Moderate A1c Reduction Lowers Heart Risks for Veterans With Diabetes

VA Researchers Warn About Too ‘Tight’ Blood-Sugar Control

By Brenda L. Mooney

Rodney Hayward, MD

Rodney Hayward, MD

ANN ARBOR, MI — The VA’s balanced approach to glycemic control — keeping blood sugar levels low but not too low — appears to be the best course for patients seeking to avoid cardiovascular side effects of type 2 diabetes.

That’s according to a major new study, published recently in the New England Journal of Medicine, which notes that a long-term average A1c of about 8% was low enough to help most veterans reduce their risk of heart attack, stroke, heart failure or amputation by 17%.1

“Taken together with findings from other large studies, we see that controlling blood sugar in diabetes can indeed decrease cardiovascular risk, though we continue to see no effect on risk of dying during the same time period,” said lead author of the VA Ann Arbor Healthcare System. “This finding reinforces the importance of combining good blood sugar control with control of other cardiovascular risk factors for a combined effect.”


Study Enrollment and Follow-up for the Primary Outcome
Study Enrollment and Follow-up for the Primary Outcome. Complete follow-up refers to participants who were followed either until a primary-outcome event occurred or until the end of the scheduled data collection. The primary outcome was the time to the first major cardiovascular event (a composite of heart attack, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, or cardiovascular-related death). Hayward RA et al. N Engl J Med 2015;372:2197-2206.

While many patients might be able to lower their A1c closer to 7%, Hayward suggested that might not increase cardiovascular benefit enough to be worth the effort for some. That’s especially the case, he said, with patients who would have to take newer drugs with unclear long-term safety issues, who already take a pillbox-full of other medications, or are likely to suffer hypoglycemia or weight gain from the medications.

“Once someone has his or her A1c around 8%,” Hayward recommended, “we need to individualize treatment to the patient, balancing his or her individual cardiovascular risk based on personal and family history, his or her age and life expectancy, smoking history and medication side effects.”

The research was conducted by the VA Center for Clinical Management Research and the Ann Arbor Healthcare System, both in Ann Arbor, MI; the Phoenix, AZ, VA Health Care System; and the Hines VA Cooperative Studies Program Coordinating Center, Edward Hines, Jr., VAMC and VA Pharmacy Benefits Management Services, all in Hines, IL.

The data for the new analysis came from the Veterans Affairs Diabetes Trial (VADT) which randomly assigned 1,791 military veterans with type 2 diabetes to receive either intensive or standard glucose control. The 6-year interventional component of the study ended on May 29, 2008, with a median follow-up of 5.6 years.

To determine the time to the first major cardiovascular event, researchers were able to continue to track 92.4% of the participants, using central databases to identify procedures, hospitalizations and deaths. Additional information came from annual surveys and chart reviews.

“The difference in glycated hemoglobin levels between the intensive-therapy group and the standard-therapy group averaged 1.5 percentage points during the trial (median level, 6.9% vs. 8.4%) and declined to 0.2 to 0.3 percentage points by three years after the trial ended,” the study noted.


Changes in Median Glycated Hemoglobin Level, According to Year since the Start of the Study.
Changes in Median Glycated Hemoglobin Level, According to Year since the Start of the Study. Data are shown starting at year 3 because that was the point at which all the participants had been enrolled and had been in the study for at least 3 months. The I bars (slightly offset for better visibility) represent interquartile ranges. The vertical line represents the end of the interventional component of the trial and the beginning of the follow-up study period. The reason for the slight decline in the difference in glycated hemoglobin levels between the two groups that was observed in the last 6 months of the trial is unclear. Hayward RA et al. N Engl J Med 2015;372:2197-2206.

Yet, over a median follow-up of 9.8 years, the intensive-therapy group had a significantly lower risk of heart attack, stroke, new or worsening congestive heart failure or amputation for ischemic gangrene than did the standard-therapy group, with an absolute reduction in risk of 8.6 major cardiovascular events per 1,000 person-years but no reduced cardiovascular mortality. Furthermore, no reduction in total mortality was documented.

The authors of the new analysis pointed out that the findings are similar to what has been seen in other studies, although the benefits in the VA investigation were somewhat smaller. In addition, the original VADT study did not find a significant cardiovascular benefit from tight glucose control after only 5 to 6 years of follow-up, but that finding emerged after longer follow-up, they added.

“Our results should not be interpreted as supporting a performance measure for evaluating the quality of care provided by clinicians and health systems that uses the proportion of patients who reach a glycated hemoglobin level of less than 7.0%,” the researchers emphasized. “Even with the support of a dedicated research team, only approximately half the participants had a glycated hemoglobin level of less than 7.0%. In addition, in the absence of a reduction in total mortality, a small-to-moderate reduction in the rate of cardiovascular events needs to be weighed against potential harm due to overly aggressive care and the burden, long-term safety profile and side effects of treatment, including weight gain and hypoglycemia.”

In a move away from a trend toward “tight” blood sugar control in type 2 diabetes, the VA launched the national Hypoglycemic Safety Initiative (HSI) late last year to encourage veterans with the disease to seek support to lower the risk of hypoglycemia.

“The Hypoglycemic Safety Initiative is designed to enable veterans and their families, partners and caregivers to create a personal plan for blood sugar management based upon the veteran’s unique health goals,” Carolyn Clancy, MD, interim Under Secretary for Health, explained at the time of the announcement. “Our objective is to change how diabetes is managed in VA and the United States and to help patients improve their personal well-being, not just manage their numbers.”

Clancy added that hypoglycemia “has only recently been prioritized as a national public health issue, but federal agencies are taking a leadership role in addressing the problem. We are proud to note the collaboration of VA with the Department of Health and Human Services in aggressively addressing this problem.”

Partly because of concerns about hypoglycemia, clinicians are being urged to look beyond glucose-lowering drugs in diabetes treatment. Hayward pointed out that a growing body of research supports the concept that type 2 diabetes patients should take four medications to reduce cardiovascular risk: metformin to control blood sugar, a statin to control cholesterol and other blood lipids, a blood pressure lowering medication and aspirin.

The quartet of drugs, plus lifestyle changes, including improved diet, smoking cessation and an exercise program, could prevent many diabetes-related comorbidities, he stressed.

Still, blood sugar control is important, according to the study, which concluded, “Our results provide further evidence that improved glycemic control can reduce the rate of major cardiovascular events. This potential benefit may be considered in conversations with patients and balanced with the burdens and side-effect profile of the specific glucose-lowering treatment being considered.”

1 Hayward RA, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, McCarren M, Duckworth WC, Emanuele NV; VADT Investigators. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015 Jun 4;372(23):2197-206. doi: 10.1056/NEJMoa1414266. PubMed PMID: 26039600.

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  1. Mark McConnell, MD says:

    Outstanding work that we can apply to patient care daily! For any interested in the Hypoglycemia Safety Initiative, please visit our website and “subscribe” for regular updates.

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