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      The Place and Value of Sodium-Glucose Cotransporter 2 Inhibitors in the Evolving Treatment Paradigm for Type 2 Diabetes Mellitus: A Narrative Review

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          Abstract

          Over recent years, the expanding evidence base for sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapies has revealed benefits beyond their glucose-lowering efficacy in the treatment of Type 2 diabetes mellitus (T2DM), resulting in their recognition as cardiorenal medicines. While SGLT2is continue to be recommended among the second-line therapies for the treatment of hyperglycaemia, their true value now extends to the prevention of debilitating and costly cardiovascular and renal events for high-risk individuals, with particular benefit shown in reducing major adverse cardiac events and heart failure (HF) and slowing the progression of chronic kidney disease. However, SGLT2i usage is still suboptimal among groups considered to be at greatest risk of cardiorenal complications. The ongoing coronavirus disease 2019 (COVID-19) pandemic has intensified financial pressures on healthcare systems, which may hamper further investment in newer effective medicines. Emerging evidence indicates that glycaemic control should be prioritised for people with T2DM in the era of COVID-19 and practical advice on the use of T2DM medications during periods of acute illness remains important, particularly for healthcare professionals working in primary care who face multiple competing priorities. This article provides the latest update from the Improving Diabetes Steering Committee, including perspectives on the value of SGLT2is as cost-effective therapies within the T2DM treatment paradigm, with particular focus on the latest published evidence relating to the prevention or slowing of cardiorenal complications. The implications for ongoing and future approaches to diabetes care are considered in the light of the continuing coronavirus pandemic, and relevant aspects of international treatment guidelines are highlighted with practical advice on the appropriate use of SGLT2is in commonly occurring T2DM clinical scenarios. The ‘SGLT2i Prescribing Tool for T2DM Management’, previously published by the Steering Committee, has been updated to reflect the latest evidence and is provided in the Supplementary Materials to help support clinicians delivering T2DM care.

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s13300-022-01228-w.

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          Most cited references105

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          Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.

          The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known.
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            Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction

            In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.
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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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                Author and article information

                Contributors
                j.p.h.wilding@liverpool.ac.uk
                Journal
                Diabetes Ther
                Diabetes Ther
                Diabetes Therapy
                Springer Healthcare (Cheshire )
                1869-6953
                1869-6961
                20 March 2022
                20 March 2022
                : 1-26
                Affiliations
                [1 ]GRID grid.411255.6, ISNI 0000 0000 8948 3192, Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, Clinical Sciences Centre, , University Hospital Aintree, ; Liverpool, UK
                [2 ]GRID grid.273109.e, ISNI 0000 0001 0111 258X, University Hospital Llandough, ; Cardiff, UK
                [3 ]North Berwick Health Centre, North Berwick, UK
                [4 ]GRID grid.5338.d, ISNI 0000 0001 2173 938X, University Hospital Clinic, , University of Valencia, ; Valencia, Spain
                [5 ]GRID grid.411967.c, ISNI 0000 0001 2288 3068, Spanish Diabetes Association, Catholic University of Murcia, , Service Murciano de Salud, ; Cartagena, Murcia Spain
                [6 ]College Lane Surgery, Ackworth, West Yorkshire UK
                [7 ]TREND Diabetes, Enfield, UK
                [8 ]GRID grid.269014.8, ISNI 0000 0001 0435 9078, University Hospitals of Leicester NHS Trust, ; Leicester, UK
                [9 ]GRID grid.430506.4, ISNI 0000 0004 0465 4079, University Hospitals Southampton NHS Foundation Trust, ; Southampton, UK
                [10 ]Royal Blackburn Hospital, Lancashire, UK
                [11 ]GRID grid.4827.9, ISNI 0000 0001 0658 8800, Swansea University and Diabetes Research Unit, ; Swansea, UK
                [12 ]GRID grid.5390.f, ISNI 0000 0001 2113 062X, University of Udine, ; Udine, Italy
                [13 ]GRID grid.83440.3b, ISNI 0000000121901201, University College London, ; London, UK
                [14 ]GRID grid.24029.3d, ISNI 0000 0004 0383 8386, Cambridge University Hospitals NHS Foundation Trust, ; Stevenage, UK
                [15 ]GRID grid.5395.a, ISNI 0000 0004 1757 3729, University of Pisa, ; Pisa, Italy
                [16 ]Centro de Salud Casco Antiguo Cartagena, Murcia, Spain
                [17 ]GRID grid.452553.0, ISNI 0000 0004 8504 7077, Primary Care Research Group, Biomedical Research Institute of Murcia (IMIB), ; 30120 Murcia, Spain
                Author information
                http://orcid.org/0000-0003-2839-8404
                Article
                1228
                10.1007/s13300-022-01228-w
                8934539
                35307801
                5e2858ee-3b9c-408a-815f-0d7cc4f2d313
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial 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-nc/4.0/.

                History
                : 20 December 2021
                : 8 February 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100014471, Mundipharma Research Limited;
                Categories
                Review

                Endocrinology & Diabetes
                sglt2 inhibitors,oral glucose-lowering medicines,type 2 diabetes mellitus,prescribing tools,heart failure,chronic kidney disease,diabetic kidney disease,cardiovascular disease,cardiovascular risk,cardiorenal protection

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