Oral Semaglutide Use in Type 2 Diabetes: A Pooled Analysis of Clinical and Patient-Reported Outcomes from Seven PIONEER REAL Prospective Real-World Studies

Abstract

Introduction

Oral semaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1RA) approved for improving glycemic control in adults with type 2 diabetes (T2D). The PIONEER REAL program evaluates clinical and patient-reported outcomes of oral semaglutide treatment as part of routine clinical practice across 13 countries. Here, data from Canada, Denmark, Italy, the Netherlands, Sweden, Switzerland, and the UK are pooled and analyzed to address treatment satisfaction as well as glycated hemoglobin (HbA_1C) and body weight changes in relevant subgroup analyses.

Methods

This pooled analysis encompasses seven country-specific, non-interventional, multicenter, phase 4, prospective, single-arm clinical studies assessing the use of oral semaglutide in adults with T2D. Primary endpoint was the change in HbA_1C from baseline to end of study (EOS), and secondary endpoints included changes in body weight and treatment satisfaction. For the analyses, results were stratified by age, T2D duration, and oral semaglutide dose at EOS as well as baseline HbA_1C, body weight, and body mass index.

Results

Oral semaglutide treatment was initiated by 1615 participants. At EOS, 1222 (76%) participants out of the 1483 (92%) who completed the study were on treatment. Estimated changes in HbA_1C and body weight from baseline to week 38 were − 1.0%-point (95% CI − 1.08 to − 0.97; P < 0.0001) and − 5.0% (CI − 5.37 to − 4.72; P < 0.0001). Treatment satisfaction increased significantly during the study. Shorter T2D duration interacted with higher HbA_1C reduction and body weight loss. Interaction was also observed between higher baseline HbA_1C and more pronounced decrease in HbA_1C. No significant interactions were detected between clinical outcomes and age or physician setting.

Conclusion

The PIONEER REAL pooled analysis shows that people initiating oral semaglutide treatment experience improved glycemic control and body weight loss across age groups and T2D duration. This occurs regardless of specialist or primary care practice setting and is accompanied by an increased treatment satisfaction.

Clinical Trial Registrations

NCT04559815 (Canada), NCT04537637 (Denmark), NCT05230615 (Italy), NCT04601740 (the Netherlands), NCT04601753 (Sweden), NCT04537624 (Switzerland), NCT04862923 (UK).

Supplementary Information

The online version contains supplementary material available at 10.1007/s13300-024-01668-6.

Key Summary Points

Why carry out this study?

In the PIONEER phase 3 clinical program, oral semaglutide demonstrated efficacy in managing glycemic control and promoting weight loss in individuals with type 2 diabetes (T2D).

The PIONEER REAL initiative was launched as a follow-up to investigate the real-world clinical outcomes of oral semaglutide treatment.

In the PIONEER REAL pooled analysis, results from seven out of 13 PIONEER REAL studies across the world are combined, encompassing 1615 participants with T2D who were prescribed oral semaglutide as part of routine clinical practice and who had not previously been treated with injectable glucose-lowering medication.

What was learned from the study?

After 34–44 weeks of oral semaglutide treatment, participants across the seven countries experienced significant glycated hemoglobin (HbA1C) and body weight reductions, also when stratifying by relevant subgroups (e.g., age, T2D duration, and dose). Notably, these outcomes were irrespective of physician setting and were seen alongside improvements in treatment satisfaction.

Data from this PIONEER REAL pooled analysis complements the findings of the PIONEER clinical program and provides broadly applicable insights into the use and safety of oral semaglutide treatment in routine clinical practice.

Introduction

Globally, more than 500 million adults were estimated to be living with diabetes in 2021, and this is expected to reach more than 700 million by 2045, mainly reflecting prevalence of type 2 diabetes (T2D) [1]. Early and effective glycemic control after diagnosis is important to prevent long-term complications for people living with T2D [2]. Pharmacological interventions, along with healthy lifestyle changes, are part of the recommended treatment options [3]. Moreover, weight loss is considered a key objective to achieve glycemic control and is recommended by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) as part of T2D management [3].

