ABSTRACT
Aims/Introduction
The study aim was to investigate sulfonylurea prescription patterns in elderly patients (age ≥65 years) with type 2 diabetes mellitus in Japan. Sulfonylurea use among older adults has been insufficiently examined, despite the associated risks of hypoglycemia.
Materials and Methods
This retrospective cross‐sectional survey entailed analysis of Japanese pharmacy data, extracted from the Musubi database, for patients (age 20–100 years) prescribed sulfonylureas between November 2022 and October 2023. Dose distribution, adherence to the Diabetes Treatment Guidelines for the Elderly 2023 and coprescription of other diabetes medications were investigated.
Results
Of the total 91,229 patients, 80.1% were prescribed glimepiride, 16.3% gliclazide and 3.6% glibenclamide. In patients aged ≥65 years, exceeding the recommended dose (>1 mg/day for glimepiride, >40 mg/day for gliclazide) was numerically higher for glimepiride (25.0%) than for gliclazide (7.8%). The most common prescribing patterns were quadruple therapy with a sulfonylurea, a dipeptidyl peptidase‐4 inhibitor, an sodium–glucose transporter 2 inhibitor and a biguanide in patients aged 65 to <75 years, and dual therapy with a sulfonylurea and a dipeptidyl peptidase‐4 inhibitor in patients aged ≥75 years. Unfortunately, glinide was coprescribed for 338 (0.5%) of elderly patients. Insulin was coprescribed for 3,682 (5.6%) of elderly patients.
Conclusions
Analysis of real‐world sulfonylurea prescription data found guideline non‐adherence, namely, excessive prescription of glimepiride, use of glibenclamide in elderly patients, and common coprescription with dipeptidyl peptidase‐4 inhibitors. These findings might provide an opportunity to reconsider the treatment of patients with type 2 diabetes mellitus who are over‐prescribed sulfonylureas to reduce residual risks, such as hypoglycemia.
Keywords: Elderly, Real‐world data, Sulfonylurea
This study examined the prescribing patterns of sulfonylureas in Japan using comprehensive real‐world clinical prescription data from pharmacies. Glimepiride was prescribed to 25.0% of patients aged ≥65 years at doses exceeding the maximum recommended dose of 1 mg/day by the Diabetes Treatment Guidelines for the Elderly 2023. In addition, 32.5% of patients prescribed glibenclamide were aged ≥65 years, despite guidelines discouraging the use of glibenclamide in elderly patients. These findings underscore the need for increased education on guideline adherence to reduce the risk of hypoglycemia and effectively manage diabetic complications in the elderly population.
INTRODUCTION
Elderly patients with type 2 diabetes mellitus are particularly susceptible to hypoglycemia, and frequently present with unrecognized symptoms 1 , 2 . Due to the potent hypoglycemic effect and the notable risk of cardiotoxicity associated with sulfonylureas, the Diabetes Treatment Guidelines for the Elderly 2023, jointly created by the Japan Geriatrics Society and the Japan Diabetes Society, recommend caution when considering their use in elderly patients with type 2 diabetes mellitus 3 . Specifically, low starting doses, administered once daily, such as 20 mg for gliclazide and 0.5 mg for glimepiride, are recommended, with a ceiling of 40 mg for gliclazide and 1 mg for glimepiride. Use of glibenclamide in the elderly is generally discouraged because of its prolonged action 3 . The results of previous studies have highlighted the increased risk of severe hypoglycemia with gliclazide or glimepiride use in patients with renal impairment or aged ≥75 years 4 , 5 . Furthermore, the use of glibenclamide in elderly patients with type 2 diabetes mellitus has been shown to increase the risk of hypoglycemia 6 .
In both the USA and Japan, a significant reduction in the use of sulfonylureas has been observed, due to the introduction of dipeptidyl peptidase‐4 (DPP‐4) inhibitors and sodium–glucose cotransporter 2 (SGLT‐2) inhibitors 7 , 8 , 9 , 10 , 11 . However, although this trend is well documented in the general population, the use of sulfonylureas among the elderly in Japan has not been adequately studied, particularly in real‐world clinical practice. Specifically, limited data are available on the types of sulfonylureas used in actual clinical practice, the dosages at which they are prescribed, their coprescription with other antidiabetic agents and the special considerations required for the elderly. Therefore, gathering and interpretation of this information is vital for optimizing diabetes management in this patient population.
