Importance  Hypoglycemia commonly occurs in patients with diabetes mellitus (DM) and may negatively influence cognitive performance. Cognitive impairment in turn can compromise DM management and lead to hypoglycemia.

Objective  To prospectively evaluate the association between hypoglycemia and dementia in a biracial cohort of older adults with DM.

Design and Setting  Prospective population-based study.

Participants  We studied 783 older adults with DM (mean age, 74.0 years; 47.0% of black race/ethnicity; and 47.6% female) who were participating in the prospective population-based Health, Aging, and Body Composition Study beginning in 1997 and who had baseline Modified Mini-Mental State Examination scores of 80 or higher.

Main Outcome Measures  Dementia diagnosis was determined during the follow-up period from hospital records indicating an admission associated with dementia or the use of prescribed dementia medications. Hypoglycemic events were determined during the follow-up period by hospital records.

Results  During the 12-year follow-up period, 61 participants (7.8%) had a reported hypoglycemic event, and 148 (18.9%) developed dementia. Those who experienced a hypoglycemic event had a 2-fold increased risk for developing dementia compared with those who did not have a hypoglycemic event (34.4% vs 17.6%, P < .001; multivariate-adjusted hazard ratio, 2.1; 95% CI, 1.0-4.4). Similarly, older adults with DM who developed dementia had a greater risk for having a subsequent hypoglycemic event compared with participants who did not develop dementia (14.2% vs 6.3%,P < .001; multivariate-adjusted hazard ratio, 3.1; 95% CI, 1.5-6.6). Further adjustment for stroke, hypertension, myocardial infarction, and cognitive change scores produced similar results.

Conclusion and Relevance  Among older adults with DM, there seems to be a bidirectional association between hypoglycemia and dementia.

The growing body of evidence that diabetes mellitus (DM) may increase risk for developing cognitive impairment, including Alzheimer disease and vascular dementia,^1– 2 has prompted interest in whether DM treatment can prevent cognitive decline. Glycemic control has been proposed as a potential mechanism to improve cognitive outcomes among those with DM.^1,3 However, trials evaluating the benefit of glycemic control have also highlighted the risk for hypoglycemia with intensive therapy.^4– 6

The brain uses glucose as a primary source of energy. Cognitive function becomes impaired when blood glucose drops to low levels,⁷ and severe hypoglycemia may cause neuronal damage.^7– 9Although the acute effects of hypoglycemia have been well documented, it is unclear if the cognitive effects of hypoglycemia are persistent. Results from the few investigations of hypoglycemia and cognitive impairment have been conflicting, with some studies^10– 11 reporting an association but not other studies.^12– 13 In addition, little is known about the cognitive effects of hypoglycemia occurring in late life, when the brain may be more vulnerable.¹⁴

The direction of the association between hypoglycemia and cognitive impairment is also debated. Those with dementia or even milder forms of cognitive impairment may be less able to effectively manage complex DM behavioral and treatment regimens and recognize the symptoms of hypoglycemia and respond appropriately, increasing the risk for severe hypoglycemia.^13,15– 19Whether a bidirectional association exists, in which hypoglycemia increases the risk for dementia and dementia increases the risk for hypoglycemia, has not been determined to our knowledge. Because the incidence of both hypoglycemia and dementia increases with age and duration of DM,^20– 21 a better understanding of the association between hypoglycemia and dementia is needed.

We prospectively examined the association between severe hypoglycemia and dementia in a biracial cohort of community-dwelling older adults with DM and without dementia at baseline. We hypothesized that severe hypoglycemia would be associated with an increased risk for dementia and that those diagnosed as having dementia would be at an increased risk for severe hypoglycemia.

DISCUSSION

Among older adults with DM who were without evidence of cognitive impairment at study baseline, we found that clinically significant hypoglycemia was associated with a 2-fold increased risk for developing dementia and a number needed to harm of 5.9. Similarly, participants with dementia were more likely to experience a severe hypoglycemic event, with a number needed to harm of 12.7. The association remained even after adjustment for age, sex, educational level, race/ethnicity, comorbidities, and other covariates. These results provide evidence for a reciprocal association between hypoglycemia and dementia among older adults with DM.

Previous studies of hypoglycemia and cognitive impairment in older adults have had mixed results. Findings from a retrospective study¹⁰ conducted using the Kaiser Permanente Northern California Diabetes Registry demonstrated an almost 2-fold increased risk for dementia among older adults with DM who had a history of 1 or more hypoglycemic episodes. Risk was even greater for those with multiple episodes. Similarly, a population-based cross-sectional study¹¹ found that a lifetime history of severe hypoglycemia was associated with poor late-life cognition, independent of premorbid cognition. Our investigation expands on these studies by prospectively investigating severe hypoglycemia and dementia among older adults who were initially free of cognitive impairment, allowing for a better evaluation of temporality. We were also able to assess the possible scenario that preclinical cognitive impairment is associated with greater risk for severe hypoglycemia and in turn with risk for dementia. Most importantly, after adjustment for change in global cognitive function, severe hypoglycemia remained associated with risk for developing dementia.

