496 NEUROLOGY, NEUROPSYCHOLOGY, NEUROPHYSIOLOGY Zdrav Vestn |November – December 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3302 Copyright (c) 2022 Slovenian Medical Journal. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Cognitive dysfunction in patients with type 2 diabetes Kognitivne motnje pri bolnikih s sladkorno boleznijo tipa 2 Andreja Špeh,1,2 Nika Šatej,3 Andrej Janež,4 Milica Gregorič Kramberger1,2 Abstract The prevalence of diabetes and dementia has been increasing in recent years. These two diseases share many risk factors, such as hypertension, dyslipidaemia, obesity, unhealthy diet, and physical inactivity. Poor glycaemic control is associated with a higher risk of cognitive decline, and both microvascular and macrovascular complications are related to a higher risk of dementia. Older people with diabetes experience deficits in several cognitive domains, especially memory and executive functions. Such problems can affect the course of the disease, individuals’ ability to gain insight into their ill- ness, and the ability to follow a treatment regimen. Cognitive dysfunction in diabetes patients relates to poorer diabetes knowledge and self-care, increased inaccuracies in blood glucose monitoring and insulin adjustment, frequently missed medical appointments, and a higher number of hypoglycaemic episodes and cardiovascular complications. It is import- ant to identify cognitive dysfunction in diabetes patients and consider these problems in treatment planning, defining target glucose levels, planning education, choosing pharmacological and non-pharmacological methods, and providing supports to patients and their family members or caregivers. An individual approach, gradual changes, and a simple treat- ment regimen (e.g., use of extended-release drugs and pill dispensers) that consider the patient’s social situation are of the utmost importance. Izvleček Prevalenci sladkorne bolezni in demence v zadnjih letih naraščata, bolezni pa si delita številne dejavnike tveganja, kot so hipertenzija, dislipidemija, čezmerna telesna teža, nezdrava prehrana in telesna neaktivnost. Pomanjkanje glikemičnega nadzora se povezuje z višjim tveganjem za kognitivni upad, mikrožilni in makrožilni zapleti sladkorne bolezni pa z viš- jim tveganjem za razvoj demence. Bolniki s sladkorno boleznijo imajo oškodovane različne kognitivne domene. Posebej izrazite so težave na področju spomina in izvršilnih funkcij. Tovrstne težave lahko vplivajo na potek sladkorne bolezni, posameznikove možnosti uvida v lastno bolezen in sposobnosti sledenja režimu zdravljenja. Kognitivne motnje pri bolni- kih s sladkorno boleznijo se povezujejo s slabšim znanjem in slabšo skrbjo za lastno bolezen, pogostejšimi napakami pri 1 Deparment of Neurology, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Community Health Centre Ljubljana, Ljubljana, Slovenia 4 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical centre Ljubljana, Ljubljana, Slovenia Correspondence / Korespondenca: Andreja Špeh, e: andreja.speh@kclj.si Key words: diabetes mellitus; cognition; risk factors; cognitive disorders; dementia Ključne besede: sladkorna bolezen; kognicija; dejavniki tveganja; kognitivne motnje; demenca Received / Prispelo: 30. 8. 2021 | Accepted / Sprejeto: 28. 12. 2021 Cite as / Citirajte kot: Špeh A, Šatej N, Janež A, Gregorič Kramberger M. Cognitive dysfunction in patients with type 2 diabetes. Zdrav Vestn. 2022;91(11–12):496–506. DOI: https://doi.org/10.6016/ZdravVestn.3302 eng slo element en article-lang 10.6016/ZdravVestn.3302 doi 30.8.2021 date-received 28.12.2021 date-accepted Neurology, neuropsychology, neurophysiology Nevrologija, nevropsihologija, nevrofiziologija discipline Review article Pregledni znanstveni članek article-type Cognitive dysfunction in patients with type 2 diabetes Kognitivne motnje pri bolnikih s sladkorno boleznijo tipa 2 article-title Cognitive dysfunction in patients with type 2 diabetes Kognitivne motnje pri bolnikih s sladkorno boleznijo tipa 2 alt-title diabetes mellitus, cognition, risk factors, cog- nitive disorders, dementia sladkorna bolezen, kognicija, dejavniki tveganja, kognitivne motnje, demenca kwd-group The authors declare that there are no conflicts of interest present. Avtorji so izjavili, da ne obstajajo nobeni konkurenčni interesi. conflict year volume first month last month first page last page 2022 91 11 12 496 506 name surname aff email Andreja Špeh 1,2 andreja.speh@kclj.si name surname aff Nika Šatej 3 Andrej Janež 4 Milica Gregorič Kramberger 1,2 eng slo aff-id Deparment of Neurology, University Medical Centre Ljubljana, Ljubljana, Slovenia Klinični oddelek za bolezni živčevja, Nevrološka klinika, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenija 1 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia