A total of 1822 patients (11%) had a diagnosis of dementia during a mean follow-up (starting in 2003) of 3.8 years and median of 4.8 years. The mean age of our cohort was 64.9 years at the time of the survey and 1465 patients (8.8%) had at least 1 episode of hypoglycemia from 1980-2002. Ten of the hypoglycemic episodes were hypoglycemic coma (ICD-9-CM code 251.0) and 535 episodes (36.5%) were from ED diagnoses. The number of hypoglycemic episodes increased sharply in 2000-2002, with almost 700 events during this period. Compared with patients without hypoglycemia, those with hypoglycemia were more likely to be older, African American, treated with insulin, and to have hypertension, stroke, and end-stage renal disease (). Those with at least 1 hypoglycemic event were also more likely to be diagnosed with dementia ().
Population characteristics by hospital or emergency department-associated hypoglycemia
Frequency of hypoglycemic episodes by dementia status
Of the 1465 patients with hypoglycemia, 68.5% had 1 episode, 18% had 2 episodes, and 13.5% had 3 or more episodes. Age-adjusted incidence rates of dementia by frequency of hypoglycemic episodes were significantly elevated for patients with at least 1 episode (566.82 cases; 95% CI, 496.52-637.48 per 10 000 person-years vs. 327.6 cases; 95% CI, 311.02-343.18 per 10,000 person-years) compared with patients with no episodes (). The attributable risk of dementia for patients with 1 or more hypoglycemic episodes compared with those with no episodes was 2.39% per year (95% CI, 1.72-3.01; ).
In the Cox proportional hazard models adjusted for age, body mass index, race/ethnicity, education, sex, and diabetes duration (), patients with at least 1 episode of hypoglycemia had an increased risk of dementia compared with those with no episodes (HR, 1.68; 95% CI, 1.47-1.93). Patients with 2 or more episodes appeared to be at somewhat greater risk with an HR of 2.15 (95% CI, 1.64-2.81), as did patients with 3 or more episodes (HR, 2.60; 95% CI 1.78-3.79). Further adjustment for diabetes-related comorbidities, HbA1c level, diabetes treatment, and years of insulin use () modestly attenuated the effect, although it remained statistically significant and clinically relevant (1 episode [HR, 1.26; 95% CI, 1.10-1.49], 2 episodes [HR, 1.80; 95% CI, 1.37-2.36], and for 3 episodes [HR, 1.94; 95% CI, 1.42-2.64]).
Hypoglycemia and risk of incident dementiaa
When examining risk of dementia using the 2-year lagged model (i.e. only considering incident dementia cases that occurred between January 1, 2005, and January 15, 2007), trends were similar. In a model fully adjusted for demographics, comorbidities, HbA1c levels, diabetes treatment, and years of insulin use, patients with 1 hypoglycemic episode had an HR of 1.15 (95% CI, 0.89-1.48), 2 episodes (HR, 1.65; 95% CI, 1.10-2.48), and 3 or more episodes (HR, 2.06; 95% CI, 1.32-3.24) vs. patients with no hypoglycemic episodes.
Backward lag models that examined only hypoglycemic events that occurred from 1980 through 1985 on risk of dementia were also performed. Although there were fewer hypoglycemic events, hypoglycemia was associated with risk of dementia (1 or more episodes vs. no episodes: HR, 1.32; 95% CI, 1.02-2.13) adjusted for age, education, race/ethnicity, body mass index, comorbidities, diabetes duration, diabetes mellitus treatment, years of insulin use, and HbA1c levels.
We also performed models in which we added other variables that could be indicative of diabetes severity to the fully adjusted model (). These 3 additional models adjusted for length of health plan membership (1 episode [HR, 1.29; 95% CI, 1.10-1.53], 2 episodes [HR, 1.88; 95% CI, 1.39-2.39], and 3 episodes or more [HR, 1.76; 95% CI, 1.29-2.40] vs. no episodes), time since initial diabetes diagnosis (1 episode [HR, 1.33; 95% CI, 1.12-1.51], 2 episodes [HR, 1.94; 95% CI, 1.48-2.54], 3 episodes or more [HR, 1.70; 95% CI, 1.24-2.31] vs. no episodes), and medical utilization rate (1 episode [HR, 1.21; 95% CI, 1.10-1.45], 2 episodes [HR, 1.63; 95% CI, 1.20-2.18], and 3 episodes or more [HR, 1.63; 95% CI, 1.17-2.27] vs. those with no episodes). These models all had results similar to the main models (), although there was some mild attenuation for those with 3 episodes or more.
Stratified analyses conducted among patients without stroke, without end-stage renal disease, or not of African American race/ethnicity demonstrated similar degrees of association between hypoglycemia and dementia (). Although history of hypoglycemia was associated with end-stage renal disease, stroke, and African American race/ethnicity, the association between hypoglycemia and dementia was not limited to these factors.
Subgroup analyses of hypoglycemia and dementia riska
Results for patients with ED events only were similar to the results for patients with any events. Compared with patients with no ED-derived hypoglycemic episodes, as determined from outpatient records, patients with 1 hypoglycemic episode resulting in an ED visit had an HR of 1.42 (95% CI, 1.12-1.78), and those with 2 or more episodes had an HR of 2.36 (95% CI, 1.57-3.55). To determine whether a hypoglycemia diagnosis from the ED may have been simply incidental, we examined the average total number of diagnoses listed for ED visits with a hypoglycemic diagnosis. The mean number was 1.6, which indicated that hypoglycemia comprised 1 of 2 diagnoses on average, and therefore was unlikely to be an incidental finding during an ED visit for an unrelated event.