The present study was designed as a comprehensive survey of sulfonylurea prescription patterns in elderly diabetes patients in Japan. By analyzing real‐world data from electronic pharmacy records, we aimed to investigate the types and dosages of sulfonylureas prescribed, and their coprescription with other diabetes medications, and thus contribute useful information for use in the development of appropriate diabetes management strategies for the elderly.
MATERIALS AND METHODS
Study design and data source
The present study was a retrospective cross‐sectional survey based on real‐world data from Japanese pharmacies. Data were extracted from Musubi (KAKEHASHI Inc., Tokyo, Japan), an electronic medication history system. Patients aged 20–100 years who were prescribed sulfonylureas at eligible pharmacies from November 2022 to October 2023 were included. Prescribed drugs were defined according to European Pharmaceutical Market Research Association classification. Patients for whom key data were missing, including for age, sex, medication and dose, were excluded. Eligible pharmacies were those implementing Musubi as of November 2021, for efficient analysis.
Musubi database
The dataset used in the present study was derived from Musubi database. Musubi is a sophisticated cloud‐based electronic system for pharmacy medication history documentation and counseling. Using interactive tablet interfaces, it supports the creation of comprehensive medication histories, including records of medication administration counseling, detailed dispensing records and other clinical information, tailored to patients' individual health conditions and lifestyle habits. Additionally, Musubi enables centralized management of medication intake data through cloud technology. The Musubi database includes detailed prescription information (drug name, dosage and route, date), medication counseling provided by pharmacists, and patient demographics, such as sex, date of birth and insurance coverage. The database was constructed using data collected from pharmacies across Japan that have implemented the Musubi. Approximately 7,000 pharmacies, representing 10% of the total number of pharmacies in Japan, have adopted the Musubi system. Compared with the Patient Survey 2020 12 , the Musubi database shows a certain degree of representativeness in terms of age distribution. The data are anonymized and collected from pharmacies that have agreed to the terms of Musubi, including the use of data for the present study.
Statistical analysis
Data on the following variables were extracted from the Musubi database for patients who were prescribed sulfonylureas during the study period: sex, age, prescribed medications (including sulfonylureas and other categories of diabetes medications, as well as antihypertensives and lipid‐lowering agents), dosage and number of added concomitant diabetes medications. Patients were categorized into three age groups: <65, 65 to <75 and ≥75 years. Elderly patients were defined as those aged ≥65 years, for consistency with the geriatric age threshold commonly used in clinical research.
In the Musubi database, glimepiride, gliclazide and glibenclamide accounted for >99% of sulfonylurea prescriptions. For each of these drugs, the distribution of patients according to daily dose, and across age groups, was determined.
The Diabetes Treatment Guidelines for the Elderly 2023 recommend that in patients aged ≥65 years, doses of glimepiride and gliclazide should not exceed 1.0 mg and 40 mg, respectively, and that once‐daily dosing is preferred for adherence in elderly patients (specific details on the rationale for the recommended dosages are not provided) 3 . The guidelines discourage the use of glibenclamide in the elderly, and no maximum dose is specified. In the present study, we defined the daily dose cutoffs as glimepiride 1.0 mg, gliclazide 40 mg and glibenclamide 2.5 mg (the largest standard tablet size available in Japan), and determined the proportion of prescriptions exceeding these cutoffs. We also determined patterns of concomitant diabetes medication prescription and the distribution of patients based on sulfonylurea dose, accounting for the presence or absence of concomitant use of a DPP‐4 inhibitor.
Descriptive statistics were used to summarize the data, with categorical variables presented as frequencies and percentages, and continuous variables presented as the mean ± standard deviation and/or medians with interquartile ranges (IQR). These analyses were carried out using Python, version 3.12.1 (Python Software Foundation, Beaverton, OR, USA).
RESULTS
Full analysis population and patient demographics
During the study period, a total of 21,979,152 patients were registered in the Musubi system, and of these, 1,026,303 were prescribed diabetes medications. Focused analyses were carried out using data for the 148,785 patients with a sulfonylurea prescription. After exclusion of data from 57,479 patients registered with non‐target pharmacies, two patients who did not meet the age criteria, and 75 for whom key data were missing, 91,229 patients comprised the full analysis population for the present study (Figure 1).
