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Utilization of glucagon‐like peptide‐1 receptor agonists and changes in clinical characteristics in patients with type 2 diabetes by chronic kidney disease stage in Japan: A descriptive observational study using a nationwide electronic medical records database

Abstract Aim To describe the utilization of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and changes in clinical characteristics before and after GLP‐1 RA initiation in patients with type 2 diabetes (T2D) by chronic kidney disease (CKD) stage. Materials and Methods In this retrospective descriptive study using a nationwide electronic medical records database in Japan, we included patients with GLP‐1 RA prescriptions from June 2010 to October 2019. Clinical characteristics at GLP‐1 RA initiation, persistence proportion, and changes in clinical measurements after GLP‐1 RA initiation were described for all patients and by CKD stage, defined by baseline estimated glomerular filtration rate (eGFR). Results We included 8049 patients. During the study period, the proportion of patients with T2D initiating GLP‐1 RAs increased from 1.5% in 2010 to 3.3% in 2019. Also, the mean (95% confidence interval) of baseline age and eGFR ranged from 58.6 (56.7‐60.4) to 66.3 (65.5‐67.2) years and from 72.9 (68.0‐77.9) to 64.0 (62.2‐65.8) mL/min/1.73m2, respectively. The persistence proportion at 12 months was 49.5% overall, 37.8% in T2D patients with CKD with a baseline eGFR of less than 30 mL/min/1.73m2, and 34.6% in those undergoing dialysis. The rate of deterioration in renal function reduced after GLP‐1 RA initiation. Conclusions The utilization of GLP‐1 RAs has been increasing over the past decade, and GLP‐1 RAs have been used in patients with limited treatment options, such as the elderly or those with CKD. In T2D patients with CKD, the persistence proportion of GLP‐1 RAs was not low, and the renal dysfunction may be moderated by GLP‐1 RA initiation.


| INTRODUCTION
Type 2 diabetes (T2D) is the leading cause of renal dysfunction in Japan. 1 Patients with T2D are at a higher risk of diabetic nephropathy and chronic kidney disease (CKD). 2 More than 40% of patients with T2D develop CKD and a significant number of them require dialysis or a transplant. 3 The effective therapeutic management of T2D patients with CKD is therefore crucial. In patients with T2D with advanced CKD, some antidiabetic drugs carry an increased risk of hypoglycaemia as a result of decreased insulin clearance, which limits the treatment options for glycaemic control. Patients with T2D with prior cardiovascular disease and CKD also have a higher risk of major adverse cardiac events, cardiovascular death, and all-cause mortality. 4 Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are antidiabetic drugs that reduce hyperglycaemia by inducing satiety and stimulating insulin secretion and postprandial glucagon release in a glucose-dependent manner. 5  We aimed to describe the utilization of GLP-1 RAs and changes in clinical characteristics around GLP-1 RA initiation in patients with T2D overall and stratified by CKD stage using a nationwide electronic medical records (EMRs) database in Japan.

| Study design and data source
This was a descriptive observational study using the RWD database

| Study cohort
The study cohort consisted of adult patients with T2D identified from Patients were excluded if they had a disease code for a diagnosis of type 1 diabetes, malnutrition-related diabetes, or secondary diabetes during the study period. The International Classification of Disease 10th Revision (ICD-10 code) was used to identify disease information (Supplemental S1). The index date was defined as the date of first GLP-1 RA prescription during the study period in the RWD-DB, and the baseline period as the period from -60 to 0 days prior to the index date, unless specified otherwise. In addition to the GLP-1RA cohort, we also established the T2D cohort as the population relative to our study cohort to capture the proportion relative to the total number of patients with T2D who initiated oral antidiabetic drugs (OADs) or insulin in each year. The T2D cohort included patients who met the following criteria: (a) a new prescription of any antidiabetic drug (ATC code: A10) (the prescribed date was used as the index date of the T2D cohort); (b) aged 20 years or older upon the index date; and (c) did not have any disease code in the exclusion criteria above. The unit of the T2D cohort was the event of the initiation of a nonpreviously prescribed antidiabetic drug in each year instead of patient-level unit, which meant that the same patients were included into the cohort more than once if they experienced several antidiabetic drug initiation events in different years (e.g. dipeptidyl peptidase-4 inhibitor [DPP-4i] initiation in 2012, then thiazolidine initiation in 2013).

| Variables
Baseline characteristics at index date, including age, sex, clinical characteristics, co-morbidities, and duration of T2D (from the first date of T2D recorded in the RWD-DB to the index date), were described.
Additionally, because there were only two measurements of BMI in 2013, we used BMI data for 2014-2019. For patients with multiple measurements during the baseline period, the one closest to the index date was used. If there was more than one measurement on the same day, the measurement providing the most conservative estimate of treatment effect was used. The co-morbidities were hypertension, ischaemic heart disease, heart failure, stroke, dyslipidaemia, hyperuricaemia, diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy, defined by the presence of ICD-10 code at baseline. Concomitant use of OADs and insulin (ATC code: A10), antihypertensive drugs (ATC codes: C02-C09 and C11), and drugs for dyslipidaemia (ATC codes: C10-C11) at the index date was evaluated. Regarding antidiabetic drugs, treatment patterns before and after the index date were also described. We described the number of patients with T2D who initiated GLP-1 RAs and the proportion relative to total patients with T2D who initiated any OADs or insulin in each year. The mean, standard error (SE), and 95% confidence interval (CI) of baseline age, HbA1c, eGFR, and BMI of patients with T2D who initiated GLP-1RAs were also evaluated annually from 2010 to 2019.

