Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial

Literature - Aroda VR, Alberle J, Bardtrum L, et al. - Lancet. 2023 Jun 23;S0140-6736(23)01127-3. [Online ahead of print]. doi: 10.1016/S0140-6736(23)01127-3

Introduction and methods

Background

Glycemic control and weight management are considered important targets for patients with T2D, alongside cardiorenal protection and CV risk reduction [1]. To achieve a reduction in bodyweight as well as improved glycemic control, GLP-1RA such as semaglutide can be used in the treatment of T2D, next to diet and exercise [2-4]. The PIONEER clinical trials demonstrated that once-daily oral semaglutide at a dose of 7 mg and 14 mg lowered HbA1c levels and bodyweight in patients with T2D [5-11]. Intensification of treatment with higher doses of semaglutide may provide additional benefits to patients.

Aim of the study

The authors evaluated the efficacy, safety, and tolerability of once-daily oral semaglutide at higher doses (25 mg and 50 mg) and compared with the highest approved dose (14 mg) in adults with T2D.

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Methods

The PIONEER PLUS trial was an active-controlled, multinational, double-blind, phase 3b trial in which 1606 adults with T2D were randomized (1:1:1) to once-daily oral semaglutide 14 mg, 25 mg, or 50 mg for 68 weeks. Adults were eligible for enrollment if they had HbA1c of 8.0−10.5% (64-91 mmol/mol), a BMI of 25.0 kg/m² or greater, and received stable daily doses of one to three oral glucose-lowering drugs (metformin, sulfonylurea, SGLT2 inhibitor, or DPP-4 inhibitor). Participants who were on a DPP-4 inhibitor at inclusion were asked to discontinue this treatment at randomization.

Dose escalation was done as following: all participants started at once-daily oral semaglutide treatment at 3 mg, then escalated to 7 mg at week 4, and to 14 mg at week 8. Participants who were assigned to 25 mg received their maintenance dose at week 12. Participants who were assigned to 50 mg escalated to 25 mg at week 12, and received their maintenance dose of 50 mg at week 16.

Outcomes

The primary outcome was the percentage change in HbA1c from baseline to week 52. The confirmatory secondary outcome was change in body weight (kg) from baseline to week 52. Supportive secondary outcomes were proportion of participants who reached HbA1c target (<7.0%; 53 mmol/mol) or 5%/10% weight loss. Supportive safety outcomes were the number of (serious) adverse events.

Main results

HbA1c and bodyweight

• HbA1c improved from baseline to week 52 in all three groups (by -1.5%, -1.8%, and -2.0% for 14 mg, 25 mg, and 50 mg, respectively). These improvements were significantly greater with 25 mg and 50 mg compared with 14 mg (estimated treatment difference [ETD]: -0.27%; 95%CI: -0.42 to -0.12; P=0.0006 for 25 mg; and ETD: -0.53%; 95%CI: -0.68 to -0.38; P=0.0001 for 50 mg).
• Participants receiving the two higher doses of oral semaglutide were more likely to reach aHbA1c level of less than 7.0% (53 mmol/mol) at week 52. These levels were reached by 39%, 51%, and 63% of the participants in the 14 mg, 25 mg, and 50 mg oral semaglutide group, respectively.
• Fewer participants required rescue medication for persistent and unacceptable hyperglycemia in the 25 mg and 50 mg groups compared with the 14 mg group (10%, 9% and 17%, respectively).
• Reductions in bodyweight of -4.4 kg, -6.7 kg and -8.0 kg were measured in the 14 mg, 25 mg, and 50 mg oral semaglutide group, respectively. Significant higher bodyweight loss was observed in the 25 mg and 50 mg groups compared with the 14 mg group (ETD: -2.32 kg; 95%CI: -3.11 to -1.53; P<0.0001 for 25 mg; and ETD: -3.63 kg; 95%CI: -4.42 to -2.84; P<0.0001 for 50 mg).
• A larger proportion of participants reached a bodyweight reduction of ≥5% at week 52 in the 25 mg and 50 mg groups compared with the 14 mg group (60%, 67%, and 41%, respectively). This was also the case for bodyweight reductions of ≥10% (29%, 37%, and 14%, respectively).
• Reductions in HbA1c and bodyweight were mostly sustained up to week 68.

Safety and tolerability

• No new safety concerns were identified for the new formulation of oral semaglutide at a dose of 25 mg and 50 mg.
• The proportion of participants reporting an adverse events was high (76% in the 14 mg group, 79% in the 25 mg group, and 80% in de 50 mg group). These events were mostly mild to moderate gastrointestinal disorders, such as nausea, vomiting and diarrhea, and occurred mostly during dose escalation.
• Adverse events leading to discontinuation of treatment occurred in 10% of participants in the 14 mg group, 12% of participants of in the 25 mg group, and 13% of participants in the 50 mg group. These events were mostly gastrointestinal.
• Hypoglycemic episodes (level 1-3) were reported by 13% of participants in the 14 mg group, 14% of participants of in the 25 mg group, and 17% of participants in the 50 mg group.
• Serious adverse events were reported by 10% of participants in the 14 mg group, 11% of participants of in the 25 mg group, and 8% of participants in the 50 mg group.
• A total of 10 deaths were reported, but these were considered to be unrelated to treatment.

Conclusion

References

Find this article online at The Lancet