Figure 1.
Patient disposition. †Pharmacies that had implemented the Musubi system as of November 2021. ‡Information related to age, sex, medication and dose.
The demographic characteristics of the patients in the full analysis population, and their medication patterns, are detailed in Table 1. The mean age of these patients was 71.2 ± 12.4 years. Their distribution across age groups was as follows: <65 years, 24,911 patients; 65 to <75 years, 25,874 patients; and ≥75 years, 40,444 patients. Most patients (55,947/91,229, 61.3%) were men. Glimepiride was the most commonly prescribed sulfonylurea (73,061/91,229 patients, 80.1%), followed by gliclazide (14,840/91,229 patients, 16.3%) and glibenclamide (3,327/91,229 patients, 3.6%).
Table 1.
Characteristics of patients with diabetes prescribed sulfonylureas in Japan between November 2022 and October 2023 †
| Characteristic | All patients (N = 91,229) | <65 years (n = 24,911) | 65 to <75 years (n = 25,874) | ≥75 years (n = 40,444) |
|---|---|---|---|---|
| Sex | ||||
| Male | 55,947 (61.3) | 17,914 (71.9) | 16,710 (64.6) | 21,323 (52.7) |
| Female | 35,282 (38.7) | 6,997 (28.1) | 9,164 (35.4) | 19,121 (47.3) |
| Age (years) | ||||
| Mean ± SD | 71.2 ± 12.4 | 54.8 ± 7.5 | 70.0 ± 2.8 | 81.9 ± 5.2 |
| Sulfonylureas ‡ | ||||
| Glimepiride | 73,061 (80.1) | 20,538 (82.4) | 21,049 (81.4) | 31,474 (77.8) |
| Daily dose, mean ± SD (mg/day) | 1.3 ± 1.1 | 1.4 ± 1.2 | 1.3 ± 1.1 | 1.2 ± 1.0 |
| Daily dose, median [IQR] (mg/day) | 1.0 [0.5, 2.0] | 1.0 [0.5, 2.0] | 1.0 [0.5, 2.0] | 1.0 [0.5, 1.0] |
| Gliclazide | 14,840 (16.3) | 3,623 (14.5) | 3,887 (15.0) | 7,330 (18.1) |
| Daily dose, mean ± SD (mg/day) | 29.4 ± 20.4 | 31.1 ± 21.1 | 30.1 ± 21.2 | 28.1 ± 19.5 |
| Daily dose, median [IQR] (mg/day) | 20.0 [20.0, 40.0] | 20.0 [20.0, 40.0] | 20.0 [20.0, 40.0] | 20.0 [20.0, 40.0] |
| Glibenclamide | 3,327 (3.6) | 749 (3.0) | 941 (3.6) | 1,637 (4.0) |
| Daily dose, mean ± SD (mg/day) | 3.4 ± 2.4 | 4.0 ± 2.7 | 3.4 ± 2.3 | 3.1 ± 2.1 |
| Daily dose, median [IQR] (mg/day) | 2.5 [1.25, 5.0] | 2.5 [2.5, 5.0] | 2.5 [1.25, 5.0] | 2.5 [1.25, 5.0] |
| Other | 30 (0.0) | 7 (0.0) | 7 (0.0) | 16 (0.0) |
| Other diabetes medications used concomitantly ‡ , § | ||||
| Dipeptidyl peptidase‐4 inhibitor | 66,426 (72.8) | 16,464 (66.1) | 19,193 (74.2) | 30,769 (76.1) |
| Biguanide | 52,023 (57.0) | 17,757 (71.3) | 16,258 (62.8) | 18,008 (44.5) |
| Sodium–glucose cotransporter 2 inhibitor | 41,658 (45.7) | 15,780 (63.3) | 12,634 (48.8) | 13,244 (32.7) |
| Alpha‐glucosidase inhibitor | 13,856 (15.2) | 3,184 (12.8) | 4,042 (15.6) | 6,630 (16.4) |
| Thiazolidinedione | 11,295 (12.4) | 3,555 (14.3) | 3,447 (13.3) | 4,293 (10.6) |
| Glucagon‐like peptide‐1 receptor agonist | 10,638 (11.7) | 4,990 (20.0) | 2,766 (10.7) | 2,882 (7.1) |
| Insulin | 5,492 (6.0) | 1,810 (7.3) | 1,516 (5.9) | 2,166 (5.4) |
| Imegrimin | 2,334 (2.6) | 920 (3.7) | 553 (2.1) | 861 (2.1) |
| Glinide | 412 (0.5) | 74 (0.3) | 101 (0.4) | 237 (0.6) |
| No. concomitant diabetes medications § | ||||
| Mean ± SD | 3.2 ± 1.1 | 3.6 ± 1.1 | 3.3 ± 1.1 | 3.0 ± 1.0 |
| Other medications used concomitantly ‡ | ||||
| Antihypertensives | 59,216 (64.9) | 13,160 (52.8) | 16,934 (65.4) | 29,122 (72.0) |
| Lipid‐lowering agents | 50,408 (55.3) | 13,844 (55.6) | 14,903 (57.6) | 21,661 (53.6) |
IQR, interquartile range; SD, standard deviation.
