New Look at VA Diabetes Trial Links Severe Hypoglycemia, Cardiovascular Events

A decade ago this week, the New England Journal of Medicine published findings from the Veterans Affairs Diabetes Trial (VADT), which had compared standard glucose control with intensive control on 2 groups of patients with longstanding type 2 diabetes (T2D).¹ Already, 40% had suffered a cardiovascular event. The study found no significant difference between the 2 groups in cardiovascular outcomes or most microvascular complications. This was important at the time, because these results differed from the ACCORD trial, which had stopped early because deaths had spiked among the intensive therapy group.

VADT was significant in that it looked specifically at the impact of glycemic control, rather than the effect of a specific agent. Now, with cardiovascular outcomes in T2D front and center among researchers, the VADT investigators have published a new a post-hoc analysis in the current issue of Diabetes Care, this time looking at differences among those veterans who suffered severe hypoglycemia—and it turns out this group did see worse outcomes.²

The original trial involved 1791 veterans, almost all men but with good geographic and racial diversity. Their average age was 60.5 years, and they had lived with T2D and for an average of 11.5 years. Their condition was poorly controlled, with an average glycated hemoglobin (A1C) of 9.4% ± 2.0%. According to a 2015 interview with Peter Reaven, MD, a VADT lead investigator (and author on this new study), the treatment goal for the standard group was just below 7.0% for the intensive group and just below 8.4% for those receiving standard care—consistent with the published findings that stated the 2 groups’ targeted A1C goals were 1.5% apart.

The Diabetes Care findings show the veterans were seen every 3 months during the study, and doctors recorded the number of severe hypoglycemia events—these were defined as a “self-reported episode of a low blood glucose value accompanied by confusion requiring assistance from another person or loss of consciousness.” Less than 0.5% of the visits had missing severe hypoglycemia data, causing 35 of the 1791 participants to be excluded from this post-hoc analysis.

Investigators found the rate of severe hypoglycemia was higher in the intensive treatment group: 10.3 per 100 patient-years, compared with 3.7 per 100 patient-years in the standard treatment group (P <.001). Severe hypoglycemia within the past 3 months was associated with an increased risk of serious cardiovascular events (P = .032), cardiovascular mortality (P = .012), and total mortality (P = .024).

However, the analysis found a relatively greater increased risk for total mortality in the group that was treated to the standard goal compared with group treated to the more intensive goal (P =0.019). The association between severe hypoglycemia and cardiovascular events increased significantly as overall cardiovascular risk increased, based on the UK Prospective Diabetes Study Risk Score (P = .012).

Also, there were several independent predictors of severe hypoglycemia: insulin use at baseline (P = .02), protein in the urine (P = .009), and autonomic neuropathy, which can affect the cardiovascular system (P = .01). Meanwhile, a higher body mass index had a protective effect (P = .017), a paradox that has been observed in other studies. The investigators write that “perhaps [this was] because of the associated insulin resistance providing some protection against the glucose-lowering effects of insulin or insulin secretagogues.”

The VADT investigators say the new analysis shows the need to customize treatment to individual needs, especially in older patients. “The serious consequences of these hypoglycemia-associated outcomes (cardiovascular events and mortality) emphasize the importance of careful selection of patients and medications when initiating intensification of therapy and close monitoring of patients for evidence of these events,” they wrote.

References

1. Duckworth W, Abraira C, Moritz T, et al., for the VADT investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009; 360(2):129-139. doi: 10.1056/NEJMoa0808431.
2. Davis SN, Duckworth W, Emanuele N, et al., for the VADT investigators. Effects of severe hypoglycemia on cardiovascular outcomes and death in the Veterans Affairs Diabetes Trial. Diabetes Care. 2019;42(1):157-163. doi.org/10.2337/dc18-1144.