Alongside the first-line glucose-lowering therapy metformin, glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter 2 (SGLT2) inhibitors are increasingly prescribed owing to their cardiovascular, glycemic, and weight management benefits [3]. Semaglutide is a human GLP-1 analogue approved as an adjunct to diet and exercise for improving glycemic control in adults with T2D. It is available for both once-weekly subcutaneous use (0.25, 0.5, 1.0, and 2.0 mg) and once-daily oral administration (3, 7, and 14 mg) [4, 5]. Through the PIONEER clinical development program [6–12], safety and efficacy of oral semaglutide has been demonstrated across different T2D population groups, e.g., different ages, race, weight, and baseline glycated hemoglobin (HbA_1C) levels.

Although GLP-1RAs are well established and recommended for treatment of T2D, they are underutilized [13]. The need for injections is often seen as a limitation for use of GLP-1RAs [14]. Oral semaglutide is a promising alternative that could enhance treatment acceptance and adherence and may lead to a wider use of GLP-1RAs in T2D treatment [13].

PIONEER REAL is a collection of 13 non-interventional studies across Europe, North America, and the Middle East that aims to complement the findings from the PIONEER clinical development program in real-world settings. The National Institute for Health and Care Excellence (NICE) in the UK is an example of real-world evidence (RWE) studies guiding clinical decision-making [15]. Additionally, a framework for a RWE program launched by the US Food and Drug Administration (FDA) [16] and the EU’s “OPerational, TechnIcal, and MethodologicAL framework” (OPTIMAL) [17] are examples of similar initiatives.

Here, we present a pooled analysis of seven PIONEER REAL studies from Canada [18], Denmark, Italy, the Netherlands [19], Sweden [20], Switzerland [21], and the UK [22]. The aim of the individual studies was to assess clinical and patient-reported outcomes of oral semaglutide use in adults with T2D in routine clinical practice. In this pooled analysis, focus is placed on treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) [23, 24] as well as real-world clinical outcomes of oral semaglutide treatment across relevant population subgroups stratified by baseline age, T2D duration, and physician setting (specialist vs. primary care). Complete datasets for the remaining six PIONEER REAL studies were not available at initiation of the current study, and therefore these results are not included in this pooled analysis.

Methods

Study Design

This PIONEER REAL pooled study included seven country-specific 34–44-week, non-interventional, multicenter, phase 4, prospective, single-arm clinical studies evaluating use of oral semaglutide in adults with T2D in routine clinical practice. Countries included are Canada (NCT04559815), Denmark (NCT04537637), Italy (NCT05230615), the Netherlands (NCT04601740), Sweden (NCT04601753), Switzerland (NCT04537624), and the UK (NCT04862923). Participants were administered oral semaglutide as decided collectively by the treating physician and participant; the decision to prescribe oral semaglutide was made prior to recruitment into the study. Data collection adhered to local clinical practices and did not involve any additional diagnostic or monitoring procedures. All country-specific protocols were approved by local independent ethics committees (IEC), institutional review boards (IRB) or equivalent authorities, and studies were conducted following good pharmacoepidemiology practices (GPP) [25] and good pharmacovigilance practices (GVP) [26] in accordance with the Declaration of Helsinki [27]. All participants signed an informed consent.

Participants

Adults with T2D were considered for inclusion if they had already decided to start oral semaglutide treatment, were naïve to treatment with injectable glucose-lowering medications, and had an HbA_1C value available ≤ 90 days prior to visit 1 or taken at visit 1 in accordance with local clinical norms. All participants were 18 years or older, and of any sex.

Study Procedures

The methodologies have been described in the individual PIONEER REAL studies [18–22], but to summarize, baseline data were collected either at the time of oral semaglutide prescription during visit 1 or from pre-existing records obtained before visit 1. Titration of oral semaglutide dose and additional treatment decisions were based on the assessment of the treating physician. All information was documented in an electronic case report form (eCRF). The first visit occurring between weeks 34 and 44 was designated as the end of study (EOS) visit. In cases where an HbA_1C value was not recorded within the 34–44-week window, the first available result thereafter was documented. Any visits between visit 1 and the EOS visit were classified as intermediate visits. If a participant stopped oral semaglutide treatment, details regarding the circumstances were recorded as close to the discontinuation date as possible. Data collection continued until the EOS visit, regardless of treatment status, unless consent was withdrawn.