Data were extracted from the Musubi electronic medication history system and are presented as n (%) unless otherwise indicated.
Duplications were allowed.
Combination drugs were counted separately for each component.
Dose distribution
Among patients aged ≥65 years, the proportion exceeding the cutoff dose (1.0 mg/day for glimepiride and 40.0 mg/day for gliclazide) was numerically higher for glimepiride (25.0%, 13,154/52,523) than for gliclazide (7.8%, 880/11,217). Similarly, among the 2,578 patients aged ≥65 years receiving glibenclamide, 32.5% (2,578/3,327) were treated with doses above the 2.5 mg/day cutoff defined in this study (Figure 2).
Figure 2.
Proportions of patients with prescribed doses exceeding prespecified cutoff levels for (a) glimepiride (>1.0 mg/day), (b), gliclazide (>40.0 mg/day) and (c) glibenclamide (>2.5 mg/day), categorized by age (65 to <75, ≥75 and ≥65 years).
Mean daily doses of glimepiride, gliclazide, and glibenclamide in patients aged ≥65 years were 1.2 ± 1.0 mg/day (median 1.0 mg/day, IQR 0.5–1.5 mg/day), 28.8 ± 20.1 mg/day (median 20.0 mg/day, IQR 20.0–40.0 mg/day) and 3.2 ± 2.2 mg/day (median 2.5, IQR 1.25–5.0 mg/day), respectively. The distribution of patients across different ranges of daily doses of glimepiride, gliclazide and glibenclamide, and categorized by age group, is shown in Figure S1. The most commonly prescribed doses were glimepiride ≤1.0 mg/day (53,699/73,061 patients, 73.5%), gliclazide ≤20.0 mg/day (9,191/14,840 patients, 61.9%) and glibenclamide >1.25 to ≤2.5 mg/day (1,222 patients, 36.7%).
Concomitant diabetes medications
The diabetes medications most commonly coprescribed with sulfonylureas were DPP‐4 inhibitors, biguanides and SGLT‐2 inhibitors, used by 72.8% (66,426), 57.0% (52,023) and 45.7% (41,658), respectively (Table 1). In patients aged ≥65 years, insulin was concomitantly used in 3,682 (5.6%) patients. Glinide was used concomitantly in 338 patients (0.5%). The mean number of concomitant diabetes medications was 3.2 ± 1.1 in the full analysis population, and 3.6 ± 1.1, 3.3 ± 1.1 and 3.0 ± 1.0 in patients aged <65, 65 to <75 and ≥75 years, respectively. Thus, a trend toward prescription of fewer diabetes medications in the older age groups was observed.
Figure 3 shows mean daily doses of glimepiride, gliclazide and glibenclamide categorized by number of concomitant diabetes medications and age group. The median daily doses of these medications are presented in Table S1. The mean daily dose of glimepiride was higher in patients using more concomitant diabetes medications, and lower in elderly patients, although the mean dose in all patients aged ≥65 years was above the 1 mg/day cutoff (Figure 3a). By contrast, for gliclazide, no clear trend in dose change was observed in relation to the number of concomitant diabetes medications or age, and the mean dose for patients aged ≥65 years was not above the 40 mg/day cutoff (Figure 3b). For glibenclamide, the mean daily dose tended to increase as the number of concomitant medications increased, and although patients aged ≥65 years generally received lower daily doses than those aged <65 years, those taking two or more concomitant medications had a mean dose above the 2.5 mg/day cutoff (Figure 3c).