Medicinska fakulteta, Univerza v Ljubljani, Ljubljana, Slovenija 2 Community Health Centre Ljubljana, Ljubljana, Slovenia Ambulanta za sladkorno bolezen, Zdravstveni dom Ljubljana, Ljubljana, Slovenija 3 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical centre Ljubljana, Ljubljana, Slovenia Klinični oddelek za endokrinologijo, diabetes in presnovne bolezni, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenia 4 Slovenian Medical Journallovenian Medical Journal 497 REVIEW ARTICLE Cognitive dysfunction in patients with type 2 diabetes 1 Introduction The global prevalence of diabetes was estimated at 171 million in 2000; this is expected to nearly double by 2030 (1). The increase in prevalence can be attribut- ed to changing lifestyle factors such as unhealthy diet, obesity and physical inactivity, as well as longer life ex- pectancy and population aging (2). The results suggest that the diabetes epidemic will continue even if the obesity prevalence remains unchanged (1). Patients with diabetes also have a higher risk of developing mild cognitive impairment (MCI) and dementia (3). Dementia refers to a syndrome, usually chronic and progressive, characterized by a more pronounced cognitive decline than would be expected with nor- mal aging (4). In dementia, dysfunctions of memo- ry, thinking, orientation, comprehension, arithmetic, learning, speech, judgment, and functioning in daily activities are found. Alzheimer’s dementia (AD) is the most common neurodegenerative dementia, followed by Lewy body dementia, mixed dementia, and vas- cular dementia. Mild cognitive impairment indicates cognitive changes in one or more domains without significant impact on daily functioning (5). Patients with MCI are at higher risk for cognitive decline and development of dementia. Population trends in dia- betes are very similar to those in dementia: 5–7% of people over the age of 60 have dementia and the prev- alence of dementia is expected to almost double every 20 years (6). 2 Risk factors 2.1 Dementia Risk factors for the development of dementia can be classified into two groups. The first group includes modifiable risk factors; with prevention or reduc- tion of their impact, we can reduce the risk of disease development or slow its progression. A recent me- ta-analysis (7) introduced 12 modifiable risk factors for dementia: low education, hypertension, hearing impairment, smoking, obesity, depression, physical spremljanju krvne glukoze in odmerjanju inzulinskih injekcij, pogosteje zamujenimi zdravstvenimi pregledi in večjim števi- lom epizod hipoglikemije ter srčnožilnih zapletov. Pomembno je, da pri bolnikih s sladkorno boleznijo prepoznamo kogni- tivne težave in jih upoštevamo pri načrtovanju zdravljenja; opredelitvi tarčnih vrednosti, edukaciji, izbiri farmakoloških in nefarmakoloških načinov zdravljenja ter nudenju podpore bolnikom in njihovim svojcem oziroma skrbnikom. Pomembni so individualni pristop, postopno uvajanje sprememb in čim bolj enostaven protokol zdravljenja (npr. uporaba zdravil s podaljšanim učinkom, uporaba razdelilcev zdravil), ki upoštevajo tudi socialno situacijo posameznika. inactivity, diabetes, social isolation, excessive alcohol consumption, traumatic brain injury, and air pollu- tion. Together the 12 modifiable risk factors account for around 40% of worldwide dementias, which, the- oretically, could be prevented or delayed. Although some risk factors are more pronounced in certain periods of life, e.g. education in early life, the authors stress that it is never too early and never too late for dementia prevention. The second group includes non-modifiable risk factors: age, female sex and the apolipoprotein (APOE) ε4 genotype, a genetic risk factor for Alzheimer’s disease (8,9). 2.2 Diabetes mellitus In recent years, metabolic syndrome, a set of clinical and metabolic factors, is frequently mentioned among the diabetes risk factors. Although the definitions for metabolic syndrome vary slightly, most include fac- tors that are commonly concurrent: central obesity, impaired glucose tolerance, atherogenic dyslipidae- mia, and arterial hypertension (10). The cause of the metabolic syndrome has not yet been completely ex- plained. Insulin resistance plays an important role in the pathogenesis and is the cause of abnormal glucose and lipid metabolism, which can also affect the devel- opment of arterial hypertension. Metabolic syndrome is thus not only a risk factor for the development of diabetes but is also associated with a higher risk of car- diovascular disease and various types of cancer (11). A recent meta-analysis has shown that the association between metabolic syndrome and cognition in the el- derly is quite inconsistent (12). The individual meta- bolic