Hypoglycaemia and dementia
Introduction
A 72 year old lady presented to her GP as she had experienced multiple hypoglycaemic (low blood sugar) events over the last 3 months. This last happened two days prior to the appointment when her daughter was visiting and her daughter had encouraged her to see her GP.
Ms AB, lived on her own and had been diagnosed with type 2 diabetes mellitus 21 years ago. She was independent and active, and apart from the diabetes, in good health. She attended her reviews regularly and was diligent about taking her medication. Over the last 6 months, she had had not been as hungry and so was eating less and had lost some weight. The GP was concerned about her hypoglycaemia and the potential impact that this could have on her health and her independence. Amongst his concerns, was the potential for development of dementia.
Diabetes mellitus is a disorder in which the balance and/or use of hormones that help to maintain a healthy level of glucose in the blood is disrupted (Amiel, et al., 2008). Diabetes mellitus is further divided into type 1 in which patients have little or no ability to produce the hormone insulin (which helps to reduce blood glucose levels), or type 2 diabetes in which the body becomes resistant to the insulin produced or produces insufficient insulin to meet the bodies needs (NICE, 2015). In the UK, it is estimated that type 2 diabetes accounts for 90% of adults diagnosed with diabetes (NICE, 2015). Type 2 diabetes is a progressive condition in which management may need to be intensified over time to include various tablets and injectable medication such as insulin (NICE, 2015).
The risk of developing both type 2 diabetes and dementia rises with age (Diabetes UK, (online); Alzheimer’s Society, (online)). Furthermore, Diabetes UK (2016) reported that patients with diabetes are 1.5 to 2 times more likely to develop dementia. Sinclair, Hillson and Bayer (2014) stated that both diabetes and dementia are long-term disabling conditions and prevalence of these is set to rise with the ageing population and therefore there is a possibility that there will be larger numbers of people in whom the disease is likely to co-exist going forward.
The literature search has focussed on hypoglycaemia in patients with type 2 diabetes and what is currently known about the relationship between hypoglycaemia and dementia as that information is relevant to Mrs AB.
Literature review
Hypoglycaemia and dementia:
Hypoglycaemia as a potential risk factor for the development of dementia has been explored in various studies over the last few years. In 2009, Whitmer et al. reported the findings of their longitudinal cohort study of type 2 diabetes patients based in California. The objective of their study was to determine if patients that experienced severe glycaemic episodes, were at greater risk of developing dementia. Their results suggested that severe hypoglycaemia was associated with an increased risk of dementia. Their study was one of the first to be conducted looking at the effect of hypoglycaemia specifically in older type 2 diabetes patients (Whitmer et al, 2009).
However, 2009 was a year of controversy with regards to determining the association between hypoglycaemia and cognitive impairment or dementia. Bruce et al. (2009) reported the findings of the Fremantle Diabetes Study and they found no evidence to support the notion that hypoglycaemia was associated with an increased risk of developing dementia. Although it should be noted that the study findings reported by Bruce et al (2009) was based on a sample of 302 patients followed for a median of 1.6 years and the study by Whitmer et al (2009) had 16,667 patients followed up for up to 27 years. The short length of follow up may potentially have been responsible for the varying outcome.
From 2013 onwards, various studies have reported their findings regarding the potential association between hypoglycaemia and dementia (Yaffe et al., 2013; Lin & Shehu, 2013; Feinkohl et al., 2014; Haroon et al., 2015 and Mehta, Mehta and Goodwin, 2016). Apart from the study conducted by Mehta, Mehta and Goodwin (2016), the other studies were all prospective studies that observed older patients (average age ranged from 60-75) for between 4-12 years. The data obtained by Mehta, Mehta and Goodwin (2016) was based on information collated from GP records in the UK and therefore looked at this retrospectively. All these studies suggested that patients who experienced severe
hypoglycaemic episodes were at greater risk of developing cognitive impairment or dementia. No papers were found from 2013 to date that reported findings suggesting that there was no relationship between hypoglycaemia and dementia.
Dementia and hypoglycaemia.
Although the main aim was to review the literature surrounding hypoglycaemia as an independent risk factor for dementia, it is important to mention and consider the relationship between dementia and hypoglycaemia as well. Bruce et al. (2009) found no association between hypoglycaemia and dementia as reported above, however, they did report that in patients with dementia, there was an increased number of more serious hypoglycaemic episodes. This was further supported by Prinz et al. (2016) in a study of 6770 patients with dementia and diabetes. In addition to these two studies, studies conducted by Feil et al. (2011) and Punthakee et al. (2012) reported similar findings. The authors attributed their findings to the impact that impaired cognitive function and dementia will have on a patients ability to care for themselves.
