Effect of preceding drug therapy on the renal and cardiovascular outcomes of combined sodium-glucose cotransporter-2 inhibitor and glucagon-like peptide-1 receptor agonist treatment in patients with type 2 diabetes and chronic kidney disease.

AIM: To conduct a post hoc subgroup analysis of patients with type 2 diabetes (T2D) from the RECAP study, who were treated with sodium-glucose cotransporter-2 (SGLT2) inhibitor and glucagon-like peptide 1 receptor agonist (GLP-1RA) combination therapy, focusing only on those patients who had chronic kidney disease (CKD), to examine whether the composite renal outcome differed between those who received SGLT2 inhibitor treatment first and those who received a GLP-1RA first. METHODS: We included 438 patients with CKD (GLP-1RA-first group, n = 223; SGLT2 inhibitor-first group, n = 215) from the 643 T2D patients in the RECAP study. The incidence of the composite renal outcome, defined as progression to macroalbuminuria and/or a ≥50% decrease in estimated glomerular filtration rate (eGFR), was analysed using a propensity score (PS)-matched model. Furthermore, we calculated the win ratio for these composite renal outcomes, which were weighted in the following order: (1) both a ≥50% decrease in eGFR and progression to macroalbuminuria; (2) a decrease in eGFR of ≥50% only; and (3) progression to macroalbuminuria only. RESULTS: Using the PS-matched model, 132 patients from each group were paired. The incidence of renal composite outcomes did not differ between the two groups (GLP-1RA-first group, 10%; SGLT2 inhibitor-first group, 17%; odds ratio 1.80; 95% confidence interval [CI] 0.85 to 4.26; p = 0.12). The win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was 1.83 (95% CI 1.71 to 1.95; p < 0.001). CONCLUSION: Although the renal composite outcome did not differ between the two groups, the win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was significant. These results suggest that, in GLP-1RA and SGLT2 inhibitor combination therapy, the addition of an SGLT2 inhibitor to baseline GLP-1RA treatment may lead to more favourable renal outcomes.

Influence of the combination of SGLT2 inhibitors and GLP-1 receptor agonists on eGFR decline in type 2 diabetes: post-hoc analysis of RECAP study.

Accumulating evidence has demonstrated that both SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1Ra) have protective effects in patients with diabetic kidney disease. Combination therapy with SGLT2i and GLP1Ra is commonly used in patients with type 2 diabetes (T2D). We previously reported that in combination therapy of SGLT2i and GLP1Ra, the effect on the renal composite outcome did not differ according to the preceding drug. However, it remains unclear how the initiation of combination therapy is associated with the renal function depending on the preceding drug. In this post hoc analysis, we analyzed a total of 643 T2D patients (GLP1Ra-preceding group, n = 331; SGLT2i-preceding group, n = 312) and investigated the differences in annual eGFR decline. Multiple imputation and propensity score matching were performed to compare the annual eGFR decline. The reduction in annual eGFR decline in the SGLT2i-preceding group (pre: -3.5 ± 9.4 mL/min/1.73 m2/year, post: -0.4 ± 6.3 mL/min/1.73 m2/year, p < 0.001), was significantly smaller after the initiation of GLP1Ra, whereas the GLP1Ra-preceding group tended to slow the eGFR decline but not to a statistically significant extent (pre: -2.0 ± 10.9 mL/min/1.73 m2/year, post: -1.8 ± 5.4 mL/min/1.73 m2/year, p = 0.83) after the initiation of SGLT2i. After the addition of GLP1Ra to SGLT2i-treated patients, slower annual eGFR decline was observed. Our data raise the possibility that the renal benefits-especially annual eGFR decline-of combination therapy with SGLT2i and GLP1Ra may be affected by the preceding drug.

Association of scan frequency with CGM-derived metrics and influential factors in adults with type 1 diabetes mellitus.

