Efficacy and safety of oral semaglutide treatment in a Danish type 2 diabetes outpatient clinic: Real‐world evidence

Type 2 diabetes (T2D) is a complex chronic metabolic disorder associated with a range of comorbidities that significantly impact patients' health and quality of life. Good glycaemic control is crucial to reduce the risk of developing diabetes-related complications. The oral glucagon-like peptide-1 agonist semaglutide (Rybelsus) has been tested thoroughly in the Peptide Innovation for Early Diabetes Treatment (PIONEER) studies and reduces both HbA1c and body weight in people with T2D.1 However, there are numerous precautions associated with the intake of Rybelsus, which must be administered fasting, with a maximum of 1 dL water and a fasting period of 30 min afterwards. The PIONEER and the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) trials found a varying plasma concentration of semaglutide when being orally administered compared to subcutaneously.1 A reason for this could be that intestinal uptake of oral semaglutide depends on patients following the instructions for intake carefully. Hence, one could speculate that the effects of oral semaglutide in a real-world setting could be different from the very controlled trial situation during the randomized clinical trials. We here investigate the effect and safety of oral semaglutide in a real-world setting. The study was designed as an observational retrospective study. Adults (>17 years) from the Steno Diabetes Center Copenhagen (SDCC) with the diagnosis of T2D and having a prescription of oral semaglutide between 5 June 2023 and 12 June 2024 were included. No exclusion criteria existed except for if patients had a note in their journal regarding not wanting to contribute to clinical research. The baseline (T0) date was set at the day of the prescription of oral semaglutide. The follow-up (T1) was 1 year after the baseline date (±200 days). The baseline date had to be before 5 June 2023 due to delivery issues of subcutaneous semaglutide in Denmark, which caused many patients to change prescription from subcutaneous to oral semaglutide. Patients were divided into two groups. Group 1, comprising those whose oral semaglutide dose was increased from 3 to 7 mg once daily (OD) during the follow-up period, and Group 2, consisting of those whose oral semaglutide dose was increased from either 3 or 7 mg to 14 mg OD during the follow-up period. The division was made to monitor the effects and adverse events (AEs) based on the dose. Data were obtained from the electronic medical record and included gender, age, duration of diabetes, concomitant diabetes treatment, smoking status, body weight, concomitant medicine (renin-angiotensin blockers, calcium channel blockers, angiotensin II receptor blockers, beta-blockers, diuretics, statins, ezetrol, fibrates, nicotine, and proprotein-convertase-subtilisin/kexin type 9-inhibitor [PCSK9 inhibitors]), blood pressure, and heart rate at T0 and T1. The laboratory data included HbA1c, creatinine, alanine transaminase (ALAT), aspartate aminotransferase (ASAT), thrombocytes, eGFR, urine albumin/creatinine ratio (UACR), total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very low-density lipoproteins (VLDL) cholesterol, triglycerides, and amylase at T0 and T1. After the trial period, every patient's electronic medical record was manually reviewed to retrieve data on oral semaglutide dose and adverse events with a special focus on nausea, vomiting, diarrhoea, obstipation, headache, appetite, admissions to the hospital, hypoglycaemia, gastroparesis, neuropathy, and pancreatitis. Descriptive statistics were used to summarize the baseline characteristics of the participants. The mean of differences between baseline and follow-up measurements was estimated using a paired t test, while the Wilcoxon matched-pairs signed-rank test was applied for non-parametric data. Normality was assessed using the Shapiro–Wilk test, as well as visual inspection of histograms and QQ plots. Missing data were not imputed. Statistical significance was p < 0.05, two sided. Statistical analyses were performed using SAS Enterprise Guide software, version 8.4. In total, 4807 adults had the diagnosis of T2D at SDCC at the time of observation (Figure 1). Of those, 258 had oral semaglutide prescribed before 5 June 2023 (T0). Five patients were excluded because they had no data within the study period. Of the remaining 253 patients, six patients were excluded due to death before T0, one patient was excluded because he was no longer a patient at SDCC, and 93 patients were excluded due to discontinuation of oral semaglutide in the follow-up period. Of the remaining 143 patients, 29 were excluded because the oral semaglutide dose was not increased in the follow-up period and 17 were excluded due to having a prescription of 14 mg oral semaglutide at baseline. Of the latter 97 patients, one never began oral semaglutide. The study ended up including 96 patients who had begun oral semaglutide at 3 and 7 mg and furthermore increased in oral semaglutide dose (from 3 to 7 mg/day in group 1 and from 3 or 7 mg/day to 14 mg per day in group 2) between baseline and follow-up. The majority of patients were males in their mid-60s with a body weight around 97 kg and a HbA1c of 69 mmol/mol (Table S1). Many of the patients were simultaneously treated with metformin (N = 73), SGLT-2 inhibitors (N = 72), or insulin (N = 19). Of the 96 patients, one was diagnosed with gastroparesis and 55 suffered from neuropathy. We found that patients escalating from 3 to 7 mg/day Rybelsus had a HbA1c reduction of 8.0 mmol/mol (2.9%) and a weight loss of 3.4 kg (Table 1). Patients escalating from 3 or 7 to 14 mg/day Rybelsus had a HbA1c reduction of 7.1 mmol/mol (2.8%) and a weight loss of 6.5 kg. There were no significant changes in cholesterol, blood pressure, kidney, or liver function. The primary AEs were nausea and diarrhoea, reported by 19% and 12%, respectively (Table S2). In total, 19 patients (19.6%) ended treatment due to AEs. Oral semaglutide has previously been tested in the PIONEER trials, in doses of 3, 7 and 14 mg. Here oral semaglutide treatment was associated with a decrease in HbA1c of 10.9–15.3 mmol/mol and a decrease in body weight of 1.6–4.4 kg compared with placebo.2, 3 Other studies have reported real-world evidence (RWE) with the use of oral semaglutide in T2D including a study from Wales,4 Switzerland5 and Croatia.6 Overall, the RWE studies demonstrate outcomes closely mirroring the large randomized controlled trials, showing comparable reductions in HbA1c and body weight and similar adverse events profiles.1, 2 Real-world evidence from Steno Diabetes Center Copenhagen outpatient T2D clinic including 96 patients, treated with Rybelsus in the doses of 3–14 mg showed a significant reduction in HbA1c and body weight loss. The effect and safety of real-world use of oral semaglutide are comparable to those reported in the clinical randomized trials. The trial was funded by financial support from Novo Nordisk A/S. AAW has nothing to declare. JIB has received lecture fees from Boehringer Ingelheim, Novo Nordisk and Zealand Pharma and received research support from Novo Nordisk. JTJ has nothing to declare. PLK has nothing to declare. TFD has received lecture fees from AstraZeneca, Boehringer Ingelheim, Medtronic, Novo Nordisk and Sanofi and received research support from AstraZeneca and Novo Nordisk. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.70208. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1. Baseline characteristics of 96 patients with T2D followed for 1 year after initiation of oral semaglutide. Group 1 (n = 49) consisted of patients up titrated from 3 to 7 mg oral semaglutide. Group 2 (n = 47) consisted of patients up titrated from 3 to 7 or 14 mg. Table S2. Adverse events registered in the electronic medical record of the 96 patients with type 2 diabetes treated with oral semaglutide for a year. 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.