| Statistical methods
We evaluated changes in the treatment patterns of antidiabetic medications before and after the index date. The proportion of patients whose prescription of OADs or insulin overlapped the preindex period (from À60 to 0 days before the index date) was compared with that whose prescription overlapped the postindex period (from 1 to 60 days after the index date).
The persistence of GLP-1 RA prescription was defined as the number of days from the index date to the first occurrence of GLP-1 RA discontinuation or censoring date. Patients who remained taking GLP-1 RAs but changed to a different agent were considered as continuing GLP-1 RA treatment. GLP-1 RA treatment was considered as discontinued if there was no subsequent prescription of a GLP-1 RA, a greater than 60-day gap between two consecutive prescriptions of a GLP-1 RA, or if the patient died, because most patients with diabetes in Japan regularly visit outpatient clinics once every 1 or 2 months.
The date of censoring was defined as the last day of presence in the database or 360 days after index date, whichever occurred first.
The persistence of GLP-1 RA prescription within 12 months after the index date was evaluated using a Kaplan-Meier plot.
We evaluated changes in laboratory test measurements, vital signs, and BMI from 0 to 24 months after the index date, divided into intervals of 3 months. Means and SEs within each interval were described. To avoid limiting the cohort to those who could maintain renal function to continue GLP-1RAs, clinical variables were followed, irrespective of continuation or discontinuation of GLP-1RAs. This analysis limited the number of patients who had more than one measurement at the index date ±1.5 months or also had more than one measurement during the 24 months from this 3-month point. For UACR and UPCR, if the laboratory test was switched from UACR to UPCR or from UPCR to UACR during follow-up, then only the measurement before switching was used, to ensure the consistency of the population. eGFR data from 9 months before and 12 months after the index date were extracted, regardless of GLP-1 RA prescription status.
Trends in eGFR by month were evaluated with longitudinal data analysis. Linear mixed-effects models using eGFR as the outcome, number of months from the index date as the explanatory variable, and individual as a random effect, were fitted separately before (from -270 to 0 days) and after (from 1 to 360 days) the index date. This analysis limited the number of patients who had more than one measurement during the preindex period (À270 to À1 days) and more than one measurement during the postindex period (1 to 360 days).
Subgroup analyses according to baseline CKD stage were performed for all the aforementioned analyses, with CKD stage stratified as grade 1 and grade 2 (G1 + G2), grade 3 (G3), grade 4 (G4) or grade 5 (G5) (G4 + G5), and undergoing dialysis. In this study, patients were classified by CKD stage based on baseline eGFR (≥60 mL/min/1.73m 2 for G1 + G2; <60 and ≥30 mL/min/1.73m 2 for G3; <30 and ≥15 mL/min/1.73m 2 for G4; and <15 mL/min/1.73m 2 for G5). Patients undergoing maintenance dialysis each month within 3 months prior to the index date were classified as part of the dialysis group, regardless of eGFR level. Patients with missing baseline eGFR values were excluded from the subgroup analysis.
The current study aimed to describe the distribution or patterns of prescription or clinical characteristics; therefore, no testing of hypotheses was performed. Additionally, no imputation was conducted for missing data. All analyses were performed using SAS 9.4 software (SAS Institute Inc., Cary, NC).

| DISCUSSION
We conducted a retrospective cohort study to describe the utilization cardioprotective effects, as well as glycaemic control. [6][7][8][9][11][12][13][14] Moreover, regarding the increasing trend of dulaglutide use, which accounted for the increment after 2016, we suggest that dulaglutide has been widely used in T2D patients with CKD because of its wider range of adaptation, and easier administration as a result of its simplified dosing (once weekly) using a dose pen. 25,26 Regarding the baseline characteristics of those patients with T2D who initiated GLP-1 RAs, some patients with advanced CKD were included (G4, 3.6%; G5, 2.6%; dialysis, 0.6%); moreover, these patients had a higher prevalence of ischaemic heart disease, heart failure, and stroke than patients without CKD. Two retrospective cohort studies showed that patients with T2D who received GLP-1 RAs had a higher prevalence of cardiovascular disease history or decreased renal function than those without GLP-1 RA therapy. 27,28 Furthermore, we detected an increasing trend in average baseline age and a reduction in the average baseline eGFR (Supplemental S3). These findings suggest that GLP-1 RAs are increasingly prescribed for elderly In the analysis of eGFR decline (Figure 4) The current study has several strengths. First, we used measured values of eGFR to determine the CKD stage. Recently, in addition to diabetic nephropathy, a broader concept of diabetes with CKD has also arisen. This concept is associated with decreased renal function, in which eGFR decreases without albuminuria, and it has also been adopted in some guidelines. 3,20 The use of eGFR values might also minimize measurement bias. Second, we used large-scale EMR data collected from a wide range of medical institutions, providing stronger evidence in clinical practice than studies conducted in limited types of facility. Third, the sample size in the current analysis is much larger than in previous studies.
The current study also has some limitations. patients with CKD, although such data collection is not feasible for a large number of patients included in our study. Finally, the approved dose of dulaglutide is 0.75 mg in Japan; in other countries this can be uptitrated to higher dose levels, based on the patient's glycaemic condition. However, the 0.75-mg dose of dulaglutide has also been evaluated in clinical research 14 and is widely used in practice. Therefore, we believe that the generalizability of our study results is not entirely limited.
In conclusion, this is the first study to investigate the use of GLP-