Efficacy and safety of oral semaglutide in older patients with type 2 diabetes: a retrospective observational study (the OTARU-SEMA study)

Efficacy and safety of oral semaglutide in older patients with type 2 diabetes: a retrospective observational study (the OTARU-SEMA study) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and safety of oral semaglutide in older patients with type 2 diabetes: a retrospective observational study (the OTARU-SEMA study) Yuki Oe, Hiroshi Nomoto, Kyu Yong Cho, Kei Yokozeki, Tsubasa Ono, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3927633/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Jul, 2024 Read the published version in BMC Endocrine Disorders → Version 1 posted 11 You are reading this latest preprint version Abstract Background: Oral semaglutide in older subjects with type 2 diabetes was as effective as in younger subjects, according to phase 3 clinical trials. However, its efficacy can be limited in very aged population, due to the presence of impaired cognitive function and the complex instructions for its use. Here, we investigated its efficacy and safety by further age bracket in older subjects in real-world. Methods: We retrospectively studied subjects >65 years of age with type 2 diabetes who started oral semaglutide treatment. The primary outcome was the change in glycosylated hemoglobin (HbA1c) over 6 months. Adverse events and cognitive function were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) and the Hasegawa Dementia Rating Scale-revised (HDS-R). The achievement rate of glycemic targets was evaluated based on the age, health status of subjects and their use of anti-diabetic agents which can cause hypoglycemia, with additional analysis between two subgroups; early (65-74) versus late (≥ 75) older. Furthermore, we evaluated the relationships between their improvements in HbA1c and the baseline characteristics of the subjects, including their cognitive function and insulin secretory capacity. Results: We studied the efficacy of the drug in 24 subjects. Their HbA1c and body weight significantly decreased (−13.1 ± 7.5 mmol/mol and −3.0±2.4 kg, respectively; P <0.01). Although cognitive function was lower in the late older group (r=−0.57, P <0.01), changes in HbA1c showed no difference between the two subgroups ( P =0.66) and it correlated with the insulin secretory capacity rather than cognitive function (r=−0.49, P <0.05). Glycemic targets were more likely to be achieved ( P <0.01), but HbA1c excessively decreased in late older subjects who were also using insulin or an insulin secretagogue. The frequency of adverse events was similar to that in the clinical trial, whereas discontinuation of medication were more frequent among the late older subjects (Early; n=2, Late; n=4). Conclusions: Oral semaglutide improves the glycemic control of older subjects, but it might be a risk for potential hypoglycemia and discontinuation in subjects of ≥75 years. Attention should be paid to insulin secretory capacity and concomitant medications rather than concern about adherence. glucagon-like peptide 1 receptor aged type 2 diabetes cognitive test oral medicine Figures Figure 1 Figure 2 Figure 3 Background In aging societies, the prevalence of cognitive impairment is increasing and the risks and progression of disease are also increasing, owing to declines in biological functions ( 1 ) ( 2 ) ( 3 ). Japan is now regarded as a super-aged society, and the population of patients with type 2 diabetes (T2D) is aging as well during last decade ( 4 ). The incidence of diabetes complications is more frequent in older patients; therefore, glycemic management is of great importance in this population ( 5 ) ( 6 ). However, some anti-hyperglycemic agents can cause severe hypoglycemia and are associated with the deterioration of arteriosclerosis and cognitive impairment ( 7 ) ( 8 ). The avoidance of such adverse events and the maintenance of appropriate glycemic control should ensure better health and life expectancy. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are anti-hyperglycemic agents delivering glucose lowering effects with low risk of hypoglycemia due to their glucose level-dependent mechanism ( 9 ). A number of large-scaled trials have demonstrated the benefits of GLP-1RAs, notably with respect to the reduction in the incidence of cardiovascular events induced and the preservation of kidney function ( 10 ) ( 11 ). However, only injectable products had been available until recent years. Thereby, patients who had difficulty in self-administering or feeling resistance to injections abandon such intensive treatments, despite its efficacy. Recently available oral semaglutide was the first peroral GLP-1RAs in the world. Although a large-scaled trial showed significant reduction of total or cardiovascular death ( 12 ), there are several limitations to its use. It must be taken on an empty before first meal or beverage, with no more than 120 mL plain water only, and the ingestion of food, beverages, and other oral medications must be avoided for at least 30 minutes after taking it ( 13 ). Such burden might prevent sufficient effectiveness especially in older patients, who may have cognitive impairment. Therefore, it is important to assess the efficacy of oral semaglutide in older subjects. However, this has only been assessed through a post-hoc exploratory analysis of a few clinical trials to date ( 14 ). The purpose of this study was to evaluate the efficacy and safety of oral semaglutide in a real-world clinical setting focusing exclusively on older subjects. In addition, we aimed to characterize the cognitive function and baseline characteristics of older subjects that are associated with the efficacy of semaglutide treatment. Methods Study design and participants We conducted a retrospective, single-arm, observational study (the OTARU-SEMA study). Older Japanese subjects with T2D who attended the Department of Diabetes, Otaru General Hospital, were recruited between December 2021 and August 2022. The eligible subjects were aged ≥ 65 years, had a glycohemoglobin (HbA1c) level ≥ 53.0 mmol/mol (7%), and were able to manage their medications themselves. Subjects who commenced the administration of oral semaglutide were followed for 6 months. The dosage was adjusted by the physician in charge and was increased as much as the subjects could tolerate. We excluded subjects who had previously been administering a GLP-1RA subcutaneously. The other exclusion criteria described in Supporting information. The study was registered with the University Hospital Medical Information Network (UMIN) (registration number UMIN 000048782). It was approved by the Institutional Clinical Research Review Board of Otaru General Hospital (approval number 04 − 001) and was conducted in accordance with the principles of the Declaration of Helsinki and its amendments. An opt-out informed consent approach was adopted for all the participants. Adverse events The presence and severity of adverse events were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), and the definitions of severe adverse events are provided in the Supporting information. In accordance with the instructions of the manufacturer, the participants were thoroughly informed regarding the known adverse events of GLP-1RAs, including gastrointestinal events and anorexia, before the administration. The administration procedure was explained by the physician in charge and a nurse, and compliance was confirmed at each hospital visit. Biochemical analyses and cognitive function testing The body weight and height of subjects were measured using a calibrated scale. Body mass index (BMI) was calculated as body weight (kg) divided by the square of height (m 2 ). Endogenous insulin secretion was evaluated by the measurement of C-peptide (CPR) and C-peptide index (CPI) ( 15 ), and the biochemical parameters, including plasma glucose, were measured in blood samples collected after an overnight fast. CPI was calculated as CPI = 100 × fasting CPR (ng/mL)/plasma glucose (mg/dL). Other parameters were measured using standard techniques, and other data, including the medical history of the participants, were collected by the attending physicians. The cognitive function of the participants was evaluated using the Dementia Assessment Sheet for Community-based Integrated Care System 8-items (DASC-8) and the Hasegawa Dementia Rating Scale-revised (HDS-R) during the study period. The criteria for a diagnosis of impaired cognitive function using these screening tests were those previously defined ( 16 ) ( 17 ). These questionnaires were completed by a single well-trained nurse in the consulting rooms. Outcomes and data analysis The primary outcome was the change in HbA1c over the 6 months of oral semaglutide treatment. The secondary outcomes were the safety of semaglutide treatment and the changes in body weight and other biochemical data. The date on which semaglutide treatment was initiated was regarded as the baseline. As Visit − 1, HbA1c and body weight were first measured 1–3 months prior to baseline to exclude the possibility that these parameters were affected by prior treatments to semaglutide administration. The achievement of glycemic targets was evaluated using the Clinical Practice Guidelines of the Japan Diabetes Society (JDS) and Japan Geriatrics Society (JGS) Joint Committee ( 18 ), based on the age, health status of subjects and their use of anti-diabetic agents which can cause hypoglycemia. Inappropriately high or low HbA1c levels were defined as values that exceeded the target or were below the lower limit recommended for subjects using insulin or insulin secretagogues, respectively. We performed a sub-analysis of the data by dividing participants into two subgroups: early (65–74 years old) and late (≥ 75 years old) older group ( 19 ). In addition, we evaluated the relationships between the baseline characteristics of the subjects and their improvements in HbA1c, and the relationships of cognitive function test scores with each parameter. Normally distributed data are expressed as mean ± SD and other data are expressed as median (interquartile range). Data were analyzed using JMP Pro 16.0.0 (SAS Inc., Cary, NC, USA) or GraphPad Prism 8.4.2 (GraphPad Software, Inc. San Diego, CA, USA). For before-and-after comparisons, Student’s t -test was used to analyze parametric data and Wilcoxon’s signed-rank test was used for non-parametric data. Fisher’s exact test was used to compare the numbers of subjects who achieved their glycemic targets. Parameters and their changes were compared between the age groups using the unpaired t -test. Pearson’s correlation coefficient was used to identify associations between parameters. All the tests performed were two-sided, and P < 0.05 was considered to represent statistical significance. The post hoc power calculation was performed using GPower® version 3.1.9.2. P < 0.05 indicated statistical significance. Results Characteristics of subjects Subjects were enrolled as described in Fig. 1 . During the observation period, 44 subjects with T2D were