Neither intensive blood pressure control nor intensive lipid management may slow cognitive decline in adults with long-standing type 2 diabetes, according to research published online ahead of print February 3 in JAMA Internal Medicine. Intensive blood pressure control, however, may be associated with a greater decrease in total brain volume, compared with standard therapy.
After 40 months, patients on intensive blood pressure treatment in the Memory in Diabetes (MIND) trial had significantly more decline in total brain volume than patients on a standard blood pressure control program. Interpreting this result will require much more study, said Jeff Williamson, MD, Chief of Gerontology and Geriatric Medicine at Wake Forest University in Winston-Salem, North Carolina, and his colleagues.
“Although a greater decline in total brain volume is associated with early cognitive impairment, a precursor to dementia, the long-term implications are unknown and remain a focus of ongoing investigation and analyses,” said Dr. Williamson. “Our finding suggests that total brain volume and white matter lesion burden cannot, to date, be used as surrogate markers for cognitive outcomes.”
A Substudy of the ACCORD Trial
The MIND trial was a substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study and encompassed 2,977 participants who were randomly assigned to receive either intensive glycemic treatment (with the goal of reducing hemoglobin A1c to less than 6.0%) or standard treatment (with the goal of reducing HbA1c to between 7.0% and 7.9%). Participants also were assigned to either intensive or standard lipid-lowering and blood pressure–lowering treatment arms.
In 2011, the investigators concluded that intensive glycemic management did not alter the trajectory of cognitive decline. They observed, however, that total brain volume had declined significantly less in the intensive therapy group. Therefore, the investigators suggested that structural changes were preceding cognitive decline and that a treatment difference might have emerged if the therapy had been extended. The point was moot, however; ACCORD was halted early because patients in the intensive-therapy group had increased overall mortality, increased hypoglycemic events, weight gain, and no evidence of cardiovascular benefit.
Focus on Prevention, Not Treatment
The newly published data focus on the blood pressure and lipid treatment arms of the MIND study. The two-by-two design randomized patients to intensive or standard blood pressure control (120 vs 140 mmHg), or to a statin plus fibrate or statin plus placebo treatment.
Cognition was assessed at baseline, at 20 months, and at 40 months. The main outcome measure was the Digit Symbol Substitution Test (DSST), which gauges psychomotor speed and working memory. Secondary measures included the Stoop Test, the Rey Auditory Verbal Learning Test, and the Mini-Mental State Exam.
By 40 months, the DSST scores had declined to similar extents in the standard and intensive treatment groups of the blood pressure and lipid cohorts. The investigators found no significant between-group differences in any of the other three cognitive measures.
A subset of patients (378 from the blood pressure arm and 236 from the lipid arm) also underwent MRI of the brain at baseline and at 40 months. Participants in the intensive blood pressure therapy group had a significantly lower total brain volume than did those in the standard therapy group. The mean difference between the groups was approximately 4.4 cm3. The researchers found no significant differences in brain volume in the lipid management cohort.
The investigators compared this finding with the MRI results of the glycemic control study, which had shown preserved brain volume to be associated with intensive management in the blood pressure and lipid therapy groups. “Participants receiving the combination of standard antihypertensive therapy and intensive glycemic control experienced approximately 50% of the decline in total brain volume observed in the other blood pressure trial groups,” noted the authors. The results seem to reinforce the idea that earlier is better when it comes to controlling the cognitive effects of diabetes, they added.
“During the past two decades, the belief that more intensive treatment strategies for controlling type 2 diabetes-related comorbidities, such as hyperglycemia, hyperlipidemia, and hypertension, would reduce clinical complications has driven large investment in new medications for this disease syndrome,” stated the researchers. “However, these results from the ACCORD MIND substudy, along with the other recent ACCORD results, make clear the decreasing returns of intensive medication-based therapy for advanced type 2 diabetes and add further evidence to the need for increased investment in disease prevention and early intervention.”
—Michele G. Sullivan