Head-to-head comparison of two SGLT-2 inhibitors on AKI outcomes in a rat ischemia-reperfusion model
The CREDENCE trial testing canagliflozin and the EMPA-REG OUTCOME trial testing empagliflozin suggest different effects on acute kidney injury (AKI). AKI diagnosis was mainly made based on changes of serum creatinine (sCr) although this also reflect mode of action of SGLT-2 inhibitors. We analyzed b...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-09-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332222007466 |
| _version_ | 1811188098890989568 |
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| author | Chang Chu Denis Delić Jana Alber Martina Feger Yingquan Xiong Ting Luo Ahmed A. Hasan Shufei Zeng Mohamed M.S. Gaballa Xin Chen Lianghong Yin Thomas Klein Saban Elitok Bernhard K. Krämer Michael Föller Berthold Hocher |
| author_facet | Chang Chu Denis Delić Jana Alber Martina Feger Yingquan Xiong Ting Luo Ahmed A. Hasan Shufei Zeng Mohamed M.S. Gaballa Xin Chen Lianghong Yin Thomas Klein Saban Elitok Bernhard K. Krämer Michael Föller Berthold Hocher |
| author_sort | Chang Chu |
| collection | DOAJ |
| description | The CREDENCE trial testing canagliflozin and the EMPA-REG OUTCOME trial testing empagliflozin suggest different effects on acute kidney injury (AKI). AKI diagnosis was mainly made based on changes of serum creatinine (sCr) although this also reflect mode of action of SGLT-2 inhibitors. We analyzed both compounds in a rat AKI model. The renal ischemia-reperfusion injury (I/R) model was used. Four groups were analyzed: sham, I/R+placebo, I/R+canagliflozin (30 mg/kg/day), I/R+ empagliflozin (10 mg/kg/day). Glucose excretion was comparable in both treatment groups indicating comparable SGLT-2 inhibition. Comparing GFR surrogate markers after I/R (sCr and blood urea nitrogen (BUN)), sCr peaked 24 h after I/R, BUN after 48 h, respectively, in the placebo treated I/R group. At all investigated time points after I/R sCr and BUN was higher in the I/R + canagliflozin group as compared to placebo treated rats, whereas the empagliflozin group did not differ from the placebo group. I/R led to tubular dilatation and necrosis. Empagliflozin was able to reduce that finding whereas canagliflozin had no effect. Treatment with empagliflozin also resulted in a significant reduction in an improved inflammatory score (p = 0.006). Renal expression of kidney injury molecule-1 (KIM-1) increased after I/R and empagliflozin but not canagliflozin significantly alleviated KIM-1 expression. I/R reduced urinary miR-26a excretion. Empagliflozin but not canagliflozin was able to restore normal levels of urinary miR-26a. This study in an AKI model confirmed safety data in the EMPA-REG OUTCOME trial suggesting that empagliflozin might reduce AKI risk. The empagliflozin effects on KIM-1 and miR-26a might indicate beneficial regulation of inflammation. These data should stimulate clinical studies with AKI risk as primary endpoint. |
| first_indexed | 2024-04-11T14:14:37Z |
| format | Article |
| id | doaj.art-6bf156b62ae1490c9a854bff0de67afa |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-11T14:14:37Z |
| publishDate | 2022-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-6bf156b62ae1490c9a854bff0de67afa2022-12-22T04:19:36ZengElsevierBiomedicine & Pharmacotherapy0753-33222022-09-01153113357Head-to-head comparison of two SGLT-2 inhibitors on AKI outcomes in a rat ischemia-reperfusion modelChang Chu0Denis Delić1Jana Alber2Martina Feger3Yingquan Xiong4Ting Luo5Ahmed A. Hasan6Shufei Zeng7Mohamed M.S. Gaballa8Xin Chen9Lianghong Yin10Thomas Klein11Saban Elitok12Bernhard K. Krämer13Michael Föller14Berthold Hocher15Department of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; The First Clinical Medical College of Jinan University, The First Affiliated Hospital of Jinan University, Guangzhou, ChinaFifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach, GermanyUniversity of Hohenheim, Department of Physiology, Stuttgart, GermanyUniversity of Hohenheim, Department of Physiology, Stuttgart, GermanyDepartment of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, GermanyThe First Clinical Medical College of Jinan University, The First Affiliated Hospital of Jinan University, Guangzhou, China; Nephrology Division, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, ChinaFifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Department of Biochemistry, Faculty of Pharmacy, Zagazig University, EgyptFifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, GermanyFifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Faculty of Veterinary Medicine, Benha University, Toukh, EgyptDepartment of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; The First Clinical Medical College of Jinan University, The First Affiliated Hospital of Jinan University, Guangzhou, ChinaThe First Clinical Medical College of Jinan University, The First Affiliated Hospital of Jinan University, Guangzhou, China; Correspondence to: Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China.Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach, GermanyFifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Klinikum Ernst von Bergmann gGmbH, Potsdam, GermanyFifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; European Center for Angioscience, Medical Faculty Mannheim, University of Heidelberg, GermanyUniversity of Hohenheim, Department of Physiology, Stuttgart, GermanyFifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China; IMD Institut für Medizinische Diagnostik Berlin-Potsdam GbR, Berlin, Germany; Correspondence to: Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.The CREDENCE trial testing canagliflozin and the EMPA-REG OUTCOME trial testing empagliflozin suggest different effects on acute kidney injury (AKI). AKI diagnosis was mainly made based on changes of serum creatinine (sCr) although this also reflect mode of action of SGLT-2 inhibitors. We analyzed both compounds in a rat AKI model. The renal ischemia-reperfusion injury (I/R) model was used. Four groups were analyzed: sham, I/R+placebo, I/R+canagliflozin (30 mg/kg/day), I/R+ empagliflozin (10 mg/kg/day). Glucose excretion was comparable in both treatment groups indicating comparable SGLT-2 inhibition. Comparing GFR surrogate markers after I/R (sCr and blood urea nitrogen (BUN)), sCr peaked 24 h after I/R, BUN after 48 h, respectively, in the placebo treated I/R group. At all investigated time points after I/R sCr and BUN was higher in the I/R + canagliflozin group as compared to placebo treated rats, whereas the empagliflozin group did not differ from the placebo group. I/R led to tubular dilatation and necrosis. Empagliflozin was able to reduce that finding whereas canagliflozin had no effect. Treatment with empagliflozin also resulted in a significant reduction in an improved inflammatory score (p = 0.006). Renal expression of kidney injury molecule-1 (KIM-1) increased after I/R and empagliflozin but not canagliflozin significantly alleviated KIM-1 expression. I/R reduced urinary miR-26a excretion. Empagliflozin but not canagliflozin was able to restore normal levels of urinary miR-26a. This study in an AKI model confirmed safety data in the EMPA-REG OUTCOME trial suggesting that empagliflozin might reduce AKI risk. The empagliflozin effects on KIM-1 and miR-26a might indicate beneficial regulation of inflammation. These data should stimulate clinical studies with AKI risk as primary endpoint.http://www.sciencedirect.com/science/article/pii/S0753332222007466Acute kidney injurySodium-glucose cotransporter 2 inhibitorsCanagliflozinEmpagliflozin |
| spellingShingle | Chang Chu Denis Delić Jana Alber Martina Feger Yingquan Xiong Ting Luo Ahmed A. Hasan Shufei Zeng Mohamed M.S. Gaballa Xin Chen Lianghong Yin Thomas Klein Saban Elitok Bernhard K. Krämer Michael Föller Berthold Hocher Head-to-head comparison of two SGLT-2 inhibitors on AKI outcomes in a rat ischemia-reperfusion model Biomedicine & Pharmacotherapy Acute kidney injury Sodium-glucose cotransporter 2 inhibitors Canagliflozin Empagliflozin |
| title | Head-to-head comparison of two SGLT-2 inhibitors on AKI outcomes in a rat ischemia-reperfusion model |
| title_full | Head-to-head comparison of two SGLT-2 inhibitors on AKI outcomes in a rat ischemia-reperfusion model |
| title_fullStr | Head-to-head comparison of two SGLT-2 inhibitors on AKI outcomes in a rat ischemia-reperfusion model |
| title_full_unstemmed | Head-to-head comparison of two SGLT-2 inhibitors on AKI outcomes in a rat ischemia-reperfusion model |
| title_short | Head-to-head comparison of two SGLT-2 inhibitors on AKI outcomes in a rat ischemia-reperfusion model |
| title_sort | head to head comparison of two sglt 2 inhibitors on aki outcomes in a rat ischemia reperfusion model |
| topic | Acute kidney injury Sodium-glucose cotransporter 2 inhibitors Canagliflozin Empagliflozin |
| url | http://www.sciencedirect.com/science/article/pii/S0753332222007466 |
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