syndrome components show different patterns of association with cognition, as these associations are also influenced by age. A slightly older meta-analy- sis confirmed an association between metabolic syn- drome and cognitive decline in younger (≤70 years), but not older (>70 years) elderly people (13). At the same time, metabolic syndrome is also associated with a higher risk of vascular dementia and higher risk of 498 NEUROLOGY, NEUROPSYCHOLOGY, NEUROPHYSIOLOGY Zdrav Vestn | November – December 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3302 Figure 1: Associations between risk factors, diabetes complications and cognitive impairment. Age Sex Genetic factors Excessive alcohol consumption Smoking Physical inactivity Unhealthy diet Head injury Hearing loss Metabolic syndrome Microvascular complications Diabetic neuropathy Nephropathy Retinopathy Hypoglycaemia Hypertension Hyperglycaemia Macrovascular complications Coronary artery disease Peripheral artery disease Stroke Cognitive impairment Depression Social isolationEducation progression from MCI to dementia (14). Early pre- vention and recognition of the metabolic syndrome is extremely important to reduce the risk of further complications. 2.3 Age-related risk factor characteristics Obesity is one of the risk factors linking diabetes and dementia. Even though obesity is a generally ac- cepted risk factor for dementia (7), the association between late-life obesity and dementia is somewhat more complex. In late life, a lower body mass index (BMI) is frequently associated with worse cognitive performance (15,16), however, with long-term fol- low-up, the detrimental effect of weight gain can be observed, a trend clearly observed in middle age. In old age, weight loss can be the result or a sign of devel- oping dementia, which makes a higher BMI to appear protective with regard to cognitive function, an effect that is observed particularly in short-term follow-up (17). Similar patterns have been observed in cho- lesterol (18) and blood pressure (18); that the elder- ly with higher cholesterol levels and blood pressure exhibit better cognition. It is important to be aware of changes in the pattern of associations between cer- tain risk factors and cognition in (late) age and to pay attention to this, particularly when rapid changes in certain areas occur, such as sudden weight loss. Associations between risk factors, diabetes com- plications and cognitive impairment are shown in Figure 1. 3 Diabetes mellitus and cognition Diabetes mellitus is an independent risk factor for poor cognitive function in the elderly (19), faster cog- nitive decline (20), and MCI (21). A systematic review of studies has shown that patients with diabetes have impairments in various cognitive domains with exec- utive function and memory being particularly affected (22). Additionally, diabetes is also associated with cog- nitive decline in the global cognition, memory, execu- tive function, and orientation over a follow-up period of 10 years (23). Some studies report that changes in the brain or cognitive problems can be detected in the pre-diabetic period (20), although the results in this area are not entirely consistent (19). 3.1 Hyperglycaemia and hypoglycaemia Poor glycaemic control in diabetes, resulting in both hyperglycaemia and hypoglycaemia, is strongly associated with cognitive impairment (24). Variations in blood glucose levels that impact the brain can cause 499 REVIEW ARTICLE Cognitive dysfunction in patients with type 2 diabetes a wide range of changes in brain function, from mild disorders to dementia or even death (25). Hypoglycae- mia is the main reason for temporarily altered brain function in patients with diabetes (25). Cognitive impairment occurs because the brain does not have enough glucose to function normally. When the blood glucose level falls below 3.5 mmol/L, this can lead to various cognitive symptoms, such as confusion, un- usual behaviour, impaired concentration or lack of focus, and poor coordination. As glucose levels rise, these symptoms usually disappear, but prolonged, re- current hypoglycaemia may lead to cognitive decline. A history of severe hypoglycaemia is associated with a higher risk of cognitive decline and dementia (26), while recurrent hypoglycaemia also leads to poorer memory and slower processing speed (27). At the same time, chronic hyperglycaemia is also associated with a higher risk of developing cognitive impairment (28). During an episode of acute hyper- glycaemia, processing speed, working memory, and attention are impaired (29). In addition, patients are more dysphoric with reduced energetic arousal and increased sadness and anxiety. A study has shown that a composite index of hyperglycaemia can explain the changes in processing