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Hypoglycaemia is one of the most serious complications during treatment of diabetes and has long been recognized as a major barrier to achieving ideal glycaemic control. It has recently been noted that an increased number of hypoglycaemic episodes might account for higher mortality in those patients with diabetes who receive either more or less intensive glycaemic therapy [1, 2].
Type 2 diabetes mellitus is associated with a 1.5- to 2.5-fold increased risk of dementia [3, 4], and cognitive dysfunction is an independent predictor of clinical outcomes in patients with type 2 diabetes . Although the aetiology of dementia and cognitive impairment in people with type 2 diabetes is probably multifactorial, poor glycaemic control with or without other associated risk factors, perhaps by promoting the development of cerebral macrovascular or microvascular lesions, has been shown to increase the risk of dementia in the diabetic population [3, 6]. The influence of hypoglycaemic episodes on subsequent risk of impaired cognitive function or vice versa has been the focus of recent studies [5, 7]. In fact, severe hypoglycaemia, which is generally reversible, has been shown to induce focal neurological deficit and transient ischaemic attacks . In subjects with type 1 diabetes, an association between hypoglycaemia and impaired cognitive function has been shown in some [9, 10], but not in all studies . In subjects with type 2 diabetes, this association is often complicated by the ageing process and the presence of several comorbidities. In a longitudinal cohort study of 16 667 elderly patients with type 2 diabetes from a claims database, Whitmer et al.  showed that severe hypoglycaemic episodes were associated with a greater risk of dementia. In the Fremantle Diabetes Study, Bruce et al.  demonstrated an association between hypoglycaemia and both cognitive impairment and dementia. However, there were no significant associations between historical hypoglycaemia and cognitive decline. In the Edinburgh Type 2 Diabetes Study, severe hypoglycaemia was found to be associated with poor cognitive ability late in life . These studies were all limited either by the use of a single healthcare delivery system , a cross-sectional design  or a self-reported questionnaire . To further explore this issue, we investigated the association between in-hospital diagnosed hypoglycaemic episodes and subsequent dementia by reviewing the medical data of a sample from a claims database that was representative of the general population.
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The mean age of the diabetes cohort was 64.2 years at the time of the survey, and 289 patients (about 2%) had at least one episode of hypoglycaemia between 1 January 2000 and 31 December 2002 (Fig. 1). Table 1 shows the demographic characteristics and comorbidities of the diabetic subjects with and without hypoglycaemic episodes. Comparing these two groups, those with hypoglycaemia were significantly older (P < 0.001), predominantly women (P < 0.001) and had a higher frequency of insulin use (P < 0.001). The rates of comorbidities, including hypertension, CVD, ischaemic heart disease and CKD, were all higher (all P < 0.001) in diabetic subjects with hypoglycaemic episodes; however, the rate of hyperlipidaemia was lower (P < 0.001).
Table 1. Comparison of demographic characteristics and comorbidities between diabetic subjects with and without hypoglycaemia
|Variable||Total (n = 15 404)||Without hypoglycaemia (n = 15 115)||With hypoglycaemia (n = 289)||P-value|
|n (%)||n (%)||n (%)|
|Age, years||64.2 ± 9.9||64.0 ± 9.9||70.3 ± 9.7||<0.001a|
|45–54||3412 (22.2)||3390 (22.4)||22 (7.6)||<0.001|
|55–64||4611 (29.9)||4559 (30.2)||52 (18.0)|
|65–74||5053 (32.8)||4935 (32.7)||118 (40.8)|
|≥75||2328 (15.1)||2231 (14.8)||97 (33.6)|
|Male||6947 (45.1)||6850 (45.3)||97 (33.6)||<0.001|
|Female||8457 (54.9)||8265 (54.7)||192 (66.4)|
|No||12 529 (81.3)||12 383 (81.9)||146 (50.5)||<0.001|
|Yes||2875 (18.7)||2732 (18.1)||143 (49.5)|
|No||5603 (36.4)||5554 (36.8)||49 (17.0)||<0.001|
|Yes||9801 (63.6)||9561 (63.3)||240 (83.1)|
|No||6670 (43.3)||6589 (43.6)||81 (28.0)||<0.001|
|Yes||8734 (56.7)||8526 (56.4)||208 (72.0)|
|Ischaemic heart disease|
|No||12 992 (84.3)||12 782 (84.6)||210 (72.7)||<0.001|
|Yes||2412 (15.7)||2333 (15.4)||79 (27.3)|
|No||14 755 (95.8)||14 512 (96.0)||243 (84.1)||<0.001|
|Yes||649 (4.2)||603 (4.0)||46 (15.9)|
|No||10 313 (67.0)||10 091 (66.8)||222 (76.8)||<0.001|
|Yes||5091 (33.1)||5024 (33.2)||67 (23.2)|
During a mean follow-up period (from 1 January 2003) of 3.8 years and median period of 4.8 years, a total of 1106 patients with diabetes (7.2%) were diagnosed with dementia (Table 2). The incidence rates of dementia were 29.9 per 1000 person-years (95% CI 22.1–39.2) and 11.1 per 1000 person-years (95% CI 10.3–11.8) for diabetic patients with and without hypoglycaemic episodes, respectively. The crude RR and age- and gender-adjusted RR values for dementia were 2.76 (95% CI 2.06–3.70, P < 0.001) and 1.60 (95% CI 1.19–2.14, P = 0.003), respectively, for all diabetic subjects either with or without hypoglycaemia. Further analysis of the number of hypoglycaemic episodes indicated that the RR of having dementia increased as the number of hypoglycaemic episodes increased (P for trend < 0.001; Table 2). Adjustment for age and gender, however, only slightly decreased the statistical significance (P for trend = 0.004).
