Pharmacoépidémiologie et pharmacologie sociale des médicaments du diabète de type 2 : des données pharmacodynamiques de base à l'utilisation des bases de données. Etudes du risque de cancer de la vessie associé à la pioglitazone et du risque de pancréatite aigüe associé aux incrétinomimétiques

Notre travail est basé sur l'étude de deux événements indésirables associés à des médicaments du diabète de type 2. Premièrement, nous étudions le risque de cancer de la vessie lié à l'utilisation de la pioglitazone. Nous montrons que des erreurs dans la caractérisation de ses propriétés pharmacodynamiques, dans l'interprétation des données animales et dans le rapport de données d'un essai clinique ont pu retarder l'évaluation correcte de ce risque. La synthèse des résultats des différentes méthodes d'évaluation permet de montrer l'existence de ce risque. Deuxièmement, nous étudions la survenue de pancréatites aigues liées à l'utilisation des médicaments utilisant l'effet des incrétines (incrétinomimétiques). Après discussion des éléments pharmacodynamiques, nous présentons une étude réalisée à partir de la Base Nationale de Pharmacovigilance française et une étude de cohorte utilisant la base de données britannique du Clinical Practice Research Database dans laquelle risque de pancréatite aiguë associé à l'utilisation d'incrétinomimétique n'était pas été augmenté par rapport à l'utilisation de sulfonylurées. Nous montrons que l'évaluation du risque médicamenteux nécessite un faisceau d'argument issu de l'utilisation des multiples sources disponibles (données pharmacodynamiques de base, essais cliniques, études des bases de notifications spontanées et études observationnelles sur le médicament). L'analyse des limites méthodologiques et des limites liées aux facteurs sociaux impliqués nous permet de discuter l'évaluation du risque médicamenteux.In this thesis, we examine two adverse reactions associated with drugs used in type 2 diabetes. First, we study the risk of bladder cancer with the use of pioglitazone. We show that characterization of its pharmacodynamic properties, interpretation of animal data and results from a clinical trial were mistaken and could have delayed the correct assessment of this risk. The numerous observational studies are also discussed. The review of data from all assessment methods published during the last 15 years demonstrates the existence of this risk. Second, we study the occurrence of acute pancreatitis associated with incretin-based drugs. After discussing pharmacodynamic issues, we present a study showing a signal of pancreatitis associated with incretin-based drugs in the French National Pharmacovigilance Database. Then, the risk of acute pancreatitis was assessed in a cohort study from the UK Clinical Practice Research Database. Adjusted for several important cofactors, the use of incretin-based drugs was not associated with an increased risk of acute pancreatitis compared to sulfonylureas use. However, these results do not exclude potential chronic pancreatic inflammation or acute pancreatic adverse effects in the long term with incretin-based drugs. These examples allow us to emphasize the importance of basic pharmacodynamic data. We show that risk assessment needs the concordance of studies from all sources of data available (pharmacodynamics data, clinical trials, adverse events database studies and observational studies). We discuss the influence of methodological limits and limits related to social factors on the quality of drug risk studies

Diabetes Obes Metab

AIM: Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have been commercialized in France for type 2 diabetes since April 2020 and later for heart and renal diseases. Given the recent developments in treating diabetes and the widening of SGLT-2i indications, we aimed to study changes in the use of glucose-lowering drugs in France and to characterize SGLT-2i new users. METHODS: We performed a nationwide utilization study using the French health insurance database. Trends in incidence and prevalence of glucose-lowering drug use were assessed by a repeated cross-sectional study in 2019 and 2021. A cohort study of incident SGLT-2i users was then conducted to describe patient characteristics and the strategy for treating diabetes. RESULTS: The prevalence of SGLT-2i use gradually reached 0.1% in the third quarter of 2021 and increased more significantly to 0.2% thereafter. SGLT-2i became the second most prescribed glucose-lowering drug class after metformin at the end of 2021 (0.1%). Among the cohort of 125 387 SGLT-2i new users (mean age 65.0 years; 60.1% of men), 87.6% presented a diabetic comorbidity. The patient profile changed over the study period with an increasing proportion of patients with cardiovascular (28.7% in 2020 vs. 40.2% in 2021) or renal (7.7% in 2020 vs. 11.8% in 2021) comorbidities at initiation. The main combinations used at SGLT-2i initiation were metformin (12.5%) and metformin plus dipeptidyl peptidase-4 inhibitors (8.1%). One-year probability of SGLT-2i persistence was estimated to be 55%. CONCLUSION: The expansion of indications for SGLT-2i and the broadening of the target population make it essential to assess the reasons for discontinuation and review their safety profile

