VADT at 15 Years Published: Lack of 'Legacy Effect' in Diabetes

The lack of a "legacy effect" of intensive glucose lowering at 15 years in the Veterans Affairs Diabetes Trial (VADT) suggests that other cardiovascular risk reduction strategies should be prioritized in patients with advanced type 2 diabetes and established cardiovascular disease.

That is the conclusion of Kasia J. Lipska, MD, Yale School of Medicine, New Haven, Connecticut, and Neda Laiteerapong, MD, University of Chicago, Illinois, in an editorial accompanying the study results, published online June 5 in the New England Journal of Medicine.

The findings were first presented at the American Diabetes Association (ADA) 2018 Scientific Sessions, as reported by Medscape Medical News.

In VADT, which originally enrolled 1791 military veterans with type 2 diabetes for an average of 11.5 years' duration, those participants who had been randomized to intensive glycemic control for a median of 5.6 years experienced lower rates of cardiovascular events than those randomized to standard therapy at a 10-year interim analysis.

But in the current 15-year follow-up, there was no difference in cardiovascular events, total mortality, or quality of life.

The lack of effect by 15 years co-occurred with the loss of separation in average HbA_1c levels over time between the two groups, eventually merging to about 8% after the trial ended and participants returned to their usual care.

"Although there was a significantly lower risk of major cardiovascular events during the 7.1 years of separation of the glycated hemoglobin curves (during the trial and observation periods), there was no evidence of a beneficial legacy effect after this period of improved glucose control," note the authors, led by Peter D. Reaven, MD, of the Phoenix VA Health Care System, Arizona.

Therefore, a major implication of the VADT follow-up study, Lipska and Laiteerapong write in their editorial, "is that older patients with advanced diabetes should not expect long-term cardiovascular benefits from intensive glycemic control."

Rather, the editorialists say, "[other] interventions that clearly reduce cardiovascular risk — such as smoking cessation, blood pressure control, statin therapy, use of antiplatelet agents, and the use of glucose-lowering agents with proven cardiovascular benefits in patients with established cardiovascular disease — should be prioritized."

Lack of "Legacy Effect"

During the trial (which lasted 5.6 years), there was a 1.5 percentage point difference in HbA_1c between the two treatment groups, averaging 6.9% with intensive treatment versus 8.4% for the controls. At the time the trial ended, there were no significant differences between the groups in cardiovascular events (a composite of myocardial infarction, stroke, cardiovascular death, congestive heart failure, and amputation), cardiovascular mortality, or all-cause mortality.

However, at a 10-year interim analysis, the intensive treatment group did have a significantly lower incidence of cardiovascular events. At that time, there was still a small difference in HbA_1c between the two groups of 0.2-0.3 percentage points.

In the current analysis of 1655 VADT participants at a median follow-up of 13.6 years, cardiovascular event rates were 47.3 vs 51.8 per 1000 person-years in the intensive and standard treatment groups, respectively, a nonsignificant difference (hazard ratio, 0.91; P = .23).

Rates of any major diabetes event (hazard ratio, 0.90), death from cardiovascular causes (0.94), or death from any cause (1.02), as well as rates of hospitalization (0.98) and health-related quality of life scores (1.6) also didn't significantly differ between groups.

These most recent results suggesting a lack of "legacy effect" that had been demonstrated in the observational follow-up of other trials, including the Diabetes Control and Complications Trial (DCCT) in type 1 diabetes and the United Kingdom Prospective Diabetes Study (UKPDS) in type 2 diabetes.

VADT Versus DCCT and UKPDS: Populations, Risk Factor Control Differed

Reaven and colleagues say that underlying atherosclerosis and cardiovascular injury may have been too advanced in the VADT participants for glucose-lowering to have made a difference.

In addition, they note, "the DCCT and UKPDS were also conducted at a time before widespread statin use and tight blood pressure control, whereas participants in the VADT and other recent trials have had aggressive treatment of all cardiovascular disease risk factors."

"It is plausible that the cardiovascular protective effects of tight glycemic control have diminishing returns once other cardiovascular disease risk factors are well controlled by medications that may also have vasoactive properties."

Lipska and Laiteerapong make these points as well. They also note that the VADT was investigating glucose lowering per se using similar medications in both treatment groups.

In contrast, more recent cardiovascular outcome trials of glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown benefits compared with placebo in reducing major cardiovascular events in patients with type 2 diabetes and established cardiovascular disease, independent of glycemic control.

"Thus, for patients with advanced diabetes, clinical focus on how glucose levels are lowered rather than on achieving intensive targets may lead to better cardiovascular outcomes," the editorialists write.

Although a glycemic "legacy" effect may still exist for younger patients, "the current era of comprehensive cardiovascular risk-factor control may reduce, if not eliminate, legacy effects," they continue.

"Glycemic goals that are likely to produce both cardiovascular and microvascular benefits and minimize harms, consistent with patient preferences and values, may be the most effective, evidence-based, and safest strategy for patients with type 2 diabetes."

The study was supported by the Office of Research and Development, VA Cooperative Studies Program. The primary VADT was supported by the VA Cooperative Studies Program, American Diabetes Association, and National Eye Institute, as well as GlaxoSmithKline, Novo Nordisk, Roche Diagnostics, Sanofi-Aventis, Amylin, and Kos Pharmaceuticals. Reaven has reported receiving grant support from AstraZeneca, Bristol-Myers Squibb, and Novo Nordisk, fees for serving on an advisory board from Sanofi and Boston Heart Diagnostics, and lecture fees from Takeda. Lipska has reported receiving grants from the National Institutes of Health/National Institute of Aging, Centers for Medicare & Medicaid Services, and personal fees from the Health Services Advisory Group outside the submitted work. Laiteerapong has reported no relevant financial relationships.

N Engl J Med. Published online June 5, 2019. Abstract, Editorial

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