EASD 2019

"The PIONEER journey: from concept to successful oral peptide delivery" session at the EASD 2019 annual meeting provided an overview of the PIONEER clinical trial programme evaluating the use of oral semaglutide. Professor Stephen Bain, Clinical Director of the Diabetes Research Unit Cymru and Medical Director for Research and Development for ABM University Health Board, Swansea University Medical School, UK introduced the session.

Timely intervention is needed to control glucose in patients with type 2 diabetes (T2D) as well as to reduce the risk of any complications, however, many patients do not reach or maintain their HbA_1c targets. GLP-1 receptor agonists (GLP-1RAs) are known to provide effective glycaemic control, help reduce weight, have a low risk of hypoglycaemia, and may provide cardiovascular (CV) benefits for patients with CV disease. Using an oral GLP-1RA may be more convenient for some patients and improve adherence compared with an injectable equivalent.

An overview of the PIONEER programme: clinical studies with oral semaglutide

*Early intervention.
†Treatment intensification.

Professor Melanie Davies, Professor of Diabetes Medicine at the University of Leicester described early intervention in T2D management with oral semaglutide, as studied in the PIONEER 1, 2 and 3 trials. Oral semaglutide has been tested at three dose levels – 3 mg, 7 mg and 14 mg – to allow optimisation of the benefit/ risk profile and to reduce gastrointestinal effects by using a dose escalation regimen.

PIONEER 1 compared the three doses of oral semaglutide with placebo over 6 months in drug-naive patients with T2D. PIONEER 2 compared 14 mg oral semaglutide with empagliflozin (SGLT-2 inhibitor) over 12 months. PIONEER 3 compared the three doses of oral semaglutide with sitagliptin (DPP-4 inhibitor) over 18 months.

The three studies showed:

• significant dose-dependent glucose-lowering effect compared with placebo and with active comparators (reduction in HbA_1c and greater proportion of patients reaching HbA_1c <7.0% target)
• significant dose-dependent reduction in bodyweight compared with placebo and with active comparators
• no unexpected safety findings (no difference in the incidence of overall adverse effects compared with placebo or active comparators; higher rates of nausea and vomiting consistent with the safety profile of subcutaneous GLP-1RAs)

Dr Ofri Mosenzon, Head of the Diabetes Clinical Research Centre in Hadassah Hebrew University Hospital, discussed the impact of treatment intensification with oral semaglutide in patients with T2D, as studied in the PIONEER 4, 5, 7 and 8 trials.

In PIONEER 7, oral semaglutide with a flexible dose adjustment was compared with sitagliptin. The dose was escalated if HbA_1c remained ≥7.0% (average baseline HbA_1c: 8.3%), unless the patient was experiencing moderate-to-severe nausea or vomiting. By the end of the 52-week trial, 10% of the oral semaglutide patients were on a 3 mg dose daily, 30% on a 7 mg dose and 60% on a 14 mg dose, demonstrating tolerability at the higher dosage. Efficacy, in terms of the proportion of patients reaching HbA_1c and average weight loss, was again proven for oral semaglutide compared with sitagliptin.

In PIONEER 4, oral semaglutide (14 mg) was compared with subcutaneous liraglutide, another GLP-1RA, or placebo in patients on a stable dose of metformin with or without an SGLT-2 inhibitor. At 52 weeks, a higher proportion of patients achieved HbA_1c <7.0% with oral semaglutide compared with liraglutide (69% vs 63%, respectively), and 49% lost ≥5% body weight versus 26% with liraglutide.

In PIONEER 8, oral semaglutide (3/7/14 mg) was tested as an add-on to basal insulin in patients with a long-standing T2D diagnosis (average of 15 years since diagnosis) versus placebo. It is known to be challenging to decrease both HbA_1c and body weight in such a population, and to avoid hypoglycaemic events. PIONEER 8 showed that 41% of patients taking a 14 mg dose of oral semaglutide achieved the composite endpoint at 52 weeks, which included HbA1c <7.0%, no hypoglycaemic events and no gain in body weight (p<0.05 compared with placebo). 45% of oral semaglutide patients achieved an HbA_1c reduction of ≥1% and weight loss of ≥3% (p<0.05 compared with placebo).

PIONEER 5 studied the use of oral semaglutide (14 mg) in patients with moderate renal impairment (estimated glomerular filtration rate; eGFR: 30-59 mL/min/1.73m₂). The patients had been treated with or without metformin, sulfonylurea and insulin, with an average of 14 years since T2D diagnosis. Efficacy of oral semaglutide in terms of both decrease in HbA_1c and decrease in body weight was superior to placebo, and independent of the stage of renal failure. No decrease in eGFR was seen at 26 weeks.

Professor Mansoor Husain, Executive Director of the Ted Rogers Centre for Heart Research and Director of Toronto General Research Institute, described the results of the cardiovascular (CV) outcomes trial, PIONEER 6. This study examined the effect of oral semaglutide (14 mg; n=1,591) on CV outcomes in patients at high risk of CV events versus placebo (n=1,592). In the primary endpoint, a major adverse CV events (MACE) composite of time to CV death, or non-fatal myocardial infarction or stroke, oral semaglutide was proven to be non-inferior to placebo (p<0.001), although did not demonstrate superiority (p=0.17). A substantial difference was seen in the individual component of CV death: 15 events in the oral semaglutide group compared with 30 events in the placebo group (HR 0.49; 95% CI 0.27-0.92). Oral semaglutide also reduced the risk of all-cause death by nearly 50% (HR 0.51; 95% CI 0.31-0.84). There were no differences in results across subgroups stratified by age, sex, BMI, HbA_1c, eGFR levels or CV risk factors.

Conclusions