Table 2. Incidence rate and hazard ratio (95% CI) of dementia by hypoglycaemic status
|Hypoglycaemic episodes||Without dementia (n = 14 298)||With dementia (n = 1106)||Incidence rate of dementia (per 1000 person-years)||Crude hazard ratio||Age- and gender-adjusted hazard ratio|
|n (%)||n (%)||Rate (95% CI)||RR (95% CI)||P-value||RR (95% CI)||P-value|
|Yes||242 (83.7)||47 (16.3)||29.9 (22.1–39.2)||2.76 (2.06–3.70)||<0.001||1.60 (1.19–2.14)||0.003|
|1||178 (84.0)||34 (16.0)||29.3 (20.5–40.3)||2.49 (1.77–3.50)||<0.001||1.47 (1.04–2.07)||0.003|
|2||51 (85.0)||9 (15.0)||31.3 (15.0–56.3)||2.54 (1.32–4.89)||0.005||1.41 (0.73–2.71)||0.311|
|≧3||13 (76.5)||4 (23.5)||44.9 (14.0–104.4)||3.74 (1.40–9.97)||0.009||2.60 (0.97–6.92)||0.056|
|Without diabetes||238 997 (97.4)||6485 (2.6)||3.9 (3.8–4.0)||0.35 (0.33–0.37)||<0.001||0.50 (0.47–0.53)||<0.001|
Kaplan–Meier survival analysis demonstrated a greater probability of dementia episodes between subjects with and without hypoglycaemic episodes, and the dementia probability curves of the two groups were significantly different after controlling for age and gender (P < 0.001, log-rank test; Fig. 2a). The increased number of hypoglycaemic episodes enhanced the risk of developing dementia (P < 0.001, log-rank test; Fig. 2b).
Figure 2. Kaplan–Meier survival analysis of probability of developing dementia amongst subjects with and without hypoglycaemic episodes (P < 0.001, log-rank test after controlling for age and gender) (a). Increased number of hypoglycaemic episodes increased the risk of developing dementia (P < 0.001, log-rank test) (b).
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Because the distributions of age, gender and comorbidities were significantly different between diabetic subjects with and without hypoglycaemic episodes, we constructed a Cox proportional hazards model to adjust for possible confounding variables (Table 3). After controlling for demographic characteristics and comorbidities, diabetic subjects with hypoglycaemic episodes had an increased risk of dementia compared to those without such episodes (HR = 1.45, 95% CI 1.07–1.95). Age was an independent predictor of dementia, and the independent HR increased by 2.70 (95% CI 2.52–2.90) for every 10-year increment in age. The risk of dementia was increased by 32% in women compared with men (HR = 1.32, 95% CI 1.17–1.50). In addition, insulin users had a 32% increased risk of developing dementia compared with nonusers (HR = 1.32, 95% CI 1.14–1.52). After controlling for demographic characteristics, there was no longer a significant difference in the effect of diabetic complications, such as CVD, hypertension, ischaemic heart disease, CKD and hyperlipidaemia, on dementia risk between those with or without hypoglycaemic episodes.
Table 3. Multivariate Cox regression proportional hazards model of dementia in diabetes
|Variable||Hazard ratio||95% CI||P-value|
|Ischaemic heart disease|
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Results from present study clearly demonstrate that adult diabetic subjects with previous in-hospital diagnosis of hypoglycaemia had an almost 3-fold increased risk of developing dementia in the subsequent 7-year follow-up period compared to those without hypoglycaemia (RR 2.76). This difference in risk was reduced but remained significant after adjustment for age and gender. The incidence rate of dementia with or without hypoglycaemic episodes was slightly lower than that previously reported , probably due to the lower age criterion in the present study (45 vs. 55 years) as well as the fact that hypoglycaemic episodes after the first 3 years were not included in the analysis. Consistent with previous findings , our data showed that patients with multiple episodes of hypoglycaemia had a graded increase in dementia risk. This was further supported by recent evidence that recurrent hypoglycaemia exacerbated cerebral ischaemic damage in streptozotocin-induced diabetic rats for increased free radical release from mitochondria .
