New VADT Data: Hypoglycemia Is a Risk Factor for CVD in Some

Miriam E Tucker

January 27, 2016

Serious hypoglycemia may be associated with progression of atherosclerosis among patients with type 2 diabetes and poor glycemic control, new data from the Veterans Affairs Diabetes Trial (VADT) suggest.

Findings from the substudy of 197 VADT patients were published online January 19, 2016 in Diabetes Care by Aramesh Saremi, MD, research scientist at the Phoenix VA Health Care System, Phoenix, Arizona, and colleagues.

Serious hypoglycemia was nearly three times more common in the intensive-control arm compared with the standard-treatment group. While hypoglycemia wasn't associated with progression of coronary artery calcification (CAC) overall or in the intensive-treatment group, patients with serious hypoglycemia in the standard-treatment group had approximately 50% greater CAC progression compared with those without serious hypoglycemia.

This finding was unexpected, Dr Saremi told Medscape Medical News. "The results were surprising. As hypoglycemic episodes were more frequent in the intensive-treatment arm, we expected to see a higher degree of progression of atherosclerotic calcification in this group.

"However, as shown in the paper, participants in the standard-treatment arm progressed significantly more if they reported serious hypoglycemic episodes during the study. The fact that the several sensitivity analyses provided similar results provides us additional confidence in these initially surprising results."

Clinically, she said, "Our study supports the individualized management of type 2 diabetes and the importance of avoiding hypoglycemia, particularly in elderly patients with longstanding poorly controlled type 2 diabetes....Hypoglycemia may be an issue even in those not receiving intensive glycemic control."

The findings should raise awareness of hypoglycemia as a risk factor for cardiovascular disease, she noted.

"There is growing evidence from randomized clinical trials in type 1 and type 2 diabetes and a number of large longitudinal population-based studies that severe hypoglycemia is associated with increased risk of CVD….Patient education regarding hypoglycemia needs to receive more attention and is one key to successful diabetes management; it would also help reduce medical costs associated with these more severe hypoglycemia episodes."

Hypoglycemia and the Heart

The VADT trial, published in 2008, randomized 1791 military veterans who had type 2 diabetes and a mean initial HbA1c level of 9.5% to standard or intensive glycemic control, which included insulin for those who didn't achieve an HbA1c below 6% (intensive-therapy group) or below 9% (standard-therapy group).

Last year, 10-year data from the trial indicated that those who were randomized to receive about 5 years of intensive vs standard glycemic therapy had a lower incidence of cardiovascular events, although no improved survival during a median 9.8-year follow-up, new findings reveal.

In this new substudy, during an average 4.5 years of follow-up, 97 of the participants reported either severe hypoglycemia, defined as episodes with loss of consciousness or requiring medical or other assistance, whether or not blood glucose values were available (n = 74), or documented blood glucose values below 50 mg/dL (n = 23).

Such episodes were significantly more common in the intensive-treatment group, 74% vs 21% in the standard group (P < .01).

Serious hypoglycemia was not associated with CAC progression in the entire cohort or in the intensive-treatment group. However, the interaction between serious hypoglycemia and treatment assignment was highly significant (P < .01) and persisted after adjustment for differences between participants with and without serious hypoglycemia, including prior hypoglycemia, diabetes duration, creatinine value, C-peptide, triglycerides, and insulin use.

Stratified by treatment group, those with serious hypoglycemia in the standard-treatment arm had significantly greater CAC progression compared with those with no serious hypoglycemia (median 11.15 vs 5.4 mm3, = .02). This relationship persisted after adjustment for the prior variables, as well as for other predictors such as age and race/ethnicity.

In a sensitivity analysis, serious hypoglycemia was associated with greater CAC progression among subjects with HbA1c levels greater than 7.5% (P = .04), but not 7.5% or below.

Progression of CAC was also associated with increasing mean HbA1c in those with serious hypoglycemia (< .01), but not in those without (P = .51). And CAC progression increased with the number of serious hypoglycemic episodes in the standard-treatment group (P = .04 for overall difference between groups), but not in the intensive-treatment group.

The reason for this phenomenon isn't clear, Dr Saremi told Medscape Medical News, but she and her colleagues have a few theories. One is that people in the standard-treatment group may have more abrupt glycemic fluctuations, which have been linked to oxidative stress and endothelial dysfunction, leading to progression of atherosclerosis.

Or, she said, because all hypoglycemic events — even nonserious ones — occurred more often in the intensive-treatment group, those individuals may have been better prepared to take immediate actions to alleviate them.

And, she noted, the progression of CAC in participants on standard therapy without serious hypoglycemia was similar to participants with intensive therapy regardless of serious hypoglycemia, suggesting that glycemic variability — perhaps greatest in those with both poor glucose control and episodes of hypoglycemia — may be a risk factor of progression of atherosclerosis.

"However, these findings should be viewed in the context of hypothesis generation and hopefully will stimulate further examination of this issue," she stressed.

The authors report no relevant financial relationships.

Diabetes Care. Published online January 19, 2016. Abstract


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