ACCORD: Younger, not older, age linked to higher cardiovascular death rates



Patients aged 65 years and older with type 2 diabetes who received intensive glucose-lowering therapy were at no greater risk of cardiovascular death than those who were given standard glucose-lowering therapy in the large ACCORD trial.

However, study participants who were under age 65 had a significantly higher risk of death from cardiovascular causes if they received intensive versus standard glucose-lowering treatment, with a hazard ratio of 1.71, compared with 0.97 for older patients.

"The ACCORD results do not indicate that significant excess mortality occurred among intensively versus standard treatment older adults, [but] there is little evidence to suggest that older adults received a CVD [cardiovascular disease] benefit," said Michael E. Miller, Ph.D., of Wake Forest University, Winston-Salem, N.C., and his associates (Diabetes Care 2013 Oct. 29, published online before print [doi: 10.2337/dc13-1545]).

Dr. Miller and his team performed a post hoc analysis of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study to determine if there was any difference in glucose control, tolerability, cardiovascular disease, or all-cause mortality according to patients’ age at randomization.

"The ACCORD results do not indicate that significant excess mortality occurred among intensively versus standard treatment older adults, [but] there is little evidence to suggest that older adults received a CVD benefit..."

ACCORD involved 10,251 patients (mean age, 62 years) with type 2 diabetes who had a median duration of diabetes of 10 years and a median hemoglobin A1c level of 8.1% at enrollment. Patients were randomized to receive either intensive or standard glucose-lowering therapy, with target glycated HbA1c levels of less than 6.0% or between 7.0% and 7.9%, respectively.

The main findings of the glucose-lowering component of the trial were published 5 years ago and showed that, rather than having a beneficial effect on cardiovascular or all-cause mortality as hypothesized, intensively lowering HbA1c levels increased cardiovascular mortality by 35% and all-cause mortality by 22% (N. Engl. J. Med. 2008;358;2545-59). This led to the intensive-therapy arm being discontinued after a mean of 3.7 years’ follow-up.

Several analyses have since tried to determine why the excess mortality might have occurred, but there still appears to be no valid answer. For the current analysis, patients’ age at randomization was used to further examine the data. In total, there were 6,776 patients under age 65 and 3,475 who were at least 65 years old at randomization.

"Our analysis on the impact of baseline age on the effect of more intensive blood sugar lowering in the ACCORD trial indicates that, relative to standard glycemic treatment, intensive treatment resulted in similar metabolic and primary/secondary endpoint effects in older and younger participants," the researchers observed. Thus, patient age does not appear to influence whether HbA1c targets can successfully be reached or not.

Hypoglycemia requiring medical assistance occurred in three times as many patients given intensive treatment as those given standard treatment, regardless of age. Rates were 15.3% versus 5.1% for older individuals, and 8.7% versus 3.0, respectively, for younger individuals.

Although the increased risk of hypoglycemia was similar for the two age groups, the absolute incidence of severe hypoglycemia was higher in older individuals, at 4.4% with intensive treatment and 1.4% with standard treatment, versus 2.5% and 0.8% for the younger patients.

The hypoglycemia findings "amplify prior findings in older patients," the researchers commented, highlighting "the need to individualize therapy in older adults with type 2 diabetes, as suggested by others."

Altogether, these new data from ACCORD can help to develop future trials in older individuals, the investigators concluded. "Exploratory analyses of the type we have performed can help to inform the design, implementation, and monitoring of future clinical trials that include older patients with type 2 diabetes and other chronic diseases."

ACCORD was supported by grants from the National Institutes of Health. Dr. Miller and several coauthors reported no conflicts of interest. Several authors disclosed ties with AstraZeneca, Bayer, and other companies.

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