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

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Abstract

A growing body of observational literature on the association between glucose-lowering treatments and all-cause mortality has been accumulating in recent years. However, many investigations present designs or analyses that inadequately address the methodological challenges involved. We conducted a systematic search with a non-systematic extension to identify observational studies published between 2000 and 2012 that evaluated the effects of glucose-lowering medications on all-cause mortality. We reviewed these studies and assessed the design and analysis methods used, with a focus on their ability to address specific methodological challenges. We described these methodological issues and their potential impact on observed associations, providing examples from the reviewed literature, and suggested possible approaches to manage these methodological challenges. We evaluated 67 publications of observational studies evaluating the association between glucose-lowering treatments and all-cause mortality. The identified methodological challenges included trade-offs associated with the outcome of all-cause mortality, incorrect temporal sequencing in administrative databases, inadequate treatment of time-varying hazards and treatment duration effects, unclear definition of the exposure risk window, improper handling of time-varying exposures, and incomplete accounting for confounding by indication. Most of these methodological challenges may be adequately addressed through the application of appropriate methods. Observational research plays an increasingly important role in assessing the clinical effects of diabetes therapy. The implementation of suitable research methods can reduce the potential for spurious findings, and thus the risk of misleading the medical community about benefits and harms of diabetes therapy.

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Acknowledgments

We thank Elvira Masso-Gonzalez for her thoughtful input on an early draft of this manuscript.

Funding

This review was partially sponsored by a research contract with Boehringer-Ingelheim. The research contract gave Brigham and Women’s Hospital the right of final wording for any manuscript arising from the contract.

Conflict of interest

Elisabetta Patorno, Elizabeth M. Garry, Amanda R. Patrick, and Victoria G. Gillet report no conflicts.

Sebastian Schneeweiss is principal investigator of the Harvard–Brigham Drug Safety and Risk Management Research Center funded by the US FDA. His work is partially funded by Grants/contracts from the Patient-Centered Outcomes Research Institute, the FDA, and the National Heart, Lung, and Blood Institute. He is also a consultant to WHISCON, LLC and Aetion, Inc., a software manufacturer of which he also owns shares, and is principal investigator of investigator-initiated Grants to the Brigham and Women’s Hospital from Novartis, unrelated to the topic of this review, and Boehringer-Ingelheim, partly related to the topic of this review.

John D. Seeger is a consultant to WHISCON, LLC and Optum.

Olesya Zorina and Dorothee B. Bartels are employees of Boehringer Ingelheim GmbH.

Authors’ contributions

Review article concept and design: Elisabetta Patorno, John D. Seeger, Sebastian Schneeweiss, Olesya Zorina, and Dorothee B. Bartels. Literature identification and organization: Elizabeth M. Garry, Amanda R. Patrick, Victoria G. Gillet, and Elisabetta Patorno. Critical review of the literature: Elisabetta Patorno, John D. Seeger, and Amanda R. Patrick. Critical revision of the manuscript for important intellectual content: Elisabetta Patorno, John D. Seeger, Amanda R. Patrick, Sebastian Schneeweiss, Olesya Zorina, and Dorothee B. Bartels. Review article supervision: Elisabetta Patorno, John D. Seeger, and Sebastian Schneeweiss.

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Authors and Affiliations

  1. Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 1620 Tremont Street (Suite 3030), Boston, MA, 02120, USA

    Elisabetta Patorno, Elizabeth M. Garry, Amanda R. Patrick, Sebastian Schneeweiss, Victoria G. Gillet & John D. Seeger

  2. Corporate Department Global Epidemiology, Boehringer Ingelheim GmbH, Ingelheim, Germany

    Olesya Zorina & Dorothee B. Bartels

  3. Hannover Medical School, Institute for Epidemiology, Social Medicine and Health Systems Research, Hannover, Germany

    Dorothee B. Bartels

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  1. Elisabetta Patorno
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Correspondence to Elisabetta Patorno.

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Patorno, E., Garry, E.M., Patrick, A.R. et al. Addressing Limitations in Observational Studies of the Association Between Glucose-Lowering Medications and All-Cause Mortality: A Review. Drug Saf 38, 295–310 (2015). https://doi.org/10.1007/s40264-015-0280-1

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