June 27, 2018
5 min read

VADT: After 15 years, a debate over glucose-lowering ‘legacy effect’

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ORLANDO, Fla. — Long-term follow-up of the Veterans Affairs Diabetes Trial suggests that adults with advanced type 2 diabetes assigned to intensive glucose-lowering therapy for an average of 5 years do not experience a “legacy effect” with respect to reduced microvascular or macrovascular complications 10 years after the intervention ends, according to an analysis presented here.

In a summary of 15-year findings from the Veterans Affairs Diabetes Trial (VADT), researchers observed that a median 5.6 years of intensive glycemic control — treating to an HbA1c of less than 7% — resulted in a nonsignificant 12% reduction in cardiovascular outcomes vs. usual care, with no between-group differences for CV death or all-cause death, and a trend for reduced adverse renal outcomes that did not rise to significance.

But the idea of a legacy effect may depend on the person defining what those words mean, according to Hertzel C. Gerstein, MD, MSc, FRCPC, professor and population health institute chair in diabetes research at McMaster University and Hamilton Health Sciences in Ontario, Canada.

“What does ‘leaving a legacy’ mean?” Gerstein said during a symposium on the VADT findings at the American Diabetes Association Scientific Sessions. “Well, VADT showed that about 5.6 years of more vs. less glucose lowering reduces CV outcomes during 10 years of follow-up, but not during 15 years of follow-up.”

“A legacy may not last forever,” Gerstein said. “People squander their inheritance and their legacy is gone. The same thing can happen in medical situations as well.”

Another way to think of a legacy, Gerstein said, is what happens after a clinical trial ends — not what happens after the contrast in HbA1c between two groups in a trial like VADT goes away.

“If you think of it that way, there is a legacy,” Gerstein said. “It becomes a semantic argument. I think there was a 10-year legacy because after the end of the clinical trial, there was still a benefit seen a few years later. But there’s no right answer here. It’s the way that you think of it.”

In the VADT, a 7.5-year, large-scale intervention trial, researchers studied the effects of intensive glucose control on CV disease risk in 1,791 U.S. veterans (97% men; 62% white; mean age, 60 years) assigned to two groups: intensive glucose control (HbA1c goal < 7%) and standard glucose control. All patients had suboptimal glycemic control at baseline, with an average HbA1c of 9.4%. After a median 5.6 years, mean HbA1c was 6.9% for the intensive group and 8.4% for the usual-care group.

Macrovascular outcomes

Initial results when the VADT intervention period ended prompted several key questions that provide the rationale for the follow-up study, according to Peter Reaven, MD, professor at the University of Arizona College of Medicine and staff endocrinologist at the Phoenix VA Health Care System. One question was: Would a post-VADT follow-up reveal an emerging CVD benefit, benefit for all-cause death or other outcomes?

“This was particularly relevant, as there was an indication that the [between-]group differences were increasing toward the end of the study, and benefits in cardiovascular outcomes, as we know, take a fair amount of time,” said Reaven, also a study co-chair of VADT. “As glucose separation between the treatment groups for VADT was greater than that of recent studies in patients with advanced type 2 diabetes and lasted for an extended period of time, this provided an excellent opportunity to examine whether there was legacy effect.”

In long-term analyses, researchers observed that a median 5.6 years of intensive glucose control in advanced type 2 diabetes led to a delayed CV benefit after nearly 10 years of improved glucose control; however, no overall CV benefit was seen during the full 15-plus years of follow-up, Reaven said. Researchers observed a neutral, long-term effect on all-cause mortality, no long-term improvement in hospitalization rates or quality of life, and noted a modest, long-term weight gain for the intensive-control group, Reaven said.

The results, he added, are relatively consistent with other recent glucose-lowering trials also examined in post-trial follow-up.

“These results suggest there are modest, long-term cardiovascular benefits for therapies directed at bringing glucose control to near-normal range in high-risk type 2 diabetes patients,” Reaven said. “Substantial and continuous glucose separation may be required to maintain these improvements.”

Microvascular complications

An analysis of the intensively treated group suggested there was a beneficial effect of intensive glycemic control on renal parameters during the intervention period, while there was an HbA1c separation between groups, according to Nicholas V. Emanuele, MD, professor at Loyola University Chicago Stritch School of Medicine, chief of the section of endocrinology at Hines VA Hospital in Illinois and a VADT study co-chair. Researchers then conducted an analysis to observe what happened after the glycemic separation wanes, he said.

In 15-year data, Emanuele said 28% vs. 26% of patients in the standard-care and intensive groups, respectively, reached the composite renal endpoint, defined as an estimated glomerular filtration rate of 45 mL/min/1.73 m2 or less, sustained macroalbuminuria or end-stage renal disease, defined as an eGFR of less than 15 mL/min/1.73 m2, dialysis or kidney transplant.

“It’s a trend in the right direction, but, with an odds ratio of 0.9, nowhere near statistically significant,” Emanuele said, adding that similar results not reaching statistical significance were observed in analyses of the individual renal endpoints.

During the VADT intervention, Emanuele said, the OR for the composite renal endpoint was 0.85, reaching statistical significance.

“Interestingly, when data was analyzed at 10 years, there was a significant benefit, in that those in the intensive group had an odds ratio of 0.68, or 32% decreased odds of reaching that [renal] endpoint,” Emanuele said. “But, as the HbA1c separation waned, so did the odds ratio.”

Additionally, researchers observed a trend for delayed composite adverse retinal events in the intensive group during the study, Emanuele said.

A lack of certainty

There is certainty missing from the data presented so far from VADT, Gerstein said during his presentation. And, that lack of certainty speaks to how clinicians should view the study findings.

“If you’re looking for certainty, you’re not a scientist and you’re not a doctor, because uncertainty is what science and medicine are all about,” he said.

Gerstein said the VADT continues to increase diabetes insights and inform care. Evidence from epidemiology, the VADT, other large randomized controlled trials, mediation analyses and mendelian randomization studies show that dysglycemia independently increases CV risk, death and other outcomes, he said, and higher glucose levels predict higher CV risk. Further, glucose lowering reduces diabetes consequences on average; however, evidence from VADT and other studies suggest that the effect size may depend on how glucose lowering is achieved.

Most important, Gerstein said, is that treatment for any person with diabetes must be individualized.

“There is no ‘statin’ for diabetes, ie, no ‘prescribe and go,’ yet,” Gerstein said. “But, we are getting closer. We’re going to get there. This is just the beginning of the next phase.” – by Regina Schaffer


Wiitala WL, et al. The Veterans Affairs Diabetes Trial (VADT) at 15 years. Presented at: American Diabetes Association 78th Scientific Sessions; June 22-26, 2018; Orlando, Fla.

Disclosures: Reaven reports he receives research support from Amgen, AstraZeneca and Bristol-Myers Squibb. Emanuele reports he serves on the speakers bureau for Merck. Gerstein reports he serves as an adviser for, receives research support from or has a financial relationship with Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi.