Hepatic pharmacoepidemiology

There is a major interplay between pharmacotherapy and the liver. On one hand, medications can affect liver function, for example through drug-induced liver injury. On the other hand, liver function can affect the metabolism and elimination of medications and thus their effectiveness and safety. However, patients with liver disease are underrepresented in randomized trials, the gold standard when it comes to the assessment of drug efficacy. Moreover, randomized trials often lack the necessary sample size to assess the risk of drug-induced liver injury. Therefore, pharmacoepidemiologic studies can provide needed evidence on the hepatotoxic risk of medications and on the effectiveness and safety of medications among patients with underlying liver disease.

In the past, we have studied the hepatotoxic risk of a wide range of medications including both prescribed and over-the-counter compounds. We have also studied the effectiveness and safety of direct oral anticoagulants (DOACs) among patients with non-valvular atrial fibrillation and liver disease in a project funded by the Canadian Institutes of Health Research. Currently, our work focuses on the effectiveness and safety of other cardiovascular medications among patients with liver disease and specifically metabolic-dysfunction associated steatotic liver disease and liver cirrhosis.

Selected publications

• Effectiveness and safety of direct oral anticoagulants among patients with non-valvular atrial fibrillation and liver disease: A multinational cohort study. Douros A, Cui Y, Platt RW, Filion KB, Sebastiani G, Renoux C. Thromb Res. 2024 May;237:71-78.
• Non-Vitamin K Antagonist Oral Anticoagulants and Risk of Serious Liver Injury. Douros A, Azoulay L, Yin H, Suissa S, Renoux C. J Am Coll Cardiol. 2018 Mar 13;71(10):1105-1113.

Geriatric pharmacoepidemiology

Older adults have distinct pharmacologic properties compared to younger adults, with changes involving decreased first-pass effect and subsequent drug metabolism due to reductions in liver mass and blood flow. Moreover, the reduction in liver mass combined with the physiological decline in renal function in advanced age can decrease the elimination of several medications. Older adults are also at a higher risk of adverse clinical outcomes and adverse drug effects compared to younger adults. Similar to patients with liver disease, older adults are underrepresented in randomized trials. Hence, pharmacoepidemiologic studies in this age group are indispensable.

Our research in geriatric pharmacoepidemiology focuses on several areas. We assess age-specific drug effects in all of our studies to explore potential effect measure modifications by age. In addition, we have established collaborations with important initiatives and experts in adjacent areas. We collaborate with the Berlin Initiative Study at Charité, an ongoing prospective cohort study among community-dwelling older adults led by Professor Elke Schaeffner. This collaboration focuses on the assessment of the effects of blood pressure, kidney function, and other biomarkers on the risk of adverse clinical outcomes in advanced age. We also collaborate with Professor Paul Brassard at the Department of Medicine at McGill University. This collaboration focuses on the assessment of the effects of common infections and vaccines on the risk of neurodegenerative conditions.

Selected publications

• Influenza Immunization at Midlife and the Risk of Parkinson Disease. Douros A, Cui Y, Dell'Aniello S, Suissa S, Brassard P. JAMA Netw Open. 2025 Dec 1;8(12):e2547140.
• Clinically apparent Helicobacter pylori infection and the risk of incident Alzheimer's disease: A population-based nested case-control study. Douros A, Ante Z, Fallone CA, Azoulay L, Renoux C, Suissa S, Brassard P. Alzheimers Dement. 2024 Mar;20(3):1716-1724.
• Kidney Measures and Risk of Incident Heart Failure Among Older Adults: Population-Based Prospective Cohort Study. Douros A, Schneider A, Ebert N, Fietz AK, Huscher D, Kuhlmann MK, Martus P, Mielke N, van der Giet M, Wenning V, Schaeffner E. JACC Heart Fail. 2023 Nov;11(11):1642-1644.
• Control of blood pressure and risk of mortality in a cohort of older adults: the Berlin Initiative Study. Douros A, Tölle M, Ebert N, Gaedeke J, Huscher D, Kreutz R, Kuhlmann MK, Martus P, Mielke N, Schneider A, Schuchardt M, van der Giet M, Schaeffner E. Eur Heart J. 2019 Jul 1;40(25):2021-2028.

Clinical effects of drug-drug interactions

The rising rates of polypharmacy are reflected in an increase in the prevalence of drug-drug interactions (DDIs). DDIs account for >10% of the overall adverse drug effects and up to 5% of hospital admissions among older adults. As a result, they have attracted increasing attention as a modifiable - and for this reason preventable - risk factor of drug toxicity. However, our knowledge about the interaction potential of a given medication is mostly limited to small pharmacokinetic studies conducted among healthy individuals and case reports. Given this important knowledge gap, there is a necessity to conduct pharmacoepidemiologic studies to assess the clinical effects of DDIs.

In the past, we have studied extensively the safety of DDIs involving the antidiabetic drug class of sulfonylureas in projects funded by the Canadian Institutes of Health Research and led by the lab’s past trainees Jenny Dimakos and Wanqi Wang. We have also studied the effectiveness and safety of interactions involving DOACs in projects led by the lab’s current trainee Fabian Meinert. Currently, our work focuses on spontaneous reports as a potential tool for hypothesis generation in the area of DDIs as part of an ongoing collaboration with Professor Christopher Gravel at the School of Epidemiology and Public Health at the University of Ottawa. Finally, we are actively involved in the Special Interest Group on DDIs at the International Society for Pharmacoepidemiology.

Selected publications

• Invited commentary: building rigorous clinical evidence for drug-drug interactions. Tassopoulou P, Douros A. Am J Epidemiol. 2025 Dec 2;194(12):3620-3623.
• Concomitant use of direct oral anticoagulants and interacting antiarrhythmic drugs and the risk of stroke and bleeding among patients with non-valvular atrial fibrillation: a multinational cohort study. Meinert FM, Dimakos J, Cui Y, Filion KB, Renoux C, Douros A. BMC Med. 2025 Oct 28;23(1):592.
• Concomitant Use of Sulfonylureas and β-Blockers and the Risk of Severe Hypoglycemia Among Patients With Type 2 Diabetes: A Population-Based Cohort Study. Dimakos J, Cui Y, Platt RW, Renoux C, Filion KB, Douros A. Diabetes Care. 2023 Feb 1;46(2):377-383.
• Concomitant Use of Sulfonylureas and Warfarin and the Risk of Severe Hypoglycemia: Population-Based Cohort Study. Dimakos J, Cui Y, Platt RW, Renoux C, Filion KB, Douros A. Diabetes Care. 2022 Oct 1;45(10):e131-e133.

Molecular pharmacoepidemiology

Molecular pharmacoepidemiology is the study of how genes alter the effectiveness and safety of medications in large populations. This novel research field applies methods from the areas of epidemiology and causal inference to answer questions from the realm of pharmacogenetics. Importantly, molecular pharmacoepidemiology has only recently become feasible due to the increasing availability of large datasets containing linked molecular and clinical information.

In our lab, we use whole-genomic sequencing data linked to electronic medical records in the UK Biobank to conduct a series of molecular pharmacoepidemiologic studies. Our aim is to assess whether genetic variability can affect the effectiveness and safety of commonly prescribed medications with a primary focus on cardiometabolic drugs. Considering the scarcity of evidence in the area, our project will aid precision medicine, thereby directly improving patient care.