Association between the Vicious Cycle of Diabetes-Associated Complications and Glycemic Control among the Elderly: A Systematic Review

Background and objectives: Improved quality of life (QoL) and life expectancy of elderly diabetic patients revolves around optimal glycemic control. Inadequate glycemic control may lead to the development of diabetes-associated complications (DAC), which not only complicate the disease, but also affect morbidity and mortality. Based on the available literature, the aim was to elucidate the vicious cycle underpinning the relationship between diabetes complications and glycemic control. Materials and Methods: A comprehensive literature search was performed to find eligible studies published between 1 January 2000 and 22 September 2018 pertaining to diabetes complications and glycemic control. Results: Initially, 261 studies were retrieved. Out of these, 67 were duplicates and therefore were excluded. From the 194 remaining articles, 85 were removed based on irrelevant titles and/or abstracts. Subsequently, the texts of 109 articles were read in full and 71 studies were removed at this stage for failing to provide relevant information. Finally, 38 articles were selected for this review. Depression, impaired cognition, poor physical functioning, frailty, malnutrition, chronic pain, and poor self-care behavior were identified as the major diabetes-associated complications that were associated with poor glycemic control in elderly diabetic patients. Conclusions: This paper proposes that diabetes-associated complications are interrelated, and that impaired glycemic control aggravates diabetes complications; as a result, patient’s self-care abilities are compromised. A schema is generated to reflect a synthesis of the literature found through the systematic review process. This not only affects patients’ therapeutic goals, but may also hamper their health-related quality of life (HRQoL) and financial status.


Introduction
Diabetes is a leading cause of multiple morbidities in the elderly population, which reduces their quality of life and life expectancy. With an estimated global prevalence of 9% among adults, diabetes is expected to be the seventh preeminent cause of death by 2030 [1]. The elderly are the major victims of diabetes specifically, type-2 diabetes mellitus (T2DM). Around 30% of people in the world aged between 65 and 85 years are afflicted by T2DM; including 11.2 million Americans [2]. Similarly, the high prevalence of the disease is found among older people (70 to 79 years) living in Europe, North America and Australia [3].
The elderly are prone to various physical and mental problems due to the natural aging process, and multiple ailments associated with diabetes make the aging process even more difficult

Methods
We systematically identified studies related to diabetes and DAC, published in the scientific literature during the period from 1 January 2000 to 22 September 2018. Inclusion and exclusion criteria for the studies are outlined in Table 1. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines [10] in the preparation of this review. We have developed a protocol of methods, which can be assessed at http://www.crd.york.ac.uk/PROSPERO/ display_record.asp?ID=CRD42016030172.
Further publications were identified by manual searching of the references of related papers and review articles. Various journals in the diabetes and endocrinology domain were searched to identify further relevant articles. All original research articles describing the association between diabetes, diabetes-associated complications, and glycemic control in the elderly, available in the scientific literature. 3 Studies conducted in elderly (≥60 years) diabetic patients. 4 Studies having quality evaluation scores of >66%.

Exclusion criteria
1 Studies published in a language other than English.
2 Studies without clear inclusion and exclusion criteria. 3 Studies without clearly stated outcomes.

Data Extraction (Selection and Coding)
A data extraction form was developed. The items on the data extraction form were finalized after discussion amongst members of the research team. The extracted data included the first author's name, year of data (the midpoint of the study's time period), study design, study setting, data collection method, characteristics of the patients (sample size and age), and major outcomes.
Retrieved articles were imported into Endnote X7 to remove duplicates, and they were included or excluded according to the predefined criteria. QS and MA independently assessed the titles and abstracts to select the studies. After preliminary screening, a full-text assessment was made to determine the final inclusion of articles for this review. Disagreement amongst the research team regarding the eligibility of any study was resolved through discussion and mutual agreement in the research team meetings. All authors agreed with the final studies selected for the review. Two independent reviewers checked all studies to verify the validity of the screening procedure.

Risk of Bias (Quality) Assessment
Two independent reviewers evaluated the data. The data were analyzed based on the quality of the data [11]. Any disagreements raised among the reviewers were resolved through discussion in the research team meeting.

Strategy for Data Synthesis
A systematic review was undertaken to ensure that synthesis produced was sourced from the maximum possible complete collection of relevant literature.

