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Renal outcomes and all‐cause death associated with sodium‐glucose co‐transporter‐2 inhibitors versus other glucose‐lowering drugs (CVD‐REAL 3 Korea)

Abstract Aims To investigate the effectiveness of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors on the risk of progression to end‐stage renal disease (ESRD) and all‐cause mortality in a broad range of patients with type 2 diabetes (T2D) using a Korean nationwide cohort. Materials and Methods Using data from the Korean National Health Insurance Service database from January 2014 to December 2017, a total of 701 674 patients were identified with T2D. We divided these patients into new users of SGLT2 inhibitors and new users of other glucose‐lowering drugs (oGLDs). Using propensity scores, patients in the two groups were matched 1:1. We assessed the risk of ESRD and all‐cause death. Results There were 45 016 patients in each group, and baseline characteristics were well balanced between the groups. The patients' mean age was 58.1 ± 10.6 years and mean estimated glomerular filtration rate (eGFR) was 89.2 ± 27.4 mL/min/1.73m2, and 8% of patients had proteinuria. We identified 167 incident ESRD cases and 1070 all‐cause deaths during follow‐up. Use of SGLT2 inhibitors versus oGLDs was associated with a lower risk of ESRD (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.34 to 0.65) and all‐cause death (HR 0.82, 95% CI 0.73 to 0.93). In a subgroup analysis by eGFR, initiation of SGLT2 inhibitor treatment, compared with oGLD treatment, was associated with lower risk of progression to ESRD among patients with eGFR 60 to 90 mL/min/1.73m2 and those with eGFR < 60 mL/min/1.73m2, and a lower risk of all‐cause death was associated with SGLT2 inhibitors versus oGLDs in patients with eGFR ≥90 and 60 to 90 mL/min/1.73m2. Conclusion In this large nationwide study of Korean patients with T2D, initiation of SGLT2 inhibitors versus oGLDs was associated with lower risk of ESRD and all‐cause death.


| INTRODUCTION
Diabetic nephropathy ranks highest, both globally and nationwide in Korea, among causes of end-stage renal disease (ESRD), and its incidence is growing exponentially. 1 However, no new medications had been approved for the treatment of diabetic kidney disease since the IDNT (Irbesartan in Diabetic Nephropathy Trial) and the RENAAL (Reduction of Endpoints in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan) study, which showed beneficial effects of angiotensin II receptor blockers in patients with type 2 diabetes mellitus (T2D) and kidney disease. 2 Very recently, sodium-glucose co-transporter-2 (SGLT2) inhibitors have shown renoprotective effects in several large outcome trials. [3][4][5][6] SGLT2 inhibitor treatment inhibits the reabsorption of glucose and sodium in the proximal tubule of the kidney, resulting in glycosuria and the lowering of blood glucose independently of the action of insulin, and can also reduce body weight and blood pressure. 7 The effects of SGLT2 inhibitors on kidney outcomes as novel treatment options for diabetic kidney disease have not been well described in regions outside of North America and Europe. Although previous large randomized controlled trials including the EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type Other Glucose-Lowering Drugs) study, a multinational retrospective observational study, included most of the data from Asian countries (the Republic of Korea, Japan and Singapore), but did not report on the effect of SGLT2 inhibitors on renal outcomes. 11 The CVD-REAL 3 (Kidney outcomes associated with use of SGLT2 inhibitors in real-world clinical practice) study recently published real-world evidence from the European Union, Israel and Asia, including Japan and Taiwan. It demonstrated that the initiation of SGLT2 inhibitors was associated with a slower rate of kidney function decline and a lower risk of major kidney events. 12 However, only approximately 11% of the total study cohort were from Asian countries. As several distinctive features are apparent in pathogenetic factors for diabetes in Asian populations, 13 it is important to assess whether the benefits of SGLT2 inhibitors are applicable across different ethnicities. The so-called "Asian phenotypes" in diabetes include low body mass index (BMI); greater amount of body fat, especially visceral adiposity; higher rate of central obesity and metabolic syndrome; insufficient β-cell response in the setting of insulin resistance; and higher risk of developing renal complications among other inter-ethnic clinical differences. 14 In the present study, we investigated the effects of SGLT2 inhibitors on the risk of progression to ESRD and all-cause mortality in a broad range of patients with T2D using a Korean nationwide cohort.

| Data source and study population
This study used the National Health Insurance Service (NHIS) database, which is government managed and includes patients' sociodemographic information, use of inpatient and outpatient services, and pharmacy dispensing claims. The NHIS is the only insurer providing regular health checkup programmes to the public in the Republic of Korea. Those enrolled in the NHIS are recommended to undergo health checkups at least biannually. Patients with T2D who initiated an SGLT2 inhibitor or any other glucose-lowering drug (oGLD) were identified, starting from the date of first prescription, in a time window selected from the date of the first SGLT2 inhibitor availability in this country until the last available data (from January 2014 to December 2017). Patients with known type 1 diabetes and gestational diabetes were excluded. No other a priori exclusion criteria were applied. We identified a total of 701 674 T2D patients who were new users of SGLT2 inhibitors or oGLDs and who had clinical and laboratory data recorded at baseline, within a time window of 30 days from the index date. Due to lack of data, we Because anonymized and deidentified information was used in the analyses, informed consent was not required.  15 The presence of proteinuria was defined as having urinary protein ≥1+ on dipstick testing in fasting morning urine.

| Measurements and definitions
The presence of diabetic retinopathy was defined according to at least one claim per year under ICD-10 code H36.0.

| Study outcomes and follow-up
The main outcomes for this study were newly diagnosed ESRD or allcause death. We defined incident ESRD using the combination of ICD-10 codes (N18-N19, Z49, Z94.0, Z99.2) and initiation of renal replacement therapy for 30 days or more, and/or kidney transplantation during hospitalization. The Korean Health Insurance Review and Assessment Service reimburses all medical care expenses for dialysis.
Patients with ESRD are also registered as special medical aid beneficiaries. Therefore, we could include each ESRD patient from the whole population and analyse the data for all ESRD patients who started dialysis or had an eGFR < 15 mL/min/1.73 m 2 . Patients without ESRD or all-cause death during their follow-up periods were considered to have completed the study at the date of their death or at the end of follow-up, whichever came first. The study population was followed from baseline to the date of ESRD or all-cause death, or until December 31, 2017, whichever came first.

| Statistical methods
Baseline characteristics are presented as means ± SD or n (%). The incidence rates for the primary outcomes were calculated by dividing  propensity-score matching from 1-to-1 to 1-to-N. We set a caliper for nearest-neighbour matching within the first four to eight digits; for example, two patients with propensity scores of 0.12345678 and 0.12347123 match on the first four digits (0.1234). The macro makes the "best" matches first and the "next-best" matches next in a hierarchical sequence until no more matches can be made. If no patient in the oGLD group has a propensity score that lies within a four-digit width of a propensity score of a patient in the SGLT2 inhibitor group, then that patient in the SGLT2 inhibitor group is left unmatched and is not used in subsequent analyses.
The primary analysis used an intention-to-treat approach, in which patients were followed from the start of an index treatment until either occurrence of the first outcome event or the censoring date (whichever was earlier), regardless of whether the index treatment was discontinued. A sensitivity analysis was performed with restriction of the follow-up period to 3 years because of the short follow-up duration of the SGLT2 inhibitor group. Also, the analyses for each outcome were conducted using an on-treatment approach, in which follow-up was censored at discontinuation of the index treatment. Statistical analyses were performed using SAS version 9.4, and a P value <0.05 was considered to indicate significance.

| Study population
Following propensity matching with 508 243 new SGLT2 inhibitor or oGLD initiation episodes, a total of 90 032 new SGLT2 inhibitor or oGLD users were identified with 45 016 in each treatment group (Table 1). The distribution of specific SGLT2 inhibitors were dapagliflozin 73.3%, empagliflozin 20.8% and ipragliflozin 6.0%, respectively, and the mean follow-up period was 1.49 ± 0.85 years.
Patient characteristics were well balanced between the two groups.  (Table S1 and Figure S1) and those of the ontreatment analysis (Table S2 and Figure S2).  Table 2). The incidence rate of all-cause death showed a substantial decrease in the SGLT2 inhibitor group compared with the oGLD group in the Kaplan-Meier curve (P values by log-rank = 0.0016; Figure 2B). The results were consistent across the baseline eGFR and regardless of the presence or absence of proteinuria (Table 2). In addition, a sensitivity analysis was performed to adjust for the differences in the person-years of follow-up and periods between the two groups; HR trends for all-cause death were similar to the 3-year follow-up results (Table S1 and Figure S1) and those of the on-treatment analysis (Table S2 and Figure S2).

| Subgroup analysis
To evaluate the effect of modifiers on the associations between SGLT2 inhibitors and outcomes, we conducted a stratified analysis using several factors including age, sex, BMI, abdominal obesity, diabetic retinopathy, hypertension and prior CVD (    25 Another proposed mechanism of SGLT2 inhibitors is mediated by metabolic effects. SGLT2 inhibitors appear to decrease energy demand by reducing sodium transport and ameliorate cellular stress by enhancing AMPK/SIRT1, eventually leading to protection from functional and structural tubular injury by diabetes. 26 In addition, SGLT2 inhibitors could limit the activity of transforming growth factor β1, a known intrarenal cytokine associated with progressive kidney failure and lowering of the expression of inflammatory molecules. 27,28 The findings of the present study should be interpreted in the context of several potential limitations. First, due to the observational nature of the study, we cannot exclude the possibility of unmeasured confounding factors, which cannot be overcome by propensity-score matching. Confounders such as socio-economic factors, or metabolic variables that were not measured after baseline in this study, could have affected both the choice of glucose-lowering medication and the outcomes. A novel drug may also be more readily prescribed to healthier patients, and those with relatively uncontrolled diabetes in the early post-marketing period in the real world. 29 Second, an immortal time bias can arise if some proportion of the follow-up time is excluded or misclassified. Third, renal function, including eGFR and the presence of proteinuria, was measured only at enrolment; therefore, subtle changes in renal function could not be included in the analyses. The presence of proteinuria was evaluated using a semiquantitative dipstick test, which has an approximately 30% falsenegative rate for microalbuminuria. Fourth, the follow-up period was relatively short considering the clinical course of renal outcomes in patients with T2D, and there was no information about the precise cause of ESRD or mortality, or uric acid levels (which can be reduced by SGLT2 inhibitors). 30