Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme

Tina K Thethi, Richard Pratley, Juris J Meier, Tina K Thethi, Richard Pratley, Juris J Meier

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended for glycaemic management in patients with type 2 diabetes (T2D). Oral semaglutide, the first oral GLP-1RA, has recently been approved for clinical use, based on the results of the randomized, Phase 3a Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) clinical trials. The PIONEER programme tested oral semaglutide in patients with T2D of duration ranging from 3.5 to 15 years, from monotherapy through to insulin add-on, in global populations and two trials dedicated to Japanese patients. Outcomes (glycated haemoglobin [HbA1c] and body weight reduction, plus other relevant efficacy and safety endpoints) were tested against both placebo and active standard-of-care medications. A separate trial evaluated the cardiovascular safety of oral semaglutide in patients with T2D at high cardiovascular risk. Over periods of treatment up to 78 weeks, oral semaglutide 7 and 14 mg once daily reduced HbA1c and body weight across the spectrum of T2D, and improved other diabetes-related endpoints, such as fasting plasma glucose. Oral semaglutide provided significantly better efficacy than placebo and commonly used glucose-lowering medications from the dipeptidyl peptidase-4 inhibitor (sitagliptin) and sodium-glucose co-transporter-2 inhibitor (empagliflozin) classes, as well as the subcutaneous GLP-1RAs liraglutide and dulaglutide. Oral semaglutide was well tolerated in line with the known safety profile of GLP-1RAs, with transient gastrointestinal events being the most common side effects reported. Cardiovascular safety was demonstrated for oral semaglutide in patients with cardiovascular disease or high cardiovascular risk. The results of the PIONEER programme suggest that oral semaglutide is efficacious and well tolerated for glycaemic control of T2D. The availability of oral semaglutide may help to broaden treatment choice and facilitate adoption of earlier GLP-1RA treatment in the paradigm of T2D management.

Trial registration: ClinicalTrials.gov NCT02906930 NCT02863328 NCT02607865 NCT02863419 NCT02827708 NCT02692716 NCT02849080 NCT03021187 NCT03018028 NCT03015220.

Keywords: GLP-1 analogue; Phase 3 study; cardiovascular disease; clinical trial; type 2 diabetes.

Conflict of interest statement

T.K.T. is on the speaker's bureau for Novo Nordisk and is one of the US national leads for the Semaglutide Cardiovascular Outcomes Trial in Patients With Type 2 Diabetes (SOUL) trial (NCT03914326). R.P. has received lecture and consulting fees from AstraZeneca; consulting fees from Boehringer Ingelheim, Eisai, GlaxoSmithKline and Mundipharma; grants and lecture/consulting fees from Glytec, Janssen, Novo Nordisk, Pfizer and Takeda; grants from Lexicon Pharmaceuticals; and grants and consulting fees from Ligand Pharmaceuticals, Lilly, Merck and Sanofi‐Aventis US. Except for consulting fees in February 2018 and June 2018 received from Sanofi US Services, all fees for services were paid directly to AdventHealth, a non‐profit organization. J.J.M. has received lecture honoraria and consulting fees from AstraZeneca, Berlin‐Chemie, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme (MSD), Novo Nordisk, Novartis and Sanofi; has received reimbursement of congress participation fees and travel expenses from MSD, Novo Nordisk and Sanofi; and has initiated projects supported by Boehringer Ingelheim, MSD, Novo Nordisk and Sanofi.

© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
Mechanism of absorption of oral semaglutide. 21 GI, gastrointestinal; SNAC, sodium N‐(8‐[2‐hydroxybenzoyl] amino) caprylate
FIGURE 2
FIGURE 2
Reduction in HbA1c with oral semaglutide and comparators. A, Primary analysis time point (26 weeks except for PIONEER 6 and 7). B, End of treatment in the PIONEER trials, by the treatment policy estimand 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 (part B adapted with permission from Rasmussen. Diabetol Int. 2020;11(2):76‐86 55 ). Data are for the treatment policy estimand (including data from patients who discontinued treatment or required rescue medication). aHbA1c reduction was not the primary endpoint in PIONEER 6 or 7; bevent‐driven trial: efficacy outcomes were not analysed statistically. *P < .05 for the estimated treatment difference with oral semaglutide vs placebo and/or active comparator; †P < .05 for the estimated treatment difference with comparator vs oral semaglutide 3 mg. CKD, chronic kidney disease; CVD, cardiovascular disease; dula, dulaglutide; empa, empagliflozin; HbA1c, glycated haemoglobin; imp, impairment; lira, liraglutide; met, metformin; OAD, oral antidiabetic drug; pbo, placebo; sema, semaglutide; SGLT2i, sodium‐glucose co‐transporter‐2 inhibitor; sita, sitagliptin; SU, sulfonylurea; T2D, type 2 diabetes
FIGURE 3
FIGURE 3
Reduction in body weight with oral semaglutide and comparators. A, Primary analysis time point (26 weeks except for PIONEER 6 and 7). B, End of treatment in the PIONEER trials, by the treatment policy estimand 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 (part B adapted with permission from Rasmussen. Diabetol Int. 2020;11(2):76‐86 55 ). Data are for the treatment policy estimand (including data from patients who discontinued treatment or required rescue medication). aEvent‐driven trial: efficacy outcomes were not analysed statistically. *P < .05 for the estimated treatment difference with oral semaglutide vs placebo and/or active comparator. CKD, chronic kidney disease; CVD, cardiovascular disease; dula, dulaglutide; empa, empagliflozin; imp, impairment; lira, liraglutide; met, metformin; OAD, oral antidiabetic drug; pbo, placebo; sema, semaglutide; SGLT2i, sodium‐glucose co‐transporter‐2 inhibitor; sita, sitagliptin; SU, sulfonylurea; T2D, type 2 diabetes

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