Endpoints and Assessments

The primary endpoint was %-point change in HbA_1C from baseline to EOS. Secondary endpoints were relative (%) and absolute (kg) change in body weight from baseline to EOS, proportion of participants with an HbA_1C level < 7% (53 mmol/mol) at EOS, composite endpoints of HbA_1C reduction ≥ 1%-points (approximately 11 mmol/mol) combined with body weight reduction of ≥ 3% or ≥ 5% from baseline to EOS, and participant-reported outcomes of change in relative (DTSQ change, DTSQc) and absolute (DTSQ status, DTSQs) treatment satisfaction at EOS. DTSQc and DTSQs assessments were not a part the PIONEER REAL study in Switzerland. Regarding safety assessments, all adverse events (AEs) including pregnancy and all fatal outcomes occurring from treatment initiation until EOS visit were recorded. Furthermore, cases of self-reported severe hypoglycemia were recorded.

Additional analyses for the pooled study included estimated mean HbA_1C level by dose (3 mg, 7 mg, 14 mg) at EOS, as well as estimated HbA_1C change (in %-point) at EOS stratified by baseline HbA_1C, age (< 50 years, ≥ 50 to < 65 years, ≥ 65 to < 75 years, ≥ 75 years), T2D duration (≤ 1 year, > 1 to ≤ 5 years, > 5 to ≤ 10 years, > 10 years), by oral semaglutide dose at EOS (3 mg, 7 mg, 14 mg), and by physician setting (specialist vs. primary care). Estimated body weight change at EOS was stratified by T2D duration, oral semaglutide dose at EOS, and by baseline body mass index (BMI) (< 25, ≥ 25 to < 30, ≥ 30 kg/m²). Correlation between change in HbA_1C level and change in body weight was investigated and, finally, estimated body weight change at EOS was visualized across quartiles of estimated HbA_1C change at EOS. All analyses were performed on the full analysis set (FAS), including all qualified participants who provided informed consent and started treatment with oral semaglutide.

Statistical Analysis

Statistical analyses were conducted similarly across the seven country-specific PIONEER REAL studies, with analyses of the change in HbA_1C and body weight (both kg and %) from baseline to EOS performed using a random coefficient mixed model for repeated measurements (MMRM), and have been described previously [18–22]. In this pooled study, MMRM analyses were carried out in a similar manner but for data pooled from the seven included countries. Within the MMRM model, analyses of interaction between the estimated change in HbA_1C at EOS and the abovementioned baseline HbA_1C, age, T2D duration, and EOS dose groups were tested. The same tests of interaction were performed for the estimated change in body weight at EOS and baseline BMI and T2D duration as well as EOS dose groups. Correlation between change in HbA_1C level and change in body weight was measured by Spearman’s coefficient. All statistical testing was two-sided with a significance level of 0.05. Statistical analyses were performed using SAS, Version 9.3 (SAS Institute, Cary, NC).

Results

Participants and Baseline Characteristics

This study presents a pooled analysis of seven country-specific PIONEER REAL studies. The pooled participant disposition is summarized in Fig. 1. Informed consent was signed by 1691 participants, out of which 1615 met the eligibility criteria and initiated oral semaglutide treatment. At EOS, 1222 (76%) participants out of the 1483 (92%) who completed the study were on treatment. Reasons to discontinue oral semaglutide treatment included, as evaluated by the physician, safety concern (175 participants), insufficient effect on glycemic control (24 participants), change in treatment strategy (18 participants), change in reimbursement status (9 participants), epi-/pandemic (3 participants), intentions to become pregnant (1 participant), and other/unknown (84 participants). Treatment status at EOS could not be determined for 79 participants.

Fig. 1.

