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      Sodium-glucose cotransporter 2 inhibitor versus metformin as first-line therapy in patients with type 2 diabetes mellitus: a multi-institution database study

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          Abstract

          Background

          Sodium-glucose co-transporter 2 inhibitors (SGLT2i) has shown evidence of cardiovascular benefit in patients with type 2 diabetes mellitus (T2DM). Currently metformin is the guideline-recommended first-line treatment. We aimed to investigate the benefit of SGLT2i vs metformin as first-line therapy.

          Methods

          Electronic medical records from Chang Gung Research Database during 2016–2019 were retrieved for patients with T2DM. Patients aged < 20, not receiving anti-diabetic medication, first-line treatment neither metformin nor SGLT2i were excluded. Primary outcomes were heart failure hospitalization, acute coronary syndrome, ischemic stroke, and all-cause mortality. Patients were followed up for events or December 31, 2019, whichever comes first.

          Results

          After exclusion criteria, a total of 41,020 patients with T2DM were eligible for analysis. There were 1100 patients with SGLT2i as first-line and 39,920 patients with metformin as first-line treatment. IPTW was used for propensity score matching. During one year follow-up, the hazard ratio (HR) of patients on SGLT2i as first-line treatment to patients on metformin as first-line treatment were HR 0.47 (95% CI 0.41–0.54, p < 0.0001) in heart failure hospitalization, HR 0.50 (95% CI 0.41–0.61, p < 0.0001) in acute coronary syndrome, HR 1.21 (95% CI 1.10–1.32, p < 0.0001) in ischemic stroke, and HR 0.49 (95% CI 0.44–0.55, p < 0.0001) in all-cause mortality.

          Conclusions

          In patients with T2DM, SGLT2i as first-line treatment may be associated with decreased events of heart failure hospitalization, acute coronary syndrome, and all-cause mortality, compared with metformin as first-line treatment. However, there may be an increased events of ischemic stroke using SGLT2i compared to metformin.

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          Most cited references36

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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
                victorcwu@hotmail.com
                Journal
                Cardiovasc Diabetol
                Cardiovasc Diabetol
                Cardiovascular Diabetology
                BioMed Central (London )
                1475-2840
                9 November 2020
                9 November 2020
                2020
                : 19
                : 189
                Affiliations
                [1 ]GRID grid.454209.e, ISNI 0000 0004 0639 2551, Department of Cardiology, , Keelung Chang Gung Memorial Hospital, ; Keelung, Taiwan
                [2 ]GRID grid.454211.7, ISNI 0000 0004 1756 999X, Division of Endocrinology and Metabolism, Department of Internal Medicine, , Linkou Chang Gung Memorial Hospital, ; Taoyuan, Taiwan
                [3 ]GRID grid.454211.7, ISNI 0000 0004 1756 999X, Department of Cardiothoracic and Vascular Surgery, , Linkou Chang Gung Memorial Hospital, ; Taoyuan, Taiwan
                [4 ]GRID grid.454212.4, ISNI 0000 0004 1756 1410, Department of Cardiology, , Chiayi Chang Gung Memorial Hospital, ; Chiayi, Taiwan
                [5 ]GRID grid.454209.e, ISNI 0000 0004 0639 2551, Department of Ophthalmology, , Keelung Chang Gung Memorial Hospital, ; Keelung, Taiwan
                [6 ]GRID grid.454211.7, ISNI 0000 0004 1756 999X, Division of Cardiology, , Linkou Medical Center, Linkou Chang Gung Memorial Hospital, ; No. 5, Fuxing Street, Guishan District, Taoyuan, 33305 Taiwan
                [7 ]GRID grid.40263.33, ISNI 0000 0004 1936 9094, Divison of Cardiovascular Medicine, Rhode Island Hospital, Warren Alpert School of Medicine, , Brown University, ; Providence, USA
                [8 ]GRID grid.454211.7, ISNI 0000 0004 1756 999X, Department of Nephrology, , Kidney Research Center, Linkou Chang Gung Memorial Hospital, ; Taoyuan, Taiwan
                Author information
                http://orcid.org/0000-0002-9918-4369
                Article
                1169
                10.1186/s12933-020-01169-3
                7654060
                33167990
                9cf12575-2687-4e2d-985b-0f8a545df933
                © The Author(s) 2020

                Open AccessThis 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/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 27 May 2020
                : 31 October 2020
                Funding
                Funded by: Chang Gung Memorial Hospital, Linkou (TW)
                Award ID: Keelung Chang Gung Memorial Hospital CGRD Research Grant.
                Award Recipient :
                Categories
                Original Investigation
                Custom metadata
                © The Author(s) 2020

                Endocrinology & Diabetes
                type 2 diabetes mellitus,sodium-glucose co-transporter 2 inhibitor,metformin,cardiovascular outcome

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