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Insights into the early use of oral semaglutide in routine clinical practice: The IGNITE study

Abstract Oral semaglutide is the first oral glucagon‐like peptide‐1 receptor agonist for the treatment of type 2 diabetes, and showed significant benefits in glycaemic control and weight reduction versus active comparators in the PIONEER phase 3a randomized controlled trial programme. In this retrospective study, we present early data on the use of oral semaglutide in clinical practice, from the US IBM Explorys electronic health record database. In 782 patients prescribed oral semaglutide, 54.5% were women, and the mean age (SD) was 57.8 years (11.3); 66.0% of patients received their prescription from a primary care practitioner. Although prescribing information recommends increasing the dose to 7 mg after 30 days, 37.0% of patients received a prescription only for the initial 3 mg dose. Mean body mass index was 36.2 kg/m2 (7.6); mean HbA1c was 8.4% (1.8%). Mean HbA1c change from baseline to approximately 6 months after oral semaglutide initiation was −0.9% (95% CI: −1.1%; −0.6%), with greater reductions in patients with higher baseline HbA1c. These data indicate prevalent early adoption of oral semaglutide in primary care, show real‐world improvements in glycaemic control, and identify potential treatment gaps.


| INTRODUCTION
Oral semaglutide (Rybelsus; Novo Nordisk) is the first glucagon-like peptide-1 receptor agonist (GLP-1 RA) developed for oral administration for the treatment of type 2 diabetes (T2D), and it has been approved by the US Food and Drug Administration 1 and the European Medicines Agency. 2 The efficacy and safety of oral semaglutide were assessed in the Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) programme of 10 phase 3a randomized controlled trials (RCTs), which included more than 9500 patients. 3 This programme studied the incorporation of oral semaglutide at multiple stages of the T2D treatment pathway: early therapy, add-on to oral therapy and addition to insulin. Oral semaglutide showed significant improvements in glycaemic control and weight reduction versus various comparator arms representing common treatment classes in T2D, 4 is based on a molecule with a favourable cardiovascular (CV) risk-benefit profile, 5 and was shown to be non-inferior to placebo in terms of CV safety in the PIONEER 6 trial. 6 The US prescribing information for oral semaglutide specifies initiation with a 3 mg starting dose for 30 days, followed by escalation to the 7 mg treatment dose, with further escalation to 14 mg after another 30 days if needed for additional glycaemic control. 7 Insights into the real-world use of oral semaglutide are needed to further understand and support clinical decision-making. The current study, InvestiGating New InitiaTors on oral semaglutidE in routine clinical practice (IGNITE), was designed to examine how trial data have been translated to US clinical practice during the early period of oral semaglutide availability, using electronic health record (EHR) data. We sought to evaluate the first patterns of routine clinical use of oral semaglutide, and to assess patients' clinical characteristics and glycaemic control.

| METHODS
This was a retrospective, observational cohort study, using EHRs extracted from the IBM Explorys EHR database (IBM Watson Health, Armonk, NY, USA). 8 Only de-identified secondary data were used; therefore, approval by an ethics committee was not required. The study period began on 28 October 2019, with database lock on 15 December 2020. For inclusion, adult patients (aged ≥18 years) required a diagnosis of T2D (Table S1) and at least one prescription for oral semaglutide (index date; Figure S1).
Patients with type 1 diabetes or gestational diabetes were excluded.
Demographic characteristics at index date, and baseline comorbidities and antidiabetic medication prescriptions (365 days preindex), were collected for the full cohort. Baseline HbA1c, weight and cholesterol measurements (90 days preindex) were recorded for patients with available data. HbA1c trajectory before and after index date was plotted ( Figure S1); to ensure that the same patients were assessed longitudinally, only data from patients who had measurements available at three or more 3-monthly time points were included (see the Figure 1 footnotes for full details).

| DISCUSSION
In this report, we describe the characteristics of some of the first patients prescribed oral semaglutide in US clinical practice, and present evidence of improvements in glycaemic control. This analysis also identifies strengths and gaps in translation of clinical innovations to care settings. The PIONEER programme showed the glycaemic efficacy of oral semaglutide across the full treatment continuum of T2D, and our data on baseline medications indicate adoption across the treatment spectrum. The majority of patients were prescribed oral semaglutide by a primary care practitioner. This is unusual for a newly available antidiabetic drug, which would typically be favoured by specialist practitioners. Obesity rates were generally higher in the study cohort than in the PIONEER programme; mean BMI was 36.2 kg/m 2 in our study, compared with 31.8, 32.8, 32.5 and 31.5 kg/m 2 in PIO-NEER 1, 10 14 which is likely to be another source of bias in our study sample. This may partly explain delays in dose escalation; however, the extent to which the pandemic has affected these patients may never be fully understood.
Finally, our analysis does not assess medication-taking behaviour or adverse events (AEs) in patients receiving oral semaglutide. In future, the inclusion of administrative claims in a similar analysis can be used to assess persistence and adherence to medication. However, the limitations of the retrospective study design and data source mean that common AEs such as nausea are unlikely to be captured accurately and systematically, resulting in under-reporting of AE incidence.
Therefore, even once larger real-world sample sizes are available, RCTs will continue to be the most reliable source of safety data for oral semaglutide.