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      Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs : The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)

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          Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) empagliflozin in patients with type 2 diabetes mellitus who have atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose-lowering drugs in 6 countries to determine if these benefits are seen in real-world practice and across SGLT-2i class.


          Data were collected via medical claims, primary care/hospital records, and national registries from the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios for HHF, death, and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany.


          After propensity matching, there were 309 056 patients newly initiated on either SGLT-2i or other glucose-lowering drugs (154 528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42%, and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteristics were balanced between the 2 groups. There were 961 HHF cases during 190 164 person-years follow-up (incidence rate, 0.51/100 person-years). Of 215 622 patients in the United States, Norway, Denmark, Sweden, and the United Kingdom, death occurred in 1334 (incidence rate, 0.87/100 person-years), and HHF or death in 1983 (incidence rate, 1.38/100 person-years). Use of SGLT-2i, versus other glucose-lowering drugs, was associated with lower rates of HHF (hazard ratio, 0.61; 95% confidence interval, 0.51–0.73; P<0.001); death (hazard ratio, 0.49; 95% confidence interval, 0.41–0.57; P<0.001); and HHF or death (hazard ratio, 0.54; 95% confidence interval, 0.48–0.60; P<0.001) with no significant heterogeneity by country.


          In this large multinational study, treatment with SGLT-2i versus other glucose-lowering drugs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of patients with type 2 diabetes mellitus in real-world practice.

          Clinical Trial Registration:

          URL: Unique identifier: NCT02993614.

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          Most cited references 39

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          Meta-analysis in clinical trials.

          This paper examines eight published reviews each reporting results from several related trials. Each review pools the results from the relevant trials in order to evaluate the efficacy of a certain treatment for a specified medical condition. These reviews lack consistent assessment of homogeneity of treatment effect before pooling. We discuss a random effects approach to combining evidence from a series of experiments comparing two treatments. This approach incorporates the heterogeneity of effects in the analysis of the overall treatment efficacy. The model can be extended to include relevant covariates which would reduce the heterogeneity and allow for more specific therapeutic recommendations. We suggest a simple noniterative procedure for characterizing the distribution of treatment effects in a series of studies.
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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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              External review and validation of the Swedish national inpatient register

              Background The Swedish National Inpatient Register (IPR), also called the Hospital Discharge Register, is a principal source of data for numerous research projects. The IPR is part of the National Patient Register. The Swedish IPR was launched in 1964 (psychiatric diagnoses from 1973) but complete coverage did not begin until 1987. Currently, more than 99% of all somatic (including surgery) and psychiatric hospital discharges are registered in the IPR. A previous validation of the IPR by the National Board of Health and Welfare showed that 85-95% of all diagnoses in the IPR are valid. The current paper describes the history, structure, coverage and quality of the Swedish IPR. Methods and results In January 2010, we searched the medical databases, Medline and HighWire, using the search algorithm "validat* (inpatient or hospital discharge) Sweden". We also contacted 218 members of the Swedish Society of Epidemiology and an additional 201 medical researchers to identify papers that had validated the IPR. In total, 132 papers were reviewed. The positive predictive value (PPV) was found to differ between diagnoses in the IPR, but is generally 85-95%. Conclusions In conclusion, the validity of the Swedish IPR is high for many but not all diagnoses. The long follow-up makes the register particularly suitable for large-scale population-based research, but for certain research areas the use of other health registers, such as the Swedish Cancer Register, may be more suitable.

                Author and article information

                Lippincott Williams & Wilkins
                18 July 2017
                18 May 2017
                : 136
                : 3
                : 249-259
                From Saint Luke’s Mid America Heart Institute and University of Missouri–Kansas City (M.K.); University of North Carolina, Chapel Hill (M.A.C.); Georgetown University Medical Center, Washington, DC (A.Z.F.); University of Liverpool, United Kingdom (J.P.W.); University of Leicester, United Kingdom (K.K.); University of Ulm, Germany (R.W.H.); Karolinska Institutet, Stockholm, Sweden (A.N., N.H.); University of Oslo, Norway (K.I.B.); Oslo University Hospital, Norway (K.I.B.); Steno Diabetes Center, Copenhagen, Gentofte, Denmark (M.E.J.); National Institute of Public Health, Southern Denmark University, Copenhagen (M.E.J.); Statisticon AB, Uppsala, Sweden (M.T.); AstraZeneca, Gaithersburg, MD (N.A.); AstraZeneca, Oslo, Norway (J.B.); AstraZeneca Gothenburg, Sweden (N.H.); and AstraZeneca, Cambridge, United Kingdom (P.F.).
                Author notes
                Correspondence to: Mikhail Kosiborod, MD, Saint Luke’s Mid America Heart Institute, 4401 Wornall Rd, Kansas City, MO, 64111. E-mail mkosiborod@
                © 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 License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.

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