Introduction: This study aimed to investigate the association between scan frequency and intermittently scanned continuous glucose monitoring (isCGM) metrics and to clarify the factors affecting scan frequency in adults with type 1 diabetes mellitus (T1D). Methods: We enrolled adults with T1D who used FreeStyle® Libre. Scan and self-monitoring of blood glucose (SMBG) frequency and CGM metrics from the past 90-day glucose data were collected. The receiver operating characteristic curve was plotted to obtain the optimal cutoff values of scan frequency for the target values of time in range (TIR), time above range (TAR), and time below range (TBR). Results: The study was conducted on 211 adults with T1D (mean age, 50.9 ± 15.2 years; male, 40.8%; diabetes duration, 16.4 ± 11.9 years; duration of CGM use, 2.1 ± 1.0 years; and mean HbA1c, 7.6 ± 0.9%). The average scan frequency was 10.5 ± 3.3 scan/day. Scan frequency was positively correlated with TIR and negatively correlated with TAR, although it was not significantly correlated with TBR. Scan frequency was positively correlated with the hypoglycemia fear survey-behavior score, while it was negatively correlated with some glycemic variability metrics. Adult patients with T1D and good exercise habits had a higher scan frequency than those without exercise habits. The AUC for > 70% of the TIR was 0.653, with an optimal cutoff of 11 scan/day. Conclusions: In real-world conditions, frequent scans were linked to improved CGM metrics, including increased TIR, reduced TAR, and some glycemic variability metrics. Exercise habits and hypoglycemia fear-related behavior might affect scan frequency. Our findings could help healthcare professionals use isCGM to support adults with T1D.Clinical Trial Registry No. UMIN000039376.

Pretreatment body mass index affects achievement of target blood pressure with sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus and chronic kidney disease.

Sodium-glucose cotransporter 2 inhibitor (SGLT2-I) shows excellent antihypertensive effects in addition to its hypoglycemic effects. However, whether body mass index (BMI) affects the antihypertensive effect of SGLT2-I remains unknown. We investigated the impact of baseline BMI on the achievement of target blood pressure (BP) with SGLT2-I treatment in Japanese patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). We retrospectively evaluated 447 Japanese patients with T2DM and CKD treated with SGLT2-I for at least 1 year. The primary outcome was achieving the target BP (<130/80 mmHg) after SGLT2-I treatment. Patients were divided into two groups according to a baseline BMI of 29.1 determined by receiver operating characteristic analysis and analyzed in a cohort model with propensity score matching. In each group, 130 patients were compared by propensity score matching. The target BP achievement rate was significantly higher in the BMI < 29.1 group than in the BMI ≥ 29.1 group (34% and 21%, respectively, p = 0.03). The odds ratio for achieving the target BP in the BMI ≥ 29.1 group was 0.50 (95% confidence interval, 0.28-0.90, p = 0.02). The BMI < 29.1 group had significantly lower systolic and diastolic BPs after SGLT2-I treatment than the BMI ≥ 29.1 group. Only the BMI < 29.1 group was showed a significant decrease in the logarithmic albumin-to-creatinine ratio from baseline after SGLT2-I treatment. In patients with T2DM and CKD, baseline BMI was associated with the antihypertensive effects of SGLT2-I. Patients in the lower baseline BMI group were more likely to achieve the target BP after SGLT2-I treatment. Pretreatment BMI affects the antihypertensice effect of SGLT2 inhibirors in patients with T2DM and CKD.

Renoprotective effects of combination treatment with sodium-glucose cotransporter inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes mellitus according to preceding medication.

