Pharmaceutical oral safety evaluation adopting pharmacoepidemiology standards and genetic epidemiology

• Applicant: Professor Dr. Sebastian-Edgar Baumeister
• Subject Area: Dentistry, Oral Surgery
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 552087827

With increasing parts of the population being in middle and older ages, many people live with multiple chronic conditions requiring drug therapy. As multimorbidity and polypharmacy are becoming pervasive in healthcare systems, drug regulators request post-marketing pharmacovigilance for drugs on the market. However, drug safety investigations often neglect oral diseases. To date, there is only weak evidence for adverse side effects on the oral cavity because the available observational pharmacoepidemiological studies are prone to bias due to inappropriate study design and statistical analysis. Our objective is to generate reliable evidence on three oral drug safety issues: (1) Do thiazide diuretics increase the risk of dental caries? (2) Do non-steroidal anti-inflammatory drugs have adverse effects on periodontitis and oral lichen planus? (3) Are systemic and inhaled glucocorticoids modifiers of periodontitis risk? We design prospective studies as target emulations of hypothetical pragmatic randomized trials using data from the All of US cohort study. Extensive bias analyses are applied to examine how sensitive trial emulation estimates are to unobserved confounding and selection bias. We triangulate the results of the target trial emulations using instrumental variable analyses. Mendelian randomization is employed to proxy pharmacologically induced regulation of gene expression and other downstream biomarkers. Genetic instruments are selected using genome-wide association studies (GWAS) of gene expression in blood and systolic blood pressure. Genetic associations for dental caries, periodontitis, and lichen planus are derived from GWAS. Consistent results from target trial emulations and instrumental variable studies will provide important insights into the oral side effects of the widely used medications, leading to stronger evidence that can be used to inform warning systems and treatment guidelines.

• DFG Programme: Research Grants