Figure 3.
Mean ± standard deviation daily dose of (a) glimepiride, (b) gliclazide and (c) glibenclamide, categorized by number of concomitant diabetes medications (vs sulfonylurea therapy alone, indicated by ‘1’ and by age (<65, 65 to <75 and ≥75 years). Dashed lines indicate prespecified cutoff levels for patients aged ≥65 years: (a) glimepiride (>1.0 mg/day), (b) gliclazide (>40.0 mg/day) and (c) glibenclamide (>2.5 mg/day).
The most common prescribing patterns for sulfonylureas, either alone or in combination with other diabetes medications, are summarized in Figure 4. In patients aged <65 years and those aged 65 to <75 years, the most common medication pattern was quadruple therapy with a sulfonylurea, a DPP‐4 inhibitor, an SGLT‐2 inhibitor and a biguanide (21.0% and 17.2%, respectively), followed by triple therapy with a sulfonylurea, a DPP‐4 inhibitor and a biguanide (11.7% and 16.4%, respectively). In patients aged ≥75 years, the most common combination was dual therapy with a sulfonylurea and a DPP‐4 inhibitor (19.3%), followed by triple therapy with a sulfonylurea, a DPP‐4 inhibitor and a biguanide (16.3%).
Figure 4.
The six most common patterns for diabetes medications added to sulfonylurea therapy, categorized by patient age (<65, 65 to <75 and ≥75 years). BG, biguanide; DPP‐4i, dipeptidyl peptidase‐4 inhibitor; GLP‐1, glucagon‐like peptide‐1 receptor agonist; SGLT‐2i, sodium–glucose cotransporter 2 inhibitor; TZD, thiazolidinedione; αGI, alpha‐glucosidase inhibitor.
Among the 66,426 (72.8%) patients who were coprescribed a DPP‐4 inhibitor, the distribution by age group was as follows: 16,464 (66.1%) were patients aged <65 years; 19,193 (74.2%) were those aged 65 to <75 years; and 30,769 (76.1%) were those aged ≥75 years (Table 1). In patients aged ≥65 years, the mean and median doses of glimepiride and gliclazide were similar regardless of whether or not a DPP‐4 inhibitor was coprescribed; however, daily doses of glibenclamide tended to be higher when it was prescribed with a DPP‐4 inhibitor (Figure S2 and Table S2).
DISCUSSION
In the present study, we analyzed large‐scale real‐world prescription data, including >90,000 patients from Japanese pharmacies to elucidate patterns in sulfonylurea use. Our main findings were that: (1) the daily dose of glimepiride often exceeded the upper limit specified by guidelines for the elderly 3 ; (2) glibenclamide was being prescribed to elderly patients; (3) the types of concomitant diabetes medications used with sulfonylureas differed between elderly and non‐elderly patients, with biguanides, SGLT2 inhibitors and glucagon‐like peptide‐1 (GLP‐1) receptor agonists being used less frequently in the elderly, and GLP‐1 receptor agonists were used less in the elderly than in the non‐elderly; and (4) a few patients were treated with combinations of sulfonylurea and glinide combinations, which is pharmacologically meaningless. These findings emphasize the need for promotion of appropriate use of sulfonylureas, particularly in cases of combination therapy, which was found to be a commonly used treatment approach.
Medication selection for type 2 diabetes mellitus involves several factors, including physician experience, patient status (glycated hemoglobin, body mass index, hypoglycemic status and frailty), access to care, social resources and patient preference 13 , 14 , 15 , 16 , 17 . However, these data were not available in the present study. The strength of our research lies in presenting the use of sulfonylureas among elderly type 2 diabetes mellitus within a large scale real‐world clinical setting, including detailed concomitant use with other diabetes medications, and our discussion focuses on this point.