speed and executive function in diabetes (30). Hyperglycaemia is associated with two groups of typical diabetes complications that increase the risk of developing dementia (24). The first group includes microvascular complications, namely dia- betic neuropathy, nephropathy, and retinopathy. The most common macrovascular complications include coronary artery disease, peripheral artery disease, and stroke (31). High glucose levels accelerate the process of atherosclerosis, leading to important micro- and macrovascular diseases affecting the heart and brain and cause changes in brain function (25). Epidemio- logical studies have shown that diabetes and related conditions are associated with both vascular and neu- rodegenerative forms of cognitive impairment, but the association between diabetes and vascular forms of cognitive impairment is stronger and more consis- tent (32). 3.2 Types of cognitive impairment in patients with diabetes Different manifestations of cognitive problems can be observed in patients with diabetes. In their article, Koekkoek et al (33) presented three stages of diabe- tes-associated cognitive dysfunction. Individual stag- es do not necessarily represent a continuous process, but they can lead to different outcomes. The authors differentiate between diabetes-associated cognitive decrements, MCI, and dementia. For the latter two, the same diagnostic criteria as for patients without di- abetes apply, but mild cognitive changes that appear in patients with diabetes are frequently missed. These minor changes occur in all age groups and progress very slowly with aging. Diabetes-associated cognitive decline is normally recognized after patients report changes in their cognitive function; normally, they report of increased mental effort without changes in their professional and social activities. At the same time, there is no alternative explanation for these com- plaints. Cognitive problems should not be so severe as to be classified as MCI. In fact, diabetes-associated cognitive decline corresponds to the clinical diagnosis of subjective cognitive complaint. Although symptoms may not be particularly severe, the diagnosis remains important as it acknowledges the patient’s experienc- es; at the same time, subjective cognitive impairment frequently reflects preclinical Alzheimer’s dementia (34). In addition to assessing the severity of cognitive im- pairment, it is extremely important to identify which cognitive domains are impaired (35), as these affect the specific symptoms that patients have. Based on these symptoms, treatment can be tailored to the patient, of- fering adequate support. Patients with memory prob- lems, for example, can forget to take medication or eat on time. Patients with executive function impairment normally have good working memory and remem- ber instructions given to them but find it difficult to abandon old behaviours and routines and start new ones. Therefore, the patient’s behaviour may be misin- terpreted as inconsistent or stubborn. Individuals who have problems with mental flexibility and processing speed will have problems if treatment regimens be- come too complex. They may experience anxiety and fear of not being able to follow the treatment plan. Those who have trouble solving problems, however, may remember the instructions but are unable to in- tegrate them into practice. They also experience prob- lems with recognizing and treating hypoglycaemia. 3.3 Recognizing patients with cognitive impairment The question arises as to whether patients with di- abetes should also be routinely screened for possible cognitive impairment. In patients with diabetes over the age of 65, the American Diabetes Association 500 NEUROLOGY, NEUROPSYCHOLOGY, NEUROPHYSIOLOGY Zdrav Vestn | November – December 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3302 (36) recommends neuropsychological assessment at first visit and yearly assessments with tests such as the Mini-Mental State Examination (MMSE), Mon- treal Cognitive Assessment (MoCA) or Mini-Cog if so required. The European Diabetes Working Party for Older People (EDWPOP) recommendations (37) state that a yearly cognitive assessment should include the global/physical, cognitive and affective domains of functioning. The authors of the previously presented three- stage model of diabetes-associated cognitive decline (33) propose a case-finding strategy, combined with appropriate support for diabetes management. Such case-finding strategies should focus on detection of MCI and dementia since these disorders are most like- ly to have implications for daily function and diabetes self-management. The focus should be on individuals who are more likely to develop cognitive impairment, such as patients with frequent hypoglycaemic