administered oral semaglutide, but at the time of analysis, 10 were excluded because they were < 65 years (n = 8) or had previously subcutaneously administered a GLP-1RA (n = 2). Thus, 34 of the subjects were eligible for inclusion; however, a further 4 were excluded for the following reasons, unrelated to the drug: presence of a malignant tumor (n = 2), self-discontinuation (n = 1), and deterioration of a comorbidity (n = 1). Details of the adverse events and the reasons for the discontinuation of semaglutide were analyzed in the remaining 30 subjects as a safety analysis. Six of the subjects discontinued the medication, and therefore the remaining 24 subjects were studied with respect to efficacy. Table 1 showed the baseline characteristics of the participants in an efficacy analysis. The prevalence of obesity (BMI ≥ 25 kg/m 2 ) was 33.3% (Early; n = 5, Late; n = 3), but their insulin secretory capacity was preserved. In evaluation of cognitive function, the DASC-8 and HDS-R scores were consistent with cognitive impairment in only 4 (Early; n = 1, Late; n = 3) and 2 (Early; n = 0, Late; n = 2) subjects, respectively, and the others were not found to have impaired cognitive function. The final doses of semaglutide were as follows: 3 mg, n = 5 (Early; n = 4, Late; n = 1); 7 mg, n = 15 (Early; n = 8, Late; n = 7); and 14 mg, n = 4 (Early; n = 1, Late; n = 3). Few drugs were being used concomitantly; dipeptidyl peptidase-4 inhibitors (DPP-4is) were the most commonly prescribed drugs prior to semaglutide administration (Early; n=,12 Late; n = 11), but all of the users were switched to oral semaglutide. Half of the subjects were being treated with anti-hyperglycemic agents that could be associated with severe hypoglycemia (sulfonylureas, glinides, and insulin), but only 1 subject who was being treated with a glinide showed severe renal dysfunction (eGFR ≤ 30 mL/min/1.73m 2 ). Table 1 Baseline characteristics Variables Total (n = 24) Age (years) 75.5 ± 6.9 Female sex (n) 12 Height (cm) 155.2 ± 8.7 Body weight (kg) 57.4 ± 11.5 BMI (kg/m 2 ) 23.7 ± 3.4 Diabetes duration (years) ¶ 17.0 [7.0, 23.0] FPG (mmol/L) ¶ 7.7 ± 2.0 HbA1c (mmol/mol) 63.1 ± 8.5 CPR (nmol/L) ¶ 0.6 ± 0.3 CPI (ng/mL per mg/dL) ¶ 1.5 ± 0.8 Evaluation for cognitive function DASC-8 9.0 [8.0, 9.0] HDS-R 25.6 ± 3.8 The proportion of anti-diabetic agent (n, %) The number of drugs 2.0 [2.0, 3.0] Biguanide 12 (50.0) DPP-4i 22 (91.7) SU 6 (25.0) Glinides 4 (16.7) Thiazolidine 1 (4.2) α-GI 1 (4.2) SGLT2i 11 (45.8) Insulin 2 (8.3) Values are expressed as mean ± SD or median (interquartile range). ¶The values were calculated except one subject for missing data. α-GI, alpha glucosidase inhibitors; BMI, body mass index; CPI, C-peptide index; CPR, C-peptide; DASC-8, dementia assessment sheet for community-based integrated care system 8-items; DPP-4i, dipeptidyl peptidase-4 inhibitor; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; HDS-R, Hasegawa dementia rating scale-revised; SGLT2i, sodium-glucose cotransporter 2 inhibitor; SU, sulfonylurea. Efficacy Oral semaglutide significantly decreased HbA1c and body weight during the 6-month study period (Fig. 2 , Supplementary table 1 ). These effects were similar in participants in each age bracket (Supplementary table 2 ). At baseline, HbA1c was high in most of the subjects and achievement rate of glycemic targets from JDS and JGS were only being met 25.0% (Fig. 3 , Supplementary table 3 ). After 6 months, HbA1c significantly declined ( P < 0.001) and many had achieved their glycemic targets (prevalence had changed from 25.0–70.8%, P < 0.01), whereas the late older subjects using insulin or an insulin secretagogue tended to be more likely to have inappropriately low HbA1c values ( P = 0.18) (Fig. 3 , Supplementary table 3 ). In addition, the change in HbA1c during the 6-month period correlated with the baseline HbA1c value and the insulin secretory capacity (Supplementary table 4). Although neither the metabolic parameters nor body mass significantly differed at baseline between the two age groups (early; 65–74 versus late; ≥ 75), the HDS-R of the late older subgroup was significantly lower ( P < 0.01) (Supplementary table 2 , Supplementary Fig. 1) and negatively correlated with age (r = − 0.57, P < 0.01) (Supplementary Fig. 1). On the other hand, the reduction of HbA1c and body weight showed no significant differences between the age groups (early versus late: HbA1c; P = 0.66, body weight; P = 0.27) (Supplementary Fig. 2). Safety Supplementary table 5 shows the details of the adverse events. Severe adverse events, defined using the CTCAE, did not occur (Supplementary information). Discontinuation of the medication was more frequent in the late older subjects and was for the following reasons: Early; vomiting (3 mg, n = 1) and anorexia (3 mg, n = 1); Late; vomiting (3 mg, n = 1; 7 mg, n = 1) and anorexia (7 mg, n = 1; 14 mg, n = 1). Most of the other adverse events that were reported were gastrointestinal symptoms, and none of the subjects experienced hypoglycemia. Sample size Since the sample size might not have been sufficient, we calculated the post hoc power. The overall detection power value under the 5% α error was 1.0 for the change in HbA1c between baseline and 6 months after switching to oral semaglutide (N = 24). In each age bracket, the overall detection power value under the 5% α error were 0.999 (Early; n = 13) and 0.999 (Late; n = 11). Discussion In the present study, we have evaluated the efficacy and safety of oral semaglutide for older subjects, and compared relevant parameters in subjects of 65–74 years and ≥ 75 years. Although severe adverse events, involving drug discontinuation, were relatively frequent in subjects of ≥ 75 years, we found that oral semaglutide treatment was effective, as shown in previous phase 3 clinical trials ( 14 ). Furthermore, we characterized the medication and cognitive function of these subjects, and given that DPP-4is were the most frequently prescribed drugs at baseline, the study may provide useful information regarding the efficacy of switching from a DPP-4i to an oral GLP-1RA in patients of this age. To the best of our knowledge, this is the first study to characterize the safety and efficacy of oral semaglutide in older patients with T2D in a real-world clinical setting. The PIONEER clinical trials showed the efficacy of oral semaglutide in subjects from around the world ( 20 ). Additional analyses for older Japanese subjects with T2D were conducted in PIONEER 9 and 10 ( 14 ) ( 21 ) ( 22 ). Japan is one of the countries with a rapidly aging population, specifically, 29.1% of the population was ≥ 65 years old and 15.5% was ≥ 75 years old in 2022. The baseline age of the previous sub-analysis was 65 years old and more precise classification was desirable to capture the real-world setting ( 14 ). Here, we compared the efficacy of semaglutide in subgroups of subjects of 65–74 years and ≥ 75 years to identify any differences between these sections of the older population ( 23 ). As in PIONEER 9 and 10, we found that semaglutide reduced HbA1c and body weight in both age groups (Supplementary table 2 ). Because older patients can be vulnerable to adverse effects of drugs ( 24 ), it is important to clarify whether new therapeutics have such effects in this population. A sub-analysis of the PIONEER trials showed that older patients of ≥ 65 years had a higher discontinuation rate of oral semaglutide than younger subjects ( 14 ). In the present study, nearly 80% of the older patients continued the medication for the full 6 months, but discontinuations were slightly more frequent in those who were ≥ 75 years old (n = 4, 26.7%) than in those of 65–74 years of age (n = 2, 13.3%), and these most frequently reason were due to gastrointestinal symptoms. Notably, two-thirds of the dropouts occurred at the starting dose (3 mg). Therefore, careful explanations should be provided when oral semaglutide therapy is commenced, especially in very aged patients, and clinicians should be aware that the glycemic targets for older patients should be determined according to their age, activity level, and the use of other medication ( 18 ). In our results, oral semaglutide use was associated with a 70.8% achievement rate with respect to glycemic targets, but also undesirably low HbA1c values in 20.8% of the participants (Fig. 3 , Supplementary table 3 ). In a sub-analysis of PIONEER 10, 2.5% of subjects administered oral semaglutide experienced symptomatic hypoglycemic episodes, and most of these were also administering sulfonylureas; however, their age and renal function were unknown ( 25 ). Although hypoglycemic symptoms were not reported in the present study, the identities of any concomitant medications, and especially of anti-hyperglycemic agents that can be associated with severe hypoglycemia, should be taken into account when the use of semaglutide is considered for patients of ≥ 75 years. DPP-4is are the most frequently prescribed anti-hyperglycemic agents in Japan, because of their convinced safety and effectiveness ( 26 ). In addition, the algorithm that was recently published by the JDS and JGS recommend their use primarily for patients who do not have obesity, and in fact DPP-4is tend to be prescribed more frequently in older patients ( 26 ) ( 27 ). This is reflected in over 90% of the participants administering a DPP-4i at the start of the present study, precisely reflecting the trends of prescription in our country. Importantly, however, the participants in the PIONEER phase 3 trials were not administering a DPP-4i at the start ( 20 ) ( 21 ) ( 22 ). Collectively, the present study provides important insights into the clinical usefulness of oral semaglutide, in particular after switching from a DPP-4i, in older patients. The complexity of the method of administration is one of the problems associated with oral semaglutide use ( 13 ), and this might be a challenge for patients with cognitive impairment. In fact, cognitive impairment does not significantly affect adherence to oral medications or self-care in patients with T2D, rather injections including insulin might be a problem ( 28 ). However, the circulating semaglutide concentration following administration is more variable following oral administration than subcutaneous injection, which might reflect poorer absorption ( 29 ). Nevertheless, the established potent antihyperglycemic effect of oral semaglutide was replicated in the present study, even though it was of older subjects. Cognitive function declined with increasing age, whereas did not correlate with improvements of HbA1c in the present study (Supplementary Fig. 1, Supplementary table 4). Although, it is worthy to note that subjects suffering severe cognitive impairment were not involved in this study. Instead, the improvement in HbA1c correlated with CPR and CPI, suggesting that the level of residual beta-cell function is associated with the efficacy of oral semaglutide treatment, which has been shown for other GLP-1RAs (Supplementary table 4) ( 30 ) ( 31 ) ( 32 ). The strengths of the present study were that we exclusively