Abstract
Background: Generation of real-world cardiovascular drug safety evidence in patients with type 2 diabetes (T2D) warrants robust methodology. Regulatory authorities are increasingly seeking to support their decision making through real-world evidence. At the time of marketing authorization, this study was required by regulatory authorities to further characterize the liraglutide safety profile in routine real-world clinical practice (external validity). Safety outcomes were compared to those of other non-insulin antidiabetic (NIAD) treatments in patients with T2D initiating NIADs in a UK real-word setting. The design was endorsed by health regulatory authorities. This paper analyzes the methodology and study results, and postulates that it was the differences in patient characteristics at NIAD initiation, not the treatment itself, that modulated the observed differences in cardiovascular risk between NIAD cohorts.Methods: Data were obtained from linked UK electronic repositories: the Clinical Practice Research Datalink primary care database (CPRD GOLD) and Hospital Episode Statistics (HES). Risks of selected outcomes with current liraglutide use were compared to current use of other NIADs. Rates of each outcome and corresponding crude and adjusted incidence rate ratios were examined using Poisson regression analysis. Results: Overall, 149 788 patients met the study inclusion criteria; of these, 3432 initiated liraglutide. Components of the metabolic syndrome were more common among liraglutide initiators than those initiating other NIADs. The risk of some macrovascular conditions was increased in liraglutide initiators versus other NIAD initiators; following stepwise adjustment, this was only seen in liraglutide initiators when compared to biguanide initiators (incidence rate ratio: 1.33 [99% confidence interval (CI): 1.11;1.59]).Conclusions: The observed increase of macrovascular outcomes in liraglutide initiators compared with other NIAD initiators emphasizes the importance of countering potential selection bias when designing studies comparing cardiovascular outcomes across treatment initiator cohorts in heterogenous populations, such as patients with T2D. Baseline differences in the NIAD cohort may have modulated cardiovascular outcomes and likely explain the observed increased cardiovascular risk in liraglutide initiators. Selection bias, channeling bias and residual confounding, inherent in such observational studies, must be considered early when designing the study if the real-world data are to support decision-making.
CARDIOVASCULAR OUTCOMES MEASURED BY ADJUDICATION VERSUS BILLING CODES IN REAL-WORLD PATIENTS TREATED WITH IMMUNE CHECKPOINT INHIBITORS