episodes or patients who have started using new drugs because they have not achieved the desired efficacy with the previous ones. One of the possible approaches is as- sessing an individual’s risk to develop dementia. An example of this is a short risk score for predicting the 10-year dementia risk, which was designed specifical- ly for patients with type 2 diabetes (38). It includes an assessment of predictors most strongly associated with dementia, namely age, education, microvascular dis- ease, diabetic foot, cerebrovascular disease, cardiovas- cular disease, acute metabolic event, and depression. In diagnosis, it is important to pay attention to de- pression as it may be associated with cognitive impair- ment. Possible explanations for cognitive complaints include hypothyroidism, vitamin deficiency, anaemia, liver disease, and kidney disease (33). 4 The effect of cognitive impairment on daily functioning and self-management Diabetes self-management involves several cogni- tive abilities such as memory, attention, planning, and calculating, which is the reason cognitive impairment is associated with poorer self-management (39,40). Problems with memory and executive function are associated with poorer knowledge of diabetes, poor- er insulin adjustment, increased inaccuracies in blood glucose monitoring, and more frequently missed medical appointments (22). At the same time, cogni- tive impairment is an important predictor of a larger frequency of hypoglycaemic episodes, cardiovascular complications, and deaths due to cardiovascular and other causes (41). With the help of focus groups, in their study, Feil et al (42) have studied what challenges caregivers face when caring for patients with diabe- tes and concurrent dementia. Three themes emerged. Memory loss caused patients to neglect self-care, lead- ing to caregiver intervention. Behavioural and psy- chological symptoms of dementia disrupted the daily diabetes care routine, with denial of having diabetes being among the most common. Caregivers also re- ported that caring for both diabetes and dementia was highly burdensome as they felt overwhelmed and wanted more support from family and patients’ healthcare providers. When planning treatment, it is important to pay attention to caregivers so that they also receive education about the disease and its treat- ment and receive appropriate support (43). 5 Treatment 5.1 Parameters of good diabetes management Before we can focus on diabetes treatment strate- gies, it is important to identify appropriate glucose tar- gets for a population of elderly patients with diabetes with associated cognitive impairment. The European Diabetes Working Party for Older People (EDWPOP) published guidelines on the treatment of patients ≥ 70 years with diabetes (37). It is recommended that treatment decisions be based on an assessment of the benefit-risk balance for each individual, taking into account factors such as hypoglycaemia risk, the ability to self-manage diabetes, the presence or absence of co- morbidities, cognitive status, and life expectancy. The recommended haemoglobin A1c (HbA1c) values thus depend on age and comorbidities. A range of 7–7.5% is suggested for older patients with type 2 diabetes without major comorbidities and 7.6–8.5% for frail patients (including those with dementia) where the hypoglycaemia risk may be high and the likelihood of benefit relatively low. The article, which describes the consensus of experts in the field of diabetes treatment, states that health status, defined by the presence and number of comorbidities or impairments of functional status, leads to the identification of three major classes of older patients (44). For each of these classes, a spe- cific glucose target value is recommended. A1c values <7.5 are recommended for healthy individuals or in- dividuals with few comorbidities and intact cognitive and functional status. Those with a complex medical history should achieve A1c values <8.0. These are in- dividuals with numerous chronic comorbidities but 501 REVIEW ARTICLE Cognitive dysfunction in patients with type 2 diabetes only mild to moderate cognitive impairment. In indi- viduals with very complex medical history and poor health, those who require long-term care, with end- stage chronic illnesses or moderate to severe cogni- tive impairment, A1c <8,5 is recommended. Recently, researchers have begun to emphasize that A1c should not be the only parameter used to define glycaemic tar- gets in the elderly population. Studies have shown that A1c values in the elderly population do not necessarily reflect the same estimated average glucose values as in the younger population (35). Glucose self-monitoring is also recommended for a more realistic assessment of A1c in elderly patients with comorbidities. 