduced HbA1c by an average of 1.3% from baseline (starting mean HbA1c 8.3%), compared to a 0.8% reduction with sitagliptin. Additionally, 57.4% of patients on semaglutide 14 mg achieved the American Diabetes Association (ADA) target HbA1c level of less than 7.0%, versus 34.2% with sitagliptin. Weight reduction was also greater with semaglutide, with the 14 mg dose leading to an average decrease of 2.5 kg compared to 0.6 kg with sitagliptin. This weight loss effect supports the broader use of semaglutide in diabetes management where weight control is a clinical priority.
Clinical Relevance:
The combination of robust HbA1c and body weight reductions makes semaglutide an attractive option for patients struggling to achieve glycaemic control on metformin alone or in combination with sulfonylurea. The pronounced HbA1c reduction and high proportion of patients reaching the <7.0% HbA1c target are clinically meaningful, particularly in light of the ADA’s goal to reduce HbA1c in diabetes patients to improve long-term outcomes. Furthermore, the additional weight loss benefits of semaglutide, especially with the 14 mg dose, offer advantages over sitagliptin, which showed minimal impact on weight. However, a higher rate of gastrointestinal adverse events with semaglutide, primarily nausea, vomiting, and diarrhoea, was noted, leading to a discontinuation rate of 11.6% in the 14 mg group. Careful dose escalation, as was done in the trial, may help mitigate these side effects and enhance treatment adherence in clinical practice.
Study Overview:
- Type of Study: Randomised, double-blind, double-dummy, phase 3a clinical trial.
- Sample Size & Population: 1864 patients with type 2 diabetes inadequately controlled on metformin alone or with sulfonylurea.
- Intervention Duration & Doses: 78-week duration with dose escalation to target maintenance doses (3, 7, or 14 mg).
- Comparison: Sitagliptin, 100 mg daily.
Outcomes:
- Primary Measure (HbA1c): Semaglutide 7 mg and 14 mg showed superior reductions in HbA1c compared to sitagliptin at 26 weeks (−1.0% and −1.3% for semaglutide vs. −0.8% for sitagliptin).
- Secondary Measure (Body Weight): Mean weight reduction was greater with semaglutide 14 mg, achieving an average decrease of 2.5 kg, compared to 0.6 kg with sitagliptin.
- Safety Profile: Gastrointestinal adverse events, especially nausea, were the most common side effects with semaglutide, occurring more frequently with the 14 mg dose and resulting in higher discontinuation rates.
Considerations:
The dose-dependent efficacy of semaglutide, coupled with higher gastrointestinal side effects at 14 mg, suggests careful patient selection and monitoring. Further studies might explore flexible dosing or titration strategies to optimise tolerability.
Reference:
Rosenstock, J., Allison, D., Birkenfeld, A. L., et al. (2019). JAMA, 321(15), 1466-1480. doi:10.1001/jama.2019.2942
Disclosure:
This article on Hormone Insight was created with both human and AI assistance. The human expert editor reviewed the article before publication to ensure accuracy, quality, and clarity.