studied older patients, that we assessed the efficacy and safety of the drug in a real-world clinical setting, and that the cognitive function of the participants was also evaluated. We have also confirmed the trends in prescribing practice in Japan and demonstrated the effectiveness of switching from a DPP-4i to oral semaglutide. However, there were also several limitations. First, it was a single-arm retrospective observational study with a small sample size. Second, the participants were exclusively Japanese, which limits the generalizability of the findings. Finally, the subjects were older, but had relatively well-preserved cognitive function. Therefore, further studies should be conducted in the next future, including larger, two-arm, prospective studies, and studies of participants with more marked cognitive impairment. Conclusions In conclusion, we have demonstrated the efficacy of oral semaglutide in older subjects in a real-world clinical setting. The frequency of adverse events for older subjects was similar to that in the clinical trial, however, discontinuation of medication and risk for potential hypoglycemia were more frequent in late older subjects. Therefore, it is important that clinicians are aware of careful explanations and the use of concomitant medications for appropriate treatment. We hope that oral semaglutide will be more widely adopted as a safe and more convenient GLP-1RA in the future. Abbreviations BMI Body mass index CTCAE the Common Terminology Criteria for Adverse Events CPI C-peptide index CPR C-peptide DASC-8 the Dementia Assessment Sheet for Community-based Integrated Care System 8-items DPP-4is dipeptidyl peptidase-4 inhibitors GLP-1RAs Glucagon-like peptide-1 receptor agonists HbA1c glycohemoglobin HDS-R the Hasegawa Dementia Rating Scale-revised JDS the Japan Diabetes Society JGS Japan Geriatrics Society T2D type 2 diabetes UMIN the University Hospital Medical Information Network. Declarations Ethics approval and consent to participate The study was approved by the Institutional Clinical Research Review Board of Otaru General Hospital (Date of approval;2022/5/10, Approval number;04-001) and was conducted in accordance with the principles of the Declaration of Helsinki and its amendments. An opt-out informed consent approach was adopted for all the participants. Consent for publication Not applicable. Availability of data and materials The data that support the findings of this study are available on request from the corresponding author. The data have not been made publicly available owing to privacy or ethical restrictions. Competing interests YO has received honoraria for lectures from Novo Nordisk Pharma Ltd.. HN has received honoraria for lectures from Novo Nordisk Pharma Ltd. and Sumitomo Pharma Co., Ltd; and has obtained research support from Kowa Pharmaceutical Co.. AN has received honoraria for lectures from Novo Nordisk Pharma Ltd.. and has obtained research support from Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim Co., Kowa Co., Ltd., and Taisho Pharmaceutical Co., Ltd.. TA has received honoraria for lectures from GlaxoSmithKline plc., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co ., Ltd. Eisai Co. Ltd., AbbVie Inc., UCB Japan Co. Ltd., Novartis Pharma K.K., Pfizer Inc. Gilead Sciences, Inc., Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Daiichi Sankyo Co., Ltd., AstraZeneca plc., Asahi Kasei Pharma Co., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd.; and research grants from Eli Lilly Japan K.K., AbbVie Inc., Bristol-Myers Squibb Co., Daiichi Sankyo Co., Ltd., Asahi Kasei Pharma Co., Eisai Co. Ltd., Chugai Pharmaceutical Co., Ltd., AstraZeneca plc., Novartis Pharma K.K., Pfizer Inc. and UCB Japan Co., Ltd.; and consultancy fees from GlaxoSmithKline plc., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co ., Ltd., Boehringer Ingelheim., Bristol-Myers Squibb Co., Amgen K.K., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Gilead Sciences, Inc. and Daiichi Sankyo Co., Ltd.. KYC, KY, TO, AM, HK, and YA have no conflicts of interest to declare. Funding No funding or sponsorship was received for this study or publication of this article. Authors' contributions YO conceived and designed the study. HN and KYC edited the study protocol and supervised the study. YO collected and analyzed the data, and wrote the manuscript. HN analyzed the data and edited the manuscript, tables, and figures. YO, KY and TO treated and recruited the participants. All the authors reviewed, and KYC, AM, HK, AN, and TA edited the manuscript. All the authors approved the final version of the manuscript. HN is the guarantor of this work and, as such, had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Acknowledgements The authors would like to express their gratitude to all the patients and staff who participated in this study. We also thank Mark Cleasby, PhD, from Edanz ( https://jp.edanz.com/ac ) for editing a draft of this manuscript. References Ogawa S. Nutritional management of older adults with cognitive decline and dementia. Geriatr Gerontol Int. 2014;14(Suppl 2):17–22. Prince MJ, Wu F, Guo Y, Gutierrez Robledo LM, O'Donnell M, Sullivan R, Yusuf S. The burden of disease in older people and implications for health policy and practice. Lancet. 2015;385(9967):549–62. Guo J, Huang X, Dou L, Yan M, Shen T, Tang W, Li J. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduct Target Ther. 2022;7(1):391. Miyazawa I, Yokoyama H, Yagi N, Araki SI, Morino K, Kume S, et al. Annual trends in glycemic control and prescribing patterns in diabetic treatment according to age in Japanese patients with type 2 diabetes between 2012 and 2019 (JDDM 71). Diabetes Res Clin Pract. 2023;198:110599. Charvat H, Goto A, Goto M, Inoue M, Heianza Y, Arase Y, et al. Impact of population aging on trends in diabetes prevalence: A meta-regression analysis of 160,000 Japanese adults. J Diabetes Investig. 2015;6(5):533–42. Jiang P, Babazono A, Fujita T. Health Inequalities Among Elderly Type 2 Diabetes Mellitus Patients in Japan. Popul Health Manag. 2020;23(3):264–70. Saremi A, Bahn GD, Reaven PD. A Link Between Hypoglycemia and Progression of Atherosclerosis in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care. 2016;39(3):448–54. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP Jr., Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA. 2009;301(15):1565–72. Nauck M. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab. 2016;18(3):203–16. Sheahan KH, Wahlberg EA, Gilbert MP. An overview of GLP-1 agonists and recent cardiovascular outcomes trials. Postgrad Med J. 2020;96(1133):156–61. Kristensen SL, Rørth R, Jhund PS, Docherty KF, Sattar N, Preiss D, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019;7(10):776–85. Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019;381(9):841–51. Hughes S, Neumiller JJ. Oral Semaglutide. Clin Diabetes. 2020;38(1):109–11. Yamada Y, Yabe D, Hertz CL, Horio H, Nakamura J, Nielsen AM, Seino Y. Efficacy and safety of oral semaglutide by baseline age in Japanese patients with type 2 diabetes: A subgroup analysis of the PIONEER 9 and 10 Japan trials. Diabetes Obes Metab. 2022;24(2):321–6. Funakoshi S, Fujimoto S, Hamasaki A, Fujiwara H, Fujita Y, Ikeda K, et al. Utility of indices using C-peptide levels for indication of insulin therapy to achieve good glycemic control in Japanese patients with type 2 diabetes. J Diabetes Investig. 2011;2(4):297–303. Toyoshima K, Araki A, Tamura Y, Iritani O, Ogawa S, Kozaki K, et al. Development of the Dementia Assessment Sheet for Community-based Integrated Care System 8-items, a short version of the Dementia Assessment Sheet for Community-based Integrated Care System 21-items, for the assessment of cognitive and daily functions. Geriatr Gerontol Int. 2018;18(10):1458–62. Y I KH. The revised Hasegawa’s Dementia Scale (HDS-R) — evaluation of its usefulness as a screening test for dementia. J Hong Kong Coll Psychiatr. 1994;4:20–4. Haneda M, Ito H. Glycemic targets for elderly patients with diabetes. Diabetol Int. 2016;7(4):331–3. Orimo HIH, Suzuki T, Araki A, Hosoi T, Sawabe M. Reviewing the definition of elderly. Geriatr Gerontol Int. 2006;6(3):149–58. Rasmussen MF. The development of oral semaglutide, an oral GLP-1 analog, for the treatment of type 2 diabetes. Diabetol Int. 2020;11(2):76–86. Yamada Y, Katagiri H, Hamamoto Y, Deenadayalan S, Navarria A, Nishijima K, Seino Y. Dose-response, efficacy, and safety of oral semaglutide monotherapy in Japanese patients with type 2 diabetes (PIONEER 9): a 52-week, phase 2/3a, randomised, controlled trial. Lancet Diabetes Endocrinol. 2020;8(5):377–91. Yabe D, Nakamura J, Kaneto H, Deenadayalan S, Navarria A, Gislum M, Inagaki N. Safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes (PIONEER 10): an open-label, randomised, active-controlled, phase 3a trial. Lancet Diabetes Endocrinol. 2020;8(5):392–406. Ouchi Y, Rakugi H, Arai H, Akishita M, Ito H, Toba K, Kai I. Redefining the elderly as aged 75 years and older: Proposal from the Joint Committee of Japan Gerontological Society and the Japan Geriatrics Society. Geriatr Gerontol Int. 2017;17(7):1045–7. Morimoto T, Sakuma M, Matsui K, Kuramoto N, Toshiro J, Murakami J, et al. Incidence of adverse drug events and medication errors in Japan: the JADE study. J Gen Intern Med. 2011;26(2):148–53. Yabe D, Deenadayalan S, Horio H, Kaneto H, Jensen TB, Terauchi Y, et al. Efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes: A subgroup analysis by baseline variables in the PIONEER 9 and PIONEER 10 trials. J Diabetes Investig. 2022;13(6):975–85. Bouchi R, Sugiyama T, Goto A, Imai K, Ihana-Sugiyama N, Ohsugi M, et al. Retrospective nationwide study on the trends in first-line antidiabetic medication for patients with type 2 diabetes in Japan. J Diabetes Investig. 2022;13(2):280–91. Bouchi R, Kondo T, Ohta Y, Goto A, Tanaka D, Satoh H, et al. A consensus statement from the Japan Diabetes Society: A proposed algorithm for pharmacotherapy in people with type 2 diabetes. J Diabetes Investig. 2023;14(1):151–64. Świątoniowska-Lonc N, Polański J, Tański W, Jankowska-Polańska B. Impact of Cognitive Impairment on Adherence to Treatment and Self-Care in Patients with Type 2 Diabetes Mellitus. Diabetes Metab Syndr Obes. 2021;14:193–203. Overgaard RV, Hertz CL, Ingwersen SH, Navarria A, Drucker DJ. Levels of circulating semaglutide determine reductions in HbA1c and body weight in people with type 2 diabetes. Cell Rep Med. 2021;2(9):100387. Jones AG, McDonald TJ, Shields BM, Hill AV, Hyde CJ, Knight BA, Hattersley AT. Markers of β-Cell Failure Predict Poor Glycemic Response to GLP-1 Receptor Agonist Therapy in Type 2 Diabetes. Diabetes Care. 2016;39(2):250–7. Takabe M, Matsuda T, Hirota Y, Hashimoto N, Nakamura T, Sakaguchi K, et al. C-peptide response to glucagon challenge is correlated with improvement of early insulin secretion by liraglutide treatment. Diabetes Res Clin Pract. 