PMID- 37883001 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240418 IS - 1869-6953 (Print) IS - 1869-6961 (Electronic) IS - 1869-6961 (Linking) VI - 15 IP - 1 DP - 2024 Jan TI - Albuminuria and Serum Tumor Necrosis Factor Receptor Levels in Patients with Type 2 Diabetes on SGLT2 Inhibitors: A Prospective Study. PG - 127-143 LID - 10.1007/s13300-023-01488-0 [doi] AB - INTRODUCTION: Large-scale clinical trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) demonstrate proteinuria-reducing effects in diabetic kidney disease, even after treatment with renin-angiotensin inhibitors. The precise mechanism for this favorable effect remains unclear. This prospective open-label single-arm study investigated factors associated with a reduction in proteinuria after SGLT2i administration. METHODS: Patients with type 2 diabetes (T2DM) who had glycated hemoglobin (HbA1c) levels >/= 6.5% despite dietary and/or oral hypoglycemic monotherapy were recruited and administered the recommended daily dose of SGLT2i for 4 months. Dual primary outcomes were changes in the urine albumin-to-creatinine ratio (uACR) and urine liver-type fatty acid-binding protein (L-FABP)-to-creatinine ratio (uL-FABPCR) at month 4 from baseline. Changes in kidney injury, inflammation, and oxidative stress biomarkers were investigated as secondary endpoints to examine the effects of this treatment on the kidney. The correlation between renal outcomes and clinical indicators, including circulating tumor necrosis factor receptors (TNFR) 1 and 2, was evaluated using univariate and multivariate analyses. RESULTS: Participants (n = 123) had a mean age of 64.1 years (SD 13.4), with 50.4% being male. The median BMI was 25.8 kg/m(2) (interquartile range (IQR) 23.1-28.9), and the median HbA1c level was 7.3% (IQR 6.9-8.3). After SGLT2i administration, the uACR declined from 19.2 mg/gCr (IQR 7.1-48.7) to 13.3 mg/gCr (IQR 7.5-31.6), whereas the uL-FABPCR was not influenced. In univariate analysis, the change in log-transformed uACR due to SGLT2i administration showed a positive correlation with the change in serum TNFR1 level (R = 0.244, p < 0.01). Multivariate regression analysis, including confounding factors, showed that the changes in serum TNFR1 level were independently associated with the changes in the log-transformed uACR (independent t = 2.102, p < 0.05). CONCLUSION: After the 4-month SGLT2i administration, decreased albuminuria level was associated with decreased serum TNFR level in patients with T2DM. TRIAL REGISTRATION NUMBER: UMIN000031947. CI - (c) 2023. The Author(s). FAU - Otoda, Toshiki AU - Otoda T AUID- ORCID: 0000-0003-2244-3403 AD - Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences, 18-15, 3 Chome, Kuramoto-cho, Tokushima, 770-8503, Japan. otoda.toshiki@tokushima-u.ac.jp. FAU - Sekine, Akiko AU - Sekine A AD - Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences, 18-15, 3 Chome, Kuramoto-cho, Tokushima, 770-8503, Japan. FAU - Uemoto, Ryoko AU - Uemoto R AD - Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences, 18-15, 3 Chome, Kuramoto-cho, Tokushima, 770-8503, Japan. FAU - Tsuji, Seijiro AU - Tsuji S AD - Department of Internal Medicine, Anan Medical Center, 6-1, Kawahara, Takarada-cho, Anan City, Tokushima, 774-0045, Japan. FAU - Hara, Tomoyo AU - Hara T AD - Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, 18-15, 3 Chome, Kuramoto-cho, Tokushima, 770-8503, Japan. FAU - Tamaki, Motoyuki AU - Tamaki M AD - Department of Diabetes and Endocrinology, Tamaki Aozora Hospital, 56-1, Kitakashiya, Aza Hayabuchi, Kokufu-cho, Tokushima, 779-3125, Japan. FAU - Yuasa, Tomoyuki AU - Yuasa T AUID- ORCID: 0000-0002-5598-6781 AD - Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences, 18-15, 3 Chome, Kuramoto-cho, Tokushima, 770-8503, Japan. FAU - Tamaki, Toshiaki AU - Tamaki T AUID- ORCID: 0000-0003-0362-9966 AD - Department of Urology, Anan Medical Center, 6-1, Kawahara, Takarada-cho, Anan City, Tokushima, 774-0045, Japan. FAU - Matsuhisa, Munehide AU - Matsuhisa M AUID- ORCID: 0000-0003-4624-939X AD - Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, 18-15, 3 Chome, Kuramoto-cho, Tokushima, 770-8503, Japan. FAU - Aihara, Ken-Ichi AU - Aihara KI AUID- ORCID: 0000-0001-8906-0920 AD - Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences, 18-15, 3 Chome, Kuramoto-cho, Tokushima, 770-8503, Japan. LA - eng GR - 18K16204/Japan Society for the Promotion of Science KAKENHI/ PT - Journal Article DEP - 20231026 PL - United States TA - Diabetes Ther JT - Diabetes therapy : research, treatment and education of diabetes and related disorders JID - 101539025 PMC - PMC10786751 OAB - Previous studies have demonstrated the synergistic proteinuria-reducing effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in combination therapy with renin-angiotensin system blockers; however, the underlying mechanisms of this effect are poorly understood. This study was based on our hypothesis that the proteinuria-reducing effect is associated with the anti-inflammatory effects of SGLT2i beyond the effect on glycemic control. In total, 123 patients with type 2 diabetes mellitus (T2DM) were administered the recommended daily dose of SGLT2i for 4 months. Dual primary outcomes were changes in the urine albumin-to-creatinine ratio (uACR) and urine liver-type fatty acid-binding protein (L-FABP)-to-creatinine ratio (uL-FABPCR) as markers of glomerular and proximal tubular damage at 4 months from the baseline. Secondary outcomes included changes in kidney injury biomarkers, inflammation, and oxidative stress to examine the effects of treatment on the kidneys. The correlation between renal outcomes and clinical indicators, including circulating tumor necrosis factor receptors (TNFR) 1 and 2, was evaluated using univariate and multivariate analyses. We found that administration of SGLT2i decreased the urine albumin-to-creatinine ratio but did not affect the urine liver-type fatty acid-binding protein-to-creatinine ratio. Further, SGLT2i may exert a proteinuria-reducing effect dependent on the anti-inflammatory effect in patients with T2DM. The inflammation-reducing and renoprotective mechanisms of SGLT2i remain to be fully clarified, but this study provides novel evidence regarding the mechanism. The study findings can help in developing anti-inflammatory agents for metabolic diseases. OABL- eng OTO - NOTNLM OT - Albuminuria OT - Diabetic kidney disease OT - Inflammation OT - Sodium-glucose cotransporter 2 inhibitors OT - Tumor necrosis factor receptor OT - Type 2 diabetes COIS- Toshiki Otoda received lecture fees from Taisho Pharmaceutical Holdings Co., Ltd. and Kowa Company, Ltd. and received speaker fees from Astellas Pharma, Inc., Nippon Boehringer Ingelheim Co., Ltd., and Mitsubishi Tanabe Pharma Corporation. Motoyuki Tamaki received speaker fees from Eli Lilly Japan K.K. Tomoyuki Yuasa received speaker fees from Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Ltd., and Mitsubishi Tanabe Pharma Corporation. Toshiaki Tamaki received speaker fees from Astellas Pharma, Inc., Ono Pharmaceutical Co., Ltd., and Mitsubishi Tanabe Pharma Corporation. Munehide Matsuhisa received speaker fees from Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K., Novo Nordisk Pharma Ltd., Sumitomo Pharma Co., Ltd., Sanofi K.K., and Kyowa Kirin Co., Ltd. Akiko Sekine, Ryoko Uemoto, Seijiro Tsuji, Tomoyo Hara, and Ken-ichi Aihara declare that they have no conflicts of interest to disclose. EDAT- 2023/10/26 12:42 MHDA- 2023/10/26 12:43 PMCR- 2023/10/26 CRDT- 2023/10/26 11:15 PHST- 2023/08/12 00:00 [received] PHST- 2023/10/06 00:00 [accepted] PHST- 2023/10/26 12:43 [medline] PHST- 2023/10/26 12:42 [pubmed] PHST- 2023/10/26 11:15 [entrez] PHST- 2023/10/26 00:00 [pmc-release] AID - 10.1007/s13300-023-01488-0 [pii] AID - 1488 [pii] AID - 10.1007/s13300-023-01488-0 [doi] PST - ppublish SO - Diabetes Ther. 2024 Jan;15(1):127-143. doi: 10.1007/s13300-023-01488-0. Epub 2023 Oct 26.