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      Cardiovascular Outcomes and Risks After Initiation of a Sodium Glucose Cotransporter 2 Inhibitor : Results From the EASEL Population-Based Cohort Study (Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter 2 Inhibitors in the Real World)

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          Abstract

          Supplemental Digital Content is available in the text.

          Abstract

          Background:

          Clinical trials have shown cardiovascular benefits and potential risks from sodium glucose cotransporter 2 inhibitors (SGLT2i). Trials may have limited ability to address individual end points or safety concerns.

          Methods:

          We performed a population-based cohort study among patients with type 2 diabetes mellitus with established cardiovascular disease newly initiated on antihyperglycemic agents within the US Department of Defense Military Health System between April 1, 2013, and December 31, 2016. Incidence rates, hazard ratios (HRs), and 95% confidence intervals (CIs) for time to first composite end point of all-cause mortality and hospitalization for heart failure event, major adverse cardiovascular events (defined as all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke), and individual end points were evaluated using conditional Cox models comparing new SGLT2i users with other antihyperglycemic agents. The exploratory safety end point was below-knee lower extremity amputation. Intent-to-treat and on-treatment analyses were performed.

          Results:

          After propensity matching, 25 258 patients were followed for a median of 1.6 years. Compared with non-SGLT2i, initiation of SGLT2i was associated with a lower rate of all-cause mortality and hospitalization for heart failure (1.73 versus 3.01 events per 100 person-years; HR, 0.57; 95% CI, 0.50–0.65) and major adverse cardiovascular events (2.31 versus 3.45 events per 100 person-years; HR, 0.67; 95% CI, 0.60–0.75). SGLT2i initiation was also associated with an ≈2-fold higher risk of below-knee lower extremity amputation (0.17 versus 0.09 events per 100 person-years; HR, 1.99; 95% CI, 1.12–3.51). Because of the disproportionate canagliflozin exposure in the database, the majority of amputations were observed on canagliflozin. Results were consistent in the on-treatment analysis.

          Conclusions:

          In this high-risk cohort, initiation of SGLT2i was associated with lower risk of all-cause mortality, hospitalization for heart failure, and major adverse cardiovascular events and higher risk of below-knee lower extremity amputation. Findings underscore the potential benefit and risks to be aware of when initiating SGLT2i. It remains unclear whether the below-knee lower extremity amputation risk extends across the class of medication, because the study was not powered to make comparisons among individual treatments.

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          Most cited references 27

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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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            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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              The Central Role of the Propensity Score in Observational Studies for Causal Effects

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                Author and article information

                Journal
                Circulation
                Circulation
                CIR
                Circulation
                Lippincott Williams & Wilkins
                0009-7322
                1524-4539
                3 April 2018
                03 April 2018
                : 137
                : 14
                : 1450-1459
                Affiliations
                [1 ]Department of Medicine, Cardiovascular Division, Peter Munk Cardiac Centre, Toronto General Hospital and Women’s College Hospital, University of Toronto, Canada (J.A.U.)
                [2 ]Janssen Research & Development, LLC, Titusville/Raritan, NJ (Z.Y., N.R.)
                [3 ]Health ResearchTx, LLC, Trevose, PA (T.R., N.M.S.)
                [4 ]Naval Medical Center, Portsmouth, VA (M.G.)
                Author notes
                Jacob A. Udell, MD, MPH, Cardiovascular Division, Peter Munk Cardiac Centre, Toronto General Hospital and Women’s College Hospital, University of Toronto, 76 Grenville St, Toronto, Ontario, M5S 1B1, Canada. E-mail jay.udell@ 123456utoronto.ca
                Article
                00005
                10.1161/CIRCULATIONAHA.117.031227
                5895161
                29133607
                © 2017 The Authors.

                Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.

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