Discussion
With age and longer duration of diabetes, patients can become less aware of the symptoms of hypoglycaemia and so may not be able to accurately report when mild hypoglycaemic events that do not require assistance occur (Meneilly and Tessier, 2015; Ariel et al, 2008). Reasons for this reduced awareness are multifactorial and include various physiological changes in older patients such as a reduction in the secretion of glucagon which is an inherent part of maintaining adequate sugar levels in the body. (Meneilly and Tessier, 2015). These changes also mean that older patients may not recognise hypoglycaemic episodes until they become quite severe and require assistance and/or hospitalisation (Abdelhafiz, McNicholas and Sinclair, 2016). The lack of awareness and increased severity of hypoglycaemic potentially puts older patients at risk of adverse outcomes such as dementia (Meneilly and Tessier, 2015). With the exception of Bruce et al. (2009) and Feinkohl et al. (2014), the other studies utilised data from hospital records which suggests that the results are based on the potential risk of severe hypoglycaemic episodes on the development of dementia. This does not imply that multiple mild or
moderate episodes do not increase the risk of dementia, just that there is insufficient data to determine this.
Mrs AB is 72 has had diabetes for 21 years. Due to the length of time that she has had diabetes, it may be necessary to assess her hypoglycaemic awareness to determine if additional monitoring is required. This may help ensure that hypoglycaemic episodes especially mild and moderate ones are identified early preventing potentially more serious episodes that require assistance or hospitalisation. Based on the results from the review, avoiding severe hypoglycaemic episodes could, although not definitively, reduce the risk of Mrs AB developing dementia.
Other factors that increase the risk of hypoglycaemia in older patients are reduced calorie intake with no corresponding reduction in the pharmacological management of diabetes (Abdelhafiz, McNicholas and Sinclair, 2016). This is particularly problematic for drugs such as sulfonylureas (which stimulate the pancreas to produce more insulin) and insulin. Both these drugs exert their action regardless of calorie intake and so therefore in reduced calorie states such as missed meals or reduced portion sizes, they can cause blood glucose levels to drop dangerously low (Amiel et al., 2008). Reviewing Mrs AB’s weight, diet and medication could provide some insight as to why she had experienced the hypoglycaemic episodes and could be used to inform on future management of her diabetes.
Despite some uncertainty with regards to the relationship between hypoglycaemia and dementia, there is some consensus that patients with dementia are at greater risk of more frequent and severe hypoglycaemic episodes (Abdelhafiz, McNicholas and Sinclair, 2015). Reasons for this are multifactorial. In part this can be attributed to the loss of ability of the patient to look after themselves, remembering to eat and eat sufficiently. It can also be due to difficulties managing more complex medication regimes necessary to achieve glycemic control as diabetes progresses. These regimes will often include medication that is likely to cause hypoglycaemia. Another reason for the increased severity may be that patients forget what the signs and symptoms of hypoglycaemia are and what they need to do if they experience them (Meneilly and Tessier, 2016).
At presentation, there was no concern about Mrs AB’s cognitive function and so the increased risk of hypoglycaemic episodes as a result of this do not currently need to be
considered. However, it is important to keep this consideration in mind as Mrs AB does live alone and any changes to her cognitive function could have a significant impact on her ability for both look after herself and manage her diabetes.
Mattishent & Loke (2016) in a recent meta- analysis of the literature surrounding hypoglycaemia and cognitive impairment in elderly patients, found that the studies demonstrated a bi-directional relationship
between the two. Abdelhafiz, McNicholas
Reciprocal relations
Clinical implications
relationship and one that can lead to a vicious
them have reported that they would not worry about harms of tight glycemic control for an older patient with an HbA1c level of 6.5% who is at high risk for hypoglycemia. A similar proportion were concerned about negative repercussions following de-intensification of therapy
cycle (see Figure 1). IfMrsABisnotadequatelymanaged,sheancdonuoldtmfineedtihngerpserlfforamtasnocmeemepaosiunrteswbitahsiendtohnatachievingHbA1c
targets b7.0%. Nearly one-quarter would even be concerned about cycle, and that would impact negatively on her independence and active lifestyle. With the
liability with de-intensification of hypoglycemic medications (Caverly et al., 2015). Therefore, health care providers should be educated about
correct support and adjustments as suggested above in figure 1, this can potentially be
setting appropriate glycemic targets based on the degree of frailty and avoided and thereby allow Mrs AB to conthineuperetsoenbceoinf dempenntidaethnattabnadlanecnegthaegbeenfuelfilytsionf hgleycremic control
busy and active life.