2012;98(3):e32–5. Yoshiji S, Hasebe M, Iwasaki Y, Shibue K, Keidai Y, Seno Y, et al. Exploring a Suitable Marker of Glycemic Response to Dulaglutide in Patients with Type 2 Diabetes: A Retrospective Study. Diabetes Ther. 2022;13(4):733–46. Additional Declarations Competing interest reported. YO has received honoraria for lectures from Novo Nordisk Pharma Ltd.. HN has received honoraria for lectures from Novo Nordisk Pharma Ltd. and Sumitomo Pharma Co., Ltd; and has obtained research support from Kowa Pharmaceutical Co.. AN has received honoraria for lectures from Novo Nordisk Pharma Ltd.. and has obtained research support from Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim Co., Kowa Co., Ltd., and Taisho Pharmaceutical Co., Ltd.. TA has received honoraria for lectures from GlaxoSmithKline plc., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co ., Ltd. Eisai Co. Ltd., AbbVie Inc., UCB Japan Co. Ltd., Novartis Pharma K.K., Pfizer Inc. Gilead Sciences, Inc., Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Daiichi Sankyo Co., Ltd., AstraZeneca plc., Asahi Kasei Pharma Co., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd.; and research grants from Eli Lilly Japan K.K., AbbVie Inc., Bristol-Myers Squibb Co., Daiichi Sankyo Co., Ltd., Asahi Kasei Pharma Co., Eisai Co. Ltd., Chugai Pharmaceutical Co., Ltd., AstraZeneca plc., Novartis Pharma K.K., Pfizer Inc. and UCB Japan Co., Ltd.; and consultancy fees from GlaxoSmithKline plc., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co ., Ltd., Boehringer Ingelheim., Bristol-Myers Squibb Co., Amgen K.K., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Gilead Sciences, Inc. and Daiichi Sankyo Co., Ltd.. KYC, KY, TO, AM, HK, and YA have no conflicts of interest to declare. Supplementary Files Supplementaryinformation.docx Supplefigure1.pptx Supplefigure2.pptx SuppleTable20240202.docx Cite Share Download PDF Status: Published Journal Publication published 23 Jul, 2024 Read the published version in BMC Endocrine Disorders → Version 1 posted Editorial decision: Revision requested 24 May, 2024 Reviews received at journal 24 Apr, 2024 Reviewers agreed at journal 18 Apr, 2024 Reviewers agreed at journal 18 Apr, 2024 Reviews received at journal 18 Apr, 2024 Reviewers agreed at journal 08 Apr, 2024 Reviewers invited by journal 29 Mar, 2024 Editor invited by journal 05 Feb, 2024 Editor assigned by journal 05 Feb, 2024 Submission checks completed at journal 05 Feb, 2024 First submitted to journal 04 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3927633","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":271055375,"identity":"6da3990f-2d42-43a0-a2b0-d4e3ef784ede","order_by":0,"name":"Yuki Oe","email":"","orcid":"","institution":"Hokkaido University","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Oe","suffix":""},{"id":271055376,"identity":"0085256b-9ddc-4543-bb9f-b53aecfe43d6","order_by":1,"name":"Hiroshi Nomoto","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIiWNgGAWjYBACAygtB2IzMzAkMDAcYGwAiTDj15LAYEy6lsQGhBYCDjOXbj664eMPm/S17c0bmAsq0hL7jh9uYPhRw8BujkOL5ZxjaTdnJKTlbjtzrIB5xpmcxJlnEhsYe44xMFs24HDYjRyz2zwJh3O33cgxYOZtq0jccADoSN4GBmYDHC6EaUk3u/8GquX8wwbGv0RoSTC7wQPSkpO44UZiAzN+W9KAfklLM9x2Jq3gMM+ZNOOZNx42HJY5JoHHL8nHbnywsZE3O35442OeimTZvvPpDx++qbFJxhViKOAAEkMi2QC3QhzAjnQto2AUjIJRMEwBAPadZUWSjHRsAAAAAElFTkSuQmCC","orcid":"","institution":"Hokkaido University","correspondingAuthor":true,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Nomoto","suffix":""},{"id":271055377,"identity":"efda9899-59c1-4b0d-b320-9ab8ff8d7943","order_by":2,"name":"Kyu Yong Cho","email":"","orcid":"","institution":"Hokkaido University","correspondingAuthor":false,"prefix":"","firstName":"Kyu","middleName":"Yong","lastName":"Cho","suffix":""},{"id":271055378,"identity":"2501679a-290a-423f-8f6d-76f251cb9c71","order_by":3,"name":"Kei Yokozeki","email":"","orcid":"","institution":"Hokkaido University","correspondingAuthor":false,"prefix":"","firstName":"Kei","middleName":"","lastName":"Yokozeki","suffix":""},{"id":271055379,"identity":"0a90e7a4-edce-4923-ba14-5e9a93f23979","order_by":4,"name":"Tsubasa Ono","email":"","orcid":"","institution":"Hokkaido University","correspondingAuthor":false,"prefix":"","firstName":"Tsubasa","middleName":"","lastName":"Ono","suffix":""},{"id":271055380,"identity":"5685f953-c52d-4c08-9aa2-2b96376763dc","order_by":5,"name":"Aika Miya","email":"","orcid":"","institution":"Hokkaido University","correspondingAuthor":false,"prefix":"","firstName":"Aika","middleName":"","lastName":"Miya","suffix":""},{"id":271055381,"identity":"b8c4ef86-2701-4227-8ce3-48ee346c8d09","order_by":6,"name":"Hiraku Kameda","email":"","orcid":"","institution":"Hokkaido University","correspondingAuthor":false,"prefix":"","firstName":"Hiraku","middleName":"","lastName":"Kameda","suffix":""},{"id":271055382,"identity":"0884adfb-289f-4ade-8eb5-83b837d94320","order_by":7,"name":"Akinobu Nakamura","email":"","orcid":"","institution":"Hokkaido University","correspondingAuthor":false,"prefix":"","firstName":"Akinobu","middleName":"","lastName":"Nakamura","suffix":""},{"id":271055383,"identity":"f9bb5f79-5d1f-4553-8ac6-d2bf6c21af7e","order_by":8,"name":"Yoshiaki Arimura","email":"","orcid":"","institution":"Otaru general hospital","correspondingAuthor":false,"prefix":"","firstName":"Yoshiaki","middleName":"","lastName":"Arimura","suffix":""},{"id":271055384,"identity":"d0e8d7ff-ade5-43e5-8057-115e6bbd5b9f","order_by":9,"name":"Tatsuya Atsumi","email":"","orcid":"","institution":"Hokkaido University","correspondingAuthor":false,"prefix":"","firstName":"Tatsuya","middleName":"","lastName":"Atsumi","suffix":""}],"badges":[],"createdAt":"2024-02-04 12:59:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3927633/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3927633/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12902-024-01658-6","type":"published","date":"2024-07-24T00:35:29+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":50813855,"identity":"717c35b8-6747-4064-b3d3-39284533dcd4","added_by":"auto","created_at":"2024-02-07 19:35:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":30511,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of subject’s enrollment\u003c/p\u003e\n\u003cp\u003eThe safety of the therapy was analyzed as a first cohort for 30 subjects and its efficacy was analyzed as a second cohort for 24 subjects that completed the study.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3927633/v1/2d38470850d528aaba1f8a2b.png"},{"id":50813861,"identity":"a361fc14-8cb5-437b-b407-53e61acaf7e0","added_by":"auto","created_at":"2024-02-07 19:35:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":27112,"visible":true,"origin":"","legend":"\u003cp\u003eOutcomes after 6 months of therapy\u003c/p\u003e\n\u003cp\u003e(a) HbA1c, (b) Body weight\u003c/p\u003e\n\u003cp\u003eBoth parameters showed significant reductions over the 6 months of the study. At baseline, the HbA1c levels were significantly higher and body weight did not differ in comparison to Visit −1. These changes were evaluated using Student’s \u003cem\u003et\u003c/em\u003e-test \u003cem\u003eversus\u003c/em\u003e the beginning of administration. Values are mean ± SD. **\u003cem\u003e P\u003c/em\u003e\u0026lt;0.01.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3927633/v1/d843af38314715f4157ab3d0.png"},{"id":50813853,"identity":"be0c4bb9-d749-420d-9ee7-c59ee2439723","added_by":"auto","created_at":"2024-02-07 19:35:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":16310,"visible":true,"origin":"","legend":"\u003cp\u003eChange in the glycemic control of the participants\u003c/p\u003e\n\u003cp\u003eHbA1c was evaluated according to the clinical practice guidelines of the Japan Diabetes Society and Japan Geriatrics Society Joint Committee. The glycemic target was set according to the baseline parameters, health status, and concomitant drug use of each subject. Fisher’s exact test was used to compare data at baseline and 6 months. **\u003cem\u003e P\u003c/em\u003e\u0026lt;0.01.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3927633/v1/719fcc1ba9438f5d24ba758e.png"},{"id":61039152,"identity":"82577dfb-2bfb-49b6-b0f3-2902102c4e08","added_by":"auto","created_at":"2024-07-25 00:35:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":601464,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3927633/v1/75cc2aeb-2034-4ced-b036-cabc17b553c7.pdf"},{"id":50813854,"identity":"094dc44e-8e95-4ff1-900e-d7d0600f3b71","added_by":"auto","created_at":"2024-02-07 19:35:35","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15058,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryinformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-3927633/v1/186787618ebb4447ceb9465d.docx"},{"id":50813857,"identity":"af0df22f-ac44-4a4d-88fd-3b25896c295b","added_by":"auto","created_at":"2024-02-07 19:35:35","extension":"pptx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":267205,"visible":true,"origin":"","legend":"","description":"","filename":"Supplefigure1.pptx","url":"https://assets-eu.researchsquare.com/files/rs-3927633/v1/fbc85841ab3ee56142e806e3.pptx"},{"id":50813856,"identity":"19b9cc4f-46ef-42f8-84ff-5e6a815f081a","added_by":"auto","created_at":"2024-02-07 19:35:35","extension":"pptx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":229739,"visible":true,"origin":"","legend":"","description":"","filename":"Supplefigure2.pptx","url":"https://assets-eu.researchsquare.com/files/rs-3927633/v1/b2f2531409ce5efe72c37cb1.pptx"},{"id":50813859,"identity":"c0e59c5a-964e-42c6-a44e-a542b1f6a8c6","added_by":"auto","created_at":"2024-02-07 19:35:35","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":38078,"visible":true,"origin":"","legend":"","description":"","filename":"SuppleTable20240202.docx","url":"https://assets-eu.researchsquare.com/files/rs-3927633/v1/add5d12283e7d84b5b171a5e.docx"}],"financialInterests":"Competing interest reported. YO has received honoraria for lectures from Novo Nordisk Pharma Ltd.. HN has received honoraria for lectures from Novo Nordisk Pharma Ltd. and Sumitomo Pharma Co., Ltd; and has obtained research support from Kowa Pharmaceutical Co.. AN has received honoraria for lectures from Novo Nordisk Pharma Ltd.. and has obtained research support from Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim Co., Kowa Co., Ltd., and Taisho Pharmaceutical Co., Ltd.. TA has received honoraria for lectures from GlaxoSmithKline plc., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co ., Ltd.\nEisai Co. Ltd., AbbVie Inc., UCB Japan Co. Ltd., Novartis Pharma K.K., Pfizer Inc.