Real‐world effectiveness and safety of oral semaglutide in people living with type 2 diabetes: A nationwide multicentre retrospective observational study ( <scp> ENDO ² S‐RWD </scp> )

Abstract

Type 2 diabetes guidelines recommend glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and/or sodium-glucose co-transporter-2 inhibitors for people living with type 2 diabetes (PLWT2D) with an established or high risk of cardiovascular disease and/or renal disease, regardless of glycated haemoglobin (HbA1c) levels.1-3 Semaglutide is the first and only GLP-1 RA available for oral use. Despite its proven safety and efficacy in randomized clinical trials,4, 5 insights into its real-world use in clinical settings are needed.6 We designed the ENDOcrinology Oral Sema Real-World Data (ENDO2S-RWD) study to evaluate the effectiveness, safety and tolerability of oral semaglutide in a large cohort of PLWT2D in Spain. We assessed the factors associated with the clinical response and drug persistence. This was a multicentre retrospective cohort study of PLWT2D aged ≥18 years who started treatment with oral semaglutide in routine clinical practice between November 2021 and November 2022 in 12 health centres of the Spanish National Health System, with at least one report of clinical follow-up (FU) data after 3 months. Individuals who were naïve or taking antihyperglycaemic medications and switchers from other GLP-1 RAs were included. This study was endorsed by the Spanish Society of Endocrinology and Nutrition and approved by the Ethics Committee of Dr Balmis General University Hospital (2022-0386). The source of recruitment was the drug prescription registry of each health centre. Clinical data were manually extracted from the digital medical records. We recorded the clinical outcomes in two periods: between 3 and 6 months (6-month FU visit) and between 6 and 12 months (12-month FU visit). Safety data were assessed for the entire cohort. In contrast, the outcome endpoints were only assessed for PLWT2D undergoing treatment with oral semaglutide. The primary endpoint was defined as a weight loss of ≥5% from the baseline weight of the patient and an HbA1c reduction of ≥1% in 6-12 months. The secondary endpoints were changes in HbA1c (%) in 6-12 months and weight loss reduction [kg and weight loss percentage (WLP)] from baseline in 6-12 months. We assessed drug safety, factors associated with response, drug persistence, and major cardiovascular adverse events (MACEs).7 The Wilcoxon signed-rank test for paired samples assessed the differences in continuous variables. Multiple logistic regression models were constructed to explore the association between baseline data and clinical outcomes at 6 months, estimating odds ratios [95% confidence interval (CI)]. All tests were two-tailed, and statistical significance was set at p < .05. IBM SPSS Statistics 25 software was used for analyses. Additional information is provided in the Supporting Information (Data S1). In total, 1018 PLWT2D [53.9% males, median age: 63 years, body mass index (BMI): 33.8 kg/m2, HbA1c: 7.8%] were included in the study, with a median semaglutide treatment duration of 19 weeks (15-25) at the 6-month FU visit and 45 weeks (36-52) at the 12-month FU visit at the time of analysis, unless censored. All demographic and baseline characteristics of the participants are provided in Table S1. Regarding baseline therapy, 135 patients switched to oral semaglutide from another GLP-1 RA, and 52.8% were on sodium-glucose co-transporter-2 inhibitors. Oral semaglutide discontinuation was observed in 185 patients [18.2% (95% CI: 15.9-20.6)]. The most common reasons were a lack of continuity of care [renewal/titration; 4.4% (95% CI: 3.3-5.8)] and gastrointestinal intolerance [9.8% (95% CI: 8.1-11.8)]. The primary composite (weight loss ≥5% plus HbA1c reduction >1%) was achieved in 19.1% of patients (95% CI: 16.8-22.8) at 6 months and in 37.5% of patients (95% CI: 31.8-43.4) at 12 months. In PLWT2D with baseline HbA1c >8% and/or a BMI >35 kg/m2, these percentages were 25.6% (95% CI: 21.7-29.9) and 44.6% (95% CI: 37.8-44.6), respectively. The median changes in HbA1c, weight and WLP at the 6-month visit were −0.7%, −4.2 kg and −4.6%, respectively (p < .001 for all). At the 12-month FU visit, these changes were −1.1%, −6.5 kg and −7.0%, respectively (p < .001 for all; Figure 1). Weight loss >10% was achieved in 14% of the patients at 6 months and in 33.3% of the patients at the end of the FU. PLWT2D with a baseline HbA1c ≥8% or BMI ≥35 kg/m2 had increased odds of achieving the primary combined endpoint; however, previous baseline GLP-1 RA use decreased these odds. Higher BMI and endocrinologist prescriptions were factors independently associated with stable semaglutide therapy over time (Figure 2). The rate of serious adverse events was 0.29%. One patient (on insulin therapy) reported severe hypoglycaemia, and two patients experienced acute pancreatitis of biliary origin. Four patients experienced MACEs, and two died (because of a traffic accident and an unknown cause). Additional results are provided in Data S1 and Figure S1. In this large, multicentre, real-world, nationwide retrospective cohort study in PLWT2D in Spain, we observed that oral semaglutide was effective and safe for treatment regardless of the patient background. Despite the difficulty in