Results
Initially, 261 studies were retrieved. Out of these, 67 were duplicates, and therefore they were excluded. From the 194 remaining articles, 85 were removed based as irrelevant titles and/or abstracts. Subsequently, the texts of 109 articles were read in full, and 71 studies were removed at this stage for failing to provide relevant information. Finally, 38 articles were selected for this review (Figure 1).
Prospective study General population Not specified N = 783 Age = 70-79 years Results indicated that 7.8% of diabetes patients had incidence of hypoglycemia, whereas 18.9% of the patients suffered from dementia. The incidence of dementia was double in patients facing hypoglycemia (p < 0.001). In the same way, the patients having dementia were at a higher risk of developing hypoglycemia (p < 0.001).  [17] To investigate the association between diabetes and the risk of falls in the elderly.

Prospective cohort study
A long-term care facility Not specified N = 139 Age ≥ 60 years The incidence rate for falls in diabetic patients as compared to non-diabetic patients was 70% and 30% respectively (p < 0.001).

Nelson, J.M. (2007) (US) [18]
Assessment of association between glycemic control and risk of falls in frail and non-frail elderly diabetes patients.
Retrospective, case-control study A health maintenance organization Not specified N = 111 Age ≥ 75 years Risk of falls increased in the patients with HbA1c levels ≤7 (p = 0.01). The prevalence of disability in GPA of the patients was found to be 73.6%, in LEM 52.2% and in IADL 43.6%. In addition, diabetes was associated with increased chances of disability by 2-3 times (p < 0.05). CVD and poor glycemic control had up to 85% more chance of diabetes-associated disabilities.

Kuo, H.K. (2005) (US) [20]
Assessment of the impact of BP and DM on physical and cognitive function.  Results show that 19.5% (p < 0.005) of the patients were non-adherent to the therapy, while 12% of the patients had major depression, which had an association with lower PF (p < 0.0001). Moreover, the depressed patients also had poor self-care activities (p < 0.0001). To evaluate the impact of depression on glycemic control and self-care.
Cross-sectional study Internal medicine clinic T2DM N = 126 Mean age of the relevant group = 62.7 ± 11.8 years Depression was negatively associated with social support (p = 0.002) and self-care activities (p = 0.004). Self-care of diabetes was partially associated with glycemic control (p = 0.08).
Gao, J. (2011) (China) [33] To assess the impact of social support, self-efficacy, and self-care on glycemic control.
Cross-sectional study Healthcare center Not specified N = 993 Age = 64 ± 10 years Diabetes patients with chronic pain showed poor diabetes self-management and self-care (p = 0.002); similarly, those with severe or very severe chronic pain also reported poor self-management (p = 0.003) of diabetes. [27] Assessment of association between diabetes and depression.
Prospective cohort study General community Not specified N = 2522 Age = 70-79 years Diabetic patients had increased risk of depressed mood (p = 0.02) and recurrent depressed mood (p < 0.001) than non-diabetic patients. Diabetes patients having MMSE scores <23 had low levels of self-care (p < 0.001) and monitoring (p < 0.001). Association between low MMSE scores and higher hospitalization (p = 0.001), lower ADL (p < 0.001) and need of help in personal care (p = 0.001) was also seen. Ulger, Z. (2002Ulger, Z. ( -2004 (Turkey) [38] Assessment of malnutrition and factors associated with it in elderly.

Cross-sectional
Out-patient clinic Not specified N = 2327 Age ≥ 65 years According to the results, 28% of the patients had poor MNA scores, which were mostly affected by depression (p = 0.0001), physical dependence (p = 0.0001), fasting plasma glucose level (p = 0.005), hematocrit (p = 0.005), ESR (p = 0.03), albumin (p = 0.002), bone mineral density (p = 0.007), and chronic diseases including diabetes (p = 0.820). The ratio of diabetes patients with and without the risk of malnutrition was 23.7%:24.2%. Diabetes was found to have significant association with increased risk of disability, OR = 1.76 (CI 95% = 1.34-2.08), among the study participants, having 13.2% of the prevalence of disability. Significant associations between diabetes and disability was seen among African Creoles OR = 2.03 (CI 95% = 1.16-3.56); whereas obesity highlighted the association between diabetes and disability, with an increased risk in South Asians and African Creoles of 26.3% and 12.1% respectively. The overall results showed a 67% increased risk of disability associated with diabetes. Results showed the mean ± (SD) scores of self-efficacy 7.33 ± (2.25) and self-care behavior was 3.76 ± (1.87); whereas, a positive association existed between these factors r = 0.538 (p < 0.001).

Study Evaluation Criteria
The studies were evaluated using a standard quality testing protocol developed by Kamet et al. [11]. The studies included in the review were tested and scored on the basis of 14 items (each item with a maximum score of 2). Three types of scores may be assigned to each item. The item was scored as 2 if the standard criteria were met, and 1 or 0 if the quality criteria were either partially met or not met at all. If a specific item did not match the nature of the study, it was not scored, and the item(s) were excluded from the summary scores. The percentage of scores for each study was calculated which indicated the quality of the study in numerical form. The quality scores of the majority of studies ranged between 80% and 100%, and nine studies had a maximum score of 100% [7,12,24,25,27,32,34,36,43]. Four studies scored between 70% and 80% [23,28,29,39], and one study scored below 70%, but it was above the inclusion criteria requirement of 66% [41]. Detailed quality scoring of the studies is provided in Table 3.