When used to treat diabetes in elderly patients, sulfonylureas are associated with a high risk of hypoglycemia 18 . In recognition of this risk, the American Diabetes Association, in its Standards of Care in Diabetes—2024, advises caution when considering treating elderly patients with sulfonylureas, and instead recommends shorter‐acting options, such as glipizide 19 . In Japan, the Diabetes Treatment Guidelines for the Elderly 2023 suggest limiting the daily doses of glimepiride to 1 mg/day and gliclazide to 40 mg/day 3 .
In the present study, one‐quarter of elderly patients receiving glimepiride were prescribed doses that exceeded the guideline limit, with a mean dose of 1.2 mg/day (median dose was 1.0 mg/day). Although the incidence of hypoglycemia was not evaluated in our study, some patients might have experienced this adverse effect. Regarding gliclazide, 7.8% of prescriptions for elderly patients were for doses >40 mg/day; however, the mean and median daily doses prescribed was 28.8 and 20.0 mg/day, respectively, which were within the guideline limit. Notably, doses exceeding guideline recommendations were more common for glimepiride than for gliclazide (25.0% vs 7.8%). Prescribing trends have been reported to differ between specialists and general practitioners, with that, gliclazide was more commonly prescribed by specialists 9 , 20 . Although physician‐specific data were not available in our study, our results may be due to gliclazide being more commonly prescribed by specialists. Gliclazide is associated with an exceptionally low incidence of severe hypoglycemic events, and does not require dose adjustment in patients with renal impairment 21 , which might explain why it is more commonly prescribed by specialists. In the present study, glimepiride accounted for an overwhelming proportion of sulfonylurea prescriptions, suggesting frequent use by general practitioners potentially unaware of guideline recommendations for the elderly 3 . In our study, over half of the patients prescribed glibenclamide were elderly, whose doses exceeded 2.5 mg/day. Japanese guidelines for the elderly and the American Diabetes Association recommend against glibenclamide in the elderly 3 , 19 , and it is listed in the Beers Criteria as potentially inappropriate 22 .
These findings suggest that there is insufficient guideline awareness among physicians, leading to overdose of sulfonylureas use in the elderly. It is important that the appropriate use of sulfonylureas in elderly patients be emphasized. Additionally, Increased education and enlightenment for physicians are recommended when using sulfonylureas.
In an analysis of Japan using health insurance data from April 2012 to March 2020, although prescription of newer diabetes medication, such as SGLT‐2 inhibitors and biguanides, is increasing, there is a notable decrease in the prescription of sulfonylureas 7 . Similar trends have been reported in the USA 8 . In Japan, DPP‐4 inhibitors (63%), biguanides (17%) and SGLT‐2 inhibitors (11%) are reported to be the first‐line diabetes medications, whereas sulfonylureas are used in only 2.9% of patients 7 .
Arai et al. 9 reported that sulfonylureas were more often used with other diabetes medications rather than as monotherapy. The present results show increased doses of glimepiride and glibenclamide according to more coprescribed diabetes medications. These findings suggest that in real‐world clinical practice, sulfonylureas are used in combination with other diabetes medications, and that the appropriateness of their doses should be discussed in the context of polypharmacy. In our study, the mean number of concomitant diabetes medications was 3.2, higher than the 2.0 in the study by Iketani and Imai 7 . Notably, the number of concomitant medications decreased with age (3.6 ± 1.1, 3.3 ± 1.1 and 3.0 ± 1.0 in patients aged <65, 65 to <75 and ≥75 years, respectively), reflecting age‐based prescription adjustment. However, as aforementioned, the mean/median dose exceeded the maximum guideline‐recommended dose 3 , so education on appropriate use is still needed.
The present results showed that 0.5% of patients used glinide with a sulfonylurea, which is pharmacologically meaningless due to similar insulin‐stimulating effects 23 . In addition, 5,492 patients (6.0%) used insulin with a sulfonylurea, including 5.6% of those aged ≥65 years. Most insulin–sulfonylurea combinations were due to basal oral therapy rather than intensive insulin therapy (data not shown). In Japan, if basal oral therapy is inadequate, DPP‐4 inhibitors are added, and if control remains poor, sulfonylureas are often added. The present study probably reflects the proportion of these cases in the real world.