\nGilead Sciences, Inc., Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Daiichi Sankyo Co., Ltd., AstraZeneca plc., Asahi Kasei Pharma Co., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd.; and research grants from Eli Lilly Japan K.K., AbbVie Inc., Bristol-Myers Squibb Co., Daiichi Sankyo Co., Ltd., Asahi Kasei Pharma Co., Eisai Co. Ltd., Chugai Pharmaceutical Co., Ltd., AstraZeneca plc., Novartis Pharma K.K., Pfizer Inc. and UCB Japan Co., Ltd.; and consultancy fees from GlaxoSmithKline plc., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co ., Ltd., Boehringer Ingelheim., Bristol-Myers Squibb Co., Amgen K.K., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Gilead Sciences, Inc. and Daiichi Sankyo Co., Ltd.. KYC, KY, TO, AM, HK, and YA have no conflicts of interest to declare.","formattedTitle":"Efficacy and safety of oral semaglutide in older patients with type 2 diabetes: a retrospective observational study (the OTARU-SEMA study)","fulltext":[{"header":"Background","content":"\u003cp\u003eIn aging societies, the prevalence of cognitive impairment is increasing and the risks and progression of disease are also increasing, owing to declines in biological functions (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Japan is now regarded as a super-aged society, and the population of patients with type 2 diabetes (T2D) is aging as well during last decade (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). The incidence of diabetes complications is more frequent in older patients; therefore, glycemic management is of great importance in this population (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). However, some anti-hyperglycemic agents can cause severe hypoglycemia and are associated with the deterioration of arteriosclerosis and cognitive impairment (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The avoidance of such adverse events and the maintenance of appropriate glycemic control should ensure better health and life expectancy.\u003c/p\u003e \u003cp\u003eGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are anti-hyperglycemic agents delivering glucose lowering effects with low risk of hypoglycemia due to their glucose level-dependent mechanism (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). A number of large-scaled trials have demonstrated the benefits of GLP-1RAs, notably with respect to the reduction in the incidence of cardiovascular events induced and the preservation of kidney function (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). However, only injectable products had been available until recent years. Thereby, patients who had difficulty in self-administering or feeling resistance to injections abandon such intensive treatments, despite its efficacy. Recently available oral semaglutide was the first peroral GLP-1RAs in the world. Although a large-scaled trial showed significant reduction of total or cardiovascular death (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), there are several limitations to its use. It must be taken on an empty before first meal or beverage, with no more than 120 mL plain water only, and the ingestion of food, beverages, and other oral medications must be avoided for at least 30 minutes after taking it (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Such burden might prevent sufficient effectiveness especially in older patients, who may have cognitive impairment. Therefore, it is important to assess the efficacy of oral semaglutide in older subjects. However, this has only been assessed through a \u003cem\u003epost-hoc\u003c/em\u003e exploratory analysis of a few clinical trials to date (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e The purpose of this study was to evaluate the efficacy and safety of oral semaglutide in a real-world clinical setting focusing exclusively on older subjects. In addition, we aimed to characterize the cognitive function and baseline characteristics of older subjects that are associated with the efficacy of semaglutide treatment.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective, single-arm, observational study (the OTARU-SEMA study). Older Japanese subjects with T2D who attended the Department of Diabetes, Otaru General Hospital, were recruited between December 2021 and August 2022. The eligible subjects were aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years, had a glycohemoglobin (HbA1c) level\u0026thinsp;\u0026ge;\u0026thinsp;53.0 mmol/mol (7%), and were able to manage their medications themselves. Subjects who commenced the administration of oral semaglutide were followed for 6 months. The dosage was adjusted by the physician in charge and was increased as much as the subjects could tolerate. We excluded subjects who had previously been administering a GLP-1RA subcutaneously. The other exclusion criteria described in Supporting information.\u003c/p\u003e \u003cp\u003eThe study was registered with the University Hospital Medical Information Network (UMIN) (registration number UMIN 000048782). It was approved by the Institutional Clinical Research Review Board of Otaru General Hospital (approval number 04\u0026thinsp;\u0026minus;\u0026thinsp;001) and was conducted in accordance with the principles of the Declaration of Helsinki and its amendments. An opt-out informed consent approach was adopted for all the participants.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAdverse events\u003c/h2\u003e \u003cp\u003eThe presence and severity of adverse events were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), and the definitions of severe adverse events are provided in the Supporting information. In accordance with the instructions of the manufacturer, the participants were thoroughly informed regarding the known adverse events of GLP-1RAs, including gastrointestinal events and anorexia, before the administration. The administration procedure was explained by the physician in charge and a nurse, and compliance was confirmed at each hospital visit.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eBiochemical analyses and cognitive function testing\u003c/h2\u003e \u003cp\u003eThe body weight and height of subjects were measured using a calibrated scale. Body mass index (BMI) was calculated as body weight (kg) divided by the square of height (m\u003csup\u003e2\u003c/sup\u003e). Endogenous insulin secretion was evaluated by the measurement of C-peptide (CPR) and C-peptide index (CPI) (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), and the biochemical parameters, including plasma glucose, were measured in blood samples collected after an overnight fast. CPI was calculated as CPI\u0026thinsp;=\u0026thinsp;100 \u0026times; fasting CPR (ng/mL)/plasma glucose (mg/dL). Other parameters were measured using standard techniques, and other data, including the medical history of the participants, were collected by the attending physicians.\u003c/p\u003e \u003cp\u003eThe cognitive function of the participants was evaluated using the Dementia Assessment Sheet for Community-based Integrated Care System 8-items (DASC-8) and the Hasegawa Dementia Rating Scale-revised (HDS-R) during the study period. The criteria for a diagnosis of impaired cognitive function using these screening tests were those previously defined (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). These questionnaires were completed by a single well-trained nurse in the consulting rooms.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes and data analysis\u003c/h2\u003e \u003cp\u003eThe primary outcome was the change in HbA1c over the 6 months of oral semaglutide treatment. The secondary outcomes were the safety of semaglutide treatment and the changes in body weight and other biochemical data. The date on which semaglutide treatment was initiated was regarded as the baseline. As Visit \u0026minus;\u0026thinsp;1, HbA1c and body weight were first measured 1\u0026ndash;3 months prior to baseline to exclude the possibility that these parameters were affected by prior treatments to semaglutide administration. The achievement of glycemic targets was evaluated using the Clinical Practice Guidelines of the Japan Diabetes Society (JDS) and Japan Geriatrics Society (JGS) Joint Committee (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), based on the age, health status of subjects and their use of anti-diabetic agents which can cause hypoglycemia. Inappropriately high or low HbA1c levels were defined as values that exceeded the target or were below the lower limit recommended for subjects using insulin or insulin secretagogues, respectively. We performed a sub-analysis of the data by dividing participants into two subgroups: early (65\u0026ndash;74 years old) and late (\u0026ge;\u0026thinsp;75 years old) older group (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). In addition, we evaluated the relationships between the baseline characteristics of the subjects and their improvements in HbA1c, and the relationships of cognitive function test scores with each parameter.\u003c/p\u003e \u003cp\u003eNormally distributed data are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD and other data are expressed as median (interquartile range). Data were analyzed using JMP Pro 16.0.0 (SAS Inc., Cary, NC, USA) or GraphPad Prism 8.4.2 (GraphPad Software, Inc. San Diego, CA, USA). For before-and-after comparisons, Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test was used to analyze parametric data and Wilcoxon\u0026rsquo;s signed-rank test was used for non-parametric data. Fisher\u0026rsquo;s exact test was used to compare the numbers of subjects who achieved their glycemic targets. Parameters and their changes were compared between the age groups using the unpaired \u003cem\u003et\u003c/em\u003e-test. Pearson\u0026rsquo;s correlation coefficient was used to identify associations between parameters. All the tests performed were two-sided, and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to represent statistical significance. The post hoc power calculation was performed using GPower\u0026reg; version 3.1.9.2. \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicated statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of subjects\u003c/h2\u003e \u003cp\u003eSubjects were enrolled as described in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. During the observation period, 44 subjects with T2D were administered oral semaglutide, but at the time of analysis, 10 were excluded because they were \u0026lt;\u0026thinsp;65 years (n\u0026thinsp;=\u0026thinsp;8) or had previously subcutaneously administered a GLP-1RA (n\u0026thinsp;=\u0026thinsp;2). Thus, 34 of the subjects were eligible for inclusion; however, a further 4 were excluded for the following reasons, unrelated to the drug: presence of a malignant tumor (n\u0026thinsp;=\u0026thinsp;2), self-discontinuation (n\u0026thinsp;=\u0026thinsp;1), and deterioration of a comorbidity (n\u0026thinsp;=\u0026thinsp;1). Details of the adverse events and the reasons for the discontinuation of semaglutide were analyzed in the remaining 30 subjects as a safety analysis. Six of the subjects discontinued the medication, and therefore the remaining 24 subjects were studied with respect to efficacy.