There are several possible explanations for the link between hypoglycaemia and subsequent development of dementia. Severe hypoglycaemia has been shown to induce focal neurological deficit and transient ischaemic attacks, which might result in neuronal cell death and accelerate the process of dementia . Using functional magnetic resonance imaging in subjects with type 1 diabetes, Bolo et al.  reported reduced cerebral efficiency during hypoglycaemia manifested by deterioration of blood oxygen level–dependent activation and deactivation. Hypoglycaemia induces abnormalities in platelet function and activation of the fibrinolytic system [18, 19]. Increased adrenaline levels during episodes of hypoglycaemia in turn lead to an increase in platelet activation, leucocyte mobilization and blood coagulability . It was also recently shown that endothelial function may be compromised during acute hypoglycaemia . Vessel wall stiffness was found to be greater during hypoglycaemia in patients with type 1 diabetes of longer duration than in those with diabetes of shorter duration . In patients with type 2 diabetes, hypoglycaemia increased the risk of both macrovascular and microvascular events found in a subset of patients with long-term diabetes .
Hypoglycaemic episodes could be considered to reflect the effects of comorbidities or other unmeasured confounding variables rather than a direct cause of development of dementia . In the present study, the attenuation of the risk estimates remained statistically significant after adjustment for age and gender, suggesting that the effects of these confounding variables are not substantial. Taking into account potential comorbidities, the results of Cox proportional hazards analysis demonstrated that only age, female gender and insulin use remained independently associated with risk of dementia. It is well known that hypoglycaemia can affect cognitive function particularly in brains that are vulnerable due to old age . The reasons why diabetic women were more susceptible to development of dementia are not clear at present. Further analysis in the present study also showed that there was no interaction between gender and hypoglycaemia with regard to the future development of dementia (data not show). Indeed, gender differences in incidence of cognitive dysfunction or dementia have not been identified to date in patients with diabetes . It is also unclear whether premature death after hypoglycaemia would be more likely to occur in men and therefore mask the dementia risk. In epidemiological studies of adults without diabetes, hyperinsulinaemia has been independently associated with poorer cognitive performance [24, 25]. Insulin has also been shown to promote secretion and inhibit extracellular degradation, of amyloid-beta protein . We also found that there was no interaction between use of insulin injection and hypoglycaemia with regard to the future development of dementia (data not show). Our observations indicate that even considering the associated comorbidities, insulin exerts its effect either directly or indirectly via causing hypoglycaemia, thus increasing the risk of dementia.
By analysing a relatively similar claim data set, Hsu et al.  reported that the risk of developing Alzheimer's disease in people with type 2 diabetes was increased 2-fold compared with nondiabetic subjects, and use of sulphonylurea and metformin partially reduced this increased risk. The authors found that the incidence of dementia was similar to or slightly lower than the present findings in diabetic subjects without hypoglycaemia (0.778–1.19 vs. 1.11), although they used different ICD coding to define hypoglycaemia.
Some potential limitations of this study should be considered. The incidence of dementia in patients with diabetes may have been underestimated as some of these subjects might have died before the appearance of dementia . Collection of data on hypoglycaemic episodes only in the first 3 years could also be considered a limitation. However, the present study design was selected because people with cognitive impairment might be prone to more episodes of hypoglycaemia , which might further complicate the cause–sequence analysis. In this regard, Whitmer and co-workers confirmed a similar trend after introducing a longer ‘backward’ lag, so that only episodes of hypoglycaemia during the first 5 years of follow-up were considered . Another potential concern is that, due to the nature of the claims database, we could not obtain all laboratory data. It was shown that uncontrolled glycaemia increased the risk of Alzheimer's disease in a diabetic population with a follow-up period of 9 years . However, in at least one previous study, it was found that the association between hypoglycaemic episodes and dementia was independent of glycaemic control as assessed by the level of glycated haemoglobin .
Furthermore, we might have underestimated the frequency of hypoglycaemia. Individuals with asymptomatic or mild to moderate symptoms of hypoglycaemia may treat themselves or receive care from relatives. Indeed, minor or self-reported symptoms of hypoglycaemia were quite common and accounted for most of the hypoglycaemic episodes , even in non-insulin-user type 2 diabetic subjects in Asia . However, in the ADVANCE study, severe, but not mild, cognitive dysfunction increased the risk of subsequent severe hypoglycaemia . Very recently, analysis from the ACCORD study also confirmed that poor baseline cognitive function increased the risk of severe hypoglycaemia in patients with type 2 diabetes both in intensive and standard glycaemic groups . Although the ICD-9-CM code 250 could not distinguish between patients with type 1 or type 2 diabetes, the likelihood of having type 1 diabetes in our study population was minimal as age at onset of type 1 diabetes is usually below 10 years , whereas we enrolled only diabetic subjects older than 45 years at the beginning of 2003. A further limitation is that physicians might unintentionally code nonspecific hypoglycaemia as 250.3 (diabetes mellitus with coma) or 250.8 (diabetes mellitus with other specified manifestations) or indeed not file any claims for hypoglycaemia. It is also possible that, before the occurrence of hypoglycaemia, dementia or cognitive impairment might have been present but undiagnosed and thus not recorded.
In conclusion, our study represents one of the largest cohorts to examine the association between severe hypoglycaemia and development of dementia in adults with diabetes. We found that adult diabetic subjects who had prior in-hospital diagnosis of hypoglycaemia were almost three times more likely to develop dementia (HR 2.76). Multiple episodes of hypoglycaemia present a graded increase in risk. The influence of hypoglycaemic episodes on brain function warrants further investigation.