In this study, DPP‐4 inhibitors were the most commonly used diabetic medication in combination with sulfonylurea. This combination might have been chosen for its stronger hypoglycemic effect. The Diabetes Treatment Guidelines for the Elderly 2023 recommend reducing sulfonylurea doses when combined with a DPP‐4 inhibitor 3 . However, our analysis showed daily doses of glimepiride and gliclazide were similar regardless DPP‐4 inhibitor use, and glibenclamide doses were higher when combined with DPP‐4 inhibitors. This also suggests a lack of awareness of the guidelines. Given the range of diabetes treatments available, general practitioners might be struggling to adhere to current protocols. Dissemination of the updated guidelines and the 2023 revised diabetes algorithm 17 to general practitioners is crucial.
In patients aged 65 to <75 years, combination therapy with GLP‐1 receptor agonists was the sixth most common prescription pattern, whereas their use was rare in patients aged ≥75 years. In addition, quadruple therapy with SGLT‐2 inhibitors, sulfonylureas, DPP‐4 inhibitors and biguanides was the most common regimen in patients aged <75 years, accounting for 17.2%, but decreased to 9.1% in patients aged ≥75 years. This indicates that Japanese clinical practice adheres closely to guideline recommendations 24 , particularly emphasizing increased caution with metformin administration in adults aged ≥75 years. In contrast, Iketani et al. 7 showed an increasing use of SGLT‐2 inhibitors, a slight increase in GLP‐1 receptor agonists and a decreasing use of sulfonylureas across all regimens from monotherapy to quadruple therapy. This shift toward SGLT‐2 inhibitors and GLP‐1 receptor agonists might be due to their reported benefits in reducing the risk of cardiovascular events and providing renal protection 25 , 26 , 27 . However, the discrepancy between the present results and those of Iketani et al. suggests that some elderly patients taking sulfonylureas do not switch to SGLT‐2 inhibitors or GLP‐1 receptor agonists, highlighting a potential gap in guideline adherence.
Medication selection for type 2 diabetes mellitus should be tailored to the patient's condition. East Asian people, including Japanese people, have lower insulin secretion and a higher prevalence of insulin secretion disorders compared with insulin resistance in white people 28 , 29 . The Japan Diabetes Society treatment algorithm for type 2 diabetes recommends sulfonylureas for non‐obese patients with suspected insulin insufficiency, while cautioning against SGLT‐2 inhibitors and GLP‐1 receptor agonists in underweight patients because of the risk of weight loss 17 . Previous studies have reported that sulfonylureas are often selected for elderly diabetes patients with low body mass index 9 , 30 . Although SGLT‐2 inhibitors and GLP‐1 receptor agonists carry risks, such as weight loss and dehydration, in the elderly, evidence from the EMPA‐ELDERLY trial 31 and the pooled analysis of the SUSTAIN 1–5 trials 32 suggests that these medications can be used safely in this population. In addition, cost‐effectiveness is an important consideration in medication selection. Sulfonylureas and metformin are considered cost‐effective treatment options compared with DPP‐4 inhibitors, SGLT‐2 inhibitors and GLP‐1 receptor agonists 33 . It is important to consider factors, such as weight, comorbidities, polypharmacy and cost, when managing diabetes in the elderly. Additional evidence is needed to support more accurate decision‐making.
The present study had several limitations that need to be considered. First, it relied on real‐world data obtained from pharmacies, which do not have clinical information, such as blood glucose levels, glycated hemoglobin, body mass index, hypoglycemic status, frailty or specific diagnoses, including details on patient comorbidities. The Japan Diabetes Society treatment algorithm for type 2 diabetes recommends treatment selection based on obesity/non‐obesity, taking into account safety and comorbidities (chronic kidney disease, heart failure, cardiovascular disease) 17 , so the present study results lacking these factors should be interpreted cautiously. Second, the Musubi database might introduce biases. It does not cover all pharmacy practices, which could lead to selection bias. Third, our approach involved a post‐hoc, cross‐sectional analysis of the data, which might have potential biases. Fourth, although our findings provide insights into sulfonylurea prescribing patterns in the Japanese clinical context, their applicability might not extend seamlessly to healthcare settings in other countries with different healthcare systems. However, similarities in prescribing trends described by Iketani and Imai 7 , and the authors of studies carried out in the USA 8 , suggest that our findings might also be clinically relevant outside Japan. In addition, our study did not take into account physician characteristics, including specialty, experience and so on. Despite these limitations, the results of the present study are based on analysis of information extracted from a substantial dataset (>90,000 patients), which itself was part of an even larger database (>20 million patients), and might therefore be considered robust and able to provide important insights into the practical dosing of sulfonylureas in real‐world clinical settings.
