In older adults who have diabetes, clinically significant hypoglycemic events are associated with a doubling of the risk for developing dementia, according to a report published online June 10 in JAMA Internal Medicine.
In addition, older adults with diabetes who already have cognitive impairment are more likely than others to experience severe hypoglycemic events, and these can further compromise their cognition, said Dr. Kristine Yaffe of the department of psychiatry, University of California, San Francisco, and her associates.
The findings "provide evidence for a reciprocal association between hypoglycemia and dementia," which can devolve into "a detrimental cycle" for some older patients, the investigators said (JAMA Intern. Med. 2013 June 10 [doi:10.1001/jamainternmed.2013.6176]).
Dr. Kristine Yaffe
"Our findings emphasize the importance of cognitive function in the clinical management of older adults with diabetes," they noted. "Certain medications known to carry a higher risk for hypoglycemia, such as insulin secretagogues and some sulfonylureas, may be inappropriate for older patients with or at risk for cognitive impairment."
Physicians "should also consider the implications for the management and care of patients with lesser, subclinical levels of cognitive dysfunction," Dr. Yaffe and her associates said. And caretakers should be educated about the symptoms and treatment of hypoglycemia.
The researchers examined the association between hypoglycemia and cognitive impairment because the few studies that have assessed the issue produced conflicting results. They used data collected in a large, prospective cohort study involving a random sample of 3,075 people aged 70-79 years who lived in Memphis or Pittsburgh at the study’s inception in 1997.
For their analysis, Dr. Yaffe and her colleagues included 783 of the study subjects who had diabetes at baseline or developed it during the 12-year follow-up. Approximately half the study population was black and half was white; approximately half of the patients were men and half were women.
During follow-up, 61 (7.8%) of the older adults with diabetes reported having at least one hypoglycemic event that required a hospital visit. Twenty-one of those patients had more than one such event.
Overall, 148 (18.9%) of the study patients developed dementia during follow-up.
The study subjects who were hospitalized for a hypoglycemic event were approximately twice as likely to develop dementia (21 of 61 patients, or 34.4%), compared with the 127 of 722 patients (17.6%) who did not have a hypoglycemic event.
After the data were adjusted to account for differences in age, sex, education level, insulin use, race/ethnicity, apo E–epsilon 4 allele status, baseline scores on the Modified Mini-Mental State Examination, and glycated hemoglobin level at baseline, analysis of the data produced similar results. Additional adjustment for MI, stroke, and hypertension did not change the results appreciably.
The association between hypoglycemia and dementia risk also remained significant in a sensitivity analysis, the investigators said.
"Hypoglycemia may contribute to the pathogenesis of dementia through several possible mechanisms," they noted. Hypoglycemia can directly induce neuronal damage, preferentially affecting the cerebral cortex and hippocampus. It also can act indirectly by causing a loss of ionic hemostasis or raising the number of reactive oxygen species, which in turn induce neuronal death.
Hypoglycemia also may contribute to the production of amyloid precursor protein, disruption of the metabolism of amyloid and tau proteins, an increase in inflammatory markers, and exacerbation of oxidative stress. In addition, it may precipitate microinfarcts in the brain, the researchers said.
This study was supported by the National Institute on Aging, the National Institute of Nursing Research, and the American Health Assistance Foundation. Dr. Yaffe reported ties to Medivation, Novartis, Pfizer, and Takeda.