Type 2 diabetes mellitus (T2DM) is associated with a 1.5 to 2.5-fold increased risk for dementia, and this trend is similar for both Alzheimer's disease (AD) and vascular dementia (VaD), which are the most common subtypes of dementia [12]. With the increasing numbers of elderly people with T2DM in the general population, dementia is especially important due to its impact on self-management and quality of life. Therefore, identifying modifiable risk factors for dementia is crucial to public health. The mechanisms underlying the association between T2DM and dementia are not fully understood, but they are multifactorial, including poor glucose control, hypoglycemia, inflammatory mediators, and rheological factors [3].

Hypoglycemia is a potentially serious complication during diabetes treatment and it may be an obstacle to optimal glycemic control. As glucose is the primary source of energy for the brain, hypoglycemia may cause mild or severe neurological deficits, including coma [45]. Although the short-term effects of hypoglycemia on cognitive function have been well documented, it is unclear whether patients with hypoglycemia will develop dementia. A few epidemiological studies have shown that severe hypoglycemia is associated with a greater risk for dementia [6789], but others have reported no significant association between hypoglycemia and subsequent dementia [1011]. In addition, because the pathogeneses of AD and VaD are very different, the same hypoglycemic assault may have different effects on the progression of dementia according to subtype. However, previous studies have not estimated dementia risk according to dementia subtype.

Therefore, the purpose of the current study was to investigate the association between hypoglycemia and subsequent dementia in older adults with T2DM by conducting a propensity score matching analysis to minimize selection bias. We also identified the effect of hypoglycemia on dementia according to each subtype. We used the Korean National Health Insurance Service Senior cohort, which contains 14 years of follow-up data for >10% of all older adults in South Korea.

In total, 48,521 patients were included in the cohort and 220,385 person-years were considered. After propensity score matching, 5,966 patients comprised both groups. The baseline characteristics of the matched group are presented in Table 1; all absolute values of standardized differences were <0.1; thus, all confounding variables were considered properly adjusted by propensity score matching. The mean follow-up period of the matched pairs was 1,591.1 days.

During the study period, 2,934 patients were newly diagnosed with dementia. The patients with at least one hypoglycemia episode showed an increased risk of all-cause dementia compared with those without hypoglycemia (hazard ratio [HR], 1.254; 95% confidence interval [CI], 1.166 to 1.349; P<0.001) (Table 2, Fig. 2). Patients with underlying hypoglycemia were prone to AD and VaD (HR, 1.264; 95% CI, 1.162 to 1.375, P<0.001 for AD; and HR, 1.286; 95% CI, 1.110 to 1.490; P<0.001 for VaD) (Table 2, Fig. 2).

According to number of hypoglycemic episodes, the HRs of dementia were 1.170, 1.201, and 1.358 in patients with one hypoglycemic episode, two or three episodes, and more than three episodes, respectively (Table 3).

In the subgroup analysis, patients were divided according to sex, age, or the presence of T2DM microvascular or macrovascular complications. Patients who experienced hypoglycemia showed an increased risk for dementia in all subgroups (Table 4).

This population-based retrospective cohort study showed that patients with a history of hypoglycemia had a higher risk of dementia using the propensity score matching method with large cohort data. This association was persistent in both the AD and VaD subtypes. Patients who experienced repeated episodes of hypoglycemia had a higher risk of dementia. In the subgroup analysis, hypoglycemia increased the risk for dementia in both sexes with or without T2DM microvascular and macrovascular complications.

This is the first cohort study using the propensity score matching method to minimize selection bias. In addition, this is the first study to estimate dementia risk of hypoglycemia according to the specific dementia subtype. Our study included the largest number of patients who have ever experienced hypoglycemia compared with previous studies.

Our study showed that hypoglycemia increased the risk of dementia by 25.4%, which conflicts with some previous studies. The Fremantle Diabetes Study found no evidence that hypoglycemia contributes to cognitive impairment in older adults with T2DM who had normal cognition at baseline [10]. However, the small sample size and relatively short follow-up duration may have limited the power to detect differences. In the Diabetes Control and Complication Trial on younger adults with T1DM, 40% of the patients experienced at least one hypoglycemic coma or seizure but did not decline cognitively [11]. Although this cohort was followed for 18 years, the mean age of the enrolled patients was 27 years, which was too young to show cognitive impairment. The same assault of hypoglycemia may have different impacts according to the age of the subject population, as levels of hippocampal neurogenesis steadily decrease with age [12]. The conflicting results may be due to differences in the demographics of the study populations.