In contrast, the Fremantle Diabetes Study¹³ found no evidence that a history of hypoglycemia was associated with cognitive decline among older adults with normal cognition at baseline, although the short follow-up duration may have limited the ability to detect differences. The Diabetes Control and Complications Trial also did not find an association between hypoglycemia and cognitive impairment among younger adults with type 1 DM.¹² Varied results may possibly be due to differences in cohort demographics, frequency or severity of hypoglycemia, or age at which the hypoglycemic event occurred. Older individuals have a higher incidence of hypoglycemia²⁰ and may be more susceptible to adverse cognitive effects than younger age groups.¹⁴ Hypoglycemia may also differentially influence cognition depending on overall brain health, perhaps aggravating underlying pathologic conditions or triggering the onset of neurodegenerative processes.

Hypoglycemia may contribute to the pathogenesis of dementia through several possible mechanisms. Recurrent severe hypoglycemia has been shown to result in brain damage,⁷ with preferential vulnerability found in the cerebral cortex and hippocampus.^7– 9 Some evidence suggests that neuronal damage resulting from hypoglycemia may be enhanced in DM compared with non-DM brains, perhaps due to altered glucose metabolism or through insulin deficiency.⁸Hypoglycemia may cause a loss of ionic homeostasis or increases in reactive oxygen species that can lead to neuronal death.⁹ Amyloid precursor protein may also be produced as a result of damage.²⁶ In addition, insulin resistance and hyperinsulinemia may have a role in neurodegeneration through disrupting the normal function of insulin within the brain.²⁷ Insulin may affect the metabolism of amyloid beta and tau proteins, and chronic hyperinsulinemia may exacerbate inflammatory markers and oxidative stress.²⁸ Cerebrovascular disease is another potential mechanism. Pathologic microinfarcts have been shown to contribute to brain atrophy and cognitive impairment.²⁹ Although we adjusted for stroke and MI and results were robust, we cannot rule out residual confounding, and we had no information on microinfarcts.

Our finding of a higher risk for hypoglycemia with dementia adds to a small body of literature demonstrating a greater incidence of hypoglycemia with impaired cognitive function.^{13,18– 19,30}However, to our knowledge, no known prior study has prospectively evaluated the association between dementia and severe hypoglycemia among a diverse group of older individuals initially free of dementia. The heightened risk for hypoglycemia among those with dementia may reflect difficulties in managing DM. Insulin therapy^13,30 and reported inability to self-manage DM medications¹³ have been previously identified as additional risk factors for hypoglycemia among those with cognitive impairment. Cognitive dysfunction, including dementia and milder forms of impairment, may also delay recognition of the symptoms of hypoglycemia and interfere with a patient’s ability to respond with corrective measures. Older adults have been shown to be less aware of the symptoms of hypoglycemia than younger persons³¹; however, it is unknown if this is more pronounced among those with cognitive impairment. More studies are needed to identify risk factors and effective management strategies to reduce the incidence of hypoglycemia among older persons with dementia, as well as in those with less severe forms of cognitive impairment.

Our findings emphasize the importance of cognitive function in the clinical management of older adults with DM. Certain medications known to carry a higher risk for hypoglycemia, such as insulin secretagogues and some sulfonylureas,²⁰ may be inappropriate for older patients with or at risk for cognitive impairment. While physicians should be aware of the higher risk for hypoglycemia in patients with dementia because symptoms of hypoglycemia in older adults could be misinterpreted,^20,32 delaying treatment, they should also consider the implications for the management and care of patients with lesser, subclinical levels of cognitive dysfunction. In addition, caretakers may not know the symptoms and treatment of hypoglycemia, and educational efforts may be needed.

This study has several strengths, including a prospective design with a long follow-up period and a large, diverse sample of community-dwelling older adults. Participants were free of dementia at study baseline, and we were able to assess temporality of hypoglycemia and dementia. Hypoglycemia was based on hospital records, which is a more objective measure than self-report. We were also able to adjust for multiple confounders. However, several study limitations also warrant consideration. While we tried to highlight the association of hypoglycemia and dementia defined by clinically important measures (hospitalization diagnostic codes or medication use), we were unable to investigate the effects of subclinical outcomes, such as moderate hypoglycemia or milder forms of cognitive impairment, nor were we able to include history of hypoglycemia before baseline. Although our case definition for dementia was likely very specific, it was probably insensitive to mild cases of cognitive impairment. In this context, power would most likely be affected, but the point estimate for the effect of hypoglycemia on dementia would not be biased.³³In addition, we had no brain magnetic resonance imaging measures, which may have helped to ascertain the subtype of dementia.

In summary, our results provide evidence for a bidirectional association between severe hypoglycemia and dementia. Hypoglycemia may impair cognitive health, and reduced cognitive function may increase the risk for a hypoglycemic event that could further compromise cognition, resulting in a detrimental cycle. Cognitive function should be considered in the clinical management of older individuals with DM.

Source: JAMA