FormalPara Key Summary Points

Why carry out this study?

The prevalence of type 2 diabetes is increasing in Sweden.

Oral semaglutide is routinely used for the treatment of type 2 diabetes but efficacy and safety data associated with its use in real-world clinical practice are scarce. The PIONEER REAL programme comprises 13 non-interventional studies, each in a different country, assessing the use of oral semaglutide in a real-world setting.

The PIONEER REAL Sweden study was designed to evaluate clinical outcomes in people with type 2 diabetes who initiated treatment with once-daily oral semaglutide in Swedish clinical practice.

What was learned from the study?

We observed clinically significant improvements in glycaemic control and body weight, and improvements in treatment satisfaction. The safety profile reported was consistent with previous phase 3 clinical trials.

The findings of PIONEER REAL Sweden corroborate the results of the phase 3 PIONEER clinical trial programme and provide valuable insight into the use of once-daily oral semaglutide in a real-world adult population with type 2 diabetes.

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Introduction

The prevalence of diabetes in Sweden among people aged 20–79 years was estimated at 5% in 2021 and it is projected to increase to 6% by 2045 [1]. Among individuals in Sweden with type 2 diabetes (T2D), delays in achieving glycaemic control and complications arising from T2D can have considerable negative impacts on individuals’ lives, in terms of work absenteeism, costs and life expectancy [2, 3]. Therefore, effective T2D management is imperative [4]. The latest Swedish national diabetes guidelines for adults emphasise the importance of preventing T2D as well as preventing diabetes complications by addressing the risk factors that have the strongest relationship to cardiovascular disease (CVD). The guidelines therefore highlight the need for use of evidence-based treatment to control blood glucose, blood pressure and blood lipids, together with the treatment of lifestyle factors [4].

Achievement and maintenance of glycaemic control is central to T2D management; weight loss is a primary target to achieve this, to reduce cardiometabolic risk factors and improve people’s quality of life [5]. Traditionally, metformin was recommended as first-line glucose-lowering therapy; more recently, glucagon-like peptide 1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter 2 (SGLT-2) inhibitors are recommended independently from metformin for individuals with, or at risk of, CVD, heart failure or chronic kidney disease (CKD), thanks to their benefits for CV and renal outcomes [6].

Semaglutide is a human GLP-1 analogue approved as an adjunct to diet and exercise for improving glycaemic control in adults with T2D; it is the first of its kind 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) [7, 8]. The phase 3 PIONEER clinical development programme demonstrated superior reductions in glycated haemoglobin (HbA1c) and body weight with oral semaglutide versus placebo and several active comparators, along with a safety profile consistent with other GLP-1RAs, in participants with T2D [9,10,11,12,13,14,15].

The ongoing PIONEER REAL programme comprises 13 non-interventional phase 4 studies in Europe, North America, the Middle East and East Asia, with each study run in a separate country. The programme is investigating the use of oral semaglutide in routine clinical practice in real-world populations of adults with T2D who had not previously been treated with injectable glucose-lowering medications, to provide insights on how oral semaglutide performs in this setting. It is anticipated that the PIONEER REAL programme will involve over 3000 adults with T2D. To date, PIONEER REAL studies in Canada, Japan, Switzerland and in the Netherlands have been completed. The aim of the PIONEER REAL Sweden study was to assess the clinical outcomes associated with the use of once-daily oral semaglutide initiated within routine clinical practice in adults with T2D in Sweden (ClinicalTrials.gov registration NCT04601753).

