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Husain, K.H.; Sarhan, S.F.; Alkhalifa, H.K.A.A.; Buhasan, A.; Moin, A.S.M.; Butler, A.E. Dementia Due to Hypoglycemia. Encyclopedia. Available online: (accessed on 20 April 2024).
Husain KH, Sarhan SF, Alkhalifa HKAA, Buhasan A, Moin ASM, Butler AE. Dementia Due to Hypoglycemia. Encyclopedia. Available at: Accessed April 20, 2024.
Husain, Khaled Hameed, Saud Faisal Sarhan, Haya Khaled Ali Abdulla Alkhalifa, Asal Buhasan, Abu Saleh Md Moin, Alexandra E. Butler. "Dementia Due to Hypoglycemia" Encyclopedia, (accessed April 20, 2024).
Husain, K.H., Sarhan, S.F., Alkhalifa, H.K.A.A., Buhasan, A., Moin, A.S.M., & Butler, A.E. (2023, July 01). Dementia Due to Hypoglycemia. In Encyclopedia.
Husain, Khaled Hameed, et al. "Dementia Due to Hypoglycemia." Encyclopedia. Web. 01 July, 2023.
Dementia Due to Hypoglycemia

Hypoglycemia, a common consequence of diabetes treatment, is associated with severe morbidity and mortality and has become a major barrier to intensifying antidiabetic therapy. Dementia generally refers to the loss of memory, language, problem-solving, and other cognitive functions, which can interfere with daily life, and there are many evidences that diabetes is associated with an increased risk of both vascular and non-vascular dementia. Neuroglycopenia resulting from a hypoglycemic episode in diabetic patients can lead to the degeneration of brain cells, with a resultant cognitive decline, leading to dementia.

hypoglycemia diabetes Alzheimer’s disease

1. Introduction

Hypoglycemia is a known adverse effect of glucose-lowering therapies. Hypoglycemia is defined as plasma glucose levels below 70 mg/dL, as per the American Diabetes Association guidelines [1]. The manifestations of hypoglycemia vary from symptomatic stress responses to cholinergic responses and cognitive decline [2][3]. Multiple diabetic drugs can induce hypoglycemia, predominantly including, but not limited to, insulin in type 1 diabetes (T1D) and type 2 diabetes (T2D), and sulfonylureas (in T2D); there have also been associations with biguanides and thiazolidinediones [4]. With the onset of hypoglycemia, multiple counterregulatory responses act to reverse the hypoglycemic state, including a reduction in pancreatic ß-cell insulin release and increased pancreatic α-cell glucagon release through ATP-sensitive potassium (KATP) channel and glucokinase expression; a sympathoadrenal response where the hypoglycemic activation of the adrenal medulla induces epinephrine and norepinephrine secretion; and a delayed cortisol and growth hormone response [5][6].
The prevalence of hypoglycemic episodes ranges from 10% in T2D to 50% in T1D; however, despite the overall prevalence, the relationship between hypoglycemia and dementia typically refers to the elderly population as, over time, there is a reduced awareness of hypoglycemic symptoms, in addition to reduced counter-regulatory glucagon secretion [7][8]. Combined, these effects amplify the hypoglycemic risk of glucose-lowering therapies in elderly patients [9][10].
Dementia is increasing in global prevalence, with the current age-standardized prevalence being 5–7% in most countries [11]. Alzheimer’s dementia (AD) accounts for approximately 60% to 70% of cases, followed by vascular dementia (VD) (25%), Lewy-body dementia (LBD) (<5%), and frontotemporal dementia (FTD) (<1%). However, in diabetic patients, VD predominates followed by AD [12]. A meta-analysis of 28 prospective observational studies determined that individuals with diabetes have a 73% greater risk of developing all-cause dementia (dementia not limited to a certain type), with a 56% and 127% increased risk of AD and vascular dementia, respectively [13].
The mechanisms underlying the relationship between diabetes and dementia are yet to be clearly defined. The available mechanistic evidence regarding hypoglycemia secondary to diabetes mellitus, and resultant dementia, suggests multiple hypotheses based on the following: structural changes as a result of a reduced volume of grey matter and cortical atrophy; cognitive decline due to damage to the hippocampus; and a higher relative risk of neuronal damage in diabetes versus non-diabetics [2]. However, a concise molecular metabolic sequence of events addressing the connection between diabetes and dementia is still lacking in the published literature, as is the relationship of microvascular, macrovascular, and inflammatory effects on these metabolic processes that serve as a link between exposure and outcome.

2. Dementia Due to Hypoglycemia

2.1. Epidemiology of Hypoglycemia, Cognition, and Dementia among Diabetics

Hypoglycemia is very common among patients with T1D and T2D. Alwafi et al. performed a systematic review encompassing 2,462,810 individuals and spanning all continents and showed that the prevalence of hypoglycemia among diabetics ranged from 0.074% to 73.0%, with the highest incidence and prevalence observed in T1D patients and those treated with insulin (prevalence range of 2.2% to 73.0%); additionally, the pooled prevalence among European and North American self-reported, cross-sectional studies included in this meta-analysis were 35.0% (95% CI, 32.0–38.0, I2 = 59%) and 11.0% (95% CI, 11.0–13.0, I2 = 38%), respectively [14]. Studies assessing cognitive status among diabetics have also suggested this as a useful metric. A study concluded that, among diabetics, 63% of the study population have reduced cognition using the Mini-Mental State Examination (MMSE), whilst 70% were reported as having reduced cognition when assessed by the modified MMSE (3MS) [15]. Higher figures were reported in Saudi Arabia, where 80% of diabetic study subjects were noted as having a form of cognitive impairment, 33.8% of which had severe impairments [16]. With regard to dementia specifically, a UK database study showed that the incidence of dementia among diabetics increased 3.7-fold from 2000 to 2016, increasing from 0.2 cases per 100 persons to 0.7 cases per 100 persons. The prevalence of diabetic females with dementia was higher than that of diabetic men (3.1% versus 2.0%), and diabetics aged 65 and over had a substantially higher prevalence of dementia than diabetics aged 18 to 65 years of age (4.2 per 100 persons versus 0.2 per 100 persons). The study concluded that the incidence and prevalence of dementia among diabetics are increasing [17]. It is therefore apparent that the prevalence and incidence of hypoglycemia and cognitive impairment among diabetics are on the rise.

2.2. Association between Hypoglycemia and Dementia

Huang et al. conducted a systematic review of 10 cohort studies that encompassed Western and Asian populations, aiming to identify the risk of developing dementia secondary to hypoglycemic episodes (1 episode or >1 episode) in both T1D and T2D, with the controls being diabetics with no experience of hypoglycemic episodes [2]. This meta-analysis showed a hazard ratio (HR) of 1.44 (95% CI: 1.26, 1.65 I2 = 89% p < 0.00001) for developing dementia as a result of single or multiple severe hypoglycemic episodes requiring hospital admission (only one study included any form of hypoglycemia and was not exclusive to severe hypoglycemia). An increased risk of dementia development was observed in studies including only T2D as well as both T1D and T2D. Subgroup analyses yielded a higher OR for diabetics who experience two or more hypoglycemic episodes (HR = 1.63, I2 = 84% p = 0.02) than for those with one hypoglycemic episode (1.21 95% CI: 1.11, 1.32 I2 = 0% p < 0.0001). However, a limitation of this review was that dementia and hypoglycemia were not predefined by the authors, and hence any definition was accepted from the included studies [2].
Another meta-analysis conducted by Mattihsent et al. on American, European, and Asian populations involved the analysis of 44 studies (N = 2,507,434) and revealed an association of hypoglycemia with dementia, with a pooled OR of 1.50 (95% CI 1.29–1.74). Taken together, the available literature on the association of hypoglycemia and dementia suggests a significant correlation amongst multiple population groups. Table 1 lists other relevant systematic reviews noting the risk of developing dementia due to hypoglycemia.
Table 1. Systematic reviews noting risk ratios between hypoglycemia and dementia.

2.3. Recurrent Hypoglycemia and Dementia

Many studies substantiate the claim that there is a positive correlation between the number of hypoglycemic episodes and the risk of dementia development. For example, as shown in Table 1, a meta-analysis study of T2D patients showed an increasing trend of statistically significant risk ratios as the number of hypoglycemic events increased [19]. Additionally, a population-based cohort study conducted in South Korea following 5966 patients who had at least one hypoglycemic episode further corroborated this positive correlation: The HR results were 1.170 (95% CI, 1.043–1.313), 1.201 (95% CI, 1.016–1.421), and 1.358 (95% CI, 1.060–1.740) for 1 hypoglycemic episode, 2–3 hypoglycemic episodes, and >3 hypoglycemic episodes, respectively [21]. Furthermore, another longitudinal cohort study conducted in California including 16,667 patients with T2D reported similar results. Patients were followed for 12 years (from 1990 to 2002), and hypoglycemic events were recorded and then followed for a further 5 years (until 2007) to screen for dementia. The adjusted HR for 1 hypoglycemic episode was 1.26 (1.10–1.49), for 2 hypoglycemic episodes was 1.80 (1.37–2.36), and for ≥3 hypoglycemic episodes was 1.94 (1.42–2.64) [22]. On a larger scale, a study conducted on 53,055 patients with T2D revealed a 26% increased risk of dementia development in those with one hypoglycemic episode, and a 50% increased risk in those with two or more hypoglycemic episodes [18]. Collectively, these studies suggest that patients with repeated hypoglycemic episodes have an increased risk of dementia development; however, the multifactorial nature of dementia limits the direct application of these results to daily living, as other confounding risk factors and comorbidities are likely to be present.