Participant disposition. ^aParticipants initiating oral semaglutide treatment and attended the EOS visit. ^bParticipants on oral semaglutide treatment and attended the EOS visit. EOS end of study, Epi-/pandemic COVID-19-related issue or similar

Participant disposition by country is summarized in Supplemental Table S1 and country-wise demographics and baseline characteristics are summarized in Supplemental Table S2. The majority of participants across countries were male (mean of 62%). At baseline, the mean HbA_1C was 8.1% (65 mmol/mol) and body weight 95.8 kg. Median baseline HbA_1C levels ranged from 7.4% (57 mmol/mol) to 8.4% (68 mmol/mol) across the countries. Baseline age ranged from 21 to 90 years, and T2D duration ranged from 0 to 39.5 years. Oral semaglutide was prescribed by primary care practitioners for 876 participants and by specialists for 739 participants.

Changes in HbA_1C

The effect of oral semaglutide treatment on participants’ HbA_1C levels is shown in Fig. 2. Estimated change in HbA_1C from baseline to week 38 across the seven country-specific studies was − 1.0%-point (95% CI − 1.08 to − 0.97; P < 0.0001) or − 11.2 mmol/mol (95% CI − 11.85 to − 10.57; P < 0.0001) (Fig. 2A). An interaction (P = 0.011) between subgroups emerged when stratifying HbA_1C change by baseline HbA_1C (Fig. 2B). The figure shows a greater reduction in HbA_1C levels with increasing baseline HbA_1C. The effect of age on the change in HbA_1C was also investigated. Figure 2C shows similar estimated HbA_1C changes at week 38 for the four age groups < 50 years, ≥ 50 to < 65 years, ≥ 65 to < 75 years, and ≥ 75 years. Estimates of HbA_1C changes when stratifying by diabetes duration (≤ 1 year, > 1 to ≤ 5 years, > 5 to ≤ 10 years, > 10 years) showed an interaction (P < 0.0001); while reductions in HbA_1C levels were observed across all intervals, participants having lived with diabetes for less than a year showed the highest estimated HbA_1C reduction, − 1.7%-points (95% CI − 1.86 to − 1.57) or − 18.8 mmol/mol (95% CI − 20.40 to − 17.17) (Fig. 2D). Stratifying the estimated change in HbA_1C by dose of oral semaglutide at EOS (3 mg, 7 mg, 14 mg) showed interaction between subgroups (P = 0.046), with slightly greater HbA_1C reductions with increasing dose (Fig. 2E). Mean HbA_1C levels were below 7% at EOS for participants receiving 7-mg (n = 492) or 14-mg (n = 583) doses of oral semaglutide at EOS, but not for participants on 3-mg doses (n = 69) (Fig. 2F). It was also investigated if the participants’ physician setting (specialist or primary care) played a role in the estimated HbA_1C change from baseline to week 38. No difference in HbA_1C reduction was estimated, regardless of the physician being a specialist or a primary care practitioner (Fig. 2G).

Fig. 2.

Changes in HbA_1C. A Observed HbA_1C at baseline and estimated HbA_1C at week 38 in % and mmol/mol as well as estimated change from baseline to week 38 in %-points and in mmol/mol (P < 0.0001). B Estimated HbA_1C change stratified by baseline HbA_1C (mean with 95% confidence interval is plotted; P = 0.011 for interaction). C Estimated HbA_1C change stratified by baseline age (mean with 95% confidence interval is plotted; interaction ns). D Estimated HbA_1C change stratified by T2D duration at baseline (mean with 95% confidence interval is plotted; P < 0.0001 for interaction). E Estimated HbA_1C change stratified by oral semaglutide dose at EOS (mean with 95% confidence interval is plotted; P = 0.046 for interaction). F Estimated mean HbA_1C by dose at EOS in % and mmol/mol. G Estimated HbA_1C change stratified by physician setting (mean with 95% confidence interval is plotted; P = 0.88 for difference between subgroups). BL baseline, EOS end of study, HbA_1C glycated hemoglobin, N total number of participants in full analysis set (FAS), n total number of participants contributing to the statistical analysis, ns non-significant, T2D type 2 diabetes. ***P < 0.0001; *P < 0.05