Methods

Study Design and Procedures

PIONEER REAL Sweden was a non-interventional, single-arm, phase 4, prospective, open-label study conducted across 28 centres in Sweden. It was part of the wider PIONEER REAL clinical programme and, as such, had a similar study design, procedures and endpoints to PIONEER REAL Switzerland [16]. In PIONEER REAL Sweden, participants received oral semaglutide in accordance with Swedish clinical practice. Treatment initiation was at the treating physician’s discretion. At the start of the study (visit 1), participants or their legally acceptable representative provided informed consent, demographic and medical history data were collected, and treating physicians recorded the reason(s) for initiating oral semaglutide. Baseline data were collected at, or ≤ 90 days before, visit 1. Visit 1 was considered to have occurred when participants initiated once-daily oral semaglutide in accordance with local clinical practice. Participants could then have intermediate visits depending on local clinical practice (visit 2.x) before the end of study (EOS) visit (visit 3) at 34–44 weeks. As a consequence of the coronavirus disease 2019 (COVID-19) pandemic participants were allowed to have EOS visits outside the study duration of 44 weeks at the discretion of the treating physician. The EOS visit between 34 and 44 weeks was registered as visit 3, but if a HbA1c measurement was not available during that period, the first HbA1c measurement taken after that time period and up to last participant last visit was recorded.

The study was conducted in line with Good Pharmacoepidemiology Practices [17] and Good Pharmacovigilance Practices [18], and physicians had to comply with applicable regulatory requirements and the requirements in the Declaration of Helsinki. Study-specific documentation was submitted to the relevant national body, and the study was approved by the independent ethics committee or institutional review board for each participating centre. The independent ethics committee for each site was Etikprövningsmyndigheten, Uppsala, Sweden. Participants provided written informed consent prior to commencement of any study-related activity.

Participants and Physicians

Male and female participants aged ≥ 18 years with a diagnosis of T2D and an available HbA1c ≤ 90 days prior to visit 1 or a HbA1c measurement at visit 1 in line with local clinical practice were included. Participants were also required to be treatment-naïve to injectable glucose-lowering drugs, except for short-term insulin treatment for acute illness lasting for a total of ≤ 14 days. Participants were excluded if they had previously participated in this study, had received treatment with an investigational drug ≤ 30 days prior to enrolment, or had mental incapacity, unwillingness or language barriers precluding understanding or co-operation.

Endpoints

Glycaemic and Weight Changes Over Time

The primary endpoint was change from baseline to EOS in HbA1c (percentage-points). Key secondary endpoints included relative (percentage) and absolute (kilograms) change from baseline to EOS in body weight. Estimated changes from baseline in HbA1c and body weight were analysed to EOS. Participants included in this analysis were those who had complete covariates dependent and variable information, and contributed to the primary analysis of mean change in HbA1c and body weight.

Glycaemic and Weight Targets

Other key secondary endpoints included the proportion of participants with HbA1c < 7% at EOS, the proportion of participants with both a reduction in HbA1c of ≥ 1%-points and a body weight reduction of ≥ 3%, and the proportion of participants with both a reduction in HbA1c of ≥ 1%-points and body weight reduction of ≥ 5% from baseline at EOS. Exploratory endpoints assessed the proportion of participants who achieved < 7% at EOS and the change from baseline in waist circumference (centimetres) to EOS.

Participant- and Physician-Reported Outcomes

The Diabetes Treatment Satisfaction Questionnaire status (DTSQs) and Diabetes Treatment Satisfaction Questionnaire change (DTSQc) were employed as key secondary endpoints and measured absolute (DTSQs) and relative (DTSQc) treatment satisfaction from baseline to EOS. The DTSQs was completed at visit 1 and visit 3, whereas the DTSQc was completed at visit 3 only. The DTSQs comprised eight items to measure participant satisfaction with their diabetes treatment, answered on a Likert scale from 0 (very dissatisfied) to 6 (very satisfied); six of the items were summed to produce a Total Satisfaction score. The DTSQc used the same eight items, but participants rated their change in treatment satisfaction with semaglutide versus before initiating oral semaglutide, on a scale of − 3 (much less satisfied now) to + 3 (much more satisfied now).

