Oral Semaglutide + Basal Insulin

Analysis of the PIONEER 8 trial reveals dose-dependent reductions in A1c and body weight when oral semaglutide is paired with various insulin regimens.

Massive amounts of research and studies have been conducted to evaluate the various aspects of oral semaglutide as the first oral glucagon-like peptide-1 (GLP-1) receptor agonist. One of the most massive sets of trials investigating oral semaglutide is the “Peptide Innovation for Early Diabetes Treatment (PIONEER)” trials. Currently, there are a total of ten PIONEER trials that have been completed, with even more trials in this series that are currently in progress. The PIONEER 8 trial was designed to explore the safety, efficacy, and tolerability of oral semaglutide when added to an insulin regimen with or without metformin. Many patients living with type 2 diabetes (T2D) rely on dual-injectable therapies consisting of a GLP-1 receptor agonist and various insulin regimens to help meet their glycated hemoglobin (A1c) goals. Looking into the subgroup analysis of the PIONEER 8 trial will help determine how efficacious oral semaglutide is in combination with various insulin regimens.

A subgroup analysis of the PIONEER 8 trial conducted by Mosenzon et al. was designed to evaluate the efficacy and safety of oral semaglutide combined with a background insulin regimen. The PIONEER 8 trial was a randomized, double-blind, placebo-controlled, parallel-group trial. The inclusion criteria were that patients were 18 years or older, had an A1c between 7.0% and 9.5%, and were on a stable dose of either basal, basal-bolus, or premixed insulin with or without metformin for 90 days or more. A total of 731 patients randomized (1:1:1:1) to once-daily oral semaglutide 3, 7, and 14 mg and placebo were analyzed using an ANCOVA model. The primary endpoints were the change from baseline to week 52 in A1c, body weight, and total insulin dose. The secondary endpoints were safety-based, which included hypoglycemia and gastrointestinal (GI) adverse events.

Oral semaglutide was either trending towards or was superior to placebo in treatment differences for the change from baseline A1c (estimated treatment difference [ETD] –0.3% [95% CI –0.6, 0.0], –0.6% [–1.0, –0.3], and –1.0% [–1.3, –0.7] for 3, 7, and 14 mg, respectively, among patients with a basal insulin regimen). The ETD for patients using premixed insulin was –0.7% [95% CI –1.2, –0.3], –0.6% [–1.1, –0.1], and –0.9% [–1.4, –0.4] for 3, 7, and 14 mg, respectively. In regards to patients using basal-bolus insulin the ETD was –0.3% [95% CI –0.6, 0.1], –0.5% [–0.8, –0.1], and –0.9% [–1.2, –0.5] for 3, 7, and 14 mg, respectively.

Treatment differences for the change from baseline in body weight were in favor of oral semaglutide vs. placebo as the ETD for patients using basal insulin was –1.8% [95% CI –3.4, –0.3], –2.4% [–4.1, –0.8], and –5.0% [–6.6, –3.4] for 3, 7, and 14 mg, respectively. Similar dose-dependent reductions in body weight were seen among patients receiving premixed and basal-bolus insulin compared to placebo. Changes in total daily insulin dose were reduced with oral semaglutide compared with placebo; however, there was no clear trend in dose reductions between insulin subgroups. On-treatment of severe or blood-glucose confirmed hypoglycemic episodes were similar among other GLP-1 receptor agonists vs. placebo with slightly more episodes in the basal-bolus group. GI adverse events were higher in patients who took oral semaglutide over placebo regardless of the insulin regimen.

When combined with various insulin regimens, oral semaglutide appears to dose-dependently reduce both A1c and body weight when compared to placebo. The lack of consistency in changes from baseline total daily insulin between the various regimens suggests that insulin dose adjustments are more likely made on a patient-by-patient basis. Higher GI adverse events are typical among GLP-1 receptor agonists, and results show that oral semaglutide has a similar safety profile, among other drugs in this class. Overall, subgroup analysis of the PIONEER 8 trial favors oral semaglutide as a useful option when added on to an insulin regimen.

Practice Pearls:

• Oral semaglutide, when combined with various basal insulin regimens, reduces A1c and body weight in a dose-dependent fashion compared to placebo.
• Hypoglycemic episodes and GI adverse events are similar between oral semaglutide and other GLP-1 receptor agonists.
• Oral semaglutide provides patients who benefit from dual-injectable therapies with a GLP-1 receptor agonist and insulin with a more patient-friendly option.

Zinman, Bernard, et al. “Efficacy, Safety, and Tolerability of Oral Semaglutide Versus Placebo Added to Insulin With or Without Metformin in Patients With Type 2 Diabetes: The PIONEER 8 Trial.” Diabetes Care, vol. 42, no. 12, 2019, pp. 2262–2271., doi:10.2337/dc19-0898.

Mosenzon, Ofri, et al. “956-P: Efficacy and Safety of Oral Semaglutide When Added to Basal, Premix, or Basal-Bolus Insulin.” Diabetes, vol. 69, no. Supplement 1, 2020, doi:10.2337/db20-956-p.

Lawand Kamal, PharmD Candidate 2021, Skaggs School of Pharmacy and Pharmaceutical Sciences

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