AIMS: Combination therapy with sodium-glucose cotransporter inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1Ras) is now of interest in clinical practice. The present study evaluated the effects of the preceding drug type on the renal outcome in clinical practice. METHODS: We retrospectively extracted type 2 diabetes mellitus patients who had received both SGLT2i and GLP1Ra treatment for at least 1 year. A total of 331 patients in the GLP1Ra-preceding group and 312 patients in the SGLT2i-preceding group were ultimately analyzed. Either progression of the albuminuria status and/or a ≥30% decrease in the eGFR was set as the primary renal composite outcome. The analysis using propensity score with inverse probability weighting was performed for the outcome. RESULTS: The incidences of the renal composite outcome in the SGLT2i- and GLP1Ra-preceding groups were 28% and 25%, respectively, with an odds ratio [95% confidence interval] of 1.14 [0.75, 1.73] (p = .54). A logistic regression analysis showed that the mean arterial pressure (MAP) at baseline, the logarithmic value of the urine albumin-to-creatinine ratio at baseline, and the change in MAP were independent factors influencing the renal composite outcome. CONCLUSION: With combination therapy of SGLT2i and GLP1Ra, the preceding drug did not affect the renal outcome.

Diselenide-bond replacement of the external disulfide bond of insulin increases its oligomerization leading to sustained activity.

Seleno-insulin, a class of artificial insulin analogs, in which one of the three disulfide-bonds (S-S's) of wild-type insulin (Ins) is replaced by a diselenide-bond (Se-Se), is attracting attention for its unique chemical and physiological properties that differ from those of Ins. Previously, we pioneered the development of a [C7UA,C7UB] analog of bovine pancreatic insulin (SeIns) as the first example, and demonstrated its high resistance against insulin-degrading enzyme (IDE). In this study, the conditions for the synthesis of SeIns via native chain assembly (NCA) were optimized to attain a maximum yield of 72%, which is comparable to the in vitro folding efficiency for single-chain proinsulin. When the resistance of BPIns to IDE was evaluated in the presence of SeIns, the degradation rate of BPIns became significantly slower than that of BPIns alone. Furthermore, the investigation on the intermolecular association properties of SeIns and BPIns using analytical ultracentrifugation suggested that SeIns readily forms oligomers not only with its own but also with BPIns. The hypoglycemic effect of SeIns on diabetic rats was observed at a dose of 150 µg/300 g rat. The strategy of replacing the solvent-exposed S-S with Se-Se provides new guidance for the design of long-acting insulin formulations.

The concomitant use of sodium-glucose co-transporter 2 inhibitors improved the renal outcome of Japanese patients with type 2 diabetes treated with glucagon-like peptide 1 receptor agonists.

Aims: This study aimed to clarify the renal influence of glucagon-like peptide 1 receptor agonists (GLP1Ras) with or without sodium-glucose co-transporter 2 inhibitors (SGLT2is) on Japanese patients with type 2 diabetes mellitus (T2DM). Methods: We retrospectively extracted 547 patients with T2DM who visited the clinics of members of Kanagawa Physicians Association. The progression of albuminuria status and/or a ≥ 15% decrease in the estimated glomerular filtration rate (eGFR) per year was set as the renal composite outcome. Propensity score matching was performed to compare GLP1Ra-treated patients with and without SGLT2i. Results: After matching, 186 patients in each group were compared. There was no significant difference of the incidence of the renal composite outcomes (17% vs. 20%, P = 0.50); however, the annual decrease in the eGFR was significantly smaller and the decrease in the urine albumin-to-creatinine ratio was larger in GLP1Ra-treated patients with the concomitant use of SGLT2is than in those without it (-1.1 ±â€…5.0 vs. -2.8 ±â€…5.1 mL/min/1.73 m2, P = 0.001; and -0.08 ±â€…0.61 vs. 0.05 ±â€…0.52, P = 0.03, respectively). Conclusion: The concomitant use of SGLT2i with GLP1Ra improved the annual decrease in the eGFR and the urine albumin-to-creatinine ratio in Japanese patients with T2DM.

Possible Relationship between the Deteriorated Accuracy of Intermittent-Scanning Continuous Glucose Monitoring Device and the Contact Dermatitis: Post-hoc analysis of the ISCHIA Study.

