Dapagliflozin Improves Erythropoiesis and Iron Metabolism in Type 2 Diabetic Patients with Renal Anemia.

Purpose: In this study, we examined the effects of dapagliflozin on changes in hematopoiesis, iron metabolism, and body composition indices in elderly type 2 diabetic patients with renal impairment and investigated the potential of dapagliflozin to treat renal anemia. Patients and Methods: The participants were elderly type 2 diabetics with renal impairment, and the indices of diabetes management, hematopoiesis, iron metabolism, and body composition were compared before and after dapagliflozin treatment. Results: Fourteen subjects were given dapagliflozin 5 mg once daily for 12 weeks, three of whom had eligibility criteria deviations, such as serum ferritin <50 ng/mL. For this purpose, 14 subjects were analyzed as full analysis set (FAS) and 11 as per-protocol set (PPS). FAS analysis revealed that dapagliflozin had no effect on hemoglobin A1c after 12 weeks but significantly decreased body mass index, significantly increased hemoglobin, hematocrit, and red blood cell count, significantly decreased log ferritin level only of iron metabolism index, and no important change in body water content. PPS analysis, on the other hand, revealed that dapagliflozin 12-week treatment showed a significant decrease in log hepcidin, serum iron, and transferrin saturation. Conclusion: These findings suggest that a 12-week course of dapagliflozin causes an increase in hemoglobin levels due to its hematopoietic effects in elderly type 2 diabetics with renal impairment, but that these effects may be independent of body water loss and iron metabolism improvement.

Comparative evaluation of clinical glycemic control markers treated with imeglimin and its effect on erythrocytes in patients with type 2 diabetes mellitus: study protocol of a single-arm, open-label, prospective, exploratory trial.

Background: Imeglimin is a novel type 2 diabetes (T2D) drug that is expected to improve mitochondrial function. In its phase 3 clinical trials in Japanese patients with T2D, the hemoglobin A1c (HbA1c) decrease following imeglimin administration was slow, reaching a plateau after 20-24 weeks of treatment. In general, the erythrocyte lifespan may be a factor when HbA1c shows an abnormal value. Therefore, this study will comparatively evaluate HbA1c and other markers of glycemic control in patients with T2D after imeglimin administration and also examine the effects of imeglimin on erythrocytes. Methods: This single-arm, open-label, prospective, exploratory study is designed to evaluate the divergence between HbA1c and glycoalbumin (GA) or 1,5-anhydroglucitol (1,5-AG) and the glycemic reduction rate in 30 patients with T2D with inadequate glycemic control when imeglimin 2,000 mg is administered for 6 months. In addition, we will examine the effect on erythrocytes, the presumed cause of this divergence. We will measure sustained glycemic variability using flash glucose monitoring and examine the relationship between changes in these indices and HbA1c. Moreover, because prolonged erythrocyte lifespan is a possible cause of falsely high HbA1c levels, erythrocyte lifespan, erythrocyte deformability, and hemoglobin concentration will be evaluated as effects of imeglimin on erythrocytes. Furthermore, if imeglimin has an ameliorative effect on erythrocyte deformability, it may improve peripheral arterial disease; thus, we will also evaluate the toe-brachial pressure index, a measure of this effect. Discussion: In this study, if imeglimin administration results in diverging rates of hypoglycemic effect between HbA1c and GA or 1,5-AG and prolongs erythrocyte lifespan, GA and 1,5-AG, rather than HbA1c, will be considered appropriate measures of the hypoglycemic effect in the early stages of imeglimin administration. If imeglimin improves erythrocyte deformability, it may also be a new treatment strategy for peripheral arterial disease, a chronic complication of T2D. Ethics and dissemination: The study protocol was scientifically and ethically reviewed and approved by the Certified Clinical Research Review Board of Toho University (approval number: THU22002). The study protocol was registered in the Japan Registry of Clinical Trials (jRCT) in December 2022 (jRCTs031220489).

Effects of barley intake on glycemic control in Japanese patients with type 2 diabetes mellitus undergoing antidiabetic therapy: a prospective study.