As an exploratory endpoint, a dosing conditions questionnaire was administered to participants at visit 3 or at the time of treatment discontinuation if discontinuation occurred prior to visit 3, to ascertain how semaglutide was taken and the ease of taking it. Physicians also assessed whether participants had achieved clinical success in relation to the reason for initiating oral semaglutide, at the EOS visit.

Treatment Patterns

Exploratory endpoints measured at EOS included the number of participants treated with oral semaglutide, semaglutide dose, and the addition or removal of glucose-lowering medications and increase or decrease in glucose-lowering medication doses.

Safety

Self-reported severe hypoglycaemia (requiring the assistance of another person to actively administer carbohydrate or glucagon, or take other corrective action) between baseline and visit 3 was recorded as an exploratory endpoint. All other adverse events (AEs) were recorded from visit 1 to visit 3 and were assessed by the treating physician.

Statistical Analysis

As outlined earlier, this study was part of the PIONEER REAL study programme and the statistical analysis has been previously described [16]. Here, we provide a brief summary. In total, 145 participants with HbA1c measurements were needed to ensure 90% and 99% probability of detecting changes in HbA1c of ≥ 0.46%-points and ≥ 1%-points from baseline, respectively. All clinical endpoints and safety evaluations were based on the full analysis set (FAS). A description of the FAS and observation periods (in-study and on-treatment) used for the primary and secondary analyses have been detailed previously [16]. Continuous secondary and exploratory endpoints were analysed using a mixed model for repeated measurements (MMRM) or analysis of covariance (ANCOVA, DTSQ endpoints) on the FAS (in-study observation period). Categorical secondary and exploratory endpoints were measured as proportions of participants at EOS, based on the FAS.

Analyses were performed with a crude and adjusted model. Estimated response and change in response analyses used the baseline measure in question (HbA1c, body weight, DTSQs), age and baseline BMI as covariates, and sex, oral antidiabetics at baseline, diabetes duration and site as fixed factors. For change from baseline in HbA1c and body weight, time and time-squared were also included as covariates; DTSQ analyses also included baseline HbA1c as a covariate. Tests were performed as two-sided tests with a significance level of 0.05, with no adjustments for multiple comparisons.

Statistical analyses were conducted using SAS version 9.4 (SAS institute, North Carolina, USA). Information on the sensitivity analyses performed can be found in the supplementary materials (Appendix 1).

Results

Participants and Physicians

The study was performed between 12 November 2020 and 3 March 2023. Participants received oral semaglutide for a median (range) of 36.1 (0.1–87.7) weeks; the corresponding in-study and on-treatment median observation periods were 40.7 (3.7–87.9) and 36.3 (0.1–87.7) weeks, respectively.

Overall, 187 participants were enrolled and received oral semaglutide (the FAS); 141 were still on oral semaglutide treatment at the EOS visit (Fig. 1).

Fig. 1
figure 1

Participant disposition. Abbreviations: EOS end of study, n number of participants. †Participants who initiated oral semaglutide and attended the EOS visit. ‡Participants who were taking oral semaglutide and attended the EOS visit

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A total of 178 participants attended visit 2, nine participants had no intermediate visit between visits 2 and 3, 68 participants had one intermediate visit, 49 participants had two intermediate visits, 31 participants had three intermediate visits and 30 participants had four or more intermediate visits. As a result of the COVID-19 pandemic, 31 (17.4%) participants attended visit 3 at 45–52 weeks and eight (4.5%) participants attended visit 3 after 52 weeks.

Participant characteristics are summarised in Table 1. Most participants were aged 45–65 years, and 17.1% were ≥ 75 years old. Participants had a mean (SD) T2D duration of 6.8 years (5.7) at baseline. Mean (SD) HbA1c was 7.7% (1.2) and 72.2% of participants had an HbA1c level of ≥ 7% at baseline.

Table 1 Participant demographics, baseline characteristics and initiation of oral semaglutide (FAS)
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The most common concomitant medications for the treatment of diabetes among participants were metformin (78.6%) and SGLT2 inhibitors (21.4%). Of participants with available data, 78 (41.7%) were current or past smokers, 54 (50%) stated that their highest level of education was high school or equivalent and 60 (42.6%) were retired.

