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Assessment of Cardiovascular Effects of Non-Insulin Blood-Glucose-Lowering Agents Nelly Herrera Comoglio

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Assessment of cardiovascular effects of non-insulin blood-glucose-lowering agents Nelly Herrera Comoglio To cite this version: Nelly Herrera Comoglio. Assessment of cardiovascular effects of non-insulin blood-glucose-lowering agents. Human health and pathology. Université de Bordeaux, 2019. English. NNT : 2019BORD0355. tel-02969556 HAL Id: tel-02969556 https://tel.archives-ouvertes.fr/tel-02969556 Submitted on 16 Oct 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE PRÉSENTÉE POUR OBTENIR LE GRADE DE DOCTEUR DE L’UNIVERSITÉ DE BORDEAUX ÉCOLE DOCTORALE SPÉCIALITÉ PHARMACOÉPIDEMIOLOGIE Option Pharmaco-épidémiologie, pharmaco-vigilance Par Nelly Raquel HERRERA COMOGLIO TITRE : ÉVÉNEMENTS CARDIOVASCULAIRES MAJEURS ET MORTALITÉ EN PATIENTS TRAITÉS AVEC DES HYPOGLYCÉMIANTS NON INSULINIQUES Étude de cohortes basée sur une population de Catalogne, Espagne Sous la direction de : Xavier VIDAL GUITART Soutenue le 17 Décembre 2019 Membres du jury : Mme. AGUSTI ESCASANY, Antonia Prof. Fundacio Institut Catala de Farmacologia Président, rapporteur Mme. BOSCH Montserrat Prof. Associée Fundacio Institut Catala de Farmacologia Examinateur M. SALVO, Francesco Prof. Université de Bordeaux Examinateur Titre : ÉVÉNEMENTS CARDIOVASCULAIRES MAJEURS ET MORTALITÉ EN PATIENTS TRAITÉS AVEC DES HYPOGLYCÉMIANTS NON INSULINIQUES Étude de cohortes basée sur une population de Catalogne, Espagne Résumé : Le diabète mellitus Type 2 (DMT2) est une maladie chronique et progressive causée par multiples facteurs. Plus de 422 millions de personnes dans tout le monde ont diabète; la maladie a un profond impact social et économique. La maladie cardiovasculaire est la cause principale de la morbilité et la mortalité chez les patients diabetiques, qui ont des taux de mortalité plues élévées que la population non-diabétique. La définition de la DMT2 est basée sur ses manifestations métaboliques – surtout celles de glucose sanguin – qui servent comme marqueurs du contrôle et de l’évolution de la maladie. Cependant, tandis qu’on reconnait l’effet du contrôle de la glucose sanguin sur les complications microvasculaires, son impact sur les complications macrovasculaires ne sont pas clairs. Depuis 2008, les nouveaux agents hypoglycémiants doivent démontrer leur sécurité cardiovasculaire, soit à travers d’une meta-analyse ou d’essais cliniques évaluant les résultat cliniques cardiovasculaires; quelques nouveaux agents ont montré une réduction des effets cliniques (comme infarctus du myocarde et accident cérébro- vasculaire) et de la mortalité. Toutefois, les populations qui faisaient partie de ces essais cliniques a grande échelle ont différences avec la population générale; donc, les résults de ces essais ne sont pas completement généralisables. Tandis que les essais cliniques randomisés sont toujours considérés le “gold- standard” pour la génération de l’évidence scientifique, les études observationelles qui sont fait à partir de grande bases de données utilisés pour d’autre propos, dites “secondaires”, sont de plus en plus utilisées pour la génération de l’évidence scientifique complémentaire ou confirmatoire de celle provenant des essais cliniques, surtout quand ces essais ne sont pas disponibles ou sont impracticables. Ce travail montre les résultats d’une étude observationnelle de cohortes, basée sur la population enregistrée en SIDIAP, une large base de données des médecins généraux de Catalogne, qui reccueil les régistres de plus de 5,5 millions de personnes. Les évenements cliniques cardiovasculares et la mortalité ont été évalués dans la population générale, non-sélectionnée, traitée avec des agents hypoglycémiants non-insuliniques. On attend que les résultats de cette investigation soient útiles pour la prise de decisions, tant au niveau des cliniciens comme au niveau de la santé publique. Mots clés : événements cardiovasculaires majeurs ; mortalité ; diabete mellitus type 2 ; hypoglycémiants non-insuliniques Title: Assessment of cardiovascular effects of non-insulin blood-glucose-lowering agents Cardiovascular outcomes and mortality in Type 2 diabetes mellitus patients treated with non-insulin blood glucose-lowering drugs in Catalonia: a six-year retrospective population-based cohort study Abstract : Type 2 diabetes mellitus (T2DM) is a multifactorial, chronic, progressive disease, affecting more than 422 million people over the world, and having a significant societal and economic impact. Cardiovascular disease is the