OBJECTIVE: We previously reported the mean average relative difference (MARD) of the sensor glucose (SG) of the first-generation FreeStyle Libre with the original algorithm, an intermittent scanning continuous glucose monitoring (isCGM) device, was 15.6% in the Effect of Intermittent-Scanning Continuous Glucose Monitoring to Glycemic Control Including Hypoglycemia and Quality of Life of Patients with Type 1 Diabetes Mellitus Study (ISCHIA Study). In the present study, we aimed to further analyze its accuracy in detail by conducting a post-hoc analysis of the study. METHODS: The ISCHIA Study was a multicenter, randomized, cross-over trial to assess the efficacy of isCGM. The SG levels of isCGM and the measured capillary blood glucose (BG) levels of 91 participants were used for the analysis. RESULTS: Bland-Altman analysis showed bias of -13.0 mg/dl when the SG levels were compared to the BG levels, however no proportional bias was observed (r = 0.085). MARD of the participants without and with contact dermatitis were 15.0 ± 6.0% and 27.4 ± 21.4% (P = 0.001), respectively. CONCLUSION: There was negative bias in the SG levels of isCGM compared to the BG levels. There is a possibility that the complication of the contact dermatitis during isCGM use may be related with deteriorated accuracy of the SG levels.

Regulation of Renin Expression by Β1-Integrin in As4.1 Juxtaglomerular Line Cells.

(1) Background: Renal dysfunction and hypertension are mutually aggravating factors; however, the details of their interaction remain unclear. In a study using renal tissue from diabetic rats, we found that ß1-integrin, a cell-substrate adhesion molecule, is specifically phosphorylated in juxtaglomerular cells that secrete renin, a blood pressure regulator. (2) Methods: A mouse juxtaglomerular cell line (As4.1 cells) was used for the following experiments: drug-induced promotion of ß1-integrin phosphorylation/dephosphorylation; knockdown of ß1-integrin and the cell adhesion molecule connexin-40 (a candidate for the main body of baroreceptor); and pressurization to atmospheric pressure + 100 mmHg. culture in hypotonic liquid medium. The expression of renin under these conditions was measured by qRT-PCR. (3) Results: Phosphorylation of ß1-integrin suppressed the expression of renin, while dephosphorylation conversely promoted it. ß1-integrin and connexin-40 knockdown both promoted the expression of renin. Pneumatic pressurization and hypotonic medium culture both decreased the expression of renin, which was restored by the knockdown of ß1-integrin. (4) Conclusions: ß1-integrin plays an inhibitory role in the regulation of the expression of renin, which may be controlled by phosphorylation and dephosphorylation. It is hypothesized that ß1-integrin and other adhesion factors regulate the expression of renin by altering the sensitivity of baroreceptors on the plasma membrane.

Factors associated with hemoglobin glycation index in adults with type 1 diabetes mellitus: The FGM-Japan study.

AIMS/INTRODUCTION: The discrepancy between HbA1c and glucose exposure may have significant clinical implications; however, the association between the hemoglobin glycation index (HGI) and clinical parameters in type 1 diabetes remains controversial. This study aimed to find the factors associated with HGI (laboratory HbA1c - predicted HbA1c derived from the continuous glucose monitoring [CGM]). MATERIALS AND METHODS: We conducted a cross-sectional study of adults with type 1 diabetes (n = 211, age 50.9 ± 15.2 years old, female sex = 59.2%, duration of CGM use = 2.1 ± 1.0 years). All subjects wore the CGM for 90 days before HbA1c measurement. Data derived from the FreeStyle Libre sensor were used to calculate the glucose management indicator (GMI) and glycemic variability (GV) parameters. HGI was defined as the difference between the GMI and the laboratory HbA1c levels. The participants were divided into three groups according to the HGI tertile (low, moderate, and high). Multivariate regression analyses were performed. RESULTS: The female sex ratio, HbA1c, and % coefficient of variation (%CV) significantly increased over the HGI tertile, while eGFR and Hb decreased over the HGI tertile. In multivariate analysis, the factors associated with HGI were %CV and eGFR, after adjusting for HbA1c level and sex (R2  = 0.44). CONCLUSIONS: This study demonstrated that HGI is associated with female sex, eGFR, and some glycemic variability indices, independently of HbA1c. Minimizing glycemic fluctuations might reduce HGI. This information provides diabetic health professionals and patients with personalized diabetes management for adults with type 1 diabetes.

