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GLP1 agonist receptor (GLP1ar) have shown cardiovascular benefits in patients with type 2 diabetes. However, potential serious adverse events have also been identified. The aim of this study is to assess their risk-benefit-ratio in patients with type 2 diabetes.

Essure® implant is a permanently implanted minimally invasive birth control device for women (female sterilisation) widely used between 2002 and 2018. Many adverse events were reported by patients. Increasingly removal procedures have been performed in symptomatic patients. However, there is a lack of in-depth studies on clinical improvement after Essure® removal. We aimed to review all clinical studies about symptoms and quality of life (QoL) after removal procedures. A review of literature in electronic search in Medline and Embase databases from January 2002 to January 2022 using the following keywords: Essure; Essure removal; quality of life; symptomatology improvement. Out of 764 articles in the initial database, 18 clinical studies were eligible for inclusion in our literature review. Overall clinical improvement rates after removal ranged from 21% to 98%. All symptoms were less frequent after Essure® removal, although with large discrepancies between studies. Lack of improvement was reported between 1% to 15% of patients. Rate of patients with improvement of QoL after removal ranged from 58 to 98%. The pain was reported as significantly reduced after the surgery. In the available literature, Essure® removal in symptomatic patients may improve symptoms and quality of life. This should be discussed in the benefits and risks ratio before deciding on the best option of management. Essure® removal in symptomatic patients may improve symptoms and quality of life.

Rationale A patient presented an orellanian syndrome which required dialysis, followed by a myocarditis a month later. The MRI showed a typical toxic pattern, while the diagnostic workup excluded any other possible cause. The aim of the present work is to review the acute cardiotoxicity induced by mushroom poisoning. Methods We searched MEDLINE and Embase for articles published before the 19/10/21 whose title or abstract included keywords related to mushrooms and cardiac injury. Studies on humans redacted in English or French were included. The main aim of the review was to estimate the prevalence of cardiac complications among reported intoxications. Causal imputation and the Poisoning Severity Score (PSS) were calculated for each study which provided sufficient individual data. Mushroom identification was registered when available. A sensibility analysis of cardiac injury prevalence, PSS and involved mushroom species was conducted on cases adjudicated at least with a “likely” (3/4) on the causal imputation scale.

Sodium Glucose Transporter 2 inhibitors (SGLT2i) have shown cardiovascular benefits in patients with type 2 diabetes. However, potential serious adverse events have also been identified. The aim of this study is to assess the benefit-risk balance of SGLT2i in patients with type 2 diabetes.

Ordinal scales of clinical status and viral load as surrogates of mortality and disease worsening in COVID-19, an aggregate data meta-analysis

Different approaches can be used to estimate individualized treatment effects with Individual Participant Data Meta-Analyses (IPD-MA). We compared four one-stage models: random effects (RE), stratified intercept (SI), rank-1 (R1) and fully stratified (FS) models, built with two different strategies constructed with a Monte Carlo simulation study in which we explored different scenarios with a binary or a time-to-event outcome. To evaluate the performance of the models, we used the c-statistic for benefit, the calibration of predictions and the mean squared error. The different models were also used on the INDANA IPD-MA, comparing an anti-hypertensive treatment to no treatment or placebo (N = 40 237, 836 events). Simulation results showed that the random effects and the stratified intercept models performed well for both binary and time-to-event outcomes. For the INDANA dataset with a binary outcome, the random effects model had the best performance.

