Observational studies of the association between glucose-lowering medications and cardiovascular outcomes: addressing methodological limitations

Abstract

Background Recent years have witnessed a growing body of observational literature on the association between glucose-lowering treatments and cardiovascular disease. However, many of the studies are based on designs or analyses that inadequately address the methodological challenges involved. Methods We reviewed recent observational literature on the association between glucose-lowering medications and cardiovascular outcomes and assessed the design and analysis methods used, with a focus on their ability to address specific methodological challenges. We describe and illustrate these methodological issues and their impact on observed associations, providing examples from the reviewed literature. We suggest approaches that may be employed to manage these methodological challenges.Results From the evaluation of 81 publications of observational investigations assessing the association between glucose-lowering treatments and cardiovascular outcomes, we identified the following methodological challenges: 1) handling of temporality in administrative databases; 2) handling of risks that vary with time and treatment duration; 3) definitions of the exposure risk window; 4) handling of exposures that change over time; and 5) handling of confounding by indication. Most of these methodological challenges may be suitably addressed through application of appropriate methods. Conclusions/interpretation Observational research plays an increasingly important role in the evaluation of the clinical effects of diabetes treatment. Implementation of appropriate research methods holds the promise of reducing the potential for spurious findings and the risk that the spurious findings will mislead the medical community about risks and benefits of diabetes medications.

Claims‐based studies of oral glucose‐lowering medications can achieve balance in critical clinical variables only observed in electronic health records

“…Our study findings indicate that proper study design choices can meaningfully reduce the likelihood of residual confounding from typically unmeasured variables, such as duration of diabetes, BMI, smoking status and HbA1c levels, in pharmacoepidemiological studies of diabetes treatment. The choice of clinically meaningful comparators, namely, initiators of other drugs that are available at the time of market authorization of a newly marketed medication of interest and that are used at a similar stage of diabetes progression, can mitigate bias attributable to confounding by indication and to differences in health system use . An incident user design, which includes patients initiating a treatment of interest or comparator agents, avoids the problem of studying prevalent users who are “survivors” of early adverse effects, allows the evaluation of drug effects that vary over time, and ensures that baseline covariates are assessed before treatment initiation and are not affected by treatment itself .…”

“…It is often assumed that the absence of this information in pharmacoepidemiological studies could be largely addressed by the application of state‐of‐the‐art study design and analytical choices. For example, in the context of safety and effectiveness research on diabetes therapy, using a new‐user study design enhanced by the proper choice of an active comparator drug, which tends to be used by patients at a similar stage of diabetes, could better distinguish drug effects from diabetes disease effects . Additionally, adjusting analyses via propensity score (PS) matching could leverage the vast information recorded in large claims databases to estimate treatment effects in a population with clinical equipoise regarding many aspects of care, including characteristics that may act as proxies for unmeasured information .…”

Addressing Limitations in Observational Studies of the Association Between Glucose-Lowering Medications and All-Cause Mortality: A Review

“…The other reviews are related to cardiovascular disease [3], malignancies, and kidney disease. Each review employed an independent search strategy, and used a different set of observational studies as the evidence base.…”

Predictive Factors for Pressure Ulcers in an Older Adult Population Hospitalized for Hip Fractures: A Prognostic Cohort Study

“…In addition, they have an important economic impact, both on the health system and on the families involved [1]. Given the increase in the older adult population, especially in Italy, the incidence of these fragility fractures is constantly increasing with 88,647 new cases per year in Italy [2] and 1.5 million all over the world every year [3,4]. Hip fractures are associated with mortality, disability and a decrease in the quality of life [5].…”