Log in to MyACC
PIONEER 4 - PIONEER 4
Contribution To Literature:
The PIONEER 4 trial showed that oral semaglutide is noninferior to injectable liraglutide and superior to placebo in improving glycemic control and weight loss at 26 weeks among patients with type 2 diabetes.
Description:
The goal of the trial was to assess the safety and efficacy of oral semaglutide compared with subcutaneous liraglutide and placebo among patients with type 2 diabetes.
Study Design
Patients were randomized in a 2:2:1 fashion to oral semaglutide (n = 285), subcutaneous liraglutide (n = 284), or placebo (n = 142) once-daily in addition to existing background glucose-lowering medication. This was a double-blind, double-dummy design (everyone received a tablet and an injection). Dose: Semaglutide 3 mg daily initially, then 7 mg at 4 weeks, 14 mg at 8 weeks; liraglutide 0.6 mg initially then 1.2 mg after 1 week, 1.8 mg at 2 weeks.
- Total screened: 950
- Total number of enrollees: 711
- Duration of follow-up: 52 weeks
- Mean patient age: 56 years
- Percentage female: 48%
Inclusion criteria:
- Type 2 diabetes
- Age ≥18 years
- Hemoglobin A1c (HbA1c): 7.0-9.5%
- Stable dose of metformin
Exclusion criteria:
- Any medication for diabetes or obesity within 90 days of screening (other than metformin, sodium-glucose co-transporter-2 [SGLT2] inhibitor, or short-term insulin [≤14 days])
- Renal impairment (estimated glomerular filtration rate <60 ml/min per 1.73 m2)
- Proliferative retinopathy or maculopathy requiring acute treatment
- History of acute or chronic pancreatitis
Other salient features/characteristics:
- White race: 73%, Asian: 13%
- Mean HbA1c: 8%
- Mean body mass index: 33 kg/m2
- Mean duration of diabetes: 7.6 years
- Baseline use of SGLT2 inhibitors: 26%
Principal Findings:
The primary outcome, change in HbA1c at 26 weeks for semaglutide vs. liraglutide vs. placebo, was -1.2% vs. -1.1% vs. -0.2% (p < 0.001 for noninferiority of semaglutide vs. liraglutide; p < 0.0001 for semaglutide vs. placebo).
Secondary outcomes for semaglutide vs. liraglutide vs. placebo:
- Weight loss at 26 weeks: -4.4 kg vs. -3.1 kg vs. -0.5 kg (p = 0.003 for semaglutide vs. liraglutide; p < 0.0001 for semaglutide vs. placebo)
- Change in HbA1c at 52 weeks: -1.2% vs. -0.9% vs. -0.2% (p = 0.0002 for semaglutide vs. liraglutide; p < 0.0001 for semaglutide vs. placebo)
- Severe or symptomatic hypoglycemia: 1% vs. 2% vs. 1%
- Gastrointestinal (GI) side effects: 8% vs. 6% vs. 2%
Interpretation:
The results of this trial indicate that oral semaglutide is noninferior to injectable liraglutide and superior to placebo in improving glycemic control and weight loss at 26 weeks among patients with type 2 diabetes. Results were sustained at 52 weeks of follow-up, with oral semaglutide showing slightly better efficacy than liraglutide. Adverse effects were more common with semaglutide, but mostly related to GI side effects.
These are important findings since the glucagon-like peptide-1 (GLP-1) agonists such as semaglutide and liraglutide have been studied only in an injectable form so far due to poor oral bioavailability. In their respective cardiovascular outcomes trials, both agents have demonstrated a favorable cardiovascular profile, but the former issue may limit patient uptake. In this trial, an oral formulation of semaglutide was tested (co-formulation with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate) and found to have equivalent glycemic control to another injectable GLP-1 agonist.
References:
Pratley R, Amod A, Tetens S, et al., on behalf of the PIONEER 4 Investigators. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet 2019;394:39-50.
Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Prevention
Keywords: Blood Glucose, Diabetes Mellitus, Type 2, Glucagon-Like Peptides, Glucose, Hemoglobin A, Hypoglycemia, Metabolic Syndrome, Metformin, Primary Prevention, Weight Loss
< Back to Listings