5.2 Non-pharmacological treatment and support Bunn et al (43) emphasize the importance of an in- dividualized approach to treatment. In the early stages of dementia, when individuals still have enough func- tionality to make treatment decisions, both an indi- vidual approach and the formation of a relationship between the patient, their caregiver, and family physi- cian are important. However, as dementia progresses and the patient’s independent functioning becomes difficult, more attention should be paid to more accu- rate disease monitoring, both on the part of the care- giver and the family physician. The authors emphasize that emotional support and practical help provided by family members are crucial in this. Munshi (35) gives a number of practical tips to help people with diabetes and associated cognitive im- pairment. In patients with memory loss (forgetting to take medications and insulin injections, monitoring glucose levels), it is recommended to use pill dispens- ers and send more than one appointment reminder. Patients should perform self-monitoring in the pres- ence of caregivers or with their help. Long-acting formulations may reduce the frequency of adminis- tration as well as the number of insulin injections. In patients who have difficulty recognizing and treating hypoglycaemia and following new instructions, it is recommended that complex treatment regimens be avoided and that changes be made gradually. Patients may also benefit from repeating training and instruc- tions at each visit. For individuals who have particu- larly severe difficulty in establishing new behaviours, we may ask caregivers for assistance when protocols are changed. Patient education is also an extremely important area, which must be adapted in the case of cognitive impairment. German researchers compared the ef- fectiveness of standard treatment and teaching pro- grammes (TTP) to the structured treatment and teaching programme for elderly patients with type 2 diabetes mellitus and impaired cognitive function (DICOF-TTP) (45). This programme focused more on practical skills (e.g. injecting insulin) and repeti- tion than on theoretical knowledge. Both groups of participants achieved the same results in the field of self-management after completing the training. How- ever, at the follow-up examination six months later, those who attended the DICOF-TTP had better results and expressed higher satisfaction with the programme itself. The authors conclude that theoretical education alone is not sufficient to guarantee long-term learning in elderly patients. 5.3 Drug treatment Poor glucose control in patients with type 2 dia- betes is known to be associated with poorer cognitive function and faster cognitive decline (46). Human studies have shown that taking certain oral antidiabet- ic drugs can improve cognition in patients with MCI and dementia, but it remains unclear whether diabe- tes treatment can also reduce the incidence of MCI and Alzheimer’s disease (Alagiakrishnan et al, 2013). Many antidiabetic drugs are thought to have a ben- eficial effect on neurogenesis and clinically improve cognitive and memory problems (47); they can also improve working memory (48). There is still an open question as to whether a strict (intensive) pharmacological treatment regimen is bet- ter than a standard treatment regimen. Some studies report certain positive effects of intensive treatment on cognition (49), while other authors have found no evidence that different treatments affect cognitive impairment at all (50). Additionally, a more intensive treatment regimen is also associated with a higher number of hypoglycaemic episodes and higher mor- tality (49,50). Each case should be evaluated individually to as- sess the benefits of a strict glycaemic control against the observed risks. Since complications are more com- mon in the elderly, strict glycaemic control may be saf- er and more recommendable for type 1 diabetes, and standard treatment is recommended for patients with type 2 diabetes (49). 502 NEUROLOGY, NEUROPSYCHOLOGY, NEUROPHYSIOLOGY Zdrav Vestn | November – December 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3302 Legend: DPP4 – dipeptidyl peptidase 4; SGLT2 – sodium glucose co-transporter 2; GLP-1 – glucagon-like peptide-1; GFR – glomerular filtration rate. Drug Efficacy Hypoglycaemia risk Warnings Dosage regimen Formulation Metformin ++ - Monitor GFR Once daily Tablet Sulfonylurea +++ + One to two times a day Tablet Repaglinide ++ + One to three times a day with meals Tablet DPP4 inhibitor ++ - Once daily, in combination with metformin twice daily Tablet SGLT2 inhibitor +++ - Dehydration, urogenital infections Once daily, in combination with metformin twice daily Tablet GLP-1 analogue +++ - Nausea, vomiting, constipation Once daily to once weekly Injection Acarbose + - Bloating, flatulence One to three times a day with meals Tablet Insulin +++ + One to four times a day Injection Table 1: Guidelines for the selection of hyperglycaemic agents in the treatment of type 2 diabetes. 