Long-term outcomes of CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) in a consecutive series of 12 patients.

BACKGROUND: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a central nervous system inflammatory disease. OBJECTIVE: To describe the disease course of CLIPPERS. DESIGN: A nationwide study was implemented to collect clinical, magnetic resonance imaging, cerebrospinal fluid, and brain biopsy specimen characteristics of patients with CLIPPERS. SETTING: Academic research. PATIENTS: Twelve patients with CLIPPERS. MAIN OUTCOME MEASURES: The therapeutic management of CLIPPERS was evaluated. RESULTS: Among 12 patients, 42 relapses were analyzed. Relapses lasted a mean duration of 2.5 months, manifested frequent cerebellar ataxia and diplopia, and were associated with a mean Expanded Disability Status Scale (EDSS) score of 4. Besides typical findings of CLIPPERS, magnetic resonance imaging showed brainstem mass effect in 5 patients, extensive myelitis in 3 patients, and closed ring enhancement in 1 patient. Inconstant oligoclonal bands were found on cerebrospinal fluid investigation in 4 patients, with an increased T-cell ratio of CD4 to CD8. Among 7 available brain biopsy specimens, staining was positive for perivascular CD4 T lymphocytes in 5 samples. Thirty-eight of 42 relapses were treated with pulse corticosteroid therapy, which led to improvement, with a mean residual EDSS score of 1.9 (range, 0-7). In 1 patient with untreated relapses, scores on the EDSS progressively increased to a score of 10 at death. Among 5 patients without long-term corticosteroid therapy, the mean annualized relapse rate was 0.5 (range, 0.25-2.8). Among 7 patients taking oral corticosteroids, no relapses occurred in those whose daily dose was 20 mg or higher. No progressive course of CLIPPERS was observed. Four patients with a final EDSS score of 4 or higher had experienced previous severe relapses (EDSS score, ≥5) and brainstem and spinal cord atrophy. CONCLUSIONS: CLIPPERS is a relapsing-remitting disorder without progressive forms. Long-term disability is correlated with the severity of previous relapses. Further studies are needed to confirm that prolonged corticosteroid therapy prevents further relapses.journal article2012 Julimporte

Harmonizing and improving European education in prescribing: An overview of digital educational resources used in clinical pharmacology and therapeutics

Aim: Improvement and harmonization of European clinical pharmacology and therapeutics (CPT) education is urgently required. Because digital educational resources can be easily shared, adapted to local situations and re-used widely across a variety of educational systems, they may be ideally suited for this purpose. Methods: With a cross-sectional survey among principal CPT teachers in 279 out of 304 European medical schools, an overview and classification of digital resources was compiled. Results: Teachers from 95 (34%) medical schools in 26 of 28 EU countries responded, 66 (70%) of whom used digital educational resources in their CPT curriculum. A total of 89 of such resources were described in detail, including e-learning (24%), simulators to teach pharmacokinetics and/or pharmacodynamics (10%), virtual patients (8%), and serious games (5%). Together, these resources covered 235 knowledge-based learning objectives, 88 skills, and 13 attitudes. Only one third (27) of the resources were in-part or totally free and only two were licensed open educational resources (free to use, distribute and adapt). A narrative overview of the largest, free and most novel resources is given. Conclusion: Digital educational resources, ranging from e-learning to virtual patients and games, are widely used for CPT education in EU medical schools. Learning objectives are based largely on knowledge rather than skills or attitudes. This may be improved by including more real-life clinical case scenarios. Moreover, the majority of resources are neither free nor open. Therefore, with a view to harmonizing international CPT education, more needs to be learned about why CPT teachers are not currently sharing their educational materials

