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      Effects of Sodium‐Glucose Cotransporter 2 Inhibitors on 24‐Hour Ambulatory Blood Pressure: A Systematic Review and Meta‐Analysis

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          Abstract

          Background

          Sodium‐glucose cotransporter 2 (SGLT2) inhibitors are a novel class of antihyperglycemic agents that improve glycemic control by increasing glycosuria. Additional benefits beyond glucose lowering include significant improvements in seated clinic blood pressure (BP), partly attributed to their diuretic‐like actions. Less known are the effects of this class on 24‐hour ambulatory BP, which is a better predictor of cardiovascular risk than seated clinic BP.

          Methods and Results

          We performed a meta‐analysis of randomized, double‐blind, placebo‐controlled trials to investigate the effects of SGLT2 inhibitors on 24‐hour ambulatory BP. We searched all studies published before August 17, 2016, which reported 24‐hour ambulatory BP data. Mean differences in 24‐hour BP, daytime BP, and nighttime BP were calculated by a random‐effects model. SGLT2 inhibitors significantly reduce 24‐hour ambulatory systolic and diastolic BP by −3.76 mm Hg (95% CI, −4.23 to −2.34; I 2=0.99) and −1.83 mm Hg (95% CI, −2.35 to −1.31; I 2=0.76), respectively. Significant reductions in daytime and nighttime systolic and diastolic BP were also found. No association between baseline BP or change in body weight were observed.

          Conclusions

          This meta‐analysis shows that the reduction in 24‐hour ambulatory BP observed with SGLT2 inhibitors is a class effect. The diurnal effect of SGLT2 inhibitors on 24‐hour ambulatory BP may contribute to their favorable effects on cardiovascular outcomes.

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          Most cited references33

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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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            Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes.

            Diabetes confers an increased risk of adverse cardiovascular and renal events. In the EMPA-REG OUTCOME trial, empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes at high risk for cardiovascular events. We wanted to determine the long-term renal effects of empagliflozin, an analysis that was a prespecified component of the secondary microvascular outcome of that trial.
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              Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications.

              Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by ≈5 mL·min(-1)·1.73 m(-2) and ≈30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate 30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis, such as the impact on blood pressure, heart failure, kidney protection, and mortality, will be a major management focus.
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                Author and article information

                Contributors
                dldixon@vcu.edu
                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                18 May 2017
                May 2017
                : 6
                : 5 ( doiID: 10.1002/jah3.2017.6.issue-5 )
                : e005686
                Affiliations
                [ 1 ] Department of Pharmacy Practice University of Connecticut School of Pharmacy Storrs CT
                [ 2 ] Department of Pharmacotherapy & Outcomes Science Virginia Commonwealth University School of Pharmacy Richmond VA
                [ 3 ] Department of Pharmacy Practice Chapman University School of Pharmacy Irvine CA
                [ 4 ] School of Nursing Virginia Commonwealth University Richmond VA
                [ 5 ] VCU Pauley Heart Center Virginia Commonwealth University Richmond VA
                [ 6 ] Department of Experimental Medicine Sapienza University of Rome Rome Italy
                Author notes
                [*] [* ] Correspondence to: Dave L. Dixon, PharmD, 410 N 12th St, P.O. Box 980533, Richmond, VA 23298‐0533. E‐mail: dldixon@ 123456vcu.edu
                Article
                JAH32250
                10.1161/JAHA.117.005686
                5524106
                28522675
                f59d33e7-e6a6-4b3d-b99b-32fe207b4093
                © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 27 January 2017
                : 12 April 2017
                Page count
                Figures: 9, Tables: 2, Pages: 12, Words: 5964
                Funding
                Funded by: American Heart Association
                Funded by: Janssen Pharmaceuticals
                Categories
                Systematic Review and Meta‐Analysis
                Systematic Review and Meta‐Analysis
                Custom metadata
                2.0
                jah32250
                May 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.3 mode:remove_FC converted:11.07.2017

                Cardiovascular Medicine
                ambulatory blood pressure monitoring,diabetes mellitus,diabetic therapy/glitazones,high blood pressure,hypertension,metformin,sodium‐glucose cotransporter 2 inhibitors,diabetes, type 2,meta analysis

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