Depression
Diabetes directly affects mood levels, and depression is the basic clinical manifestation of significantly altered mood. Diabetes-related hyperglycemia and hypoglycemia are the primary causes of depression in elderly diabetic patients [8,46]. Studies have illustrated that there is a high prevalence of depression among elderly diabetic patients [12,27]. Depressed diabetic patients are more prone to other health-related problems, for instance: malnutrition, poor cognition, disability, and tendency for falls [4]. Similarly, diabetic patients can demonstrate low self-esteem as well as motivational problems for achieving good glycemic control. Consequently, they show poor adherence to therapy [5,6,8]. Studies have also revealed that depressed elderly patients show minimum interest in self-care behavior [23,47] and thus, their glycemic targets remain hard to achieve [38]. Supportive behavior of healthcare professionals and family members can play a vital role in tackling depression in elderly diabetic patients. Prescribing antidepressants and efficient management of glycemic levels can also help to ameliorate depression in these patients.

Impaired Cognition
Cognitive decline is a component of the normal aging process, but diabetes accelerates cognitive decline in the elderly [14,16]. This is due to a reduction of extracellular glucose levels in the hippocampus, which limits activity in memory processing [5]. Studies have supported the fact that the risk of vascular dementia (1.3-3.4 folds) and Alzheimer's disease increases with diabetes [2,4]. Prolonged and intensive insulin therapy in elderly diabetes patients has been shown to increase the risk of hypoglycemia, which has a direct association with impaired cognitive function [15]. Compromised cognition further aggravates hypoglycemia by making the patient less aware of hypoglycemic symptoms [15]. A forgetful patient also becomes unable to recognize the importance of glycemic control and self-management of their diabetes. The result is that patients suffer from poor glycemic condition which continues to afflict them as the disease progresses [13,31].
A timely diagnosis and prescribing medicines which decrease the risk of developing cerebrovascular anomalies may help prevent the expected cognitive dysfunction over time in these patients. Moreover, improving the glycemic control with pharmacotherapy may also help avert the transformation from mild cognitive decline to severe dementia in this cohort [48,49]. Healthcare professionals need to devise ways to increase concordance with prescribed medication regimens. Patients' families and caregivers can also play a major role in supporting the diabetic patient to be more adherent of their treatment regimen, and thereby achieving positive disease outcomes.

Poor Physical Functioning
Low levels of physical functioning (LPF) and mobility are associated with the aging process because of reduced bone strength, muscle tone, and elasticity [50]. An association between LPF and diabetes has been established [7,22]. Functional decline is seen in most elderly people with diabetes who have elevated HbA1c levels [19]. Such patients show impaired activities of daily living (ADL) and instrumental activities of daily living (IADL) [7]. Poor PF may reduce self-care in patients which can adversely affect the self-management of diabetes and may result in poorer health outcomes [4,22]. Providing physiotherapy and functional aids to patients can improve their self-management by enabling them to adhere to a healthy diet plan, regular blood glucose monitoring, exercising, and foot care with ongoing monitoring [33].

Frailty
Hypoglycemia-induced falls are very common in elderly diabetic patients [18]. Studies have shown that the elderly diabetic patient has a greater risk of falling than any other group of older adults [17,25]. Correlation between frailty and glycemic control has been shown in a study where 77% of patients with HbA1c levels ≤7 had a fall [18]. This reveals that poor glycemic control not only increases the chances of falls in frail diabetic patients but also in non-frail elderly diabetic patients [40]. Frailty in diabetes patients is also associated with reduced ADL. Moreover, impaired cognition and depression that are associated with poor glycemic control also contribute to frailty in these patients [47]. Similarly, a direct association between frailty, poor self-efficacy, and inadequate self-care has also been established in elderly diabetes patients [51]. These associations can further aggravate the disease, and the patients suffer in terms of morbidity and mortality. Improving self-care activities and managing hypoglycemia can prevent the probability of falls occurring in these patients [35]. These patients must be counseled about keeping immediate-acting sugar substitutes on-hand in order to treat hypoglycemia in an emergency situation.