Evaluation of ABCG2-mediated extra-renal urate excretion in hemodialysis patients.

Two-thirds of urate is excreted via the renal pathway and the remaining one-third via the extra-renal pathway, the latter mainly via the intestine in healthy individuals. ABCG2, a urate exporter, is expressed in various tissues including the kidney and intestine, and its dysfunction leads to hyperuricemia and gout. ABCG2 is regarded as being responsible for most of the extra-renal urate excretion. However, the extra-renal urate excretion capacity via ABCG2 remains undefined in end-stage kidney diseases. Therefore, we evaluated the capacity of extra-renal ABCG2 using 123 anuric hemodialysis patients whose urate excretion depended on only the extra-renal pathway. ABCG2 function in each participant was estimated based on ABCG2 dysfunctional variants. We computed the uric acid pool (PoolUA) from bodyweight and serum urate level (SUA) using previously reported radio-isotopic data, and we analyzed the association between ABCG2 function and the PoolUA. SUA and PoolUA increased significantly with ABCG2 dysfunction, and extra-renal ABCG2 could excrete up to approximately 60% of the daily uric acid turnover in hemodialysis patients. Our findings indicate that the extra-renal urate excretion capacity can expand with renal function decline and highlight that the extra-renal pathway is particularly important in the uric acid homeostasis for patients with renal dysfunction.

To Use or Not to Use a Self-monitoring of Blood Glucose System? Real-world Flash Glucose Monitoring Patterns Using a Cluster Analysis of the FGM-Japan Study.

Objective This study investigated self-monitoring of blood glucose (SMBG) adherence and flash glucose monitoring patterns using a cluster analysis in Japanese type 1 diabetes (T1D) patients with intermittently scanned continuous glucose monitoring (isCGM). Methods We measured SMBG adherence and performed a data-driven cluster analysis using a hierarchical clustering in T1D patients from Japan using the FreeStyle Libre system. Clusters were based on three variables (testing glucose frequency and referred Libre data for hyperglycemia or hypoglycemia). Patients We enrolled 209 participants. Inclusion criteria were patients with T1D, duration of isCGM use ≥3 months, age ≥20 years old, and regular attendance at the collaborating center. Results The rate of good adherence to SMBG recommended by a doctor was 85.0%. We identified three clusters: cluster 1 (low SMBG test frequency but high reference to Libre data, 17.7%), cluster 2 (high SMBG test frequency but low reference to Libre data, 34.0%), and cluster 3 (high SMBG test frequency and high reference to Libra data, 48.3%). Compared with other clusters, individuals in cluster 1 were younger, those in cluster 2 had a shorter Libre duration, and individuals in cluster 3 had lower time-in-range, higher severe diabetic distress, and high intake of snacks and sweetened beverages. There were no marked differences in the incidence of diabetic complications and rate of wearing the Libre sensor among the clusters. Conclusion We stratified the patients into three subgroups with varied clinical characteristics and CGM metrics. This new substratification might help tailor diabetes management of patients with T1D using isCGM.

Clinical Phenotypes and the Clinical Course of Bullous Pemphigoid Receiving Dipeptidyl Pepitidase-4 Inhibitor Treatment: An Analysis of Cases in a Single Japanese Center.