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e showed the baseline characteristics of the participants in an efficacy analysis. The prevalence of obesity (BMI\u0026thinsp;\u0026ge;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e) was 33.3% (Early; n\u0026thinsp;=\u0026thinsp;5, Late; n\u0026thinsp;=\u0026thinsp;3), but their insulin secretory capacity was preserved. In evaluation of cognitive function, the DASC-8 and HDS-R scores were consistent with cognitive impairment in only 4 (Early; n\u0026thinsp;=\u0026thinsp;1, Late; n\u0026thinsp;=\u0026thinsp;3) and 2 (Early; n\u0026thinsp;=\u0026thinsp;0, Late; n\u0026thinsp;=\u0026thinsp;2) subjects, respectively, and the others were not found to have impaired cognitive function. The final doses of semaglutide were as follows: 3 mg, n\u0026thinsp;=\u0026thinsp;5 (Early; n\u0026thinsp;=\u0026thinsp;4, Late; n\u0026thinsp;=\u0026thinsp;1); 7 mg, n\u0026thinsp;=\u0026thinsp;15 (Early; n\u0026thinsp;=\u0026thinsp;8, Late; n\u0026thinsp;=\u0026thinsp;7); and 14 mg, n\u0026thinsp;=\u0026thinsp;4 (Early; n\u0026thinsp;=\u0026thinsp;1, Late; n\u0026thinsp;=\u0026thinsp;3). Few drugs were being used concomitantly; dipeptidyl peptidase-4 inhibitors (DPP-4is) were the most commonly prescribed drugs prior to semaglutide administration (Early; n=,12 Late; n\u0026thinsp;=\u0026thinsp;11), but all of the users were switched to oral semaglutide. Half of the subjects were being treated with anti-hyperglycemic agents that could be associated with severe hypoglycemia (sulfonylureas, glinides, and insulin), but only 1 subject who was being treated with a glinide showed severe renal dysfunction (eGFR\u0026thinsp;\u0026le;\u0026thinsp;30 mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;24)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75.5\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale sex (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e155.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody weight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57.4\u0026thinsp;\u0026plusmn;\u0026thinsp;11.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes duration (years) \u003csup\u003e\u0026para;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17.0 [7.0, 23.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFPG (mmol/L) \u003csup\u003e\u0026para;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHbA1c (mmol/mol)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCPR (nmol/L) \u003csup\u003e\u0026para;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCPI (ng/mL per mg/dL) \u003csup\u003e\u0026para;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEvaluation for cognitive function\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDASC-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.0 [8.0, 9.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDS-R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe proportion of anti-diabetic agent (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe number of drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.0 [2.0, 3.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiguanide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDPP-4i\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (91.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (25.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlinides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (16.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThiazolidine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eα-GI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSGLT2i\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (45.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInsulin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (8.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eValues are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median (interquartile range). \u0026para;The values were calculated except one subject for missing data. α-GI, alpha glucosidase inhibitors; BMI, body mass index; CPI, C-peptide index; CPR, C-peptide; DASC-8, dementia assessment sheet for community-based integrated care system 8-items; DPP-4i, dipeptidyl peptidase-4 inhibitor; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; HDS-R, Hasegawa dementia rating scale-revised; SGLT2i, sodium-glucose cotransporter 2 inhibitor; SU, sulfonylurea.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy\u003c/h2\u003e \u003cp\u003eOral semaglutide significantly decreased HbA1c and body weight during the 6-month study period (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). These effects were similar in participants in each age bracket (Supplementary table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). At baseline, HbA1c was high in most of the subjects and achievement rate of glycemic targets from JDS and JGS were only being met 25.0% (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Supplementary table \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). After 6 months, HbA1c significantly declined (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and many had achieved their glycemic targets (prevalence had changed from 25.0\u0026ndash;70.8%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), whereas the late older subjects using insulin or an insulin secretagogue tended to be more likely to have inappropriately low HbA1c values (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.18) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Supplementary table \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In addition, the change in HbA1c during the 6-month period correlated with the baseline HbA1c value and the insulin secretory capacity (Supplementary table 4).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAlthough neither the metabolic parameters nor body mass significantly differed at baseline between the two age groups (early; 65\u0026ndash;74 \u003cem\u003eversus\u003c/em\u003e late; \u0026ge; 75), the HDS-R of the late older subgroup was significantly lower (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Supplementary table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Supplementary Fig.\u0026nbsp;1) and negatively correlated with age (r\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.57, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Supplementary Fig.\u0026nbsp;1). On the other hand, the reduction of HbA1c and body weight showed no significant differences between the age groups (early \u003cem\u003eversus\u003c/em\u003e late: HbA1c; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.66, body weight; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.27) (Supplementary Fig.\u0026nbsp;2).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eSupplementary table 5 shows the details of the adverse events. Severe adverse events, defined using the CTCAE, did not occur (Supplementary information). Discontinuation of the medication was more frequent in the late older subjects and was for the following reasons: Early; vomiting (3 mg, n\u0026thinsp;=\u0026thinsp;1) and anorexia (3 mg, n\u0026thinsp;=\u0026thinsp;1); Late; vomiting (3 mg, n\u0026thinsp;=\u0026thinsp;1; 7 mg, n\u0026thinsp;=\u0026thinsp;1) and anorexia (7 mg, n\u0026thinsp;=\u0026thinsp;1; 14 mg, n\u0026thinsp;=\u0026thinsp;1). Most of the other adverse events that were reported were gastrointestinal symptoms, and none of the subjects experienced hypoglycemia.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eSince the sample size might not have been sufficient, we calculated the post hoc power. The overall detection power value under the 5% α error was 1.0 for the change in HbA1c between baseline and 6 months after switching to oral semaglutide (N\u0026thinsp;=\u0026thinsp;24). In each age bracket, the overall detection power value under the 5% α error were 0.999 (Early; n\u0026thinsp;=\u0026thinsp;13) and 0.999 (Late; n\u0026thinsp;=\u0026thinsp;11).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the present study, we have evaluated the efficacy and safety of oral semaglutide for older subjects, and compared relevant parameters in subjects of 65\u0026ndash;74 years and \u0026ge;\u0026thinsp;75 years. Although severe adverse events, involving drug discontinuation, were relatively frequent in subjects of \u0026ge;\u0026thinsp;75 years, we found that oral semaglutide treatment was effective, as shown in previous phase 3 clinical trials (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Furthermore, we characterized the medication and cognitive function of these subjects, and given that DPP-4is were the most frequently prescribed drugs at baseline, the study may provide useful information regarding the efficacy of switching from a DPP-4i to an oral GLP-1RA in patients of this age. To the best of our knowledge, this is the first study to characterize the safety and efficacy of oral semaglutide in older patients with T2D in a real-world clinical setting.\u003c/p\u003e \u003cp\u003eThe PIONEER clinical trials showed the efficacy of oral semaglutide in subjects from around the world (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Additional analyses for older Japanese subjects with T2D were conducted in PIONEER 9 and 10 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Japan is one of the countries with a rapidly aging population, specifically, 29.1% of the population was \u0026ge;\u0026thinsp;65 years old and 15.5% was \u0026ge;\u0026thinsp;75 years old in 2022. The baseline age of the previous sub-analysis was 65 years old and more precise classification was desirable to capture the real-world setting (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Here, we compared the efficacy of semaglutide in subgroups of subjects of 65\u0026ndash;74 years and \u0026ge;\u0026thinsp;75 years to identify any differences between these sections of the older population (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). As in PIONEER 9 and 10, we found that semaglutide reduced HbA1c and body weight in both age groups (Supplementary table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBecause older patients can be vulnerable to adverse effects of drugs (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e), it is important to clarify whether new therapeutics have such effects in this population. A sub-analysis of the PIONEER trials showed that older patients of \u0026ge;\u0026thinsp;65 years had a higher discontinuation rate of oral semaglutide than younger subjects (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In the present study, nearly 80% of the older patients continued the medication for the full 6 months, but discontinuations were slightly more frequent in those who were \u0026ge;\u0026thinsp;75 years old (n\u0026thinsp;=\u0026thinsp;4, 26.7%) than in those of 65\u0026ndash;74 years of age (n\u0026thinsp;=\u0026thinsp;2, 13.3%), and these most frequently reason were due to gastrointestinal symptoms. Notably, two-thirds of the dropouts occurred at the starting dose (3 mg). Therefore, careful explanations should be provided when oral semaglutide therapy is commenced, especially in very aged patients, and clinicians should be aware that the glycemic targets for older patients should be determined according to their age, activity level, and the use of other medication (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). In our results, oral semaglutide use was associated with a 70.8% achievement rate with respect to glycemic targets, but also undesirably low HbA1c values in 20.8% of the participants (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Supplementary table \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In a sub-analysis of PIONEER 10, 2.5% of subjects administered oral semaglutide experienced symptomatic hypoglycemic episodes, and most of these were also administering sulfonylureas; however, their age and renal function were unknown (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Although hypoglycemic symptoms were not reported in the present study, the identities of any concomitant medications, and especially of anti-hyperglycemic agents that can be associated with severe hypoglycemia, should be taken into account when the use of semaglutide is considered for patients of \u0026ge;\u0026thinsp;75 years.