Glycemic Variation and Cardiovascular Risk in the Veterans Affairs Diabetes Trial

Abstract

Objective: There is uncertainty about the importance of glycemic variability in cardiovascular complications in patients with type 2 diabetes. Using the Veterans Affairs Diabetes Trial (VADT), we investigated the association between variation in fasting glucose and glycated hemoglobin (HbA1c) over time and the incidence of cardiovascular disease (CVD) and assessed whether this is influenced by intensive or standard glycemic control.

Research design and methods: During the VADT, fasting glucose and HbA1c were measured every 3 months for up to 84 months in 1,791 individuals. Variability measures included coefficient of variation (CV) and average real variability (ARV) for fasting glucose and HbA1c. Overall mean glucose and HbA1c measures as well as their maximum and the most recent measurement were also examined.

Results: Variability measures (CV and ARV) of fasting glucose were significantly associated with CVD even after adjusting for other risk factors, including mean fasting glucose. When considering separately groups receiving intensive and standard glycemic control, this relationship was evident in the intensive treatment group but not in the standard group. Additional adjustment for severe hypoglycemic episodes did not alter the relationship between fasting glucose variability and CVD. Interestingly, no HbA1c measures were associated with CVD after adjusting for multiple baseline risk factors.

Conclusions: Our analysis indicates that in the VADT, variability of fasting glucose plays a role in the development of CVD complications beyond the influence of standard fasting glucose measures. The adverse consequences of fasting glucose variability on CVD appear greatest in those receiving intensive glucose control.

© 2018 by the American Diabetes Association.

Figures

Figure 1

HR estimates for quintiles of log(CV)-glucose and ARV-glucose for the primary CVD outcome adjusted for ethnicity (non-Hispanic white or not), diabetes duration, prior CVD event, history of hypertension, baseline systolic blood pressure, baseline HDL cholesterol, baseline triglycerides as well as the cumulative mean of glucose. Vertical bars shown are the 95% CIs associated with HR estimates. ***Indicates estimated HR in the related variability quintile is significantly higher than the HR of lowest variability quintile (quintile 1). Trend test results are presented as the text annotations in the figure.

Figure 2

HRs of log(CV) and ARV and their 95% CI for the primary CVD outcome with and without adjustment for severe hypoglycemia (Hypo) events. Adj, adjusted.