Objective Several studies have shown an increased risk of bullous pemphigoid (BP) when receiving dipeptidyl pepitidase-4 inhibitor (DPP-4i) treatment. The present study explored the associations of DPP-4i treatment with the clinical phenotypes and clinical course of BP. Methods We analyzed data of 146 patients with BP at Tokai University School of Medicine from December 1, 2009, to December 31, 2021. We obtained data by a retrospective medical record review and compared the bullous pemphigoid disease area index (BPDAI) between diabetes patients receiving DPP-4i treatment and those not receiving DPP-4i treatment. We employed multivariable linear regression models to explore the association between the DPP-4i treatment and the BPDAI scores. Results Among 53 BP patients with diabetes, 33 had developed BP during treatment with DPP-4i agents, among which vildagliptin was the most frequently used. The urticaria/erythema scores of the BPDAI were significantly lower in patients who developed BP while receiving DPP-4i treatment than among others. Of note, 69.2% of the patients who stopped DPP-4i treatment experienced complete remission, and the clinical course was more favorable in patients with lower scores for urticaria/erythema than among others. Conclusion These findings suggest that, in patients who developed BP while receiving DPP-4i treatment, a noninflammatory phenotype may indicate a high likelihood that DPP-4i treatment contributes to the development of BP. The discontinuation of DPP-4i should be carefully considered in close consultation with dermatologists.

Fibroblast growth factor 23-Klotho and mineral metabolism in the first year after pediatric kidney transplantation: A single-center prospective study.

BACKGROUND: The role of fibroblast growth factor 23 (FGF23) levels in mineral metabolism before and after kidney transplantation in pediatric patients is poorly understood. METHODS: We prospectively evaluated 24 patients under 18 years of age (4.5 [3.3-9.8] years) who underwent living kidney transplantation between July 2016 and March 2018, and measured intact FGF23 and serum αKlotho levels, and other parameters of mineral metabolism before and after transplantation (Day 7, 1 and 4 months, and 1 year). Relationships between parameters were examined by linear analysis. RESULTS: FGF23 level was 440.8 [63.4-5916.3] pg/ml pre-transplant and decreased significantly to 37.1 [16.0-71.5] pg/ml at Day 7 post-transplant (-91.6%, p < .001). Thereafter, it remained at normal levels until 1 year. αKlotho level was 785 [568-1292] pg/ml pre-transplant and remained low at Day 7 and 1 month post-transplant, with an increasing trend at 4 months. Post-transplant phosphorus levels were significantly decreased compared with pre-transplant, with a lowest level of 1.7 [1.3-2.9] mg/dl, -5.7 [-6.8, -3.8] SD at Day 4, followed by gradual recovery. Phosphorus levels and the ratio of tubular maximum phosphate reabsorption were significantly and negatively associated with pre-transplant FGF23 until 4 months of post-transplant. Pre-transplant αKlotho was negatively associated with pre-transplant FGF23 but not FGF23 or other parameters after transplantation. CONCLUSION: FGF23 in pediatric kidney transplant patients decreased rapidly after transplantation and associated with post-transplant hypophosphatemia and increased phosphorus excretion. Post-transplant αKlotho was low early post-transplant but tended to increase subsequently. Post-transplant αKlotho was unaffected by pre-transplant FGF23 or other factors, suggesting pre-transplant chronic kidney disease status has no effect.

Comparison of the blood pressure management between sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists.

The cardiovascular and renal protective effects of sodium-glucose cotransporter 2 inhibitors (SGLT-2is) and glucagon-like peptide 1 receptor agonists (GLP-1Ras) are enhanced by low/controlled blood pressure (BP). However, the BP-lowering efficacy of SGLT-2is and GLP-1Ras have not been compared directly. We compared the rates of achieving target BP with SGLT-2i and GLP-1Ra treatments in Japanese patients with type 2 diabetes mellitus (T2DM). This retrospective study included 384 SGLT-2i- and 160 GLP-1Ra-treated patients with BP > 130/80 mmHg before treatment. Inverse probability weighting methods using propensity scores were used in this study. The integrated odds ratios (OR) for BP control rates were calculated and clinical changes were analyzed using a generalized linear model. SGLT-2i treatment resulted in significantly higher BP control rates than that in the GLP-1Ra treatment (integrated OR = 2.09 [1.80, 2.43]). Compared with GLP-1Ra, SGLT-2i treatment demonstrated significantly larger decreases in diastolic BP, mean arterial pressure, and body weight (- 3.8 mmHg, P = 0.006; - 4.1 mmHg, P = 0.01; and - 1.5 kg, P = 0.008, respectively) and increased annual estimated glomerular filtration rate (eGFR; 1.5 mL/min/1.73 m2/year, P = 0.04). In T2DM patients with poorly controlled BP, compared with GLP-1Ra, SGLT-2i treatment significantly improved BP management and increased eGFR.

The Importance of Patient and Family Engagement, the Needs for Self-Monitoring of Blood Glucose (SMBG) - Our Perspectives Learned Through a Story of SMBG Assistive Devices Made by a Husband of the Patient with Diabetes.

Despite some negative reports regarding the need for the self-monitoring of blood glucose (SMBG), including the issue of cost-effectiveness, there are still many users, and in diabetes treatment, which is largely dependent on the patient's self-care, SMBG remains an important tool in establishing such self-care habits, with several reports supporting this notion. In addition, devices are needed to assist in SMBG for patients with diabetes who have difficulty performing SMBG, such as the elderly or those with visual impairment. In current diabetes care, it is reported that patient-centered care that respects the preferences, needs, and values of individual patients and personalized care that consider the characteristics and comorbidities of each patient are important. Through a case study of a patient with diabetes who had difficulty performing SMBG due to visual impairment, we learned of the needs of SMBG and its assistive devices and the importance of patient and family engagement with emphasis on patient-centered and personalized care. We herein report what we learned through this case in the form of perspectives. Through this report, we hope that medical professionals involved in diabetes care will learn of the importance and needs of these issues and apply them to their actual clinical practice.

Concomitant treatment with insulin and sodium-glucose cotransporter 2 inhibitors was associated with the renal composite outcome in Japanese patients with type 2 diabetes and chronic kidney disease: A propensity score-matched analysis.

AIMS/INTRODUCTION: We previously reported that sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment was associated with an improvement of the albumin-to-creatinine ratio in Japanese patients with type 2 diabetes mellitus and chronic kidney disease. The present study clarified how concomitant insulin treatment (IT) with SGLT2i therapy influences the renal composite outcome (RCO). MATERIALS AND METHODS: We retrospectively evaluated 624 Japanese patients with type 2 diabetes mellitus and chronic kidney disease who underwent SGLT2i treatment. The renal composite outcome was set as progression of the stage of albuminuria or a ≥15% decrease in the estimated glomerular filtration rate per year. We developed a cohort model of patients managed with and without IT (Ins [+], Ins [-]) using propensity score matching methods. Furthermore, all patients in our study population were stratified into quintiles according to their propensity score. RESULTS: The incidence of the RCO was in Ins (+) patients significantly higher than that in Ins (-) (P = 0.033). The estimated hazard ratio for the RCO was 1.55 (P = 0.035) in Ins (+) patients. The change in the estimated glomerular filtration rate and albumin-to-creatinine ratio in the groups was not statistically significant. The analysis, which was based on the quintiles, showed a statistically significant difference between the Ins (+) and Ins (-) groups (P = 0.01); the odds ratio for the RCO in patients managed with IT was 2.20 (P = 0.01). CONCLUSIONS: Concomitant administration of IT with SGLT2is influenced the RCO in Japanese patients with type 2 diabetes mellitus and chronic kidney disease. We might need to consider the influence of concomitant agents on the renoprotective effects of SGLT2i therapy.

Rationale, design and baseline characteristics of the effect of canagliflozin in patients with type 2 diabetes and microalbuminuria in the Japanese population: The CANPIONE study.

