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      Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial

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          Abstract

          Aims/hypothesis

          In previous work, we reported the HR for the risk (95% CI) of the secondary kidney composite endpoint (time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death) with ertugliflozin compared with placebo as 0.81 (0.63, 1.04). The effect of ertugliflozin on exploratory kidney-related outcomes was evaluated using data from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881).

          Methods

          Individuals with type 2 diabetes mellitus and established atherosclerotic CVD were randomised to receive ertugliflozin 5 mg or 15 mg (observations from both doses were pooled), or matching placebo, added on to existing treatment. The kidney composite outcome in VERTIS CV (reported previously) was time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death. The pre-specified exploratory composite outcome replaced doubling of serum creatinine with sustained 40% decrease from baseline in eGFR. In addition, the impact of ertugliflozin on urinary albumin/creatinine ratio (UACR) and eGFR over time was assessed.

          Results

          A total of 8246 individuals were randomised and followed for a mean of 3.5 years. The exploratory kidney composite outcome of sustained 40% reduction from baseline in eGFR, chronic kidney dialysis/transplant or renal death occurred at a lower event rate (events per 1000 person-years) in the ertugliflozin group than with the placebo group (6.0 vs 9.0); the HR (95% CI) was 0.66 (0.50, 0.88). At 60 months, in the ertugliflozin group, placebo-corrected changes from baseline (95% CIs) in UACR and eGFR were −16.2% (−23.9, −7.6) and 2.6 ml min −1 [1.73 m] −2 (1.5, 3.6), respectively. Ertugliflozin was associated with a consistent decrease in UACR and attenuation of eGFR decline across subgroups, with a suggested larger effect observed in the macroalbuminuria and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) high/very high-risk subgroups.

          Conclusions/interpretation

          Among individuals with type 2 diabetes and atherosclerotic CVD, ertugliflozin reduced the risk for the pre-specified exploratory composite renal endpoint and was associated with preservation of eGFR and reduced UACR.

          Trial registration

          ClinicalTrials.gov NCT01986881

          Graphical abstract

          Supplementary Information

          The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-021-05407-5.

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          Most cited references31

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          Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

          Background Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. Conclusions In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS-R ClinicalTrials.gov numbers, NCT01032629 and NCT01989754 , respectively.).
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            Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes

            The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined.
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              Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

              Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes.
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                Author and article information

                Contributors
                david.cherney@uhn.ca
                Journal
                Diabetologia
                Diabetologia
                Diabetologia
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0012-186X
                1432-0428
                4 March 2021
                4 March 2021
                2021
                : 64
                : 6
                : 1256-1267
                Affiliations
                [1 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, University of Toronto, ; Toronto, ON Canada
                [2 ]GRID grid.4817.a, University of Nantes, ; Nantes, France
                [3 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Unit of Cardiology, , Karolinska Institute & Karolinska University Hospital, ; Stockholm, Sweden
                [4 ]GRID grid.267301.1, ISNI 0000 0004 0386 9246, University of Tennessee Health Science Center, ; Memphis, TN USA
                [5 ]GRID grid.267313.2, ISNI 0000 0000 9482 7121, University of Texas Southwestern Medical Center, ; Dallas, TX USA
                [6 ]GRID grid.417169.c, ISNI 0000 0000 9359 6077, Parkland Health and Hospital System, ; Dallas, TX USA
                [7 ]AdventHealth Translational Research Institute, Orlando, FL USA
                [8 ]GRID grid.430387.b, ISNI 0000 0004 1936 8796, Rutgers School of Public Health, ; New Brunswick, NJ USA
                [9 ]GRID grid.430387.b, ISNI 0000 0004 1936 8796, Rutgers Cancer Institute of New Jersey, ; New Brunswick, NJ USA
                [10 ]GRID grid.410513.2, ISNI 0000 0000 8800 7493, Pfizer Inc., ; Collegeville, PA USA
                [11 ]MSD Limited, London, UK
                [12 ]GRID grid.417993.1, ISNI 0000 0001 2260 0793, Merck & Co., Inc., ; Kenilworth, NJ USA
                [13 ]GRID grid.38142.3c, ISNI 000000041936754X, Cardiovascular Division, Brigham and Women’s Hospital, , Harvard Medical School, ; Boston, MA USA
                Author information
                https://orcid.org/0000-0003-4164-0429
                Article
                5407
                10.1007/s00125-021-05407-5
                8099851
                33665685
                1c9a085e-f382-44bf-b635-fb0c04e0a57e
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 25 August 2020
                : 11 December 2020
                Funding
                Funded by: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc
                Funded by: Pfizer Inc.
                Categories
                Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2021

                Endocrinology & Diabetes
                cardiovascular disease,diabetic nephropathies,ertugliflozin,type 2 diabetes mellitus

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