VADT at 15 Years: No Legacy Effect From Intensive HbA1c Control

Marlene Busko

June 28, 2018

ORLANDO — The Veterans Administration Diabetes Trial (VADT) in patients who had longstanding uncontrolled type 2 diabetes did not find a "legacy effect" of fewer future cardiovascular events in the 15-year follow-up.

Compared with patients in the standard treatment group, those in the intensive glucose-lowering group had fewer cardiovascular events (a composite of myocardial infarction [MI], stroke, cardiovascular death, congestive heart failure, and amputation) at the 10-year follow-up, but this did not extend out to 15 years.  

Rresearchers reported these latest findings from the VADT follow-up study (VADT-F) on June 24 here at the American Diabetes Association (ADA) 2018 Scientific Sessions.   

"The VADT shows that [5.6] years of more versus less glucose lowering reduces your 10-year risk of cardiovascular events, but there's no effect after 15 years," Hertzel C. Gerstein, MD, an endocrinologist and professor at McMaster University, Hamilton, Ontario — who gave a talk on the trial's clinical implications — told Medscape Medical News.

"So it tells us that there is a benefit of more versus less intense glucose lowering, which doesn't last forever."

Intensive Control Hard to Achieve, Has Downsides   

This means that "in day-to-day clinical practice, you have to treat the patient; you cannot treat a number," he said.

"Patients are not numbers; they are complex beings," Gerstein stressed. "Some of my patients, I target an HbA1c less than 7%, some of them I target an HbA1c less than 7.5% — it depends on the holistic story."

Moreover, "guidelines are recommendations...not rules," he continued, and "are meant to inform your clinical judgment. Anybody who treats guidelines like rules is not practicing medicine appropriately."

Peter Reaven, MD, director of the Diabetes Research Program at the Phoenix VA Health Care System, Arizona, and co-principal investigator of VADT-F, who presented the macrovascular findings, had a similar interpretation.

"The take-home message is that the benefits of glucose lowering appear to be there, but they're relatively modest and there needs to be a persistent glucose lowering to have that effect continue," he told Medscape Medical News.

"We're not seeing the strong evidence of 'metabolic memory' or a 'legacy effect.' "

Cardiovascular events, he noted, take a fair amount of time to develop. "It takes around 10 years to get a benefit of a 17% reduction in risk of a cardiovascular event" — which has a very different meaning for a 70 year old versus a 40 year old who both have advanced type 2 diabetes.

The patients in VADT all had advanced type 2 diabetes, so to extrapolate the results to the general population, you would have to carefully consider "all the other studies along with this," said Reaven.

Moreover, lowering HbA1c to below 7% in the intensive control group was difficult and induced a two- to three-fold higher risk of severe hypoglycemia as well as an increased risk of less severe hypoglycemia.

"You saw how rapidly the HbA1c started to rise when we turned over these people — who were in good glycemic control — to the primary care environment," he continued. "After 2 years, they were already up in the 8% range and ended up at 8.2%. So it's not so easy [to attain tight glycemic control] with the older medications."

The patients in VADT were not prescribed any sodium-glucose cotransporter 2 (SGLT2) inhibitors or glucagon-like peptide (GLP)-1 receptor agonists during active treatment.

It may be easier to attain tight glycemic control with these newer medications, Reaven speculated.

Men With Uncontrolled Longstanding Diabetes

VADT randomized 1791 mainly older male veterans with poor glycemic control who had a mean HbA1c of nearly 9.5% to intensive glycemic control versus standard treatment.

On average, patients were 60 years old and had been diagnosed with type 2 diabetes 11.5 years earlier.

After a mean active treatment phase of 5.6 years, with a target HbA1c of less than 6.0% in the intensive treatment group, the median HbA1c was 6.9% in the intensive versus 8.4% in the standard care group — a "glucose contrast" of 1.5%.

In comparison, HbA1c attained in the active versus standard treatment group was 7.0% vs 7.9% in UKPDS, 6.4% vs 7.5% in ACCORD, and 6.5% vs 7.3% in ADVANCE — for glucose contrasts of 0.9%, 1.1%, and 0.8%, respectively, Gerstein noted, which shows that VADT was successful in attaining a good glycemic contrast.

After the active phase of VADT, HbA1c levels in both groups merged – so that at 10 years from the study start (a median of 9.8-years follow-up), HbA1c levels in both groups were about 8.5%.

At 15 years from study start (a median of 13.6-year follow-up), HbA1c levels in both groups were about 8.8%.

17% Reduction in Cardiovascular Events at 10 Years, None at 15 Years

In VADT, intensive treatment significantly reduced the primary outcome of cardiovascular events (MI, stroke, cardiovascular death, congestive heart failure, amputation) by 17% at 10 years of follow-up (hazard ratio [HR], 0.83; 95% CI, 0.70 – 0.99).

But after 15 years of follow-up, this difference was no longer significant (HR, 0.91; 95% CI, 0.78 – 1.06).

There was also no significant difference in cardiovascular mortality with intensive vs standard treatment at 10 years (HR, 0.88; 95% CI, 0.64 – 1.20) or 15 years (HR, 0.94; 95% CI, 0.73 – 1.20).

And there was no significant difference in overall mortality at 10 years (HR, 1.05; 95% CI, 0.64 – 1.20) or 15 years (HR, 0.94; 95% CI, 0.73 – 1.20).

VADT does tell us that, at least for about 6 years, HbA1c less than 7% is better for cardiovascular health than HbA1c over 8%, Gerstein summarized.

Becuase 97% of trial participants were men, it is unclear if the same findings would have been seen in women, and the trial's power was relatively low, with 657 primary outcomes (cardiovascular events) at 15 years.

Nevertheless, Gerstein said, "the VADT continues to increase diabetes insights and inform care."  

VADT, epidemiologic trials, other large randomized controlled trials, mediation analyses, and Mendelian randomization studies, he noted, "all show that diabetes and prediabetes independently increase cardiovascular events, death, and other outcomes — and higher glucose levels predict higher risk."

However, glucose lowering therapy needs to be individualized, he reiterated. For example, frail patients are unlikely to benefit from intensive glucose lowering.

And "there is no 'statin' for diabetes — ie, "prescribe and go" — yet!"

Gerstein has reported being on advisory panels for Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi, and has other relationships with AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, and Sanofi. He receives research support from AstraZeneca, Eli Lilly, Merck, and Sanofi. Reaven has reported receiving research support from Amgen, AstraZeneca, and Bristol-Myers Squibb.

American Diabetes Association 2018 Scientific Sessions. June 24, 2018; Orlando, Florida. Symposium: The Veterans Affairs Diabetes Trial (VADT) at 15 years symposium.

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