AIM: To evaluate the effect of canagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, on albuminuria and the decline of estimated glomerular filtration rate (eGFR) in participants with type 2 diabetes and microalbuminuria. METHODS: The CANPIONE study is a multicentre, randomized, parallel-group and open-labelled study consisting of a unique 24-week preintervention period, during which the rate of eGFR decline before intervention is estimated, followed by a 52-week intervention and a 4-week washout period. Participants with a geometric mean urinary albumin-to-creatinine ratio (UACR) of 50 and higher and less than 300 mg/g in two consecutive first-morning voids at two different time points, and an eGFR of 45 ml/min/1.73m2 or higher, are randomly assigned to receive canagliflozin 100 mg daily or to continue guideline-recommended treatment, except for SGLT2 inhibitors. The first primary outcome is the change in UACR, and the second primary outcome is the change in eGFR slope. RESULTS: A total of 258 participants were screened and 98 were randomized at 21 sites in Japan from August 2018 to May 2021. The mean baseline age was 61.4 years and 25.8% were female. The mean HbA1c was 7.9%, mean eGFR was 74.1 ml/min/1.73m2 and median UACR was 104.2 mg/g. CONCLUSIONS: The CANPIONE study will determine whether the SGLT2 inhibitor canagliflozin can reduce albuminuria and slow eGFR decline in participants with type 2 diabetes and microalbuminuria.

Comparison of renal outcomes between sodium glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists.

AIMS: This study aimed to clarify the differences in how sodium glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1Ra) influence kidney function in Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: We retrospectively built two databases of patients with T2DM who visited the clinics of members of Kanagawa Physicians Association. We defined the renal composite outcome as either progression of albuminuria status and/or > 15% deterioration in estimated glomerular filtration rate (eGFR) per year. We used propensity score matching to compare patient outcomes after SGLT2i and GLP1Ra treatments. RESULTS: The incidence of renal composite outcomes was significantly lower in SGLT2i-treated patients than in GLP1Ra-treated patients (n = 15[11%] and n = 27[20%], respectively, P = 0.001). Annual eGFR changes (mL/min/1.73 m2/year) between the two groups differed significantly (-1.8 [95 %CI, -2.7, -0.9] in SGLT2i-treated patients and - 3.4 [95 %CI, -4.6, -2.2] in GLP1Ra-treated patients, P = 0.0049). The urine albumin-to-creatinine ratio changed owing to a significant interaction between the presence or absence of a decrease in systolic blood pressure and the difference in treatments (P < 0.04). CONCLUSION: Renal composite outcome incidence was lower in SGLT2i-treated patients than in GLP1Ra-treated patients.

Polypharmacy influences the renal composite outcome in patients treated with sodium-glucose cotransporter 2 inhibitors.

Polypharmacy is a serious concern in general practice, especially among elder patients; however, the evidence showing significantly poor renal outcomes is not sufficient. This survey was performed to evaluate the effect of polypharmacy on the incidence of the renal composite outcome among a sample of patients with sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment. We assessed 624 Japanese patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease who received SGLT2i treatment for greater than 1 year. The patients were classified as those with concomitant treatment, that was limited to the medications for hypertension, T2DM, and dyslipidemia, with greater than or equal to seven medications (n = 110) and those with less than seven medications (n = 514). Evaluation of the renal composite outcome was performed by propensity score matching and stratification into quintiles. A subgroup analysis of patients of greater than or equal to 62 years of age and less than 62 years of age was also performed. The incidence of the renal composite outcome was larger in patients with greater than or equal to seven medications than in those with less than seven medications in the propensity score-matched cohort model (6% vs. 17%, respectively, p = 0.007) and also in the quintile-stratified analysis (odds ratio [OR], 2.23, 95% confidence interval [CI, 1.21-4.12, p = 0.01). The quintile-stratified analysis of patients of less than 62 years of age-but not those of greater than or equal to 62 years of age-also showed a significant difference (OR, 3.29, 95% CI, 1.41-7.69, p = 0.006). Polypharmacy appears to be associated to the incidence of the renal composite outcome, especially in young patients.