5.4 Guidelines for the pharmacological treatment of hyperglycaemia in patients with diabetes mellitus (and associated cognitive impairment) Drug treatment represents an additional step of non-pharmacological treatment. Subsequently, based on the Slovenian guidelines for the clinical treatment of type 2 diabetes (51), we summarize the recommen- dations for the treatment of hyperglycaemia in pa- tients with diabetes (Table 1). Lifestyle changes should be the basis of treatment, but efforts to make these changes are not a reason to delay the start of pharma- cological treatment. The hyperglycaemia treatment protocol should be as simple as possible to ensure regular taking of medications. Gradually introducing drugs according to the level of glycaemia (HbA1c) and the severity of the hyperglycaemia symptoms is recommended. Treatment is usually started with a low dose of metformin, which is gradually increased. Re- nal function should be monitored. Metformin is con- traindicated if the glomerular filtration rate (GFR) is below 30 ml/min/1.73 m2. If symptoms of hyperglycaemia persist despite the use of metformin, treatment with a sulphonylurea or insulin is required. Both drugs increase the risk of hypoglycaemia, so treatment should be started with low doses, which are gradually increased until glycae- mic control is achieved. When the patient has no symptoms of hypergly- caemia, treatment that does not increase the risk of hypoglycaemia, such as dipeptidyl peptidase 4 (DPP- 4) inhibitors, sodium glucose transporter inhibitors 2 (SGLT2-1) or glucagon-like peptide-1 (GLP-1), is pre- ferred. DPP-4 inhibitors are safe drugs because side effects are uncommon; at the same time, they are less effective in lowering glucose compared to sulphony- lureas and metformin. A fixed combination with met- formin is possible, with taking medication on time being important. SGLT2 inhibitors are very effective drugs as they lower glucose by acting on the pancreas. The most common side effect is urogenital infection, and the risk of hypovolaemia and dehydration is also increased. In patients taking SGLT2 inhibitors, good hydration and consistent genital hygiene are import- ant, which can be difficult to achieve in patients with cognitive decline. GLP-1 analogues are safe drugs as they do not cause hypoglycaemia. Side effects are common, particularly at the start of treatment, but normally disappear within a few weeks. They are suit- able for people with a BMI over 30. Weekly formula- tions are available, which is important if the burden of 503 REVIEW ARTICLE Cognitive dysfunction in patients with type 2 diabetes administering medication to a patient falls on relatives. If patients express problems related to the ability to follow treatment, they can also be alleviated by ad- justing the treatment protocol (35). In case patients frequently forget to take insulin with a meal, the use of basal insulin and non-insulin preparations to control postprandial hyperglycaemia is recommended. If pa- tients make mistakes in insulin dosing, it may be more sensible to determine the doses in advance. If the use of the scheme cannot be avoided, it can be simplified somewhat. For example: for glucose> 15 mmol/L we prescribe the use of one unit and for glucose> 20 mmol / l the use of four units of insulin. If patients experience hypoglycaemia for several hours after a meal and have high glucose levels during the day, it is recommend- ed to use basal insulin in the morning and dose titra- tion to ensure glucose control until the next morning. A possible solution is also the previously mentioned combination of insulin with non-insulin preparations. In case patients need a caregiver to administer insulin, a treatment regimen with as few injections as possible should be chosen. Problems with taking medications on time can be alleviated by using pill dispensers and using long-acting formulations. It is currently unclear whether the use of acetyl- cholinesterase inhibitors (drugs registered to treat Alzheimer’s dementia) brings specific benefits to pa- tients with diabetes, as this has not yet been evaluated specifically for this subgroup of patients. 