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Cited by 1,128Diabetes Management and ResearchDementia and Cognitive Impairment ResearchDiabetes Treatment and Management

Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus

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Whitmer, Rachel A.·2009·JAMA
DOI 10.1001/jama.2009.460PMC PMC2782622
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Abstract

CONTEXT: Although acute hypoglycemia may be associated with cognitive impairment in children with type 1 diabetes, no studies to date have evaluated whether hypoglycemia is a risk factor for dementia in older patients with type 2 diabetes. OBJECTIVE: To determine if hypoglycemic episodes severe enough to require hospitalization are associated with an increased risk of dementia in a population of older patients with type 2 diabetes followed up for 27 years. DESIGN, SETTING, AND PATIENTS: A longitudinal cohort study from 1980-2007 of 16,667 patients with a mean age of 65 years and type 2 diabetes who are members of an integrated health care delivery system in northern California. MAIN OUTCOME MEASURE: Hypoglycemic events from 1980-2002 were collected and reviewed using hospital discharge and emergency department diagnoses. Cohort members with no prior diagnoses of dementia, mild cognitive impairment, or general memory complaints as of January 1, 2003, were followed up for a dementia diagnosis through January 15, 2007. Dementia risk was examined using Cox proportional hazard regression models, adjusted for age, sex, race/ethnicity, education, body mass index, duration of diabetes, 7-year mean glycated hemoglobin, diabetes treatment, duration of insulin use, hyperlipidemia, hypertension, cardiovascular disease, stroke, transient cerebral ischemia, and end-stage renal disease. RESULTS: At least 1 episode of hypoglycemia was diagnosed in 1465 patients (8.8%) and dementia was diagnosed in 1822 patients (11%) during follow-up; 250 patients had both dementia and at least 1 episode of hypoglycemia (16.95%). Compared with patients with no hypoglycemia, patients with single or multiple episodes had a graded increase in risk with fully adjusted hazard ratios (HRs): for 1 episode (HR, 1.26; 95% confidence interval [CI], 1.10-1.49); 2 episodes (HR, 1.80; 95% CI, 1.37-2.36); and 3 or more episodes (HR, 1.94; 95% CI, 1.42-2.64). The attributable risk of dementia between individuals with and without a history of hypoglycemia was 2.39% per year (95% CI, 1.72%-3.01%). Results were not attenuated when medical utilization rates, length of health plan membership, or time since initial diabetes diagnosis were added to the model. When examining emergency department admissions for hypoglycemia for association with risk of dementia (535 episodes), results were similar (compared with patients with 0 episodes) with fully adjusted HRs: for 1 episode (HR, 1.42; 95% CI, 1.12-1.78) and for 2 or more episodes (HR, 2.36; 95% CI, 1.57-3.55). CONCLUSIONS: Among older patients with type 2 diabetes, a history of severe hypoglycemic episodes was associated with a greater risk of dementia. Whether minor hypoglycemic episodes increase risk of dementia is unknown.

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  • In a large population study, hypoglycemic episodes that required hospitalization or a visit to the emergency department between 1980 and 2002 were associated with approximately double the risk of incident dementia after 2003.

    “In a large population study, hypoglycemic episodes that required hospitalization or a visit to the emergency department between 1980 and 2002 were associated with approximately double the risk of incident dementia after 2003 (6).”

    From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [6]

    The Methods and Results describe hospital or emergency-department hypoglycemic events from 1980–2002 and incident dementia follow-up beginning in 2003. The Results support an association, but the approximately doubled risk applies to multiple episodes: fully adjusted hazard ratios were 1.80 for two episodes and 1.94 for three or more, versus 1.26 for one episode. Page numbers are unavailable in our copy. (LLM, conf=0.90)

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  • Young children with type 1 diabetes and older adults, including those with type 1 and type 2 diabetes, are particularly vulnerable to hypoglycemia because of their reduced ability to recognize hypoglycemic symptoms and effectively communicate their needs.

    “Young children with type 1 diabetes and older adults, including those with type 1 and type 2 diabetes (124,125), are noted as being particularly vulnerable to hypoglycemia because of their reduced ability to recognize hypoglycemic symptoms and effectively communicate their needs.”

    From 6. Glycemic Goals, Hypoglycemia, and Hyperglycemic Crises: Standards of Care in Diabetes-2026. (2026) · cites this paper as [124]

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  • In a medical-records study, high midlife cholesterol increased the risk for VaD over 30 years.

    “In a study based on medical records, high midlife cholesterol level increased the risk for VaD that developed over a 30-year period.355”

    From Vascular Contributions to Cognitive Impairment and Dementia: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association (2011) · cites this paper as [355]

    The Methods and Results examine hypoglycemic episodes and subsequent dementia in patients with type 2 diabetes; the Abstract lists hyperlipidemia only as an adjustment variable. A search for midlife cholesterol and vascular dementia found no passage reporting the claimed association over 30 years. The References list related dementia studies, but do not establish this finding in the cited paper. (LLM, conf=0.76)

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  • Hypoglycemic episodes that required hospitalization or a visit to the emergency department between 1980 and 2002 were associated with approximately double the risk of incident dementia after 2003.

    “In a large population study, hypoglycemic episodes that required hospitalization or a visit to the emergency department between 1980 and 2002 were associated with approximately double the risk of incident dementia after 2003 (6).”

    From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [6]

  • Young children with type 1 diabetes and the elderly, including those with type 1 and type 2 diabetes, are particularly vulnerable to hypoglycemia because of their reduced ability to recognize hypoglycemic symptoms and effectively communicate their needs.

    “Young children with type 1 diabetes and the elderly, including those with type 1 and type 2 diabetes (84,93), are noted as particularly vulnerable to hypoglycemia because of their reduced ability to recognize hypoglycemic symptoms and effectively communicate their needs.”

    From 6. Glycemic Targets: <i>Standards of Care in Diabetes—2023</i> (2023) · cites this paper as [84]

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Research works printed but not linked: 1

  1. [47]Allen KV Frier BM Strachan MW The relationship between type 2 diabetes and cognitive dysfunction: longitudinal studies and their methodological limitations Eur J Pharmacol 2004 490 1-3 169 175 15094083

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Authors
Whitmer, R. A.
Affiliations
Kaiser Permanente (US)
Corresponding author
Whitmer, Rachel A.
ORCID
Whitmer, Rachel A.
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2009-04-15
Volume
301
Issue
15
Pages
1565
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2009.460
PMC
PMC2782622
OpenAlex
W2021446295
Semantic Scholar
8e791181bbd95962c306c0a49567a3d60ade0a2a
Cited by
1,128
References
69
Citations by year
2026: 29 · 2025: 26 · 2024: 56 · 2023: 33 · 2022: 72 · 2021: 65 · 2020: 64 · 2019: 71 · 2018: 79 · 2017: 82 · 2016: 71 · 2015: 87 · 2014: 89 · 2013: 74 · 2012: 67
FWCI
55.42
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (K24AG031155)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK081796, K01DK066308, DK081796, DK066308)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
hypoglycemia, dementia risk, type 2 diabetes, older adults, severe hypoglycemia, hospitalization, cognitive impairment, insulin use, HbA1c, long-term follow-up, attributable risk, mild cognitive impairment, memory impairment, cardiovascular disease, stroke, transient cerebral ischemia, end-stage renal disease, hyperlipidemia, hypertension, integrated care
MeSH terms
Aged, Dementia, Diabetes Mellitus, Type 2, Female, Humans, Hypoglycemia, Longitudinal Studies, Male, Risk Factors, Comorbidity, Proportional Hazards Models

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