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      Authors’ Reply to the Letter by Shoar et al. on “Glycosylated Hemoglobin as a Surrogate for the Prevention of Cardiovascular Events in Cardiovascular Outcome Trials Comparing New Antidiabetic Drugs to Placebo”

      a , b , * , a , a , c


      S. Karger AG

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          Lifestyle, Glycosylated Hemoglobin A1c, and Survival Among Patients With Stable Ischemic Heart Disease and Diabetes

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            Prognostic value of HbA1c for in-hospital and short-term mortality in patients with acute coronary syndrome: a systematic review and meta-analysis

            Background HbA1c, the most commonly used indicator of chronic glucose metabolism, is closely associated with cardiovascular disease. However, the relationship between HbA1c and the mortality of acute coronary syndrome (ACS) patients has not been elucidated yet. Here, we aim to conduct a systematic review assessing the effect of HbA1c on in-hospital and short-term mortality in ACS patients. Methods Relevant studies reported before July 2019 were retrieved from databases including PubMed, Embase, and Central. Pooled relative risks (RRs) and the corresponding 95% confidence interval (CI) were calculated to evaluate the predictive value of HbA1c for the in-hospital mortality and short-term mortality. Results Data from 25 studies involving 304,253 ACS patients was included in systematic review. The pooled RR of in-hospital mortality was 1.246 (95% CI 1.113–1.396, p: 0.000, I2 = 48.6%, n = 14) after sensitivity analysis in studies reporting HbA1c as categorial valuable. The pooled RR was 1.042 (95% CI 0.904–1.202, p: 0.57, I2 = 82.7%, n = 4) in random-effects model for studies reporting it as continuous valuable. Subgroup analysis by diabetic status showed that elevated HbA1c is associated increased short-term mortality in ACS patients without diabetes mellitus (DM) history and without DM (RR: 2.31, 95% CI (1.81–2.94), p = 0.000, I2 = 0.0%, n = 5; RR: 2.56, 95% CI 1.38–4.74, p = 0.003, I2 = 0.0%, n = 2, respectively), which was not the case for patients with DM and patients from studies incorporating DM and non-DM individuals (RR: 1.16, 95% CI 0.79–1.69, p = 0.451, I2 = 31.9%, n = 3; RR: 1.10, 95% CI 0.51–2.38), p = 0.809, I2 = 47.4%, n = 4, respectively). Conclusions Higher HbA1c is a potential indicator for in-hospital death in ACS patients as well as a predictor for short-term mortality in ACS patients without known DM and without DM.
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              Glycosylated Hemoglobin as a Surrogate for the Prevention of Cardiovascular Events in Cardiovascular Outcome Trials Comparing New Antidiabetic Drugs to Placebo

               Pierre Ambrosi (corresponding) ,  Aurélie Daumas,  Patrick Villani (2020)
              Background and Objectives: The value of glycosylated hemoglobin (HbA1c) as a surrogate marker for the prevention of cardiovascular outcomes on antidiabetic drugs is debated. The 2008 FDA guidance led to multiple large clinical trials to evaluate the effect of new antidiabetic drugs versus placebo on major adverse cardiac events (MACE). The aim of this study was to evaluate the relation between MACE and HbA1c decrease between antidiabetic drug and placebo across the spectrum of cardiovascular outcome trials (CVOT). Methods: In this systematic review, we included randomized controlled trials that compared an antidiabetic drug to placebo in addition to current standard of care with the primary intention of demonstrating cardiovascular safety. We investigated the relationship between MACE decrease on antidiabetic drug and HbA1c reduction on antidiabetic drug using the coefficient correlation. We also studied the effects of potential confounders on MACE decrease. Results: Fourteen eligible trials including 128,149 patients were included, 12,114 of whom experienced MACE. Mean achieved HbA1c absolute reductions on antidiabetic treatment versus placebo varied from 0.29 to 1%. The decrease of MACE on antidiabetic drug was significantly correlated with mean HbA1c reduction ( r = 0.88, 95% CI: 0.67–0.96, p < 0.001) and weight loss ( r = 0.81, 95% CI: 0.46–0.94, p < 0.001). In a bivariate model including weight loss, only HbA1c reduction remained significantly correlated with the decrease of MACE on antidiabetic drug ( p = 0.019). Conclusion: Across CVOT, the decrease in MACE incidence on various antidiabetic drugs is significantly correlated with HbA1c reduction. This meta-analysis supports HbA1c as an appropriate surrogate endpoint for cardiovascular events. Our analysis supports that changes in HbA1c should be taken into account while interpreting effects of new antidiabetic drugs on cardiovascular outcomes.

                Author and article information

                S. Karger AG
                June 2020
                08 May 2020
                : 145
                : 6
                : 387
                aDepartment of Therapeutics, Hôpital de la Timone, Marseille, France
                bDepartment of Cardiology, Hôpital de la Timone, Marseille, France
                cAix Marseille Univ, APHM, INSERM, IRD, SESSTIM, Sciences Economiques et Sociales de la Santé et Traitement de l’Information Médicale, Hop Timone, BioSTIC, Biostatistique et Technologies de l’Information et de la Communication, Marseille, France
                Author notes
                *Pierre Ambrosi, Department of Cardiology, Hôpital de la Timone, Rue Saint-Pierre, FR–13385 Marseille (France),
                507361 Cardiology 2020;145:387
                © 2020 S. Karger AG, Basel

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                Page count
                Pages: 1
                Cardiovascular Prevention: Reply

                General medicine, Neurology, Cardiovascular Medicine, Internal medicine, Nephrology


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