Changes in Body Weight

The effect of oral semaglutide treatment on the body weight of participants is shown in Fig. 3. A significant reduction from baseline to 38 weeks was estimated in both absolute and relative body weight: − 4.9 kg (95% CI − 5.19 to − 4.55; P < 0.0001) and − 5.0% (CI − 5.37 to − 4.72; P < 0.0001), respectively (Fig. 3A). A trend toward greater weight loss with increasing baseline BMI was observed (Fig. 3B). When results were stratified by diabetes duration, weight loss reduction was estimated for all intervals, with greatest weight reduction in participants having lived with diabetes for less than 1 year (Fig. 3C). A statistically significant interaction (P = 0.047) was found between diabetes duration and weight loss. Estimated weight reductions were similar across oral semaglutide doses at EOS (Fig. 3D). The majority (57.9%) of all participants had an HbA_1C level below 7.0% (53 mmol/mol) at EOS. Composite analysis of changes in HbA_1C and body weight from BL to EOS showed that 33.2% of participants obtained at least 1%-point (approximately 11 mmol/mol) reduction in HbA_1C in combination with at least 3% reduction in body weight, and 25.5% obtained at least 1%-point reduction in HbA_1C in combination with at least 5% reduction in body weight (Fig. 3E). Correlation between change in HbA_1C level and change in body weight was also investigated (Fig. 3F). The density plot provides a visualization of how body weight change varies across HbA_1C change quartiles. Generally, change in body weight varied most in participants with the least change in HbA_1C level, although probability density was lowest for these quartiles (Q1 and Q2). Conversely, higher probability densities were observed for quartiles representing greater HbA_1C changes, which correlated with less variability in body weight change (Q3 and Q4). A trend towards greater median body weight reduction in participants with least change in HbA_1C could be observed, albeit this trend was correlated with reduced probability density and higher body weight change variability. On the other hand, a significant correlation was observed between increasing HbA_1C reduction and increasing absolute (kg) body weight reduction (Spearman’s r 0.29, P < 0.0001).

Fig. 3.

Changes in body weight. A Absolute and relative estimated body weight change from baseline to week 38 in kg and in % (mean with 95% confidence interval is plotted). B Estimated body weight change (kg) by BL BMI (mean with 95% confidence interval is plotted; interaction ns). C Estimated body weight change (kg) stratified by T2D duration at baseline (mean with 95% confidence interval is plotted; P = 0.047 for interaction). D Estimated body weight change (kg) stratified by oral semaglutide dose at EOS (mean with 95% confidence interval is plotted; interaction ns). E Proportion of participants at HbA_1C target (7%) at EOS and composite endpoints of HbA_1C and body weight reduction at EOS. F Density plot for estimated body weight change based on quartiles of estimated HbA_1C change (%) at EOS. Q1 minimum value of HbA_1C change to 1st quartile based on HbA_1C change, Q2 1st quartile − 2nd quartile, Q3 2nd quartile − 3rd quartile, Q4 3rd quartile to maximum value of HbA_1c change. BL baseline, EOS end of study, BW body weight, HbA_1C glycated hemoglobin, N total number of participants in full analysis set (FAS), n total number of participants contributing to the statistical analysis, ns non-significant, T2D type 2 diabetes. *P < 0.05

Treatment Satisfaction

Absolute DTSQ (DTSQs) is measured by participants on a scale from 0 to 36, and answers indicating a very satisfying and convenient treatment score the highest. Relative DTSQ (DTSQc) is measured on a scale from − 18 to 18 and implies the change in treatment satisfaction, which is very useful when baseline treatment satisfaction is high [23]. An improvement in both DTSQ scores was observed at EOS (Fig. 4): estimated mean DTSQs increased by 3.5 points (95% CI 3.06–3.89; P < 0.0001) from baseline and the estimated mean DTSQc score was 12.2 (95% CI 11.79–12.58; P < 0.0001).

Fig. 4.