\u003c/p\u003e \u003cp\u003eDPP-4is are the most frequently prescribed anti-hyperglycemic agents in Japan, because of their convinced safety and effectiveness (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). In addition, the algorithm that was recently published by the JDS and JGS recommend their use primarily for patients who do not have obesity, and in fact DPP-4is tend to be prescribed more frequently in older patients (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). This is reflected in over 90% of the participants administering a DPP-4i at the start of the present study, precisely reflecting the trends of prescription in our country. Importantly, however, the participants in the PIONEER phase 3 trials were not administering a DPP-4i at the start (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Collectively, the present study provides important insights into the clinical usefulness of oral semaglutide, in particular after switching from a DPP-4i, in older patients.\u003c/p\u003e \u003cp\u003eThe complexity of the method of administration is one of the problems associated with oral semaglutide use (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), and this might be a challenge for patients with cognitive impairment. In fact, cognitive impairment does not significantly affect adherence to oral medications or self-care in patients with T2D, rather injections including insulin might be a problem (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). However, the circulating semaglutide concentration following administration is more variable following oral administration than subcutaneous injection, which might reflect poorer absorption (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Nevertheless, the established potent antihyperglycemic effect of oral semaglutide was replicated in the present study, even though it was of older subjects. Cognitive function declined with increasing age, whereas did not correlate with improvements of HbA1c in the present study (Supplementary Fig.\u0026nbsp;1, Supplementary table 4). Although, it is worthy to note that subjects suffering severe cognitive impairment were not involved in this study. Instead, the improvement in HbA1c correlated with CPR and CPI, suggesting that the level of residual beta-cell function is associated with the efficacy of oral semaglutide treatment, which has been shown for other GLP-1RAs (Supplementary table 4) (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe strengths of the present study were that we exclusively studied older patients, that we assessed the efficacy and safety of the drug in a real-world clinical setting, and that the cognitive function of the participants was also evaluated. We have also confirmed the trends in prescribing practice in Japan and demonstrated the effectiveness of switching from a DPP-4i to oral semaglutide. However, there were also several limitations. First, it was a single-arm retrospective observational study with a small sample size. Second, the participants were exclusively Japanese, which limits the generalizability of the findings. Finally, the subjects were older, but had relatively well-preserved cognitive function. Therefore, further studies should be conducted in the next future, including larger, two-arm, prospective studies, and studies of participants with more marked cognitive impairment.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003e In conclusion, we have demonstrated the efficacy of oral semaglutide in older subjects in a real-world clinical setting. The frequency of adverse events for older subjects was similar to that in the clinical trial, however, discontinuation of medication and risk for potential hypoglycemia were more frequent in late older subjects. Therefore, it is important that clinicians are aware of careful explanations and the use of concomitant medications for appropriate treatment. We hope that oral semaglutide will be more widely adopted as a safe and more convenient GLP-1RA in the future.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBody mass index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCTCAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethe Common Terminology Criteria for Adverse Events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCPI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eC-peptide index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCPR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eC-peptide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDASC-8\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethe Dementia Assessment Sheet for Community-based Integrated Care System 8-items\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDPP-4is\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edipeptidyl peptidase-4 inhibitors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGLP-1RAs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGlucagon-like peptide-1 receptor agonists\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHbA1c\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eglycohemoglobin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHDS-R\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethe Hasegawa Dementia Rating Scale-revised\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eJDS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethe Japan Diabetes Society\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eJGS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eJapan Geriatrics Society\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eT2D\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etype 2 diabetes\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUMIN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethe University Hospital Medical Information Network.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Institutional Clinical Research Review Board of Otaru General Hospital (Date of approval;2022/5/10, Approval number;04-001) and was conducted in accordance with the principles of the Declaration of Helsinki and its amendments. An opt-out informed consent approach was adopted for all the participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author. The data have not been made publicly available owing to privacy or ethical restrictions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYO has received honoraria for lectures from Novo Nordisk Pharma Ltd.. HN has received honoraria for lectures from Novo Nordisk Pharma Ltd. and Sumitomo Pharma Co., Ltd; and has obtained research support from Kowa Pharmaceutical Co.. AN has received honoraria for lectures from Novo Nordisk Pharma Ltd.. and has obtained research support from Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim Co., Kowa Co., Ltd., and Taisho Pharmaceutical Co., Ltd.. TA has received honoraria for lectures from GlaxoSmithKline plc., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co ., Ltd.\u003c/p\u003e\n\u003cp\u003eEisai Co. Ltd., AbbVie Inc., UCB Japan Co. Ltd., Novartis Pharma K.K., Pfizer Inc.\u003c/p\u003e\n\u003cp\u003eGilead Sciences, Inc., Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Daiichi Sankyo Co., Ltd., AstraZeneca plc., Asahi Kasei Pharma Co., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd.; and research grants from Eli Lilly Japan K.K.,\u0026nbsp;AbbVie Inc., Bristol-Myers Squibb Co., Daiichi Sankyo Co., Ltd., Asahi Kasei Pharma Co., Eisai Co. Ltd., Chugai Pharmaceutical Co., Ltd., AstraZeneca plc., Novartis Pharma K.K., Pfizer Inc. and UCB Japan Co., Ltd.; and consultancy fees from GlaxoSmithKline plc., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co ., Ltd., Boehringer Ingelheim., Bristol-Myers Squibb Co., Amgen K.K., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Gilead Sciences, Inc. and Daiichi Sankyo Co., Ltd.. KYC, KY, TO, AM, HK, and YA have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo funding or sponsorship was received for this study or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYO conceived and designed the study. HN and KYC edited the study protocol and supervised the study. YO collected and analyzed the data, and wrote the manuscript. HN analyzed the data and edited the manuscript, tables, and figures. YO, KY and TO treated and recruited the participants. All the authors reviewed, and KYC, AM, HK, AN, and TA edited the manuscript. All the authors approved the final version of the manuscript. HN is the guarantor of this work and, as such, had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to express their gratitude to all the patients and staff who participated in this study. We also thank Mark Cleasby, PhD, from Edanz (\u003ca href=\"https://jp.edanz.com/ac\" target=\"_blank\"\u003ehttps://jp.edanz.com/ac\u003c/a\u003e) for editing a draft of this manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOgawa S. Nutritional management of older adults with cognitive decline and dementia. Geriatr Gerontol Int. 2014;14(Suppl 2):17\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrince MJ, Wu F, Guo Y, Gutierrez Robledo LM, O'Donnell M, Sullivan R, Yusuf S. The burden of disease in older people and implications for health policy and practice. Lancet. 2015;385(9967):549\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo J, Huang X, Dou L, Yan M, Shen T, Tang W, Li J. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduct Target Ther. 2022;7(1):391.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiyazawa I, Yokoyama H, Yagi N, Araki SI, Morino K, Kume S, et al. Annual trends in glycemic control and prescribing patterns in diabetic treatment according to age in Japanese patients with type 2 diabetes between 2012 and 2019 (JDDM 71). Diabetes Res Clin Pract. 2023;198:110599.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCharvat H, Goto A, Goto M, Inoue M, Heianza Y, Arase Y, et al. Impact of population aging on trends in diabetes prevalence: A meta-regression analysis of 160,000 Japanese adults. J Diabetes Investig. 2015;6(5):533\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang P, Babazono A, Fujita T. Health Inequalities Among Elderly Type 2 Diabetes Mellitus Patients in Japan. Popul Health Manag. 2020;23(3):264\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaremi A, Bahn GD, Reaven PD. A Link Between Hypoglycemia and Progression of Atherosclerosis in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care. 2016;39(3):448\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWhitmer RA, Karter AJ, Yaffe K, Quesenberry CP Jr., Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA. 2009;301(15):1565\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNauck M. