The recent article by Davis et al. (1) reports on the relationship between severe hypoglycemic events (SHEs) and the subsequent risk of cardiovascular (CV) events or death observed in the Veterans Affairs Diabetes Trial (VADT). Unfortunately, the authors did not acknowledge our article published earlier this year in Diabetes Care, “Increased Risk of Severe Hypoglycemic Events Before and After Cardiovascular Outcomes in TECOS Suggests an At-Risk Type 2 Diabetes Frail Patient Phenotype” (2). Accordingly, they missed an opportunity to potentially confirm the intriguing reverse scenario we identified, i.e., a relationship between nonfatal CV events and the subsequent risk of SHEs. Given that there appear to be common traits for patients suffering SHEs and/or CV events or death, it would clearly be of interest to explore the situation in VADT. Furthermore, the hazard ratios given in Table 3 of the article by Davis et al., suggesting increased risks of CV events and death subsequent to SHEs within the prior 3 months, do not appear to be adjusted fully for potential confounders. Their Table 2 shows that, for example, autonomic neuropathy and proteinuria were significant predictors of SHEs in VADT. However, these characteristics were not included in the adjustment of the hazard ratios listed in Table 3, despite these findings and the widespread recognition that these variables are also strong predictors of CV events and death. It would be helpful to know whether the Table 3 hazard ratios remain significant after complete adjustment for all characteristics found to be associated with increased risk of SHEs. It would also be of interest to provide the difference in absolute numbers between the two randomized treatment arms in VADT for CV events and deaths in the first 3 months after an SHE, to better understand the potential worst-case scenario for the overall “contribution” of SHEs to the VADT primary outcome (3).
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Acknowledgments. Peter Hoffmann, an employee of Duke Clinical Research Institute, provided editorial support.
Funding and Duality of Interest. The Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS) was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ. The study was designed and run independently by the Duke Clinical Research Institute and the University of Oxford Diabetes Trials Unit in an academic collaboration with the sponsor. E.S. has received personal fees from the University of Oxford Diabetes Trials Unit, AstraZeneca, Bayer, BERLIN-CHEMIE, Boehringer Ingelheim, Merck Serono-EXCEMED, Novartis, Novo Nordisk, and Sanofi. J.B.G. has received grants from AstraZeneca and GlaxoSmithKline, grants and personal fees from Merck Sharp & Dohme Corp., and personal fees from Boehringer Ingelheim and Daiichi Sankyo. R.R.H. is a National Institute for Health Research Senior Investigator and reports receiving grants from AstraZeneca during the conduct of the study as well as grants and personal fees from Bayer, Boehringer Ingelheim, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; personal fees from Novartis, Amgen, and Servier; and financial support from Elcelyx, GlaxoSmithKline, Janssen, and Takeda outside the submitted work. No other potential conflicts of interest relevant to this article were reported.
The authors of the cited article did not respond.