EurOP2E – the European Open Platform for Prescribing Education, a consensus study among clinical pharmacology and therapeutics teachers

Purpose Sharing and developing digital educational resources and open educational resources has been proposed as a way to harmonize and improve clinical pharmacology and therapeutics (CPT) education in European medical schools. Previous research, however, has shown that there are barriers to the adoption and implementation of open educational resources. The aim of this study was to determine perceived opportunities and barriers to the use and creation of open educational resources among European CPT teachers and possible solutions for these barriers. Methods CPT teachers of British and EU medical schools completed an online survey. Opportunities and challenges were identified by thematic analyses and subsequently discussed in an international consensus meeting. Results Data from 99 CPT teachers from 95 medical schools were analysed. Thirty teachers (30.3%) shared or collaboratively produced digital educational resources. All teachers foresaw opportunities in the more active use of open educational resources, including improving the quality of their teaching. The challenges reported were language barriers, local differences, lack of time, technological issues, difficulties with quality management, and copyright restrictions. Practical solutions for these challenges were discussed and include a peer review system, clear indexing, and use of copyright licenses that permit adaptation of resources. Conclusion Key challenges to making greater use of CPT open educational resources are a limited applicability of such resources due to language and local differences and quality concerns. These challenges may be resolved by relatively simple measures, such as allowing adaptation and translation of resources and a peer review system

Les études cas–non cas : principe, méthodes, biais et interprétations

International audienceCase-non case studies belongs to the methods assessing drug safety by analyzing the disproportionality of notifications of adverse drug reactions in pharmacovigilance databases. Used for the first time in the 1980s, the last few decades have seen a significant increase in the use of this design. The principle of the case-non case study is to compare drug exposure in cases of a studied adverse reaction with that of cases of other reported adverse reactions and called "non cases". Results are presented in the form of a reporting odds ratio (ROR), the interpretation of which makes it possible to identify drug safety signals. This article describes the principle of the case-non case study, the method of calculating the ROR and its confidence interval, the different modalities of analysis and how to interpret its results with regard to the advantages and limitations of this design.Les études de type cas–non cas appartiennent aux méthodes ayant pour objectif d’évaluer la sécurité d’emploi des médicaments en analysant la disproportionnalité des notifications d’effets indésirables médicamenteux dans les bases de données de pharmacovigilance. Utilisé pour la première fois dans les années 1980, les dernières décennies ont vu une augmentation importante de l’utilisation de ce design d’étude. Le principe des études cas–non cas réside dans la comparaison de l’exposition médicamenteuse de cas d’un effet indésirable d’intérêt avec celle de cas ayant présenté d’autres effets et appelés « non cas ». Leurs résultats sont présentés sous la forme de reporting odds ratio (ROR) dont l’interprétation permet de mettre en évidence des signaux de pharmacovigilance. Cet article décrit le principe des études cas–non cas, la méthode de calcul du ROR et de son intervalle de confiance, les différentes modalités d’analyse et présente comment interpréter ses résultats au regard des avantages et des limites de ce type d’étude

Indication bias or protopathic bias?

International audienc

Surcharge pondérale des élèves de 6ème scolarisés en Languedoc-Roussillon (prévalence, évolution et facteurs associés)

MONTPELLIER-BU Médecine UPM (341722108) / SudocMONTPELLIER-BU Médecine (341722104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

DPP-4 inhibitors and severe course of illness in patients with COVID-19

International audienc