Most of the participants had a physician in primary care (n = 184; 98.4%) and 149 (79.7%) participants had a physician with previous experience with prescribing GLP-1RAs. Nearly all physicians prescribed a starting oral semaglutide dose of 3 mg. Oral semaglutide was primarily prescribed to improve glycaemic control and/or reduce body weight (Table 1).

Approximately two thirds of participants had a CV-related medical history and nearly three quarters of participants met an expanded definition of CV disease, including CKD, haemoglobinopathy, dyslipidaemia and microalbuminuria (Table 1).

Glycaemic and Weight Changes Over Time

There was a significant reduction from baseline to EOS in HbA1c, assessed in 177 participants, as shown by an estimated mean (95% CI) change of − 0.88%-points (− 1.01 to − 0.75; P < 0.0001) or − 9.64 mmol/mol (− 11.05 to − 8.22; P < 0.0001; Fig. 2A). The estimated mean decreases in HbA1c occurred primarily within the first 28 weeks of treatment (Fig. 2B).

Fig. 2
figure 2

Estimated change from baseline to week 38 in HbA1c and body weight, for A HbA1c (N = 177), B HbA1c over time (N = 177), and C body weight (N = 165) (FAS); D Proportion of participants achieving HbA1c < 7%, and composite endpoints of HbA1c and body weight reduction. Figure 2B At week 0, observed mean at baseline for participants having at least one post-baseline assessment is plotted. The outer lines of the band represent 95% CI. Abbreviations: CI confidence interval, FAS full analysis set, HbA1c glycated haemoglobin, N number of participants included in the analyses

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Secondary and sensitivity analyses of the primary endpoint yielded comparable results. The secondary analysis of the primary endpoint revealed little difference between the ‘in-study’ and ‘on-treatment’ periods. The additional sensitivity analysis showed that the COVID-19-related amendment to extend visit 3 to outside the 34–44-week window had very little impact on the primary endpoint (Fig. S1).

Body weight decrease from baseline to EOS was assessed in 165 participants. Body weight significantly decreased, as shown by estimated mean (95% CI) relative and absolute changes of − 4.72% (− 5.58 to − 3.86; P < 0.0001) and − 4.62 kg (− 5.46 to − 3.79; P < 0.0001), respectively (Fig. 2C). The percentage of participants who had a body weight reduction ≥ 10% from baseline to EOS was 13.7%.

Glycaemic and Weight Thresholds

Overall, 64.6% of participants had a HbA1c < 7% by EOS, compared with 27.8% at baseline; among the 72.2% of participants with a baseline HbA1c of ≥ 7%, over half achieved HbA1c < 7% (Fig. 2D). In addition, 28.5% and 22.9% of participants achieved the composite endpoints of a reduction in HbA1c of ≥ 1%-point with body weight reduction of ≥ 3% and ≥ 5% by EOS, respectively (Fig. 2D). Furthermore, the estimated mean change from baseline in waist circumference (cm) was − 4.15 (SD [95% CI], 0.64 [− 5.44 to − 2.87]; P < 0.0001).

Participant- and Physician-Reported Outcomes

Participants reported a significant increase in their treatment satisfaction with oral semaglutide compared with treatment before initiating oral semaglutide (Fig. 3A, B). The dosing conditions questionnaire revealed that most participants found oral semaglutide very easy to consume (Fig. 3C); further details on dosing conditions are in Table S1.