In conclusion, the present analysis of pharmacy data has shown prescribing patterns of sulfonylureas in real‐world clinical settings in Japan. Although elderly patients generally received lower doses, reflecting guidelines 3 to an extent, glimepiride – the most commonly used sulfonylurea – was often prescribed at higher than recommended doses, especially in elderly patients. This trend intensified when it was coprescribed with other antidiabetic drugs. Additionally, we observed that glibenclamide continues to be prescribed, and at high doses (>2.5 mg/day), although less frequently. These findings might provide an opportunity to reconsider the treatment of patients with type 2 diabetes mellitus who are over‐prescribed sulfonylureas to reduce residual risks, such as hypoglycemia.
DISCLOSURE
M Yamazaki, T Takebe, M Hosokawa and T Saika are employees of KAKEHASHI Inc. Y Nakao serves as the President of KAKEHASHI Inc. M Sakamoto has received lecture fees from Eli Lilly Japan K.K., Novo Nordisk Pharma Ltd., Mitsubishi Tanabe Pharma Corporation, Sanofi K.K., MSD K.K. and Daiichi Sankyo Co., Ltd., and has also received a consulting fee from KAKEHASHI Inc. S Ikeda declares no conflict of interest.
Approval of the research protocol: This study was approved (approval number: 23‐Im‐045) by the institutional review board of the International University of Health and Welfare, Japan, and was carried out according to the principles of the Declaration of Helsinki (as revised in Fortaleza, Brazil, October 2013).
Informed consent: The institutional review board of International University of Health and Welfare determined that the requirement for informed consent could be waived owing to the terms of the contract with pharmacies, which included the use of Musubi data for research purposes, and the prior anonymization of the data for research purposes.
Registry and the registration no. of the study/trial: N/A.
Animal studies: N/A.
Supporting information
Table S1. Median [IQR] daily dose of (a) glimepiride, (b) gliclazide, and (c) glibenclamide, categorized by number of concomitant diabetes medications (vs sulfonylurea therapy alone, indicated by ‘1’) and by age (<65, 65 to <75, and ≥75 years).
Table S2. Median [IQR] daily doses of (a) glimepiride, (b) gliclazide, and (c) glibenclamide prescribed with or without a dipeptidyl peptidase‐4 inhibitor (DPP‐4i), in patients aged ≥65 years.
Figure S1. Patient distribution across different daily doses of (a) glimepiride, (b) gliclazide, and (c) glibenclamide, and categorized by age (65 to <75, ≥75, and ≥65 years).
Figure S2. Mean ± SD daily doses of (a) glimepiride, (b) gliclazide, and (c) glibenclamide prescribed with or without a dipeptidyl peptidase‐4 inhibitor (DPP‐4i), in patients aged ≥65 years.
ACKNOWLEDGMENTS
All authors thank Professor Tsutomu Yamazaki of the International University of Health and Welfare for reviewing the manuscript.
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Associated Data
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Supplementary Materials
Table S1. Median [IQR] daily dose of (a) glimepiride, (b) gliclazide, and (c) glibenclamide, categorized by number of concomitant diabetes medications (vs sulfonylurea therapy alone, indicated by ‘1’) and by age (<65, 65 to <75, and ≥75 years).
Table S2. Median [IQR] daily doses of (a) glimepiride, (b) gliclazide, and (c) glibenclamide prescribed with or without a dipeptidyl peptidase‐4 inhibitor (DPP‐4i), in patients aged ≥65 years.
Figure S1. Patient distribution across different daily doses of (a) glimepiride, (b) gliclazide, and (c) glibenclamide, and categorized by age (65 to <75, ≥75, and ≥65 years).
Figure S2. Mean ± SD daily doses of (a) glimepiride, (b) gliclazide, and (c) glibenclamide prescribed with or without a dipeptidyl peptidase‐4 inhibitor (DPP‐4i), in patients aged ≥65 years.