The trials in the PIONEER series are testing various aspects of the oral version of the glucagon-like peptide (GLP)-1 receptor agonist semaglutide. All trials are sponsored by semaglutide’s manufacturer, Novo Nordisk.
Here’s our guide to the trials, with results and links to the journal publications where available, including the cardiovascular efficacy trial SOUL.
See also:
- A quick guide to the SURPASS and SURMOUNT trials (tirzepatide)
- A quick guide to the STEP trials (semaglutide for obesity)
- A quick guide to the SUSTAIN trials (semaglutide)
- A quick guide to the AWARD trials (dulaglutide)
- A quick guide to the GetGoal trials (lixisenatide)
- A quick guide to the LEAD trials (liraglutide)
- A quick guide to the DURATION trials (exenatide)
PIONEER 1: Published
Trial population: Medication-naïve people with type 2 diabetes | Comparator treatment: Placebo |
As reported in Diabetes Care, 703 patients with glycated hemoglobin (HbA1c) levels between 7.0% and 9.5% (53 and 80 mmol/mol) were randomly assigned to receive daily oral semaglutide 3, 7, or 14 mg, or placebo.
By week 26, patients taking semaglutide had average placebo-adjusted HbA1c reductions ranging from 0.6% to 1.1%, with all being statistically significant. The highest dose also produced a significant bodyweight reduction versus placebo.
PIONEER 2: Published
Trial population: People with type 2 diabetes taking metformin only | Comparator treatment: Empagliflozin |
In this trial, involving 821 participants, oral semaglutide 14 mg/day proved significantly more efficacious than the sodium-glucose cotransporter (SGLT)2 inhibitor empagliflozin, with the two producing respective 1.3% and 0.9% reductions in HbA1c over 26 weeks of treatment.
The results reported in Diabetes Care show a larger effect of semaglutide than empagliflozin on weight loss emerging by 52 weeks of treatment, after accounting for medication discontinuations and rescue medication, with average reductions of 4.7 versus 3.8 kg, respectively.
Related news story: PIONEER 2, PIONEER 4 show benefits of oral semaglutide in type 2 diabetes
PIONEER 3: Published
Trial population: People with type 2 diabetes taking metformin, with/without a sulfonylurea | Comparator treatment: Sitagliptin |
This trial, which is published in JAMA, pitted oral semaglutide against the dipeptidyl peptidase-4 inhibitor sitagliptin. It proved significantly more efficacious at the two higher of the three doses tested (3, 7, and 14 mg/day) in 1864 participants over 26 weeks of treatment. It reduced HbA1c by an additional 0.3–0.5%, on average, and bodyweight by an additional 1.6–2.5 kg.
Related news story: PIONEER 3: Oral semaglutide proves worth against sitagliptin
PIONEER 4: Published
Trial population: Patients with type 2 diabetes taking metformin, with/without a SGLT2 inhibitor | Comparator treatment: Liraglutide (daily, subcutaneous) or placebo |
As reported in The Lancet, a daily GLP-1 receptor agonist in oral form was noninferior to the subcutaneous form. Semaglutide and liraglutide produced average HbA1c reductions that were similar to each other and significantly better than that of placebo, at 1.2% and 1.1%, respectively, versus 0.2%, in 711 patients after 26 weeks of treatment.
However, semaglutide produced significantly greater weight loss than liraglutide, at an average of 4.4 versus 3.1 kg, and both were better than placebo, at 0.5 kg.
Related news story: PIONEER 2, PIONEER 4 show benefits of oral semaglutide in type 2 diabetes
PIONEER 5: Published
Trial population: Patients with type 2 diabetes and an estimated glomerular filtration rate of 30–59 mL/min per 1.73 m², taking metformin, a sulfonylurea, or both, or basal insulin with/without metformin | Comparator treatment: Placebo |
During this trial, conducted in 324 patients with moderately impaired renal function, oral semaglutide (dose escalated to 14 mg/day) was associated with an average 1.0% reduction in HbA1c, versus a 0.2% reduction with placebo.
Renal function remained unchanged in both groups during the 26 weeks of treatment.
The findings are published in The Lancet Diabetes & Endocrinology.
Related news story: PIONEER trials test oral semaglutide in moderate renal impairment, flexible dosing
PIONEER 6: Published
Trial population: Patients with type 2 diabetes and high cardiovascular risk (85% with established disease) | Comparator treatment: Placebo |
PIONEER 6, the cardiovascular safety trial for oral semaglutide, is published in The New England Journal of Medicine.
The trial demonstrated noninferior cardiovascular safety of semaglutide versus placebo, but being an event-driven trial (ie, halted for data analysis as soon as it accumulated the necessary number of events to demonstrate noninferiority) did not have the statistical power to show superiority.
Nevertheless, there was a strong trend in that direction. The composite primary cardiovascular endpoint occurred in 3.8% of the 1591 people randomly assigned to receive oral semaglutide 14 mg/day and in 4.8% of the 1592 people in the placebo group, giving a nonsignificant hazard ratio of 0.79, with a confidence interval of 0.57–1.11.
Related news story: Oral semaglutide falls just short of cardioprotection in event-driven PIONEER 6
Expert commentary: WATCH: The PIONEER 6 lead investigator discusses the findings
PIONEER 7: Published
Trial population: People with type 2 diabetes taking metformin, with/without a sulfonylurea | Comparator treatment: Sitagliptin |
This open-label trial, involving 504 patients and published in The Lancet Diabetes & Endocrinology, tested a flexible dosing regimen. Participants assigned to semaglutide started on the 3 mg/day dose, but could be titrated up to 7 or 14 mg/day according to HbA1c and tolerability.