2.4. Glycemic Control and Dementia

HbA1c is widely used to determine glycemic control over the previous 3-month time span. Hence, the majority of studies use HbA1c when assessing glycemic control and dementia risk, with tight glycemic control referring to HbA1c levels below 7.0% (53 mmol/mol). Many studies identified an association between increasing HbA1c levels and increased risk of dementia. A large UK cohort study including 372,287 patients with both T1D and T2D reported an HR of 1.08 (1.07, 1.09) of developing dementia for every 1% increase in HbA1c. If tight glycemic control can be attained (HbA1c level below 6%), the HR for dementia development drops to 0.86 (0.83–0.89) [23]. A meta-analysis by Tang et al. also showed that tight glycemic control can slow cognition decline, especially in terms of memory [24].

2.5. Risk Factors of Hypoglycemia-Induced Alzheimer’s Dementia in Diabetes Mellitus

It is important to identify the risk factors of hypoglycemia-induced dementia in diabetics to allow for early intervention. Many therapeutic glucose-lowering agents can induce hypoglycemia. Such drugs include insulin and sulphonylureas, as well as co-administered medications such as beta-blockers, fluoroquinolones, and ACE inhibitors [25]. A retrospective survey conducted between 1995 and 1996 of 24,793 medical admissions in teaching hospitals showed that 0.5% of patients were hospitalized due to hypoglycemia, with 55% of these admissions due to sulphonylureas. Patients treated with insulin are particularly vulnerable to hypoglycemia, especially those who use vials and syringes rather than disposable pens [26][27].
In addition to drug-induced risks, in a longitudinal cohort study conducted in northern California, for which 16,667 patients enrolled, 11% of patients had a diagnosis of dementia. Among these patients, those who had hypoglycemic events were more likely to be of advanced age, African American, treated with insulin, or hypertensive, and to have had a previous stroke, or have end-stage renal disease than patients without hypoglycemia [22]. Other risk factors include prolonged fasting (during Ramadan, for example), concurrent infections, cardiovascular disease, and renal insufficiency [25][28]. Patients with renal insufficiencies, such as chronic kidney disease (CKD), often present with impaired gluconeogenesis (as approximately 20% of plasma glucose is produced by renal gluconeogenesis), and altered renal drug metabolism puts them at risk for hypoglycemia. Furthermore, renal insufficiency and hypoglycemia in T2D have been reported to have independent effects on all-cause mortality, highlighting the multiple risk factors in patients with comorbid conditions [29][30]

2.6. Hypoglycemia and Vascular Dementia: Are They Connected?

As mentioned in a bioinformatic study by Saik and Klimontov, there appears to be a genetic link between hypoglycemia and cardiovascular disease/diabetic microvascular complications [31]. This suggests that there may consequently be a connection between hypoglycemia and VD as well. There are limited studies assessing the pathophysiology of this purported relationship, but a study on a rat model revealed that severe hypoglycemia can cause the leakage of the blood–brain barrier and consequent brain edema. Using Evans blue extravasation into the brain as a read-out method, this experimental group observed significantly increased Evans blue content in the brain versus controls, implying that severe hypoglycemic events aggravate brain edema in diabetic mice models [32]. Furthermore, other animal and human studies demonstrated that severe hypoglycemic events with coma can also cause selective neuronal cell death in susceptible areas of the brain, particularly the hippocampus and cortex, as evidenced by magnetic resonance imaging [33].

2.7. Is Pre-Existing Dementia a Risk Factor for Hypoglycemia in Type 2 Diabetes?

There is scarce literature on whether pre-existing dementia acts as a risk factor for hypoglycemia in T2D. A 2015 meta-analysis screened 1175 citations, from which 10 studies (including 535,317 participants) were prioritized to include geographical diversity in patients with T2D who were receiving insulin and/or oral agents. The results suggested a reciprocal link between hypoglycemia and cognitive impairment/dementia in older patients with diabetes [34]. Patients who already had cognitive deterioration had a considerably higher chance of developing hypoglycemia, with a pooled OR of 1.61 (1.25, 2.06) [35]. In order to prevent additional cognitive deterioration in elderly patients with pre-existing dementia, less stringent blood glucose targets should be employed, coupled with the strict monitoring of hypoglycemic events.


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