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

Jul 19, 2023
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC; Amit Saha, MD
Summary Reviewer:
Kim A. Eagle, MD, MACC
Trial Sponsor:
Novo Nordisk
Date Published:
06/25/2023
Date Updated:
07/19/2023
Original Posted Date:
07/19/2023
References

Contribution To Literature:

The PIONEER PLUS trial showed that in adults with type 2 diabetes mellitus already on an oral antihyperglycemic regimen, once-daily oral semaglutide 25 mg and 50 mg achieved greater reduction in HbA1c and body weight with a similar safety profile compared to 14 mg once daily.

Description:

The goal of this trial was to compare the effect on glycated hemoglobin (HbA1c) and body weight of higher doses of once-daily oral semaglutide 25 mg and 50 mg versus the maximum approved dose of 14 mg once daily in patients with type 2 diabetes mellitus (T2DM) already receiving an oral medication regimen.

Study Design

  • Randomized
  • Multicenter
  • Double-Blind
  • Active-controlled (semaglutide 14 mg daily)

Patients with T2DM and an HbA1c of 8.0-10.5%, a body mass index (BMI) ≥25 kg/m2, and on a stable oral medication regimen as described below were randomized in 1:1:1 fashion to oral semaglutide 14 mg (n = 536), 25 mg (n = 535), or 50 mg (n = 535) once daily. Semaglutide was up-titrated from a starting dose of 3 mg daily every 4 weeks until target dose was achieved.

  • Total number of enrollees: 1,606
  • Duration of follow-up: 68 weeks
  • Mean patient age: 58.2 years
  • Percentage female: 41.7%

Inclusion criteria:

  • Age ≥18 years
  • T2DM diagnosed ≥6 months prior
  • HbA1c 8.0-10.5%
  • BMI ≥25 kg/m2
  • Stable daily dose(s) for ≥90 days of up to 3 of the following:
  • Metformin ≥1500 mg daily or maximum tolerated dose
  • Sulfonylurea ≥1/2 maximum approved dose or maximum tolerated dose
  • Sodium glucose co-transporter 2 inhibitor (SGLT2i) maximum tolerated dose
  • Dipeptidyl peptidase-4 (DDP-4) inhibitors AND willing to stop at randomization

Exclusion criteria:

  • Any other medication for T2DM or obesity within past 90 days (excluding insulin use limited to ≤14 days)
  • Estimated glomerular filtration rate <30 mL/min/1.73 m2
  • Uncontrolled diabetic retinopathy
  • Myocardial infarction, unstable angina, stroke, or transient ischemic attack within 180 past days
  • Planned coronary, carotid, or peripheral vascular intervention
  • History of pancreatitis

Other salient features/characteristics:

  • Baseline mean HbA1c: 9.0%
  • Baseline mean body weight: 96.4 kg
  • Baseline mean BMI: 33.8 kg/m2
  • Percentage already on 3 oral glucose-lowering agents: 31%
  • Percentage on concomitant SGLT2i: 30%
  • Percentage on previous DDP-4 inhibitor: 25%

Principal Findings:

The primary outcome, change in HbA1c at 52 weeks, for semaglutide 25 mg and 50 mg vs. 14 mg, was -1.8% (p = 0.0006) and -2.0% (p < 0.0001) vs. -1.5%.

Secondary outcomes for semaglutide 25 mg and 50 mg vs. 14 mg:

  • Follow-up HbA1c ≤6.5%: 40% and 51% vs. 26% (p < 0.0001 for both)
  • Percent change in body weight: -7.3% and -8.5% vs. -4.7% (p < 0.0001 for both)
  • Mean change in body weight: -6.7 kg and -8.0 kg vs. -4.4 kg (p < 0.0001 for both)
  • Percentage with weight loss ≥5%: 60% and 67% vs. 41% (p < 0.0001 for both)
  • Percentage requiring rescue medication for uncontrolled hyperglycemia: 10% and 9% vs. 17%

Safety outcomes for semaglutide 25 mg and 50 mg vs. 14 mg:

  • Discontinuation of study drug: 12% and 13% vs. 10%
  • Gastrointestinal complaints: 53% and 54% vs. 42%
  • Pancreatitis: 1 and 1 vs. 2 (<1% for all)
  • Hypoglycemia <54 mg/dL: 4% and 4% vs. 4%

Interpretation:

The PIONEER PLUS trial demonstrates greater reduction in HbA1c with higher doses of oral semaglutide once daily in overweight patients with T2DM. A similar dose-dependent relationship was also observed with respect to proportion of patients achieving HbA1c ≤6.5%, which occurred in over half of patients receiving semaglutide 50 mg daily, as well as weight loss and proportion of participants requiring rescue medication for poor glycemic control. Despite an increase in gastrointestinal complaints, which occurred primarily during the dose escalation phase, drug adherence was numerically similar across cohorts, suggesting acceptable tolerability with greater efficacy.

In particular, the reductions in HbA1c and body weight with semaglutide 50 mg are comparable to those observed in the STEP 2 trial of subcutaneously administered semaglutide 2.4 mg once weekly, although differences in trial populations preclude true head-to-comparison between the two strategies. The current data may therefore support dose escalation of oral semaglutide in patients requiring additional glycemic control who would otherwise benefit from a GLP-1 receptor agonist but are not amenable to starting injections.

References:

Aroda VR, Aberle J, Bardtrum L, et al. 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 multicenter, randomized, phase 3b trial. Lancet 2023;Jun 25:[Epub ahead of print].

Editorial Comment: Sherrill CH, Hwang AY. The pursuit of optimal semaglutide dosing in type 2 diabetes continues. Lancet 2023;Jun 25:[Epub ahead of print].

Clinical Topics: Prevention

Keywords: Body Mass Index, Diabetes Mellitus, Type 2, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Glucose, Glycated Hemoglobin A, Hyperglycemia, Hypoglycemia, Metformin, Overweight, Pancreatitis, Secondary Prevention, Sodium-Glucose Transporter 2 Inhibitors, Sulfonylurea Compounds


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