Although the main objective of this review was to look at the relationship between
with the risks of hypoglycemia.
3. Conclusion
Hypoglycemia, frailty and dementia have a reciprocal relationship
which may lead to a viscous circle (Fig. 1). Hypoglycemic events seem hypoglycaemia and dementia, it is also important to keep in mind the adverse outcomes
Hypoglycaemia
A.H. Abdelhafiz et al. / Journal of Diabetes an
Fig. 1. Interaction of hypoglycemia, frailty and dementia comprising a vicious circle and and Sinclair (2016) in a review of the considerations for clinical implications.
literature surrounding hypoglycaemia, frailty
Figure 1. Interaction of hypoglycaemia, frailty and dementia comprising a vicious circle and considerations for clinical implications (from
(Wright&AFbrdieerl,h2a0fi0z8,)M.cPNrimchaorlyascarnedpSroinfcelsasiro(n2a0ls16()P)CPs)mayhave and dementia describe this as a reciprocal
Relax targets.
De-intensify or withdraw medications. Patient and health care professionals’ education.
some misconception about the benefits of tight glycemic control in older people. In a survey of a random national sample of PCP, almost half of
to be common in older people with diabetes especially in those who
related to hypoglycaemia particularly witharegfrarildsantdo sthufefedredvefrlompmsiegntifiocfanfrtawilteyi.gFhtigluosres. 2This group of
patients currently appear to be overtreated and seem to be
provides a summary of potential causes of hypoglycaemia and its consequences. In the
inappropriately using medications that likely increase the risk of hypoglycemia. Therefore, as patients with diabetes get older or
context of future management of Mrs AB, it is important not only to keep the potential
develop dementia, overtreatment should be avoided, targets need to
implications of the development of demenbteiarei-nsemt aindt,hbeuetffaeclstoftfhraeiltcyaaunsdewse,iaghntdloossthsehoruld be considered
adverse outcomes that are associated with hypoglycaemia.
with a view of reducing or even completely withdrawing hypoglyce-
mic medications. New guidelines are needed to clarify when to de-intensify hypoglycemic medications and to balance the perfor- mance measures that incentivize both appropriate intensification and appropriate de-intensification of hypoglycemic medications.
References
Abbatecola, AM, Bo, M, Barbagallo, M, Incalzi, RA, Pilotto, A, Bellelli, G, et al. (2015).
Severe hypoglycemia is associated with antidiabetic oral treatment compared with insulin analogs in nursing home patients with type 2 diabetes and dementia: Results from the DIMORA study. Journal of the American Medical Directors Association, 16, 349.e7–349.e12.
Frailty
Dementia
d
Figure 2. Hypoglycaemia and frailty – risk factors, complication and consequences (from Abdelhafiz et al., 2015)
Limitations
Mattishent and Loke (2016) found substantial differences in how hypoglycaemic events were measured. This ranged from the use of hospital records only to self-reported hypoglycaemic episodes. Both of these can introduce potential biases to the result as they are dependent on accurate recording and adequate recall respectively. These differences also mean that comparing and combining results and data is more difficult. Another potential limitation is that the studies used different methods to measure cognitive impairment. Some relied on diagnoses from patient records and others on various cognitive tests (Mattishent & Loke, 2016).
Determining whether hypoglycaemia is an independent risk factor for the development of dementia is challenging. This is because of the difficulty in obtaining all the necessary data such as hypoglycaemic events that do not require hospitalisation. Diabetes UK (online) state that the patients with diabetes are two times more likely to develop dementia. The exact mechanism by which this happens is not yet fully understood but it is thought that as
well as hypoglycaemia, hyperglycaemia may have a role to play (Bordier et al., 2014; Seaquist, 2015). None of the papers reviewed reported on periods of hyperglycaemia and so it was not possible to determine whether or not that may have had an impact on the results.
Conclusion
At present, whether or not hypoglycaemia is an independent risk factor for the development of dementia has yet to be determined. Recent studies have suggested that there may be a relationship between the two, but it has not been possible to determine causality. There is however acknowledgement that having some degree of cognitive impairment or dementia can negatively impact on a patient’s ability to manage their diabetes. This can be as a result of taking too much medication or not taking any at all and so the complications include both hypergylcaemia and hypoglycaemia. Recent NICE guidelines on the management of type 2 diabetes allude to more personalised glycaemic targets and much of the literature supports the deintensification of treatment in older patients. Considering the potential impact on independence that both hypoglycaemia and dementia can have, this appears to be a pragmatic approach. To determine whether or not hypoglycaemia is an independent risk factor in the development of dementia needs to be further explored.