Severe Hypoglycemia Begets Dementia, and Vice Versa

Miriam E. Tucker

June 12, 2013

Severe hypoglycemia is associated with the development of dementia in adults with diabetes and vice versa, a new prospective study finds.

A doubling of the risk for dementia among older adults with diabetes who experience severe hypoglycemia was among the findings reported in the study, published online June 10 in JAMA Internal Medicine, by Kristine Yaffe, MD, from the department of psychiatry at the University of California, San Francisco, and colleagues.

In addition, the investigators found an approximate 3-fold increase in the risk of experiencing a subsequent severe hypoglycemic event among older adults with diabetes who already had 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," Dr. Yaffe and colleagues say. Cognitive function "should be considered in the clinical management of older adults with [diabetes mellitus]," they add.

The findings suggest that pushing for tight glucose control may be doing more harm than good among some elderly patients, say Kasia J. Lipska, MD, from Yale University School of Medicine, New Haven, Connecticut, and Victor M. Montori, MD, from the Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, Minnesota, in an accompanying editorial.

Dr. Lipska told Medscape Medical News she suspects that hypoglycemia is both underrecognized and underreported in clinical practice. "Clinicians should ask patients taking insulin or insulin secretagogues about symptoms of hypoglycemia at every visit. The recent [American Diabetes Association] ADA and Endocrine Society Workgroup consensus paper provides some examples of questionnaires to be used for this purpose," she noted.

And she added that decisions about specific therapies for diabetes must be made individually, with each patient, depending on their individual circumstances.

Severe Hypoglycemia With Hospitalization Associated With Dementia

Subjects came from the Health, Aging and Body Composition (Health ABC) study, a prospective cohort of 3075 community-dwelling black (47%) and white adults who were aged 70 to 79 years in 1997. The current work involved 783 of these people with no cognitive impairment who either had diabetes at ABC baseline (51%) or developed it subsequently (49%). No information about diabetes type was available to the researchers.

Over a 12-year study period, 61 of those with diabetes (8%) had reported a severe hypoglycemic event associated with a hospital visit, with 21 (3%) reporting more than 1 such incident.

A total of 148 patients had developed dementia, identified as a primary or secondary diagnosis related to a hospitalization or by a record of a prescribed dementia medication (such as rivastigmine [Exelon, Novartis], memantine hydrochloride, or tacrine hydrochloride).

Dementia was more likely to develop among those who had been hospitalized with a hypoglycemic event (34%) compared with those without a severe hypoglycemic event (18%) (P < .001). The unadjusted risk for dementia was 2-fold greater for those who had experienced severe hypoglycemia compared with those who had not, and adjustment for confounding factors did not change that association, with a hazard ratio of 2.1.

On the flip side, those with dementia were also more likely to have a subsequent hypoglycemic event resulting in hospitalization (14% of 148 vs 6% of 635, P < .001). That increased risk was 3-fold (hazard ratio 3.1) after adjustment for age, sex, education, insulin use, race/ethnicity, prevalent diabetes at baseline, and baseline Modified Mini-Mental State Examination score.

Possible Mechanisms and Clinical Implications

Dr. Yaffe and colleagues say that hypoglycemia might contribute to the development of dementia through a variety of mechanisms, including damage to the cerebral cortex and/or hippocampus, neuronal damage, loss of ionic homeostasis, increases in reactive oxygen species, and development of amyloid precursor proteins resulting from damage.

The finding of an increased risk for hypoglycemia among those with dementia has been reported previously, but the current study is believed to be the first to evaluate the relationship prospectively among a heterogeneous adult population without dementia at baseline, they observe.

The cognitive impairment of dementia may mean that detecting and preventing hypoglycemia is more difficult, the authors hypothesize.

The results suggest that sulfonylureas and insulin, which increase the risk for hypoglycemia, may be inappropriate for older patients with or at risk for cognitive impairment, they add.

But editorialist Dr. Lipska points out that glucose-lowering agents that do not promote hypoglycemia carry other potential downsides: metformin is associated with lactic acidosis and pioglitazone with edema, heart failure, bladder cancer, and fractures. The newer glucagonlike peptide-1 (GLP-1) agonists and dipeptidyl peptidase (DPP-4) inhibitors are expensive and lack long-term safety data.

All of these issues need to be discussed with the patient, she told Medscape Medical News.

Engage Patient in Decision-Making

"There are some downsides to non–hypoglycemia-inducing medications in the elderly patients, but whether or not they outweigh the advantage of avoiding hypoglycemia is a question that is best directly discussed with each patient," she says.

"The answer may differ based on both clinical factors and patient preferences. An elderly patient on metformin with stable renal insufficiency may accept the potential small risk of lactic acidosis against the risk of hypoglycemia with insulin."

To help physicians sort through the choices with patients, Dr. Lipska recommends a decision aid developed by the Mayo Clinic.

"We need to invest in preparing physicians to share these decisions with patients," she says. "In my medical education, I was taught how to answer questions like: 'What is the best choice of treatment for this patient?' Instead, we need better training in discussing the evidence behind several viable options and engaging patients in decision making."

The study was supported by grants from the National Institute on Aging, the National Institute on Nursing Research, and the American Health Assistance Foundation. Dr. Yaffe has served on data monitoring boards for Takeda, Pfizer, and Medivation and has served as a consultant for Novartis. The coauthors have reported no relevant financial relationships. Drs. Lipska and Montori have reported no relevant financial relationships.

JAMA Intern Med. Published online June 10, 2013. Article Editorial

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