In the Veteran's Affairs Diabetes Trial (VADT) of mainly older men with poor glycemic control, those who were randomized to receive about 5 years of intensive vs standard glycemic therapy had a lower incidence of cardiovascular events, but no improved survival during a median 9.8-year follow-up, new findings reveal.

"Our study is the first to show that tight glucose control using a modern multidrug glucose-lowering regimen can be safely achieved in older patients with type 2 diabetes and can significantly reduce cardiovascular events," lead author Dr Rodney A Hayward (VA Ann Arbor Healthcare System, MI), told Medscape Medical News.

However, since there was no reduction in total mortality, the benefit of a 17% reduction in the rate of cardiovascular events with intensive glycemic therapy "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," he and his colleagues say.

"Striving [to get a patient's] HbA1c below 8% will depend on many considerations, including patient life expectancy, risk of hypoglycemia, safety evidence for the medication being considered, and patient preference," Dr Hayward added.

Asked to comment, Dr William C Cushman (University of Tennessee Health Science Center, Memphis), an author on the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, a similar trial of intensive vs standard glycemic control, agrees.

"This is an important contribution to the totality of evidence but does not clearly support treating patients with type 2 diabetes more aggressively than an HbA1c goal of <8%," he commented.

Tight vs Standard Glycemic Control and Later CV Events, Survival

VADT randomized 1791 military veterans who had type 2 diabetes and a mean initial HbA1c level of 9.5% to standard or intensive glycemic control (N Engl J Med 2009;360:129-139). The participants had a mean age of 60, had had diabetes for an average of 11.5 years, and were generally overweight (mean weight of 214 lb; average body-mass index [BMI] of 31.2 kg/m2).

Those with a BMI of >27 kg/m2 were started on metformin plus rosiglitazone and those with a BMI of <27 kg/m2 were started on glimepiride plus rosiglitazone (maximal doses in the intensive-therapy group and half-maximal doses in the standard-therapy arm).

Insulin was added for patients who did not achieve an HbA1c below 6% (intensive-therapy group) or below 9% (standard-therapy group). Investigators could then alter the medications as they saw fit.

After 5.6 years of treatment (ending in May 2008), the median HbA1c levels were 6.9% for patients in the intensive-therapy group vs 8.4% in the standard-therapy group. There were no significant effects on major cardiovascular events or death with intensive vs standard therapy when the main results were reported in 2009.

The current analysis included about 5 additional years of observational follow-up, after participants returned to usual care. A total of 1391 participants completed annual follow-up surveys that asked about cardiovascular events. The researchers had complete data for 9.8 years of follow-up and partial data for 11.8 years of follow-up.

The primary outcome was the time to the first major cardiovascular event (a composite of heart attack, stroke, new or worsening congestive heart failure, death from cardiovascular causes, or amputation for ischemic gangrene). Secondary outcomes were cardiovascular mortality and all-cause mortality.

A year after the intervention was stopped, HbA1c levels were 7.8% vs 8.3%, for patients who had previously received intensive vs standard glycemic therapy, respectively.

During the extended follow-up, there were 8.6 fewer major cardiovascular events per 1000 person-years in the patients who had received intensive glycemic therapy compared with those who had received standard therapy.

However, cardiovascular or total deaths were not significantly reduced in the intensive-therapy group

Risk of Outcomes, Intensive vs Standard Glycemic Therapy

Outcome HR (95% CI)  P
Major CV eventa 0.83 (0.70–0.99)b 0.04
CV mortality 0.88 (0.64–1.20)c 0.42
All-cause mortality 1.05 (0.89–1.25)c 0.54
a. Composite of heart attack, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, or death from cardiovascular cause
b. 9.8 years of follow-up
c. 11.8 years of follow-up

"A Clearer Picture of the Effect of Improved Glycemic Control"

When the current study results are combined with those of the three other large, randomized, controlled trials of improved glucose control in patients with type 2 diabetes—the United Kingdom Prospective Diabetes Study (UKPDS), the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, and the ACCORD study—"a clearer picture of the effect of improved glycemic control seems to be emerging," Dr Hayward and colleagues write.

The 17% relative reduction in the rate of cardiovascular events with intensive therapy compared with standard therapy was "similar to that observed in the follow-up studies of the ACCORD trial and UKPDS, after accounting for the greater reduction in glycated-hemoglobin level observed in VADT," they note.

"The main thing is that about a 10% to 12% reduction in cardiovascular events per one-point drop in HbA1c is a pretty consistent finding in all four studies," Dr Hayward observed.

However, this new VADT analysis found no evidence of a reduction in total mortality even after almost 12 years of follow-up, which was similar to the long-term results of the ADVANCE study, known as ADVANCE-ON.

"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," Dr Hayward said.

This reduction in risk of cardiovascular events coupled with a lack of a survival benefit is not unique, he noted.

"For example, daily aspirin for coronary artery disease primary prevention reduces the chance of having a heart attack but has little to no impact on mortality, at least over a 5- to 10-year period," he said.

Dr Hayward also noted the importance of control of other cardiovascular risk factors for a combined effect in patients with type 2 diabetes. A growing body of evidence supports the concept of taking four medications for cardiovascular protection: metformin to control blood glucose, a statin to reduce cholesterol, a blood-pressure lowering medication, and aspirin.

This quartet of drugs, combined with diet, stopping smoking, and exercise, could help millions of people stave off the MIs, strokes, heart failure, and amputations that cause so much premature death and disability among people with diabetes, he added. They may also help prevent microvascular complications, including diabetic retinopathy, neuropathy, and nephropathy.

ACCORDION Results Not Yet Presented

In contrast to the mortality findings in VADT and ADVANCE, patients in the UKPDS trial, who were younger (mean age of 53 years) and had newly diagnosed diabetes, had a significantly reduced mortality with intensive glycemic control.

But patients in ACCORD, who received more aggressive therapy in the intensive-treatment arm, had a significant increase in mortality.

"We have not presented or published the extended follow-up of ACCORD (ACCORDION) yet," Dr Cushman noted.

"One difference in VADT and ACCORD from ADVANCE and UKPDS is the larger and stable HbA1c differences maintained during the trials. However, VADT has a much smaller sample some results could be more influenced by chance and reduced power," he observed.

Indeed, the new VADT findings do not support setting a global HbA1c target of 7%, Dr Hayward cautioned.

"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%," since even with a dedicated research team, "only about half the participants attained this HbA1c level."

The researchers are continuing to follow this population to see whether there is a "legacy effect, [in which] the absolute risk reduction [for a major cardiovascular event] does not just persist but continues to grow," Dr Hayward explained.

The study was supported by the VA Cooperative Studies Program, a grant from the National Institute of Diabetes and Digestive and Kidney Diseases, and grants from the National Institutes of Health. Support for obtaining data from the VA system or the Centers for Medicare & Medicaid Services was provided by the Information Resource Center of VA Health Services Research and Development. Hayward reports having no relevant financial relationships. Disclosures for the coauthors are listed in the article.

N Engl J Med. 2015;372:2197-2206.



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