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07-03-2019 | Semaglutide | At a glance | Article

Updated October 2019

A quick guide to the PIONEER trials

There are a total of 10 trials in the PIONEER series, 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.

And click here for our guide to the SUSTAIN trials, testing the weekly injectable version.

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 outcomes 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: Completed, not yet published

Trial population: Japanese people with type 2 diabetes taking one antidiabetes medication or treated with diet/exercise only

Comparator treatment: Liraglutide or placebo

https://clinicaltrials.gov/ct2/show/NCT03018028

A randomized, double-blind trial involving 243 Japanese people with type 2 diabetes, to meet Japanese regulatory requirements.

Although not yet published, a company press release reported significantly greater HbA1c reductions with 3, 7, and 14 mg/day oral semaglutide than with placebo, with the highest dose also producing a significantly larger reduction than liraglutide did.

PIONEER 10: Completed, not yet published

Trial population: Japanese people with type 2 diabetes taking one antidiabetes medication

Comparator treatment: Dulaglutide

https://clinicaltrials.gov/ct2/show/NCT03015220

A randomized, open-label trial, which has enrolled 458 Japanese people with type 2 diabetes.

By Eleanor McDermid

medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group

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