Background: Barley reportedly reduces postprandial hyperglycemia in healthy individuals. However, its effects in patients with type 2 diabetes mellitus (T2DM) undergoing antidiabetic therapy remains unclear. This study aimed to clarify the effects of barley intake on postprandial hyperglycemia in T2DM patients who use metformin or acarbose. Methods: T2DM patients who were undergoing dietary therapy without medications (naive), with metformin, or with acarbose (n = 10/group) were recruited. They were instructed to eat white rice twice per day for 5 days, followed by barley-mixed rice twice per day for 6 or 7 days. Subsequently, blood glucose fluctuations in the interstitial fluid glucose were measured using a continuous glucose monitoring device. Meal tolerance tests were performed using test diets containing white rice and barley-mixed rice before and after the trial, respectively. Results: Postprandial hyperglycemia was lower in patients taking barley-mixed rice than in those taking white rice in each group. However, the AUC of blood glucose concentration in the acarbose-treated patients showed only a trend. Mean amplitude of glycemic excursions (MAGEs) decreased in patients who consumed barley-mixed rice. Additionally, although MAGEs in the naive decreased, it did not in the metformin- (P = 0.098) and acarbose-treated (P = 0.29) patients. Conclusion: Barley-mixed rice lowers postprandial glucose concentrations in treatment-naive and metformin-treated T2DM patients, and shows a trend in acarbose-treated patients. Therefore, using barley-containing diets as dietary therapy may be useful in improving glycemic control in diabetes patients. Trial registration: UMIN000028623. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-021-00552-z.

Efficacy and safety of switching from febuxostat to dotinurad, a novel selective urate reabsorption inhibitor, in hyperuricemic patients with type 2 diabetic kidney disease: Protocol for a single-arm, open-label, prospective, exploratory study.

Background: Dotinurad is a novel uricosuric drug in Japan with selective and potent urate transporter 1 (URAT1) inhibitory activity. This study aims to evaluate the efficacy and safety of dotinurad in hyperuricemic patients with type 2 diabetic kidney disease by comparing serum levels of urate and plasma and urinary levels of indoxyl sulfate excreted via the urate excretion transporter ATP binding cassette subfamily G member 2 (ABCG2), as indices, with baseline levels after switching from febuxostat to dotinurad. Methods: This single-center, single-arm, open-label, prospective, exploratory study aims to evaluate the effect of switching from febuxostat to dotinurad on serum urate levels and its background factors. The study will include 50 hyperuricemic patients with type 2 diabetic kidney disease and urate levels exceeding 6 mg/dL despite administration of febuxostat 20 mg/day for at least 3 months. The primary outcome is the achievement rate of serum urate levels of ≤6 mg/dL after 24 weeks of treatment with dotinurad at 0.5 mg to a maximum of 4 mg once daily. Secondary outcomes include the changes in serum urate levels, plasma and urinary indoxyl sulfate levels, and renal injury-related markers from baseline to observation points at weeks 4, 12, and 24. Discussion: The study hypothesizes that switching to dotinurad may reduce the plasma levels of indoxyl sulfate and increase its urinary levels in patients with hyperuricemia. These suggest that dotinurad can potently lower the serum urate level by inhibiting URAT1 without adversely affecting ABCG2. Thus, findings of this study are expected to provide useful insights into the treatment of hyperuricemia associated with type 2 diabetic kidney disease and the discovery of new possibilities for dotinurad. Ethics and Dissemination: Prior to the study, its study protocol was scientifically and ethically reviewed and approved by the Japan Physicians Association Clinical Research Review Board (approval number: JPA007-2204-02). In addition, patients who provide written informed consent will participate in the study. The results of this study will be published through submission to a peer-reviewed scientific journal. Clinical trial registration: https://jrct.niph.go.jp/en-latest-detail/jRCTs031220080, identifier jRCTs031220080.

Add-On Therapy with DPP-4 Inhibitors May Improve Renal Function Decline in α-Glucosidase Inhibitor and Metformin Users: A Retrospective Observational Study.

PURPOSE: We retrospectively evaluated the long-term effect of dipeptidyl peptidase (DPP)-4 inhibitors on estimated glomerular filtration rate (eGFR) slopes, and then evaluated the beneficial interaction between DPP-4 inhibitor initiation and baseline use of α-glucosidase inhibitor and/or metformin in patients with diabetic kidney disease. PATIENTS AND METHODS: Altogether, 1512 patients with type 2 diabetes were receiving DPP-4 inhibitor therapy over 1 year and were followed up for a maximum of 2 years before and after 7 years of treatment. The decline in renal function was estimated as the slope of the individual linear regression line of eGFR over 2-year follow-up. Prescription data on medications before and after DPP-4 inhibitor treatment were examined. RESULTS: The mean length of DPP-4 inhibitor treatment was 5.3 ± 2.6 years. The baseline mean eGFR slope (mL/min/1.73m2/year) was -2.24 ± 6.05. After DPP-4 inhibitor treatment, mean eGFR slope was significantly improved (-1.53 ± 6.36, P < 0.01) in patients with type 2 diabetes. This effect appeared more pronounced for baseline use of α-glucosidase inhibitor and/or metformin in patients with diabetic kidney disease. These non-users showed a trend towards attenuation or no effects. CONCLUSION: In the present study, patients treated with DPP-4 inhibitors had a significantly slower annual loss of kidney function. The benefit appears pronounced in α-glucosidase inhibitor and metformin users with advanced renal dysfunction. These results suggest that the beneficial effects of DPP-4 inhibitors on kidney function may have occurred in the presence of an α-glucosidase inhibitor and/or metformin.