Change in treatment satisfaction. A Change in absolute treatment satisfaction at EOS (n = 968, P < 0.0001). B Relative treatment satisfaction at EOS (n = 983, P < 0.0001). (DTSQc and DTSQs assessments were not completed in the PIONEER REAL study for Switzerland.) DTSQc Diabetes Treatment Satisfaction Questionnaire-Change, DTSQs Diabetes Treatment Satisfaction Questionnaire-Status, EOS end of study, FAS full analysis set

Safety

Across the seven PIONEER REAL studies, 1226 adverse events (AEs) in 551 participants (34.1%) were reported during the in-study observation period, and most of these were non-serious (1153 events in 528 participants) and mild or moderate in severity (Table 1). A total of 73 serious AEs were reported in 56 participants (3.5%). Eight AEs lead to a fatal outcome, but all were assessed as unlikely to be related to oral semaglutide treatment. Twenty-eight self-reported events of severe hypoglycemia were reported by 14 participants. As a consequence of AEs, oral semaglutide was withdrawn in 181 participants (11.2%), interrupted in 87 participants (5.4%), and the dose was reduced in 58 participants (3.6%).

Table 1.

Adverse events

	Serious			Non-serious			Total
	N (%)	E	R	N (%)	E	R	N (%)	E	R
Adverse events	56 (3.5)	73	5.9	528 (32.7)	1153	93.0	551 (34.1)	1226	98.9
Mild	7 (0.4)	8	0.6	403 (25.0)	779	62.8	407 (25.2)	787	63.5
Moderate	23 (1.4)	28	2.3	191 (11.8)	351	28.3	209 (12.9)	379	30.6
Severe	30 (1.9)	37	3.0	15 (0.9)	22	1.8	44 (2.7)	59	4.8
Deaths	8 (0.5)	8	0.6	0	–	–	8 (0.5)	8	0.6
Self-reported severe hypoglycemiaa	N/A	N/A	N/A	N/A	N/A	N/A	14 (0.9)	28	–
Actions taken
Drug interrupted	5 (0.3)	5	0.4	83 (5.1)	147	11.9	87 (5.4)	152	12.3
Drug withdrawn	14 (0.9)	18	1.5	169 (10.5)	275	22.2	181 (11.2)	293	23.6
Dose reduced	1 (0.1)	1	0.1	57 (3.5)	89	7.2	58 (3.6)	90	7.3
Dose increased	0	–	–	13 (0.8)	18	1.5	13 (0.8)	18	1.5
Dose not changed	29 (1.8)	37	3.0	293 (18.1)	584	47.1	304 (18.8)	621	50.1
N/A	10 (0.6)	12	1.0	23 (1.4)	40	3.2	32 (2.0)	52	4.2

Data are for the in-study observation period, which represents the time period during which participants were part of the study, regardless of oral semaglutide treatment status

% percentage of participants, E number of events, N number of participants, N/A not applicable, R event rate per 100 years of observation time

^aSevere hypoglycemia can be defined as a severe event characterized by altered mental and/or physical functioning that requires assistance from another person for recovery

Discussion

Our pooled analysis of seven country-specific RWE studies assessing the use of oral semaglutide in adults with T2D shows that clinically relevant reductions in HbA_1C and body weight are seen regardless of baseline HbA_1C, body weight, age, or T2D duration. Moreover, outcomes are similar for participants treated by either primary care physicians or specialists. Even though treatment satisfaction among participants was high at study start, it significantly increased during the study.

Generally, glycemic control in participants receiving oral semaglutide treatment was similar across the seven country-specific studies, estimated mean HbA_1C change ranging from − 0.9%-point in Sweden (− 9.6 mmol/mol) [20], Denmark (unpublished) (− 9.9 mmol/mol), Switzerland (− 9.9 mmol/mol) [21], and Italy (− 10.0 mmol/mol) to − 1.2%-point (− 12.7 mmol/mol) in the Netherlands [19]. The pooled estimated change in HbA_1C from baseline to week 38 was − 1.0%-point (− 11.2 mmol/mol). The estimated change in body weight of − 4.9 kg (− 5.0%) reflects the corresponding results in individual countries, except for Canada, where the estimated body weight change was − 7.19 kg (− 7.17%) [18]. A USA-based retrospective observational cohort study (IGNITE) has also studied oral semaglutide use in adults with T2D in clinical practice [28]. In the IGNITE population, a 0.9%-point (approximately 10 mmol/mol) reduction in HbA_1C was observed for the full study cohort after 5.7 months of treatment while the reduction was 1.0%-point (approximately 11 mmol/mol) in GLP-1RA-naïve individuals.

