(ASPOT30) The prevalent new-user design to study drug-drug interactions: the example of sulfonylureas and warfarin interaction on the risk of severe hypoglycemia

Background: The optimal design for pharmacoepidemiologic studies that aim to assess the clinical effects of drug-drug interactions is unclear.

Objectives: To assess whether the prevalent new-user design can be applied for the study of drug-drug interactions

Methods: We used the pharmacokinetic interaction between sulfonylureas and warfarin and the risk of severe hypoglycemia, a drug-drug interaction with little or no clinical impact, as an example. The data source was the United Kingdom’s Clinical Practice Research Datalink linked to the Hospital Episode Statistics and the Office for National Statistics databases. We initially assembled a base cohort including all patients who initiated a sulfonylurea between January 1998 and December 2022. Out of the base cohort, we identified all patients who added warfarin while on a sulfonylurea (co-exposed). For each co-exposed patient, we defined prescription-based exposure sets that comprised other sulfonylurea users not adding warfarin (comparators) at the same time point. Within each exposure set, we matched each co-exposed patient to up to five comparators on time-conditional propensity scores that included 30 potential confounders (demographics, lifestyle variables, anthropometric information, comorbidities, comedications, proxies of diabetes severity and overall health); matched patients were followed using an as-treated exposure definition. Severe hypoglycemia was defined as either hospitalization with or death due to hypoglycemia. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) of the study outcome associated with the concomitant use of sulfonylureas and warfarin as compared with the use of sulfonylureas alone. Sensitivity analyses addressed the impact of different potential sources of bias including misclassification of exposure and outcome, informative censoring due to drug discontinuation, and residual and time-dependent confounding.

Results: The study cohort included 17,890 co-exposed patients and 88,749 matched comparators. Baseline patient characteristics were well-balanced between groups. Compared with use of sulfonylureas alone, concomitant use of sulfonylureas and warfarin was not associated with the risk of severe hypoglycemia (HR, 1.04; 95% CI, 0.92 to 1.17). Sensitivity analyses yielded findings that were highly consistent with those of the primary analysis (HRs ranging from 1.02 to 1.15).

Conclusions: Our large population-based study suggests that the prevalent new-user design could be a useful tool to study the clinical effects of drug-drug interactions.