This prospective, observational, real-world study conducted in the Netherlands forms part of the wider PIONEER REAL programme undertaken to provide insights on how oral semaglutide is prescribed, used and perceived in everyday clinical practice in an adult population of participants living with T2D. The results of PIONEER REAL Netherlands further support the use of oral semaglutide for glycaemic control and body weight reduction in a real-world population, with no new safety signals, and revealed an improvement in treatment satisfaction. The oral formulation provides a useful treatment option for patients with a preference for oral therapy [22], which, when coupled with the improvement in treatment satisfaction, may encourage a wider uptake of GLP-1RAs.

Over the course of the study, clinically significant improvements in the key therapeutic goals of glycaemic control and body weight loss were achieved, with more than one third of participants achieving a reduction in both HbA1c of ≥ 1.0%-points and body weight of ≥ 5%. In addition, study participants reported a greater degree of both absolute and relative treatment satisfaction at EOS than at baseline, as measured by responses to the DTSQs and DTSQc.

Participants enrolled in this real-world study were from both primary and secondary/tertiary care settings and their characteristics can be considered representative of the general population living with T2D. Observations for glycaemic control were consistent with those reported in RCTs for oral semaglutide. The decrease in HbA1c of 1.2%-points observed in this study (with a mean dose of 10.6 mg), reflects the reductions of between 1.2 and 1.3%-points with oral semaglutide 14 mg after 52 weeks in the PIONEER phase 3 programme (PIONEER 2, 3 [78 weeks], 4, 7 [flexibly dosed, including 3, 7 and 14 mg] and 8; based on the treatment policy estimand) [14,15,16,17, 29]. The HbA1c reduction observed in PIONEER REAL Netherlands is furthermore consistent with the reduction reported in the PIONEER REAL Switzerland study, which reported an HbA1c change of − 0.91%-points at EOS [26]. Differences in characteristics at baseline such as HbA1c levels (8.6% in this study, and 7.7% in PIONEER REAL Switzerland) and the mean number of concomitant glucose-lowering medications (1.6 in this study and 0.8 in PIONEER REAL Switzerland) may contribute to the slightly greater reduction in HbA1c observed in PIONEER REAL Netherlands than in PIONEER REAL Switzerland. Despite some differences in the populations, improvements in glycaemic control also closely reflect those reported with once-weekly subcutaneous semaglutide in the prospective 30-week real-world SURE Netherlands study, in which participants also had an HbA1c reduction of − 1.2%-points (95% CI − 1.3 to − 1.0; p < 0.0001) [30]. Reductions in HbA1c were marginally higher in this study than reported in the real-world US-based IGNITE study in which there was an HbA1c reduction of 0.9%-points (95% CI − 1.1 to − 0.6) after a mean treatment duration of 5.7 months in people prescribed oral semaglutide [31]. This may be due to differences in study population and design, such as the IGNITE study using retrospective data from electronic health records [31].

Only 8.0% of study participants had an HbA1c level < 7.0% at baseline; however, this increased to approximately half (47.5%) of participants at EOS. Although this observation is slightly lower than the range seen at 26 weeks in PIONEER trials (56–72%) [13,14,15], it is greater than reported in the SURE Netherlands study in which 36.9% of participants had an HbA1c level < 7.0% at EOS [30].

The reported body weight reduction was 5.84 kg (5.65%). This is a slightly higher weight reduction than has been previously reported in other PIONEER studies; however, it is still similar to the upper end of the range observed after 52 weeks in PIONEER 2, 4, 7 and 8 (approximately 2.9–5.0 kg for oral semaglutide 14 mg) [14,15,16,17]. The weight-loss effects of subcutaneous semaglutide at a dose of 2.4 mg have also been reported in studies in both people with overweight or obesity with or without T2D [32, 33]. There is also evidence of a reduction in major adverse CV events (MACE) with GLP-1RAs in people living with obesity and T2D; weekly GLP-1RAs (exenatide, dulaglutide and semaglutide) were reported to reduce the risk of MACE versus placebo [34]. The reduction in body weight, independent of HbA1c levels, may contribute to the CV benefits that have been associated with GLP-1RA treatment in people living with T2D [2, 35], alongside the impact of GLP-1RAs on other risk factors for CV disease such as anti-inflammatory effects, reduction in blood pressure and increased microvascular and coronary blood flow [18].

Physicians considered treatment to be a clinical success in > 80% of participants; however, clinical success is a subjective assessment and dependent on individual treatment targets for each participant. Observations from DTSQs and DTSQc assessments do, however, support physician sentiment, with satisfaction among participants significantly improved with oral semaglutide treatment.