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab. 2016;18(3):203\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSheahan KH, Wahlberg EA, Gilbert MP. An overview of GLP-1 agonists and recent cardiovascular outcomes trials. Postgrad Med J. 2020;96(1133):156\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKristensen SL, R\u0026oslash;rth R, Jhund PS, Docherty KF, Sattar N, Preiss D, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019;7(10):776\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHusain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019;381(9):841\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHughes S, Neumiller JJ. Oral Semaglutide. Clin Diabetes. 2020;38(1):109\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamada Y, Yabe D, Hertz CL, Horio H, Nakamura J, Nielsen AM, Seino Y. Efficacy and safety of oral semaglutide by baseline age in Japanese patients with type 2 diabetes: A subgroup analysis of the PIONEER 9 and 10 Japan trials. Diabetes Obes Metab. 2022;24(2):321\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFunakoshi S, Fujimoto S, Hamasaki A, Fujiwara H, Fujita Y, Ikeda K, et al. Utility of indices using C-peptide levels for indication of insulin therapy to achieve good glycemic control in Japanese patients with type\u0026emsp;2 diabetes. J Diabetes Investig. 2011;2(4):297\u0026ndash;303.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eToyoshima K, Araki A, Tamura Y, Iritani O, Ogawa S, Kozaki K, et al. Development of the Dementia Assessment Sheet for Community-based Integrated Care System 8-items, a short version of the Dementia Assessment Sheet for Community-based Integrated Care System 21-items, for the assessment of cognitive and daily functions. Geriatr Gerontol Int. 2018;18(10):1458\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eY I KH. The revised Hasegawa\u0026rsquo;s Dementia Scale (HDS-R) \u0026mdash; evaluation of its usefulness as a screening test for dementia. J Hong Kong Coll Psychiatr. 1994;4:20\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaneda M, Ito H. Glycemic targets for elderly patients with diabetes. Diabetol Int. 2016;7(4):331\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrimo HIH, Suzuki T, Araki A, Hosoi T, Sawabe M. Reviewing the definition of elderly. Geriatr Gerontol Int. 2006;6(3):149\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRasmussen MF. The development of oral semaglutide, an oral GLP-1 analog, for the treatment of type 2 diabetes. Diabetol Int. 2020;11(2):76\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamada Y, Katagiri H, Hamamoto Y, Deenadayalan S, Navarria A, Nishijima K, Seino Y. Dose-response, efficacy, and safety of oral semaglutide monotherapy in Japanese patients with type 2 diabetes (PIONEER 9): a 52-week, phase 2/3a, randomised, controlled trial. Lancet Diabetes Endocrinol. 2020;8(5):377\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYabe D, Nakamura J, Kaneto H, Deenadayalan S, Navarria A, Gislum M, Inagaki N. Safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes (PIONEER 10): an open-label, randomised, active-controlled, phase 3a trial. Lancet Diabetes Endocrinol. 2020;8(5):392\u0026ndash;406.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOuchi Y, Rakugi H, Arai H, Akishita M, Ito H, Toba K, Kai I. Redefining the elderly as aged 75 years and older: Proposal from the Joint Committee of Japan Gerontological Society and the Japan Geriatrics Society. Geriatr Gerontol Int. 2017;17(7):1045\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorimoto T, Sakuma M, Matsui K, Kuramoto N, Toshiro J, Murakami J, et al. Incidence of adverse drug events and medication errors in Japan: the JADE study. J Gen Intern Med. 2011;26(2):148\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYabe D, Deenadayalan S, Horio H, Kaneto H, Jensen TB, Terauchi Y, et al. Efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes: A subgroup analysis by baseline variables in the PIONEER 9 and PIONEER 10 trials. J Diabetes Investig. 2022;13(6):975\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBouchi R, Sugiyama T, Goto A, Imai K, Ihana-Sugiyama N, Ohsugi M, et al. Retrospective nationwide study on the trends in first-line antidiabetic medication for patients with type 2 diabetes in Japan. J Diabetes Investig. 2022;13(2):280\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBouchi R, Kondo T, Ohta Y, Goto A, Tanaka D, Satoh H, et al. A consensus statement from the Japan Diabetes Society: A proposed algorithm for pharmacotherapy in people with type 2 diabetes. J Diabetes Investig. 2023;14(1):151\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eŚwiątoniowska-Lonc N, Polański J, Tański W, Jankowska-Polańska B. Impact of Cognitive Impairment on Adherence to Treatment and Self-Care in Patients with Type 2 Diabetes Mellitus. Diabetes Metab Syndr Obes. 2021;14:193\u0026ndash;203.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOvergaard RV, Hertz CL, Ingwersen SH, Navarria A, Drucker DJ. Levels of circulating semaglutide determine reductions in HbA1c and body weight in people with type 2 diabetes. Cell Rep Med. 2021;2(9):100387.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJones AG, McDonald TJ, Shields BM, Hill AV, Hyde CJ, Knight BA, Hattersley AT. Markers of β-Cell Failure Predict Poor Glycemic Response to GLP-1 Receptor Agonist Therapy in Type 2 Diabetes. Diabetes Care. 2016;39(2):250\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakabe M, Matsuda T, Hirota Y, Hashimoto N, Nakamura T, Sakaguchi K, et al. C-peptide response to glucagon challenge is correlated with improvement of early insulin secretion by liraglutide treatment. Diabetes Res Clin Pract. 2012;98(3):e32\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshiji S, Hasebe M, Iwasaki Y, Shibue K, Keidai Y, Seno Y, et al. Exploring a Suitable Marker of Glycemic Response to Dulaglutide in Patients with Type 2 Diabetes: A Retrospective Study. Diabetes Ther. 2022;13(4):733\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"glucagon-like peptide 1 receptor, aged, type 2 diabetes, cognitive test, oral medicine","lastPublishedDoi":"10.21203/rs.3.rs-3927633/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3927633/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eOral semaglutide in older subjects with type 2 diabetes was as effective as in younger subjects, according to phase 3 clinical trials. However, its efficacy can be limited in very aged population, due to the presence of impaired cognitive function and the complex instructions for its use. Here, we investigated its efficacy and safety by further age bracket in older subjects in real-world.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe retrospectively studied subjects \u0026gt;65 years of age with type 2 diabetes who started oral semaglutide treatment. The primary outcome was the change in glycosylated hemoglobin (HbA1c) over 6 months. Adverse events and cognitive function were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) and the Hasegawa Dementia Rating Scale-revised (HDS-R). The achievement rate of glycemic targets was evaluated based on the age, health status of subjects and their use of anti-diabetic agents which can cause hypoglycemia, with additional analysis between two subgroups; early (65-74) versus late (≥ 75) older. Furthermore, we evaluated the relationships between their improvements in HbA1c and the baseline characteristics of the subjects, including their cognitive function and insulin secretory capacity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eWe studied the efficacy of the drug in 24 subjects. Their HbA1c and body weight significantly decreased (−13.1 ± 7.5 mmol/mol and −3.0±2.4 kg, respectively; \u003cem\u003eP\u003c/em\u003e\u0026lt;0.01). Although cognitive function was lower in the late older group (r=−0.57, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.01), changes in HbA1c showed no difference between the two subgroups (\u003cem\u003eP\u003c/em\u003e=0.66) and it correlated with the insulin secretory capacity rather than cognitive function (r=−0.49, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). Glycemic targets were more likely to be achieved (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.01), but HbA1c excessively decreased in late older subjects who were also using insulin or an insulin secretagogue. The frequency of adverse events was similar to that in the clinical trial, whereas discontinuation of medication were more frequent among the late older subjects (Early; n=2, Late; n=4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Oral semaglutide improves the glycemic control of older subjects, but it might be a risk for potential hypoglycemia and discontinuation in subjects of ≥75 years. Attention should be paid to insulin secretory capacity and concomitant medications rather than concern about adherence.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of oral semaglutide in older patients with type 2 diabetes: a retrospective observational study (the OTARU-SEMA study)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-07 19:35:30","doi":"10.21203/rs.3.rs-3927633/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-05-24T15:43:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-24T08:56:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"227c4d68-7d3f-4e14-8165-1822e942fc80","date":"2024-04-18T20:02:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"90c10d3b-5328-4248-87b7-82e048620f26","date":"2024-04-18T10:37:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-18T06:45:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"a0c166e4-e339-4f21-bb9f-9bbbf927d32b","date":"2024-04-08T13:24:08+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-29T18:05:51+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-02-05T05:41:02+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-05T05:37:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-02-05T05:20:29+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Endocrine Disorders","date":"2024-02-04T12:47:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"040363e3-0795-4466-9109-d3ef9a29156c","owner":[],"postedDate":"February 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-07-25T00:35:29+00:00","versionOfRecord":{"articleIdentity":"rs-3927633","link":"https://doi.org/10.1186/s12902-024-01658-6","journal":{"identity":"bmc-endocrine-disorders","isVorOnly":false,"title":"BMC Endocrine Disorders"},"publishedOn":"2024-07-24 00:35:29","publishedOnDateReadable":"July 24th, 2024"},"versionCreatedAt":"2024-02-07 19:35:30","video":"","vorDoi":"10.1186/s12902-024-01658-6","vorDoiUrl":"https://doi.org/10.1186/s12902-024-01658-6","workflowStages":[]},"version":"v1","identity":"rs-3927633","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3927633","identity":"rs-3927633","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}