Consistent with our results, three retrospective studies showed that at least one hypoglycemic episode increases the risk of dementia [679]. Additionally, repeated episodes of hypoglycemia were correlated with a higher risk of dementia [69]. Lin and Sheu [7] showed an increased risk of dementia in subjects with a history of hypoglycemia. However, they adjusted only for age, sex, insulin use, and five comorbidities, and included only 289 patients who had had at least one hypoglycemic episode, which is a relatively small sample size [7]. Another retrospective cohort study using the Kaiser Permanente Northern California Diabetes Registry of around 17,000 patients, with a mean age of 65 years, who were followed for 27 years, showed that one, two, and three or more episodes of hypoglycemia increased the risk of dementia, with HRs of 1.26, 1.80, and 1.94, respectively [6]. However, this cohort involved only approximately 1,500 patients with a hypoglycemic experience and did not control for either economic status, which is among the important risk factors for dementia, or medication use, including class of oral hypoglycemic agent or statins, which can affect dementia [131415161718]. The third study, using the Clinical Practice Research Datalink (CPRD), which contains the medical records from 674 general practices in the United Kingdom, showed that hypoglycemia is associated with a higher risk of dementia [9]. Furthermore, the risk of dementia increased with the number of hypoglycemia episodes. However, CPRD is collected from general practice and may be biased relative to our data, which was collected from a primary hospital to a tertiary hospital, and this study also did not compensate for socioeconomic status, or medication use, such as each oral hypoglycemic agent class or statins. Compared to all of these previous studies using Cox proportional hazards models that compensated for insufficient confounding factors and included small numbers of patients with hypoglycemia, we used the propensity score matching method and more than 40 confounding variables, including socioeconomic status, oral hypoglycemic agent class, statin use, and many underlying diseases, and included the largest number of patients with hypoglycemia.

Several possible mechanisms have been suggested from animal studies for how hypoglycemia can cause dementia. Multiple animal and human magnetic resonance imaging studies have reported that severe hypoglycemia with coma can lead to selective neuronal cell death in vulnerable brain regions, such as the cortex and hippocampus [19]. This can lead to a decline in memory. In a rat model, significant learning and memory deficits were identified with behavioral testing 6 weeks after inducing 30 minutes of EEG isoelectricity with severe hypoglycemia, which could be attributed to neuronal death observed in the hippocampus of these animals [20]. In another animal study, prolonged moderate hypoglycemia without coma also caused neuronal damage in the prefrontal medial cortex, piriform cortex, and orbital cortex in rats [21].

Other explanations related to vascular and AD pathology are plausible. Increased adrenaline levels during hypoglycemic events enhance platelet and leucocyte activities, and increase the formation of fibrinogen [2223]. Endothelial function may also be compromised during a hypoglycemic attack [24]. All of these factors contribute to micro- or macro-infarcts in the brain, causing vascular cognitive decline. Several studies have shown a possible link between hypoglycemia and AD pathology. In a study with rat primary cortical astroglial cells, hypoglycemia enhanced the expression of mRNA encoding the β-amyloid precursor protein. In a study with neuroblastoma cells, hypoglycemia induced tau hyperphosphorylation, which can lead to the formation of neurofibrillary tangles [25]. In the present study, a history of hypoglycemia increased both the AD and vascular subtypes of dementia. Although it is common to have a single patient with both AD and VD pathology, these subtypes can be difficult to distinguish. This study suggests that hypoglycemia can be related to both pathomechanisms and may make the brain more vulnerable to both pathologies.

This study had several strengths. First, we investigated the largest senior cohort, which contains all of the claims data for >10% of the entire elderly population in South Korea for 14 years. Second, we tried to exclude bidirectional effects as much as possible. Dementia is one of the major risk factors for hypoglycemia; thus, dementia and hypoglycemia have a bi-directional effect. All subjects in our study were free of dementia at baseline, as we excluded patients who were diagnosed with dementia or prescribed dementia medications during the 9-year period before the index date, to assess temporality in the relationship. Third, as described above, we minimized selection bias by using propensity score matching with 48 variables, such as demographics, socioeconomic status, medication use, and comorbidities.

However, several limitations should be considered. This was a retrospective analysis, and the claims database lacked results of any measurements, such as glycated hemoglobin or Mini-Mental State Exam scores, which may have influenced the results. Specifically, patients with mild cognitive impairment are more difficult to identify using a claims database without cognitive testing results. Thus, prospective cohort studies that include cognitive function tests to exclude mild cognitive impairment before enrollment are needed to confirm our results. Additionally, we analyzed the incidence of dementia and hypoglycemia according to ICD-10 diagnostic codes; however, there may have been some discrepancies between the medical diagnoses and the diagnostic codes in the claims data. However, a previous study showed that the dementia diagnoses in claims data were quite correct when compared with clinically diagnosed dementia [26]. In addition, because >99% of South Koreans are registered with National Health Insurance, and the dementia diagnostic codes are mandatory to earn insurance benefits when being prescribed dementia medication, it is highly unlikely that dementia would be found without the relevant diagnostic codes in the claims data. In terms of hypoglycemia, clinicians tend not to record hypoglycemia in actual practice, especially when it is mild, when entering diagnostic codes. Thus, this study is limited by the possibility that we underestimated the incidence of hypoglycemic episodes and were unable to assess the effects of mild hypoglycemia on dementia. Last, because this study only included the South Korean population, the results may not be generalizable to all ethnic groups. The incidence and proportion of dementia subtypes vary among ethnic groups [2728]. Previous studies have shown that the Asian population has a greater proportion of VaD and a lower proportion of AD [29].

In summary, our study indicates that a history of hypoglycemia increases the risk for dementia in older adults with T2DM. This association is consistent for both AD and VaD. Caution is advised when treating T2DM in older individuals with hypoglycemia, to prevent deterioration of their cognitive ability.