Evidence based medicine requires randomized clinical trials for estimating a mean treatment effect. The personalization of this treatment effect needs prognostic biomarker for assessing the spontaneous risk of the disease and the absolute benefit of the treatment; and the search for potential theranostic biomarker, associated with a different relative treatment effect. Surrogate endpoints are also proposed, as their measure would reflect the treatment effect on the clinical outcome of interest. Taking care of patients with type 2 diabetes is based on hypoglycemic drugs. Several of them have been retrospectively associated with serious adverse events. They need to be assessed with cardiovascular outcome trials. Taking care of those patients also include handling other cardiovascular risk factor, as high blood pressure. Antihypertensive treatment is based on a “target to treat” strategy, which raise several questions. Finally, many theranostic biomarkers of the hypoglycemic drugs effect have been studied, with conflicting results. Statistical power is a high challenge in randomized trial looking for such interaction. We aimed to provide a mean treatment effect estimation of hypoglycemic drugs on cardiovascular outcomes and to explore potential tools for personalizing the treatment effect estimation. The first part of this thesis reports a network meta-analysis assessing the contemporary hypoglycemic drugs in type 2 diabetes patients on overall mortality, cardiovascular mortality and major adverse cardiovascular events. We confirmed the superiority of SGLT2 inhibitors and of GLP1 receptor agonists compared to control and to DPP4 inhibitors. We also showed the need for direct comparison, especially for clarifying the position of metformin in the pharmacological strategy. The second part of this thesis reports a meta-regression analysis, assessing the association between the decrease in blood pressure through antihypertensive drugs and the risk of cardiovascular events. We confirmed the association between the blood pressure control and the risk of stroke, but did not find any association regarding overall mortality, cardiovascular mortality and myocardial infarction. The third part reports a statistical comparison of the parallel group design and the cross-over design, regarding their capacity to assess a potential theranostic biomarker. We showed that the advantage of the cross-over for reducing the sample size lead on the intra-subject correlation, as already known for estimating the treatment effect. Finally, we highlighted the need for comparisons of hypoglycemic drugs for preventing macrovascular events. We emphasized pitfalls in estimating benefit—risk balance. Individual patient data meta-analyses would help better assessing the effect of glucose control on macrovascular events. High-throughput genome sequencing technologies would help to identify both prognostic and theranostic biomarkers. Lastly, we proposed an extended version of the effect model, which allow to grasp the benefit—risk balance of a treatment, according to different biomarkers. To conclude, assessing a mean and a stratified treatment effect should be conducted taking into account the global benefit—risk balance estimation; La médecine basée sur les preuves requiert des essais cliniques randomisés, qui permettent d'estimer un effet moyen du traitement. La personnalisation de l'estimation de l'effet du traitement nécessite l'estimation du risque spontané de la maladie (biomarqueur pronostique), la recherche de facteurs modifiant l'effet du traitement (biomarqueur théranostique). Des critères de substitution sont également proposés, dont la mesure devrait permettre d'évaluer l'effet du traitement sur l'événement clinique. La prise en charge des patients présentant un diabète de type 2 repose sur les médicaments hypoglycémiants. Plusieurs d'entre eux ont été associés à différents effets indésirables graves. Des études évaluant leur bénéfice cardiovasculaire sont nécessaires. La prise en charge de ces patients inclue également la prise en charge de l'hypertension artérielle. Celle-ci est basée sur des médicaments antihypertenseurs, dont l'intensité est ajustée au niveau de pression artérielle recherché. Cette stratégie basée sur la cible soulève plusieurs questions. Enfin, plusieurs biomarqueurs prédictifs de différents effets des médicaments hypoglycémiants ont été étudiés chez des patients présentant un diabète de type 2, avec des résultats contrastés. Une difficulté majeure dans la validation de biomarqueur théranostique est la puissance statistique nécessaire pour détecter une interaction dans un essai clinique randomisé. L'objectif de cette thèse était d'estimer les effets moyens des traitements hypoglycémiants sur les complications cardiovasculaires ; d'évaluer un potentiel critère de substitution ; et d'étudier les caractéristiques des études cliniques évaluant des biomarqueurs théranostiques. La première partie présente une méta-analyse en réseaux comparant les effets des hypoglycémiants contemporains chez des patients avec un diabète de type 2, sur la mortalité totale, cardiovasculaire et les évènements cardiovasculaires majeurs. Nous avons confirmé la supériorité des gliflozines et des agonistes du récepteur au GLP1 par rapport au traitement contrôle et aux inhibiteurs de la DPP4. Nous avons montré le besoin de comparaisons directes entre les différentes classes, notamment pour préciser la place de la metformine dans la stratégie thérapeutique. La deuxième partie présente une méta-régression évaluant l'association entre la diminution de la pression artérielle par des médicaments antihypertenseurs et les évènements cardiovasculaires majeurs. Nous avons confirmé la relation entre la baisse de la pression artérielle et le risque d'accident vasculaire cérébrale. Il n'y avait pas d'association avec la mortalité totale, la mortalité cardiovasculaire, les infarctus du myocarde. La troisième partie présente une comparaison statistique du plan expérimental en cross-over par rapport au plan en bras parallèle, concernant leur capacité à évaluer un marqueur théranostique. Nous avons montré que l'intérêt du cross-over, pour réduire le nombre de sujet nécessaire, dépend de la corrélation intra-sujet de la mesure du critère de jugement choisi, de façon similaire à l'estimation de l'effet propre du traitement. Ce travail met en lumière le besoin de comparaisons des médicaments hypoglycémiants sur les complications cardiovasculaires, et la difficulté d'évaluer une balance bénéfice—risque d'un traitement. Des approches de méta-analyses sur données individuelles permettraient de mieux estimer l'impact du contrôle glycémique sur les complications cardiovasculaires. L'accès aux technologies de séquençage du génome à haut débit permettrait d'identifier des facteurs pronostiques et théranostiques. Finalement, nous proposons une extension du modèle d'effet, qui permet d'appréhender la balance bénéfice—risque d'un traitement en fonction de différents biomarqueurs. L'évaluation d'un effet traitement moyen ou stratifié doit s'inscrire dans une vision globale de la balance bénéfice—risque du médicament concerné