We also explored the relationship between improvement in glycemic control and body weight changes during oral semaglutide treatment. Similar investigations have been performed for subcutaneous treatment with tirzepatide, a combined glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist [29], as well as for the GLP-1RAs liraglutide, exenatide, dulaglutide, and semaglutide [30–34]. These analyses generally showed that greater HbA_1C reductions correlated with greater weight loss, albeit weakly. In this PIONEER REAL pooled study, a similar correlation between HbA_1C change and body weight change was observed.

Comparing results between country-specific PIONEER REAL studies should be done with caution, as results are based on real-world settings that vary in characteristics (e.g., different baseline HbA_1C or T2D duration). Combining results from the seven individual studies into a statistically powerful dataset, on the other hand, allows an attempt to extract information that is both highly relevant and widely applicable. That is what we have sought to take advantage of in this pooled analysis. Our results show that participants receiving oral semaglutide treatment experience improved HbA_1C levels across age groups from under 50-year-old to over 75-year-old in a real-world setting. This is in line with other studies where other GLP-1RAs, liraglutide and dulaglutide, have proven to be effective in the treatment of T2D across various age groups [32, 35–37]. Clinical studies, such as the PIONEER program for oral semaglutide, have demonstrated robust glucose-lowering and weight reduction effects in diverse age demographics [6].

When changes in HbA_1C levels were stratified by baseline diabetes duration, pooled results showed a reduction across all intervals, in line with the clinical PIONEER program [38]. Reduction in HbA_1C levels in the current study was more than twice as high in participants having lived with diabetes for less than a year compared to participants with a diabetes duration of more than 5 years. A similar albeit weaker trend was seen when stratifying body weight change by baseline diabetes duration; participants with a shorter duration of T2D often experienced more substantial reductions in body weight compared to those with a longer disease duration. These findings suggest that improvements seen in glycemic control and weight management may be more pronounced in participants with a shorter T2D duration, which may help in motivating affected individuals to an early and adequate intervention. It is important to note that participants receiving oral semaglutide treatment experienced improvements in glycemic control and weight management regardless of T2D duration.

A major objective for the PIONEER REAL pooled study was to investigate if the participants’ physician setting (specialist or primary care) played a role in the estimated HbA_1C change from baseline to EOS. No difference in HbA_1C reduction was observed, regardless of the physician being a specialist or a primary care practitioner. The numbers of participants prescribed oral semaglutide by a primary care practitioner or specialist were very similar in this dataset (876 and 739, respectively). This distribution is unusual for a relatively newly available antidiabetic drug, which would typically be favored by specialists. A partial explanation for this could be that primary care practitioners are less hesitant to prescribe oral semaglutide owing to ease of administration and, in some cases, higher adherence to an oral option compared to injections [13]. It should be noted that the selected study sites for the individual PIONEER REAL studies may limit interpretability of this result.

Treatment satisfaction among individuals with T2D is a multifaceted concept that encompasses various dimensions such as glycemic control, weight management, ease of use, side effects, and overall quality of life. Treatment satisfaction among participants, as assessed by both DTSQs and DTSQc [23, 24], was generally high at baseline across the seven pooled countries, but treatment with oral semaglutide significantly increased both DTSQs and DTSQc scores at the EOS: estimated mean DTSQs increased by 3.5 points and the estimated mean DTSQc score was 12.2. This indicates that participants highly valued the treatment with oral semaglutide, even if their level of satisfaction was already good at baseline. The observed improvement in treatment satisfaction is important as it may enhance participants’ self-efficacy and adherence to therapy, leading to long-term stable glycemic control and reduced risk of complications [39]. No new safety concerns were observed in the seven completed studies of the PIONEER REAL program.

