VADT

VADT published: Intensive glucose control fails to reduce cardiovascular eventsDecember 18, 2008 Michael O'Riordan
Phoenix, AZ - Results of the Veterans Affairs Diabetes Trial (VADT), a long-term study of US veterans with type 2 diabetes receiving intensive blood glucose control, is now published online December 17, 2008 in the New England Journal of Medicine [1].
First presented at the American Diabetes Association (ADA) 2008 Scientific Sessions in San Francisco, CA and reported by heartwire at that time, the VADT showed that intensive blood glucose lowering in patients with elevated glycated hemoglobin A1c (HbA1c) levels despite medical treatment had no significant effect on the rates of cardiovascular events, death, or microvascular complications.
"We picked the toughest group of patients we could find because we figured if we could do some good there the benefit would be pretty obvious," lead VADT investigator Dr William Duckworth (Phoenix Veterans Affairs Health Care Center, AZ) told heartwire. "As the results show, though, we weren't able to do any good."
The results of the study are in line with the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease (ADVANCE) studies. The ADVANCE trial showed a reduction in the progression of albuminuria with intensive glucose control but no effect on cardiovascular event rates. ACCORD, on the other hand, was stopped early because of an increased risk of death in patients who underwent intensive blood glucose lowering.Tough-to-treat patients
Speaking with heartwire, Duckworth said that when the VADT was initiated nearly five years ago, there was little to no evidence that glucose control altered the risk of cardiovascular events. Some studies, including the United Kingdom Prospective Diabetes Study (UKPDS), suggested improvements in microvascular end points, but there were no effects on hard clinical end points such as mortality or MI.
In VADT, investigators randomized 1791 military veterans with diabetes, mean age 60 years, who had a suboptimal response to medical therapy to intensive glucose control or standard glucose control. At the time of randomization, median HbA1c levels were 9.4%. In addition, nearly 75% of patients had hypertension, 40% had a previous cardiovascular event, and patients had been diagnosed with diabetes for a mean 11.5 years.
In both study groups, obese patients were started on two drugs, metformin and rosiglitazone, whereas nonobese patients were started with glimepiride plus rosiglitazone. Patients in the intensive arm started on maximal doses. Insulin was added to most participants to achieve HbA1c levels less than 6.0% in the intensive-treatment arm and less than 9.0% in the standard-therapy arm.
After a median follow-up of 6.5 years, median HbA1c levels were reduced to 8.4% in the standard-lowering arm and to 6.9% in the intensive-glucose-control arm. During this time, 264 patients in the standard-therapy group and 235 patients in the intensive-therapy group experienced a major cardiovascular event, the composite primary end point consisting of MI, stroke, death from cardiovascular causes, congestive heart failure, vascular surgery, inoperable coronary disease, and amputation for ischemic gangrene.
"One of the things we wanted to do was reduce or eliminate as many controllable risk factors as we possibly could," said Duckworth. "We treated blood pressure and lipids very intensely and got those down to very good numbers. We also had the patients on aspirin and encouraged diet and exercise—all the things that you're supposed to do—and once that was done, I was not surprised that glucose lowering had no additional effect. Maybe a little disappointed, but not particularly surprised."
Commenting on the results for heartwire, Dr Roger Blumenthal (Johns Hopkins, Baltimore, MD) pointed out that tight glycemic control earlier in the disease process—ACCORD, ADVANCE, and VADT were carried out in individuals with established disease for a mean duration of eight to 11 years—might have been more successful.
Dr Sherita Golden (Johns Hopkins) echoed Blumenthal's sentiments.
"We all do still wonder if tight control earlier after diagnosis is most beneficial. After an individual has had diabetes for a prolonged time, the horse is out of the barn, so to speak, and tight glucose control is not as effective," said Golden.
She added that getting HbA1c levels down to 7% is still effective in preventing macrovascular complications, "so tight control to this level is still beneficial." In addition, tight control of blood pressure and cholesterol are proven strategies for primary and secondary prevention of cardiovascular disease in diabetes, she said.
Position statement on intensive glycemic control issued
With the publication of VADT and the earlier publications of ACCORD and ADVANCE, the ADA, American Heart Association (AHA), and American College of Cardiology (ACC) issued a position and scientific statement on intensive glycemic control and the prevention of cardiovascular events [2].
"The lack of significant reduction in cardiovascular disease events with intensive glycemic control in ACCORD, ADVANCE, and VADT should not lead clinicians to abandon the general target of an A1c less than 7.0% and thereby discount the benefit of good control on serious and debilitating microvascular complications," write first author Dr Jay Skyler (University of Miami, FL) and colleagues in the statement, published online December 17, 2008 in Circulation.
The report emphasizes the importance of controlling nonglycemic risk factors, such as blood pressure and lipids (using statins), as well as using aspirin and lifestyle modifications as the primary strategies for reducing the burden of cardiovascular disease in people with diabetes.
The group states that based on ACCORD, ADVANCE, and VADT, there is no need for major changes in glycemic-control targets but does offer some "clarification of the language that has consistently stressed individualization."
Lowering HbA1c levels to <7% to reduce microvascular and neuropathic complications in type 1 and 2 diabetes remains a class I recommendation. Less than 7% is also a reasonable target for reducing the risk of macrovascular complications, a class IIb recommendation, at least until more evidence becomes available, they add.
The scientific statement is also published in the Journal of the American College of Cardiology and Diabetes Care.Treat the cardiovascular risk factors
Regarding the clinical implications of the study, Duckworth, like the ADA, AHA, and ACC, emphasized the importance of treating blood pressure and lipid abnormalities to reduce the risk of cardiovascular and microvascular complications from diabetes. He added that VADT, as well as ACCORD and ADVANCE, included older patients and that younger patients might be treated differently.
"I have a practice with my elderly patients, those older than 60 years or 65 years, to not try to get their A1c down to very low levels," he said. "If I have a 45-year-old patient, then I'm considerably more aggressive—again, we don't have any evidence that it makes difference, but these patients have much longer to live and have much more time to develop complications. It's reasonable to think they might benefit from lower glucose levels. It's one of those patient-specific things: we really should be treating patients and not numbers."
The ADA, AHA, and ACC also emphasize the importance of individualizing treatment. In its statement, the group notes that for those with a short duration of disease, long life expectancy, and no significant cardiovascular disease, a more aggressive HbA1c goal might be appropriate, whereas for older patients, those with advanced microvascular and macrovascular disease, less stringent targets are recommended. These last two recommendations have weak evidence supporting them and are based on consensus opinion of experts, case studies, or standards of care.
In their paper, the VADT investigators suggest that one possibility for the lack of observed effect of intensive therapy could be that the cardiovascular benefit is delayed. Ten-year data from UKPDS showed that early intensive glucose lowering, either with a sulfonylurea or metformin, reduced the risk of MI or all-cause mortality. Long-term follow-up from the Diabetes Control and Complications Trial—Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) study also showed a reduction in cardiovascular events in patients whose blood sugar was lowered most.
"If you can manage to get glucose down without risking severe hypoglycemia, then I think it's a good thing to do regardless," said Duckworth. "It might make a difference long term, even though we don't have definite proof of it."
Duckworth reports consulting fees from Novo Nordisk, GlaxoSmithKline, and Caremark and lecture fees from Sanofi-Aventis.
Sources
Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; DOI: 10.1056/NEJMoa0808431. Available at: http://www.nejm.org.
Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials. A position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Circulation 2008; DOI: 10.1161/CIRCULATIONAHA.108.191305. Available at: http://circ.ahajournals.org.