Oral semaglutide in this real-world study was used in accordance with the label and local clinical practice in the Netherlands; most participants (98.4%) were initiated on the 3 mg dose, and three participants (1.6%) received the 7 mg dose at baseline. At EOS, only 53.7% of participants were receiving the maximum approved oral semaglutide dose of 14 mg, whereas 42.2% were treated with 7.0 mg and 4.1% with 3 mg.

Most participants reported concomitant glucose-lowering medication at baseline in this study, with only 19 (10.2%) participants reporting no medication at V1; given that duration of diabetes was reported as ≥ 1 year in over 90% of participants, high baseline treatment use was to be expected. Metformin and sulphonylureas were the most prescribed agents, with SGLT2 and DPP-4 inhibitors used in < 5% of participants. In a recent study of people with T2D in specialist care in Italy initiating oral semaglutide treatment, a similar proportion of people were naïve to glucose-lowering medication (9.6%) and 43.5% were taking two or more oral glucose-lowering treatments at the point of oral semaglutide initiation [36]. In the Italian cohort, at baseline, the most common glucose-lowering treatment was metformin (79.9%) [36], which was similar to PIONEER REAL Netherlands (81.3%). In contrast to PIONEER REAL Netherlands, the next two most common categories used by people in Italian clinical practice were DPP-4 inhibitors and SGLT2 inhibitors (24.9% and 20.9%, respectively) with sulphonylureas being used by 14.6% of people [36]. This may reflect differences in the prescription of glucose-lowering medication in a specialist versus non-specialist setting, with only 34.2% of participants in PIONEER REAL Netherlands treated by diabetes specialists. It could also be attributed to differences between countries with respect to treatment guidelines for people with T2D. In the Netherlands, stepwise treatment for T2D begins with biguanides such as metformin, followed by the addition of a sulphonylurea when biguanides do not adequately control hyperglycaemia, followed by the addition of basal insulin and eventually intensive pharmacotherapy with insulin [9]. Reimbursement policies may contribute to the pattern of therapies observed at baseline, with restrictions based on BMI and previous/ongoing therapies such as metformin, sulphonylureas and/or basal insulin [37]; at the time of the study, in the Netherlands, GLP-1RAs were restricted to reimbursement in people with a BMI ≥ 30 kg/m2 with inadequate glycaemic control on metformin and a sulphonylurea, and in people with a BMI ≥ 30 kg/m2 with inadequate glycaemic control on basal insulin for more than 3 months [37]. This pattern could also be influenced by limited familiarity of primary care physicians with GLP-1RAs, clinical inertia or physician preferences for established, generically available agents [22,23,24,25]. The results of this study may help overcome patient-held barriers to treatment and reimbursement restrictions in the Netherlands.

In PIONEER REAL Netherlands, adverse events with oral semaglutide were consistent with those observed in the PIONEER phase 3 RCTs. Reflective of the GLP-1RA class, gastrointestinal effects, including nausea, diarrhoea and vomiting, were the most common adverse events [12, 14,15,16,17, 29, 38]. The discontinuation rate (19.8%) was higher than reported for the PIONEER trials (7–13% with oral semaglutide 14 mg) [12, 14,15,16,17, 29, 38] and for the SURE Netherlands study for subcutaneous semaglutide (approximately 5%) [30]. It should be noted that this study focussed on participants naïve to treatment with injectable glucose-lowering therapy, with no individuals reporting prior GLP-1RA experience at baseline; the most common reason for discontinuation was a safety concern related to oral semaglutide. Notably, no new safety concerns were observed and the benefit–risk balance for oral semaglutide remains positive.

Participant enrolment in PIONEER REAL Netherlands was at the discretion of the treating physician. As such, the broad population included in the study may more closely reflect real-world practice, making it more generalisable than data from RCTs. It should be noted that there were slightly more male participants enrolled in the study, participants were predominantly white (reflective of the demographics of the study location) and a high proportion of participants had CV-related medical history. This study has limitations: it was an observational study that did not include a comparator arm, hence, alternative explanations for changes from baseline in HbA1c and other evaluated endpoints cannot be ruled out. In addition, data were collected as part of routine clinical practice, meaning results are less robust than those based on clinical trial data and potential confounding factors cannot be excluded. The observed changes in HbA1c may have been influenced by the clinical reason to initiate semaglutide treatment.

Observations from PIONEER REAL Netherlands add to those previously reported in the SURE Netherlands study and highlight that both formulations of semaglutide (oral and subcutaneous) can provide clinical improvements in the key management goals (glycaemic control and weight loss) for individuals living with T2D [30]. Availability of an oral formulation of semaglutide offers people living with T2D an alternative to injectable GLP-1RA therapy and could potentially improve acceptance and adherence in addition to facilitating earlier use of GLP-1RAs, even in a primary care setting [39].