Typical limitations for a real-world study also apply for the individual PIONEER REAL studies, where limitations are described in more detail [18–22]. Briefly, the studies were purely observational and designed without a comparator arm. As data were collected as part of routine clinical practice, the robustness and completeness of the data and conclusions may be affected. Finally, the studies were conducted during the COVID-19 pandemic, leading to several participants not completing their EOS assessment in the predefined timeframe.

Conclusion

The PIONEER REAL pooled analysis provides broadly applicable insights into the use and safety of oral semaglutide treatment in everyday clinical practice. Participants experienced substantial enhancements in glycemic control and body weight reduction after 34–44 weeks of treatment across participating countries and investigated population subgroups. Notably, these outcomes were irrespective of physician setting and were seen alongside improvements in treatment satisfaction.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Data were analyzed by the sponsor. Gottfried Rudofsky, Hanan Amadid, Uffe Christian Braae, Sergiu-Bogdan Catrina, Anastas Kick, Kabirdev Mandavya, Klaus Roslind, Ponnusamy Saravanan, William van Houtum, and Akshay Bhanwarlal Jain contributed to interpretation of data as well as writing, reviewing and editing the manuscript. All authors approved the final version of the manuscript.

Funding

The PIONEER REAL studies and this pooled anaysis are sponsored by Novo Nordisk A/S. The journal’s Rapid Service Fee was funded by Novo Nordisk A/S.

Data Availability

Data are available upon reasonable request. Data will be shared with bona fide researchers submitting a research proposal approved by the independent review board. Access request proposals can be found at novonordisk-trials.com. Data will be made available after research completion and approval of the product and product use in the European Union and the United States. Individual participant data will be shared in datasets in a de-identified/anonymized format.

Declarations

Conflict of Interest

Gottfried Rudofsky: receives lecture fees from Novo Nordisk. Hanan Amadid: employee and shareholder of Novo Nordisk A/S. Uffe C. Braae: employee and shareholder of Novo Nordisk A/S. Sergiu-Bogdan Catrina: No conflict of interest. Anastas Kick: Lecture/other fees from NovoNordisk and Abbott. Kabirdev Mandavya: employee of Novo Nordisk A/S. Klaus Roslind: Honorarium/Moderator at Novo Nordisk meetings. Ponnusamy Saravanan: International Doctoral Training scholarship Grant from Novo Nordisk; PhD studentship funding from BHR Pharmaceuticals, UK; Joint MRC—Abbott project grant for Magic study; Lecture/other fees from Novo Nordisk, Sanofi, Lilly, Boehringer, Abbott. William van Houtum: No conflict of interest. Akshay B. Jain: Grants from Abbott, Amgen, Novo Nordisk; Honorarium from Abbott, AstraZeneca, Amgen, Bausch Healthcare, Bayer, Boehringer Ingelheim, Care to Know, CCRN, Connected in Motion, CPD Network, Dexcom, Diabetes Canada, Eli Lilly, GSK, HLS Therapeutics, Janssen, Master Clinician Alliance, MDBriefcase, Merck, Medtronic, Moderna, Novartis, Novo Nordisk, Partners in Progressive Medical Education, Pfizer, Timed Right, WebMD; Lecture/other fees from Abbott, AstraZeneca, Amgen, Bausch Healthcare, Bayer, Boehringer Ingelheim, Dexcom, Eli Lilly, Gilead Sciences, GSK, HLS Therapeutics, Insulet, Janssen, Medtronic, Novartis, Novo Nordisk, Partners in Progressive Medical Education, Pfizer, PocketPills, Roche, Takeda, Ypsomed.

Ethical Approval

The PIONEER REAL study protocols were approved by local independent ethics committees (IEC), institutional review boards (IRB) or equivalent authorities, and studies were conducted following good pharmacoepidemiology practices (GPP) [25] and good pharmacovigilance practices (GVP) [26] in accordance with the Declaration of Helsinki [27]. All participants signed an informed consent.