leading cause of morbidity and mortality in T2DM patients, who have higher rates of mortality than the non-diabetic population. T2DM is defined by its metabolic -mainly glucose-related- manifestations which serve as markers for controlling the evolution of disease. However, while the effect of control serum glucose levels on microvascular complications is acknowledged, its impact on macrovascular complications remains uncertain. Since 2008, new blood glucose-lowering agents have to demonstrate cardiovascular safety, and some have shown to reduce cardiovascular outcomes and mortality. However, the populations included in these large cardiovascular outcome trials differ from the general population, making results no fully generalisable. While randomised controlled trials are the gold standard for generating scientific evidence, observational studies conducted with secondary data of Electronic medical records (EMRs) are increasingly used as a source of complementary or confirmatory evidence, especially when RCTs are not feasible or unavailable. This work report an observational, population-based cohort study conducted in SIDIAP, a large Catalan general practitioners database that contains health data of 5,5 million people. We assessed cardiovascular outcomes and mortality in general, unselected T2DM population treated with non-insulin blood-glucose-lowering agents. The results are expected to be useful both for clinical and public health decision-making. Keywords : cardiovascular outcomes ; mortality ; Type 2 diabetes mellitus ; non- insulin blood-glucose-lowering agents Unité de recherche Institut Catala de Farmacologia European Programme de Pharmacovigilance and Pharmacoepidemiology PhD Thesis Assessment of cardiovascular effects of non-insulin blood glucose-lowering agents Cardiovascular outcomes and mortality in Type 2 diabetes mellitus patients treated with non-insulin blood glucose-lowering drugs in Catalonia: a six-year retrospective population-based cohort study. PhD candidate Nelly Raquel Herrera Comoglio Prof. Xavier Vidal Guitart Director Universitat Autonoma de Barcelona, Spain Supervisors Prof. Antonia Agusti Prof. Montserrat Bosch Plenary Doctoral Committee Prof. Antonia Agusti President of Jury Prof. Montserrat Bosch Prof. Francesco Salvo Year: 2019 Bordeaux, France. PhD Thesis Assessment of cardiovascular effects of non- insulin blood glucose-lowering agents Cardiovascular outcomes and mortality in Type 2 diabetes mellitus patients treated with non-insulin blood glucose-lowering drugs in Catalonia: a six-year retrospective population-based cohort study PhD candidate Nelly Raquel Herrera Comoglio Director Prof. Xavier Vidal Guitart Fundacio lnstitut Catala de Farmacología Universitat Autonoma de Barcelona, Spain Supervisors Prof. Antonia Agusti Fundacio lnstitut Catala de Farmacología Prof. Montserrat Bosch Fundacio lnstitut Catala de Farmacología Plenary Doctoral Committee President of Jury: Prof. Antonia Agusti Prof. Montserrat Bosch Prof. Francesco Salvo Université de Bordeaux Year: 2019 Bordeaux, France Declaration of good academic conduct “I Nelly Raquel HERRERA COMOGLIO, hereby certify that this dissertation, Which is 47,571 words in length, has been written by me’that it is a record ofwork carried out by me, and that it has not been submitted in any previous application for a higher degree. All sentences or passages quoted in this dissertation from other people’s work (with or without trivial changes) have been placed within quotation marks, and specifically acknowledged by reference to the author, WOrk and page. I understand that plagiarism - the unacknowledged use of such passages - Will be considered grounds for fail皿e in this dissertation and in the degree prograITme aS a Whole. I also a触m that’Wi血the exception of the specific acknowledgements, the following dissertation is entirely my own work.一一 Signature of the Acknowledgements To the thesis director, Prof. Xavier Vidal, who was always present and supported all the instances of this project, since its early beginnings to the final result. To the director of Catalan Institut of Pharmacology, Prof. Albert Figueras, to all the team of professionals and its founder, Prof. Joan-Ramon Laporte, for the permanent contribution to the education and investigation in Pharmacoepidemiology in Spain and Latin-American countries. To the members of Institut Jordi Gol, for the participation in this research iv Table of contents Abstract x Abbreviations xii Part I Background 1 I Introduction 2 II Cardiovascular Outcomes trials assessing the effect of non-insulin blood-glucose-lowering
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