6 MOPEAD Results 6.1 Study description In the following, we present the Slovenian results of the European project MOPEAD (Models of Patient Engagement for Alzheimer’s Disease) (52), aimed at introducing new approaches for the early detection of individuals with signs of Alzheimer’s disease. By com- paring new approaches, we wanted to discover better ways to identify and diagnose this disease. We focused on individuals whose problems in the community are frequently overlooked, comparing four different strat- egies: a) online neuropsychological testing b) neuro- psychological testing at the Department of Neurology at the University Medical Centre Ljubljana with an “open house” strategy c) testing in individual family medicine clinics and d) testing in specialist tertiary diabetes clinics. In individuals from specialist diabe- tes clinics, the criteria for inclusion in the study were a score of ≤ 27 on the MMSE and ≥ 7 points on the diabetes specific dementia risk score (DSDRS), which included several clinical and demographic variables, namely age, sex, education, diabetic foot, acute met- abolic events, depression, microvascular disease, car- diovascular disease, and cerebrovascular disease. In study participants, a full diagnostic evaluation was performed, which included a neurological and phys- ical examination, neuropsychological assessment, as- sessment of functional status, assessment of resource utilization, affective symptom evaluation, standard blood workup, neuroimaging evaluation with magnet- ic resonance imaging, and optionally, cerebral spinal fluid analysis and APOE genotype determination. 6.2 Results Of all the four groups, the worst results in most areas were achieved by participants referred through diabetes clinics. Table 2 presents the results for the Slo- venian cohort, namely a comparison of groups of par- ticipants who were included through family medicine clinics (N = 16) and diabetes clinics (N = 18). Indi- viduals with diabetes achieved lower results in most of the tested areas, and these differences were statistically significant at MMSE (p <0.001). The difference in cog- nitive function was also detected with the Repeatable Battery for the Assessment of Neuropsychological Sta- tus test battery (RBANS) (p = 0.051). Interestingly, pa- tients from diabetes clinics reported lower anxiety (p = 0.004) and depression (p = 0.072). Nevertheless, the average anxiety and depression scores for both groups were within normal limits, suggesting that there are no clinically significant mood disorders in our sample. The same can be concluded with regard to frailty in both groups. Cerebrospinal fluid biological markers of dementia (Tau, PTAu, Aß42, Aß40 and 10x Aß42/40) show that the groups did not differ in the cerebrospi- nal fluid characteristics of dementia. In the group of participants referred through diabetes clinics, a higher proportion was diagnosed with MCI or dementia (83% vs. 63%). Similarly, a high prevalence of cognitive im- pairment was reported in the Spanish MOPEAD di- abetes cohort (53), with 87.2% of participants having MCI and 7.7% AD. We can conclude that the groups differ significantly in cognitive functioning, and based on current results, these differences cannot be ex- plained by the presence of vascular or neurodegenera- tive processes. One possible explanation would be that differences in cognition are affected by diabetes. 504 NEUROLOGY, NEUROPSYCHOLOGY, NEUROPHYSIOLOGY Zdrav Vestn | November – December 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3302 Legend: Frailty – Result on the Edmonton Frail Scale (0–17 points); Anxiety – anxiety subgroup score on the Hospital Anxiety and Depression Scale (0–21 points); Depression – depression subgroup score on the Hospital Anxiety and Depression Scale (0– 21 points); MMSE – Mini–Mental State Examination; RBANS – The Repeatable Battery for the Assessment of Neuropsychological Status; BMI – body mass index; MRI – magnetic resonance imaging; FAZEKAS – visual assessment of white matter vascular lesions (0–3); Aß42 – amyloid beta 42; Aß40 – amyloid beta 40; Aß42/20 –amyloid beta 42/40 ratio. Family medicine clinic Diabetes clinic p N 16 18 Age, M (SD) 73.9 (43) 73.5 (5.7) .807 Years of education, M (SD) 12.7 (2.4) 12.2 (3.0) .588 Frailty, M (SD) 3.3 (1.8) 3.8 (1.5) .564 Anxiety, M (SD) 7.1 (3.9) 3.5 (2.2) .004 Depression, M (SD) 4.9 (3.0) 3.2 (2.1) .072 MMSE, M (SD) 27.9 (1.4) 25.6 (1.9) .000 RBANS, M (SD) 90.5 (14.2) 81.7 (8.1) .051 BMI, M (SD) 32.6 (9.1) 30.6 (4.8) .458 MRI, Fazekas, Deep 1.00 (0.6) 1.33 (0.7) .187 Tau [pg/ml] 412.9 (150.1) 424.7 (248.8) .915 Ptau [pg/ml] 67.7 (23.7) 69.0 (32.0) .932 Aß42 [pg/ml] 990.4 (375.5) 1144.4 (359.4) .456 Aß40 [pg/ml] 14,682.7 (3,362.8) 14,850.5 (7,628.5) .957 10x Aß42/40 0.7 (0.2) 0.9 (0.3) .225 Table 2: Comparison of descriptive statistics of two groups of participants from family medicine clinics and diabetes clinics. 7 Conclusion Recognizing the increasing incidence of diabetes and dementia is crucial for appropriate, timely, and quality treatment of patients. 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