07 Feb 2014

Since diabetes and cardiovascular disease heighten the risk of cognitive decline, would treating the symptoms of these chronic diseases protect cognition? It’s a logical assumption, but the answer is no, according to a study in the February 3 JAMA Internal Medicine online. Researchers led by Jeff Williamson at Wake Forest School of Medicine, Winston-Salem, North Carolina, reported that lowering blood pressure and cholesterol below current standards in older people with chronic diabetes did not slow cognitive decline, and in fact the brain shrank faster in people given more blood pressure medication. The data comes from the large Action to Control Cardiovascular Risk in Diabetes (ACCORD) Memory in Diabetes (MIND) trial led by Lenore Launer at the National Institute on Aging, Bethesda, Maryland. The findings complement earlier data from this trial that showed that intensive treatment to reduce elevated blood sugar likewise failed to preserve cognition, although that intervention did slow brain atrophy (see Oct 2011 news story).

Together, the findings imply that such interventions may be too little, too late. “There is a limit to what medication can do to prevent diabetes-related complications, especially once the disease duration or severity reaches a certain point,” Williamson said. Future research should be directed more toward preventing diabetes and heart disease in the first place at younger ages, not mitigating their consequences later, he suggested. In an accompanying commentary, Carole Dufouil at INSERM, Bordeaux, France, and Carol Brayne at the University of Cambridge, England, wrote, “In people with uncontrolled Type 2 diabetes mellitus, the ACCORD MIND findings suggest that treatments other than those targeting glycemia, blood pressure, or lipid levels should be explored.”

Both heart disease and diabetes are closely linked to cognitive problems (see Jan 2014 webinar; see AlzRisk analysis). To learn what is gained from treating these disorders, the ACCORD trial recruited more than 10,000 older people with Type 2 diabetes and cardiovascular risk factors. Nearly 3,000 of them participated in the MIND substudy. Their average age was 62 and they had struggled with diabetes for about 10 years, with poor control of blood sugar and blood pressure. The researchers split the cohort in half to test two interventions, one targeting blood pressure and the other, cholesterol. In the hypertension study, half the participants received high-dose medication that dropped systolic pressure below 120 mm Hg, while the other half received standard treatment aiming for the 130-140 mm range. In the cholesterol study, the control group took statins while the rest took statins plus fenofibrate, a drug that further lowers cholesterol and other fats in the blood. 

After 40 months of treatment, all participants performed worse on cognitive tests than they had at baseline. There were no significant differences between standard and treatment arms in either study.

More than 500 MIND participants volunteered for MRI as well. These scans showed that whole brain volume shrank over 40 months in all participants, but the intensive blood pressure-intervention group had significantly more atrophy. Although treatment has since ended, the researchers continue to follow the cohort to see if cognitive differences between arms will show up over time, and if such changes will reflect the alterations in brain volume. Participants recently completed 75-month follow-up cognitive tests and brain scans; those results may be available within the year, Williamson told Alzforum.

Why does lowering blood pressure make the brain shrink faster in older diabetics? Costantino Iadecola at Weill Medical College of Cornell University, New York City, noted that the finding makes sense given the pathophysiology of diabetes. This disease causes lesions to form in the brain’s blood vessels and destroys their ability to adjust their diameter in response to changes in blood pressure in order to keep blood flow constant. With the loss of this autoregulation, lowering blood pressure in diabetics simply results in less blood reaching the brain, making brain tissue vulnerable to ischemia, Iadecola said. Thus, once the brain’s blood vessels are already damaged, a slightly higher blood pressure can be protective. This agrees with epidemiologic research. The AlzRisk blood pressure analysis found that hypertension in midlife increases the risk of Alzheimer’s disease, but by old age, higher blood pressures seem to be beneficial.

Overall, the ACCORD MIND results indicate that the current standard of care provides the best health outcomes for people who have had diabetes for a long time, and there is no need for physicians to lower blood pressures further in these patients. 

Williamson cautioned that the findings may not apply to other groups. It is possible that people newly diagnosed with diabetes could benefit from tighter control of cholesterol, blood pressure, and blood sugar. Many questions remain about the best blood pressure treatment for younger patients and non-diabetics. Epidemiologic studies consistently show that people whose blood pressure is around 120 live longer without disabilities than their peers with higher readings. “But we don’t know if treating to 120 is the best or safest way to go, especially for older people,” Williamson said. Currently, little evidence exists to support aggressive hypertension control; this recently led experts to recommend relaxing the standards for blood pressure management (see James et al., 2014). 

To collect better data, the National Heart Lung and Blood Institute, in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute on Aging, are conducting the Systolic Blood Pressure Intervention Trial. SPRINT enrolls 10,000 older people with heart or kidney disease and will examine what lowering blood pressure below 120 does for the heart and kidney, and for cognition (see NIH press release). The trial will conclude in 2018. “This is an important trial nationally for determining how best to manage the growing population of older people with high blood pressure,” Williamson noted. Currently, nearly one-third of adult Americans have hypertension.—Madolyn Bowman Rogers.

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References

News Citations

1. Aggressive Diabetes Treatment Slows Atrophy But Not Mental Slide 6 Oct 2011

Webinar Citations

1. Neurovascular Underpinnings of Alzheimer's Dementia 6 Dec 2013

External Citations

1. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Memory in Diabetes (MIND) trial
2. AlzRisk analysis
3. AlzRisk blood pressure analysis
4. James et al., 2014
5. Systolic Blood Pressure Intervention Trial
6. NIH press release

Further Reading

News

1. AlzRisk Adds Fifth Factor to Database: Meta-Analysis of Hypertension 24 Jun 2011
2. Search for AD Drugs Turns to a Hypertension Medicine 12 Jul 2011
3. Does Brain Hypoxia Help Kick Off Alzheimer’s Pathology? 16 Dec 2011
4. Silent Vascular Disease May Hasten Dementia Progression 10 Feb 2012
5. ApoE4 Makes Blood Vessels Leak, Could Kick Off Brain Damage 17 May 2012
6. Can Blood Pressure Drug Put the Squeeze on Brain Amyloid? 17 Sep 2012
7. Vascular Dementia or Alzheimer’s: Is the Delineation Emerging? 22 Feb 2013
8. Controlling Blood Pressure May Lower Amyloid in ApoE4 Carriers 22 May 2013
9. Research Brief: Diabetes—Risk Factor That Slows Cognitive Decline? 27 Oct 2009
10. Paris: Diabetes, Insulin, and Alzheimer Disease 17 Jun 2009
11. Type 2 Diabetes and Neurodegeneration—The Plot Caramelizes 29 Jan 2009
12. Better Models Weigh In on AD-Diabetes Link 19 Mar 2010