Liraglutide Improves Estimated Glomerular Filtration Rate Slopes in Patients with Chronic Kidney Disease and Type 2 Diabetes: A 7-Year Retrospective Analysis.

Background: Liraglutide was administered to patients with type 2 diabetes, and its effects on estimated glomerular filtration rate (eGFR) slopes and albuminuria were retrospectively evaluated. Methods: This study included 568 patients with type 2 diabetes who received liraglutide therapy (up to 0.9 mg/day) >1 year and were followed-up for a maximum of 2 years before and 7 years after treatment. The decline in renal function was estimated as the slope of the individual linear regression line of eGFR over the follow-up time. Spot urine samples were collected to measure albuminuria, which were calculated using creatinine levels. In addition, HbA1c, body weight, blood pressure, and heart rate were monitored. Results: The mean liraglutide treatment period was 3.1 ± 2.0 years. The mean baseline eGFR slope [mL/(min ·1.73 m2·year)] was -2.75 ± 6.04. After liraglutide treatment, the mean eGFR slope significantly improved (-1.42 ± 4.30, P < 0.01). This effect appeared more pronounced for baseline eGFRs <45 mL/(min ·1.73 m2). Albuminuria, HbA1c, body weight, and systolic blood pressure levels were significantly reduced after treatment with liraglutide for 1 year, whereas diastolic blood pressure and heart rates were increased. Conclusions: Patients treated with liraglutide experienced a significantly slower annual decline in kidney function. The benefit appeared more pronounced in patients with the development and progression of diabetic kidney disease. These results suggest that the benefits of liraglutide on kidney function identified in clinical trials appear to be well generalizable to clinical practice.

Canagliflozin Increases Postprandial Total Glucagon-Like Peptide 1 Levels in the Absence of α-Glucosidase Inhibitor Therapy in Patients with Type 2 Diabetes: A Single-Arm, Non-randomized, Open-Label Study.

INTRODUCTION: To investigate canagliflozin-induced changes in postprandial total glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels in patients with type 2 diabetes mellitus (T2DM). METHODS: Forty-five patients with T2DM who had inadequate glycemic control (glycated hemoglobin ≥ 6.5%) with diet and exercise alone (n = 15, drug naïve) and in combination with either a stable dose of the α-glucosidase inhibitor acarbose (n = 15) or metformin (n = 15) received canagliflozin, a sodium-glucose cotransporter 2 inhibitor, at 100 mg once daily for 12 weeks. The primary endpoint was the change from baseline to week 12 in postprandial glucose and plasma levels of total GLP-1 and GIP during a meal tolerance test (MTT). RESULTS: Canagliflozin significantly reduced postprandial blood glucose (mean difference - 40.2 mg/mL at 60 min) and increased postprandial total GLP-1 (mean difference 1.8 pg/mL at 60 min) during an MTT. A transient reduction in the postprandial GIP level at only 30 min (mean difference - 80.3 pg/mL) during an MTT was observed. No changes in postprandial GLP-1 or GIP levels were seen after canagliflozin treatment as an add-on to acarbose in patients with T2DM. Acarbose treatment significantly decreased postprandial total GIP levels (P < 0.05) and tended to increase postprandial total GLP-1 levels (P = 0.07) compared to the other two treatments prior to canagliflozin. CONCLUSION: Canagliflozin 100 mg increased postprandial total GLP-1 levels in the absence of acarbose, suggesting that it may upregulate GLP-1 secretion through delayed glucose absorption in the upper intestine, as with the α-glucosidase inhibitor. TRIAL REGISTRATION: University Hospital Medical Information Network, UMIN000018345. FUNDING: Mitsubishi Tanabe Pharma Corporation.