comparing our results with those of available real-world studies, given the significant baseline differences, our patient subpopulation with HbA1c ≥8% showed a similar decrease in HbA1c at 6 months (−1.3%) as that reported in the IGNITE (−1.4%), PIONEER REAL Canada (−1.1%) and Japanese population (−1.2%) studies.8-10 However, it was higher than that reported in a recent study (−0.9%).11 WLP was similar to that reported in a Canadian population10 (−7.0 vs. −7.2%) and higher than that in a Japanese study.9 These data were unavailable from database-sourced studies.8, 11 The composite endpoint in the PIONEER REAL Canada study was similar to that in our study (31.6 vs. 37.5%).10 The percentage of patients with HbA1c <7% or weight loss ≥10% is similar to that in other real-world data studies with subcutaneous semaglutide, such as the Marzullo et al. study, SPARE trial, and SURE post-hoc pooled analysis.12-14 The safety profile in our study was consistent with that in previous reports.15 Our discontinuation rates with oral semaglutide were similar to those in retrospective studies with subcutaneous semaglutide12, 13 and lower than those in pooled prospective SURE studies.14 Our findings highlight the associations among the high initial weight of the patient, endocrinology prescriptions and ongoing oral semaglutide use at 6 months. We hypothesized that severe obesity leads to better adherence and initial acceptance of gastrointestinal effects, with endocrinologist expertise and enhanced continuity of care also playing significant roles. Our results should be interpreted with caution owing to the retrospective observational design of this study and the lack of information on patient adherence. Although attempts were made to control potential confounding factors, there may be a risk of selection bias. However, the analysis of factors associated with response and drug persistence after adjusting for confounders and detailed reporting of serious adverse events, MACEs and mortality support the robustness of our findings. More information on the comparisons with available evidence and the limitations/strengths can be obtained in Data S1. In conclusion, the ENDO2S-RWD study is the largest multicentre real-world study of PLWT2D treated with oral semaglutide in routine clinical practice. Oral semaglutide was effective and safe for an unselected population, with one-third reporting weight loss >10% and more than two-thirds achieving HbA1c <7%. No safety concerns were observed. Given the global supply chain issues for subcutaneous GLP-1 RAs, the findings of this study can be helpful to support clinical decision-making. OMP and RRG contributed to the study design. All authors recruited patients and collected data for the study. OMP, RRG and JCFG conducted data analysis and interpretation. OMP, RRG and JCFG wrote the manuscript. All authors reviewed and commented on the manuscript. OMP and RRG are the guarantors of this work and take responsibility for the integrity of the data and the accuracy of the data analysis. We would like to thank the collaboration of the health staff of each of the Health Departments involved in this study, the Instituto de Investigación Sanitaria y Biomédica de Alicante (REDCap support) and the Sociedad Española de Endocrinología y Nutrición (SEEN), and especially the members of the Diabetes Area of the SEEN. A grant was received from the Spanish Society of Endocrinology and Nutrition Foundation (FSEEN) to cover open acces costs. JCFG was supported by the Intensification Research Program (INT21/00078, ISCIII, Spain; co-funded by the Fondo Europeo de Desarrollo Regional FEDER). The funding organisation played no role in the design of the study, review and interpretation of the data, or final approval of the manuscript. OMP received honoraria as a speaker and consulting fees from Eli Lilly, Boehringer-Ingelheim, Astra Zeneca and Novo Nordisk. RRG received speaker honoraria sand consulting fees from Eli Lilly, Astra Zeneca, Dexcom and Novo Nordisk. MP-I received speaker honoraria from Novo Nordisk, Nestle and AstraZeneca. CTP received speaker honoraria and consulting fees from Novo Nordisk, Astra Zeneca, Eli Lilly, MSD, Boehringer-Ingelheim, Esteve, MSD and Abbott. JCFG received speaker honoraria from Novo Nordisk, Lilly, Boehringer-Ingelheim, Esteve, Menarini and AstraZeneca. CSJ received speaker honoraria from Novo Nordisk, Eli Lilly, Boehringer-Ingelheim, Sanofi Aventis and AstraZeneca. LSB received speaker honoraria from Novo Nordisk, Boehringer Ingelheim, AstraZeneca, Lilly, Merck Sharp & Dohme, Sanofi and Mundipharma. PP received speaker honoraria from Astra Zeneca, Boehringer-Ingelheim, Dexcom, Eli Lilly, Novo Nordisk and Sanofi. VKKDG, NAMNAM, SMF, CGM, CCC and RMP have no conflicts of interest to declare. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.15431. Data available on request due to privacy/ethical restrictions. Supplementary Data S1. Supplementary text material. Contains additional information on materials and methods, additional results and detailed comparison with the available evidence and study limitations and strengths. Table S1. Baseline demographic and clinical characteristics. Figure S1. Distribution of weight and HbA1c change in the overall cohort. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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