Cognitive impairment predicted risk of major cardiovascular events, stroke, and death in patients with type 2 diabetes, according to a large retrospective analysis.
In the 8,772 patients of the REWIND trial that was followed for approximately 5 years, subjects with intrinsic cognitive impairment had an increased risk of major cardiovascular events such as myocardial infarction (HR 1.30, 95% CI 1.11-1.62, s= 0.003) as well as the stroke or death composite (HR 1.60, 95% CI 1.33-1.91, s<0.001)), according to Hertzel Gerstein, MD of McMaster University in Ontario, Canada, and colleagues.
Cognitive impairment was defined as a score of 1.5 standard deviations or more below the mean on either of the two cognitive tests taken at baseline. However, when the researchers combined the results of both tests, the association between cognition and heart disease was stronger for both outcomes: major cardiovascular events (HR 1.61, 95% CI 1.28–2.01, s<0.001) and stroke or death (HR 1.85, 95% CI 1.50-2.30, s<0.001).
“The fact that these relationships generally persisted after adjustment for age, gender, education, and prior stroke or TIA [transient ischemic attack]and several other potentially confounding variables suggest that cognitive status provides additional relevant information regarding an individual’s risk of future vascular outcomes, the team wrote in Journal of Endocrinology and Metabolism.
In a statement accompanying the study, Gerstein added: “Our study found low scores on cognitive tests that predicted heart disease in patients with diabetes and other heart risk factors. Although the explanation for this remains unclear, these patients should be offered proven heart medications in order to reduce their risk. in the future for a heart attack or stroke.”
In the paper, researchers discuss several mechanisms of action that may link cognitive impairment and heart disease. For example, cognitive impairment may be associated with white matter, small vessel disease, or brain infarcts also present elsewhere. Another possibility is that cognitive dysfunction is associated with a lower ability to self-care, risk avoidance, and the ability to manage diabetes.
In addition, the team continued, cognitive function is known to be associated with other risk factors for cardiovascular outcomes such as socioeconomic status. Finally, research has suggested that cognitive impairment and cardiovascular outcomes can share common causes such as mitochondrial dysfunction, dysregulation of the Sortlin pathway, pituitary-adrenal axis activation, inflammation, dysglycemia, or resistance to Brain and systemic insulin.
Gerstein and co-authors reported preliminary results of the REWIND trial in 2019. It included 9,901 adults from 24 countries with established or newly diagnosed type 2 diabetes, with an HbA1c of 9.5% or less. After approximately 5 years of follow-up, those who received weekly injections of 1.5 mg dulaglutide had a 12% lower risk of experiencing the combination endpoint of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes compared to those who received weekly injections of 1.5 mg dulaglutide. In the placebo group (HR 0.88, 95% CI 0.79-0.99, s= 0.026).
The new post-hoc analysis included 8,772 participants from 24 countries who completed both the Montreal Cognitive Assessment (MoCA) and the Number Substitution Test (DSST) at baseline. The raw MoCA and DSST score for each participant were converted into a standardized score by country to account for potential geographic differences. The researchers also combined each participant’s MoCA and DSST scores into the composite cognitive score, and used Cox proportional hazards models to examine associations between these test scores and cardiovascular outcomes.
The investigators noted that the limitations of the analyzes included their retrospective nature. In addition, they said, although they took two tests, the assessment of cognitive function was not comprehensive and did not include all cognitive domains. Finally, the results may not be generalizable to patients who are younger or at lower risk of CVD than those in the REWIND study.
“In summary, these results demonstrate two ways to use results from more than one cognitive test to identify cognitive impairment in large international studies,” Gerstein and colleagues write. “These findings also highlight the importance of these new indicators of cognitive impairment for future vascular outcomes and suggest that application of recent guidelines recommending routine screening for cognitive impairment in older adults with diabetes may identify individuals who are most likely to benefit from proven cardiac therapies.”
The REWIND trial was funded by Eli Lilly.
Gerstein disclosed his financial relationships with Eli Lilly, Boehringer Ingelheim, Novo Nordisk, Sanofi, DKSH, Roche, Zulge, Abbott, AstraZeneca, Merck, Covance, Pfizer, Koa and Hanmi; Co-authors also reported multiple financial relationships with industry.