However, the average HbA1c reduction of 0.5% versus sitagliptin was little different to that achieved in PIONEER 3 using the fixed doses.
Related news story: PIONEER trials test oral semaglutide in moderate renal impairment, flexible dosing
PIONEER 8: Published
Trial population: Patients with type 2 diabetes using basal insulin with/without metformin | Comparator treatment: Placebo |
During 26 weeks of treatment of 731 participants, those taking the 3, 7, and 14 mg/day doses of oral semaglutide achieved average HbA1c reductions of 0.6%, 0.9%, and 1.3%, respectively, versus 0.1% for those taking placebo. The corresponding average bodyweight reductions were 1.4, 2.4, and 3.7 kg versus 0.4 kg.
Using semaglutide also allowed participants to reduce their average daily insulin dose, and the benefits were maintained for the full 52 weeks of the trial.
The results are published in Diabetes Care.
Related news story: PIONEER 8: Semaglutide add-on lowers HbA1c in type 2 diabetes insulin users
PIONEER 9: Published
Trial population: Japanese people with type 2 diabetes taking one antidiabetes medication or treated with diet/exercise only | Comparator treatment: Liraglutide or placebo |
This phase 2/3a trial, published in The Lancet Diabetes & Endocrinology, involved 243 Japanese people with type 2 diabetes.
HbA1c reductions at week 26 (the primary endpoint) ranged from 1.1% to 1.7% (all significant) with 3, 7, and 14 mg/day oral semaglutide versus placebo. At the highest dose there was also a significant reduction of 0.3% versus liraglutide 0.9 mg, although this was not sustained at week 52.
Related news story: PIONEER 9, 10 confirm oral semaglutide efficacy in Japanese population
PIONEER 10: Published
Trial population: Japanese people with type 2 diabetes taking one antidiabetes medication | Comparator treatment: Dulaglutide |
This phase 3a trial also published in The Lancet Diabetes & Endocrinology and involved 458 Japanese people with type 2 diabetes.
The primary endpoint was adverse events up to approximately week 57, reported in up to 85% of participants taking semaglutide and 82% of those taking dulaglutide. Gastrointestinal events were the most common, with constipation more frequent than nausea.
The 14 mg dose of semaglutide produced a significant 0.3% HbA1c reduction versus dulaglutide at a dose of 0.9 mg, there was no difference with the 7 mg semaglutide dose, and the 3 mg dose was significantly less efficacious.
Related news story: PIONEER 9, 10 confirm oral semaglutide efficacy in Japanese population
PIONEER 11: Completed, not yet published
Trial population: Medication-naïve, predominantly Chinese people with type 2 diabetes | Comparator treatment: Placebo |
This trial recruited 533 people, mostly from China, but also from Taiwan, Algeria, and eastern Europe, to assess HbA1c changes over 26 weeks.
PIONEER 12: Completed, not yet published
Trial population: Predominantly Chinese people with type 2 diabetes | Comparator treatments: Sitagliptin, placebo |
This trial involves 1344 participants, mostly from China, but also from Taiwan, Hong Kong, Algeria, Brazil, South Africa, and eastern Europe. They took semaglutide, sitagliptin, or matching placebos for 26 weeks.
PIONEER PLUS: Completed, not yet published
Trial population: People with type 2 diabetes taking antidiabetes medications (not insulin or a GLP-1 receptor agonist) | Comparator treatment: Oral semaglutide 14 mg/day |
The PIONEER PLUS trial is testing two higher doses of oral semaglutide – 25 and 50 mg/day – against the approved 14 mg/day dose over 52 weeks. It aims to recruit 1224 participants and has an estimated primary completion date of August 2022.
PIONEER TEENS: Active, not recruiting
Trial population: Children aged 10 to 17 years with type 2 diabetes | Comparator treatment: Placebo |
This trial is designed to support approval of oral semaglutide in children and adolescents with type 2 diabetes, potentially giving this group the option of an oral GLP-1 receptor agonist. It aims to enroll 132 participants and the primary outcome is HbA1c change over 26 weeks, although treatment will continue for a full 52 weeks. The estimated primary completion date is May 2024.
PIONEER REAL: Enrolling by invitation/active, not recruiting/completed
Trial population: People with type 2 diabetes naïve to injectable glucose-lowering medications | Comparator treatment: None |
As the name suggests, the PIONEER REAL trial is assessing use of oral semaglutide at the currently approved dose in clinical practice. It is recruiting people whose physicians decided to offer them oral semaglutide independently of the study, and will assess HbA1c changes over 34–44 weeks of use.
The trial is taking place in the following locations: Canada (NCT04559815); Denmark (NCT04537637); Sweden (NCT04601753); the Netherlands (NCT04601740); Switzerland (NCT04537624); the UK (NCT04862923); and Japan (NCT04878393).
SOUL: Active, not recruiting
Trial population: People with type 2 diabetes, at least 50 years old, who have one or more of coronary heart disease, cerebrovascular disease, symptomatic peripheral artery disease, or chronic kidney disease | Comparator treatment: Placebo |
https://clinicaltrials.gov/ct2/show/NCT03914326 | |
SOUL is the cardiovascular efficacy trial for oral semaglutide, aiming to recruit approximately 9600 people and monitor them for major adverse cardiovascular events. The trial duration is event-driven; it is expected to complete in July 2024.
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