Fig. 3
figure 3

Participant-reported satisfaction and ease of treatment to consume: A absolute treatment satisfaction measured with DTSQs, B relative treatment satisfaction measured by DTSQc, and C ease of consumption for oral semaglutide, measured by the dosing conditions questionnaire. Abbreviations: CI confidence interval, DTSQc Diabetes Treatment Satisfaction Questionnaire change, DTSQs Diabetes Treatment Satisfaction Questionnaire status, EOS end of study, N number of participants in the analysis, SD standard deviation. †Observed change was also 12.3 (SD 6.98)

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Overall, when judged against their reason for initiating oral semaglutide (Table 1), physicians considered treatment a clinical success in 130 (73.9%) cases. More specifically, physicians reported that glycaemic control was improved in 72.9% of participants, body weight was reduced in 71.6% of participants and convenience was achieved for 60.0% of participants. In addition, there were no issues with hypoglycaemia in 95.7% of participants while they were receiving oral semaglutide. Almost half (46.2%) of participants achieved clinical success in relation to addressing CV risk as reported by their physicians and 40.2% in relation to simplifying the current treatment regimen for participants (Table S2).

In the dosing conditions questionnaire, 60.0% of participants who responded rated oral semaglutide as 6 on the easy to consume scale (0 being very difficult and 6 being very easy) and 86.4% of participants gave a 4, 5 or 6 for this response (Table S1).

Treatment Patterns

At EOS, among 141 participants still taking oral semaglutide, only nine (6.4%) remained on semaglutide 3 mg, whereas 56 (39.7%) participants were taking semaglutide 7 mg at EOS. Additionally, 75 participants (53.2%) had increased to the maximum 14 mg dose and one participant had temporarily discontinued oral semaglutide at EOS.

Twenty-four participants (12.8%) had a new glucose-lowering medication added, or increased the baseline glucose-lowering medication dose, during the study period. Conversely, 13 participants (7.0%) had a glucose-lowering medication removed or the dose reduced during the study period.

Safety

Overall in the in-study observation period, 48 participants (25.7%) experienced a total of 68 AEs; most were mild or moderate in severity and nine participants (4.8%) experienced serious AEs. Most AEs were considered probably related to study drug (Table 2). AEs that led to study-drug withdrawal were reported in 25 participants. The most common AEs occurred in the system organ class of gastrointestinal disorders. One case of severe hypoglycaemia was reported by one participant (0.5%); this participant was not receiving insulin or sulfonylurea. The participant also had known hypertension and was receiving treatment with empagliflozin, metformin and enalapril in addition to oral semaglutide. The blood glucose levels of this participant are unavailable, and the severe hypoglycaemia was classified according to the criteria stated in the endpoints safety section.

Table 2 Summary of AEs over the in-study period (FAS)
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One fatal AE was reported in a 77-year-old woman who died as a result of disseminated uterine cancer 250 days after treatment initiation; the death was deemed unlikely to be related to study drug.

Discussion

In this prospective, non-interventional study in participants with T2D in routine clinical practice in Sweden, oral semaglutide was associated with significant decreases in HbA1c and body weight; more than 20% of participants achieved a reduction in HbA1c of ≥ 1.0%-points and a reduction in body weight of ≥ 5%. Furthermore, participant satisfaction with treatment improved over the course of the study, and the majority of the participants found the medication easy to take. The treatment was also considered clinically successful by physicians in more than 70% of cases. These results further reinforce the use of oral semaglutide. Further, the safety profile was consistent with that reported in the oral semaglutide phase 3 clinical study programme and no new safety findings were observed [9,10,11,12,13,14,15]. In addition, the extent of weight loss with oral semaglutide in this study was consistent with that reported in the subcutaneous semaglutide clinical study programme in T2D [19,20,21,22,23,24]. Taken together, these findings show that the benefit–risk profile of oral semaglutide remains positive.

