Oral semaglutide in patients with type 2 diabetes and cardiovascular disease, renal impairment, or other comorbidities, and in older patients

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ABSTRACT

Patients with type 2 diabetes (T2D) often have comorbidities, such as cardiovascular disease or chronic kidney disease, and a large and growing proportion of the T2D patient population is over 65 years. There are many therapies for the treatment of T2D but not all are suitable for patients with comorbidities. Oral semaglutide is a tablet formulation of a glucagon-like peptide-1 receptor agonist (GLP-1RA) and was recently approved for the treatment of T2D, representing an oral alternative to injectable GLP-1RAs. This article reviews data from: PIONEER 6, a phase 3a cardiovascular outcomes trial in patients at high cardiovascular risk; PIONEER 5, a phase 3a trial in patients with moderate renal impairment; a post-hoc analysis of PIONEER data by age; and pharmacokinetic trials investigating the effects of renal impairment, gastrointestinal disease, and hepatic impairment on the exposure of oral semaglutide. PIONEER 6 demonstrated the cardiovascular safety of oral semaglutide compared with placebo (hazard ratio: 0.79; 95% confidence interval [CI]: 0.57, 1.11; p < 0.001 for noninferiority), ruling out excess cardiovascular risk. In PIONEER 5, oral semaglutide was superior to placebo in decreasing glycated hemoglobin over 26 weeks (estimated treatment difference [ETD]: –0.8%; 95% CI: –1.0, –0.6; p < 0.0001) and body weight (ETD: –2.5 kg; 95% CI: –3.2, –1.8; p < 0.0001), and renal function was unchanged in both treatment groups. There was no effect of age on glycemic efficacy of oral semaglutide and the presence of upper gastrointestinal disease or hepatic impairment did not affect the pharmacokinetics of semaglutide. Across the trials, the safety profile of oral semaglutide was as expected for a GLP-1RA, with gastrointestinal adverse events most commonly reported. As such, oral semaglutide provides an effective oral GLP-1RA treatment option in older patients and/or those with comorbidities, with no requirements for dose adjustment.

KEYWORDS:

• Oral semaglutide
• type 2 diabetes
• cardiovascular disease
• chronic kidney disease
• older
• renal impairment
• hepatic impairment

Acknowledgments

Under the direction of the authors, medical writing and editorial support were provided by Nicola Beadle of Axis, a division of Spirit Medical Communications Group Ltd. (funded by Novo Nordisk Inc.). The authors were involved with drafting and/or critically editing all drafts during the development of the article, and all authors provided their final approval for submission.

Declaration of interest

O.M. reports: advisory board for AstraZeneca, Boehringer Ingelheim, BOL Pharma, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, and Sanofi; research grant support through Hadassah Hebrew University Hospital: AstraZeneca and Novo Nordisk; speaker’s bureau: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Sanofi.

E.M. reports: advisory board and speaker’s bureau for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi.

M.W. reports: advisory board and speaker’s bureau for Eli Lilly, Novo Nordisk, and Sanofi; speaker’s bureau for AstraZeneca and Merck; research support from AstraZeneca, Eli Lilly, Novo Nordisk, and Sanofi.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This peer reviewed article was supported by Novo Nordisk Inc.; the company was provided with the opportunity to perform a medical accuracy review.