The decrease in HbA1c of 0.88%-points (9.64 mmol/mol) in this study compares to a mean 0.9%-point decrease reported in the IGNITE study, an observational study (n = 211) evaluating oral semaglutide use in routine clinical practice in participants with T2D in the USA [25], and to a mean 1.3% reduction in the Swedish cohort (n = 195) of the SURE study, an observational study of subcutaneously administered semaglutide use in routine clinical practice [26]. In the same analysis of SURE, the reduction in body weight among Swedish participants (n = 193) was 5.7 kg, as compared to 4.6 kg in the present study [26]. It should be noted that Swedish participants in the SURE study had higher HbA1c (8.0%) and body weight (101.9 kg) values at baseline, a much longer disease duration (10.3 years) than participants included in the current study, and that the study used a different analysis which only included participants on-treatment at EOS, limiting comparisons between these study populations. Similarly, in the PIONEER REAL Canada study, participants achieved a slightly greater decrease in HbA1c of 1.1%-points; however, the participants in the Canada study had higher baseline HbA1c than those in this study, and this is reflected in the proportion of participants achieving HbA1c of < 7%, which was 53.7% in the PIONEER REAL Canada study and 64.6% in the present study. Participants in the PIONEER REAL Canada study also achieved greater reductions in body weight (7.2%) than in the present study (4.7%) [27]. However, these real-world populations will vary in their characteristics (e.g. different baseline HbA1c or T2D duration), and caution is required when comparing results between studies.

The relatively high proportions of participants achieving HbA1c < 7% further indicates that oral semaglutide could help individuals with poorly controlled T2D to achieve the proposed glycaemic target of HbA1c ≤ 7% [5], thus preventing complications. The oral formulation may also be preferred by some individuals with aversions to injections. However, in this study, over 90% of the participants were white, while in Sweden, the risk of T2D appears to be higher in minority ethnic groups, particularly in individuals with South Asian or Middle Eastern ethnicity [28, 29]. These individuals were underrepresented in the present study; however, the vast majority of people with T2D in Sweden are white which implies good generalisability of these findings to the wider T2D population in Sweden [30]. Other ongoing studies may provide more specific information about the CV effects of semaglutide in individuals living with T2D and established CVD and/or CKD [31].

The majority of participants in PIONEER REAL Sweden reported concomitant glucose-lowering medication use at baseline (78.6% were on concomitant metformin and 21.4% were on concomitant SGLT2 inhibitors), which is to be expected since more than 90% of participants had T2D for longer than 1 year (mean duration of T2D was 6.8 years in participants who provided a date of T2D diagnosis). In a recent survey study conducted in almost 4500 Italian patients with T2D initiating oral semaglutide treatment in specialist care, the most common glucose-lowering treatment reported at baseline was also the concomitant use of metformin (79.9%) [32], similar to PIONEER REAL Sweden.

As a real-world evidence study, the PIONEER REAL Sweden study provides insights into how oral semaglutide performs in a diverse population of adults with T2D encountered in routine clinical practice in Sweden, and into the perceptions of physicians and participants in using oral semaglutide. However, this study also had a few limitations. The observational nature of the study and lack of a comparator arm mean that other explanations for the changes in HbA1c and body weight, such as changes in medication throughout the study, cannot be excluded. In addition, the clinical reasons to initiate semaglutide could have affected the observed changes in HbA1c, potentially influencing the results of this study. The data were collected as part of routine clinical practice rather than through mandatory assessments at prespecified time points, which could impact the robustness and completeness of data. Given the design of this study, it is not possible to make causal inferences between treatment and observed outcomes. A placebo effect cannot be ruled out with regard to participant- and physician-reported outcomes; however, questionnaires, such as the Diabetes Treatment Satisfaction Questionnaire, are a common method for assessing treatment satisfaction and participant and physician viewpoints and as a result of the observational nature of the study would mirror their use in everyday clinical practice.

Conclusions

The clinical outcomes observed in PIONEER REAL Sweden showed significant improvement in glycaemic control, with no new safety concerns, and an improvement in treatment satisfaction among adults with T2D who were prescribed once-daily oral semaglutide, in the clinical practice setting. As part of the wider PIONEER REAL study programme, this provides insights into the use of oral semaglutide in routine clinical practice in a diverse real-world population of adults with T2D.