Pain
The prevalence of pain is high in elderly diabetic patients [24]. Diabetes is a major determinant of axonal and sensory neuropathy, which is expected to develop in half of diabetic patients who have suffered from the disease for two decades or more [26]. Neuropathy causes intense pain in some patients in the peripheral areas of the body [52,53]. A study has revealed a 26.4% prevalence of painful diabetes-related peripheral neuropathy, affecting their quality of life in many ways [32]. Another study has shown the significant impact of pain associated with diabetes-related neuropathy, affecting patients' physical and mental wellbeing [26]. Consistent hyperglycemia associated with diabetes is the major reason for the development of neuropathy, which has been evidenced by studies that have shown that hyperglycemia and increased levels of HbA1c are observed in patients with neuropathy [18,26]. Additionally, diabetic patients also feel pain due to skin and soft tissue infections [54]. Pain reduces PF and self-care activities [55], such that patients who feel persistent pain are unable to perform much needed tasks, for example, glucose monitoring or following a diet plan. Prescribing analgesics and educating patients that they need to keep blood glucose levels within the normal range can be beneficial in preventing development of painful neuropathy and skin infections [52]. Adopting self-care activities relating to foot care is also important in this regard.

Malnutrition
Malnutrition is another significant and debilitating issue that elderly people are faced with. About 5-10% of independently living and 30-60% of hospitalized elderly patients are malnourished [38]. Malnutrition diminishes the health and well-being of diabetic patients, and affects their PF as well. The association between diabetes and the high prevalence of malnutrition in elderly diabetes patients is well established [29,41]. In a study it was found that nearly one quarter (23.7%) of diabetic patients were malnourished, despite having elevated plasma glucose levels, probably because of being in a hypermetabolic state [38]. Besides, protein catabolism and weight loss seen in elderly patients with diabetes is another reason for being malnourished. Depression and poor IADL also result in malnutrition in a way that depressed patients lack appetite, which consequently leads to poor nutritional status [29]. Irrespective of the reason, malnutrition is a risk factor for hypoglycemia that may further worsen physical and mental wellbeing [3], and thereby negatively affect levels of self-care. Consequently, poor self-care may lead to poor glycemic control and poor clinical outcomes [33]. A balanced diet containing optimum levels of essential nutrients is necessary for elderly diabetic patients. Healthcare practitioners can prescribe supplements and provide a balanced diet plan to help prevent malnutrition. Improving physical and mental health and self-care activities can also improve the diabetic patient's nutritional status by assisting the patient to plan, prepare, and eat a balanced diet.

Poor Self-Care
Self-care is described as all the activities performed by a diabetic patient to adhere to a prescribed diet plan, and a drug therapy regime to achieve standard glycemic targets to effectively manage diabetes [56]. The extent to which patients undertake self-care has a direct relationship with glycemic control. Studies demonstrate that effective self-care translates into better glycemic control, leading to improved health outcomes and vice versa [23,33]. DAC also has links with self-care, as depression, impaired cognition, poor PF, frailty, malnutrition, and pain may hamper the ability to undertake self-care in diabetic patients, due to the associated physical and mental discomfort. Consequently, the patient cannot keep pace with self-management of the disease because of poor self-care, and may suffer from worse clinical outcomes [8,13,24,41]. The best way to improve self-care abilities and to achieve adequate glycemic control is through the prevention of DAC in the first place. In this regard, there is a need for the early detection and management of DAC to boost the level of self-care among elderly diabetic patients. Figure 2 is a schematic interpretation of our synthesis of the literature associated with diabetes-related complications in the older adult. The schema demonstrates in a visual form the association of DAC with glycemic control, and how these linkages are connected to self-care abilities, potentially forming a vicious cycle. Impaired glycemic control (hyperglycemia or hypoglycemia) leads to the development of DAC that again results in poor glycemic control. If it continues, such a mechanism may result in worse health outcomes, and subsequent high societal burden. The aim of developing this schema is to pictorially represent the complexity associated with diabetes management, and to draw the literature together around diabetes-associated complications (DAC) whilst thinking about how the relationships between the various complications might manifest. Of course, outcomes for patients and wider society are ultimately thought about and implicated. diabetes [56]. The extent to which patients undertake self-care has a direct relationship with glycemic control. Studies demonstrate that effective self-care translates into better glycemic control, leading to improved health outcomes and vice versa [23,33]. DAC also has links with self-care, as depression, impaired cognition, poor PF, frailty, malnutrition, and pain may hamper the ability to undertake selfcare in diabetic patients, due to the associated physical and mental discomfort. Consequently, the patient cannot keep pace with self-management of the disease because of poor self-care, and may suffer from worse clinical outcomes [8,13,24,41]. The best way to improve self-care abilities and to achieve adequate glycemic control is through the prevention of DAC in the first place. In this regard, there is a need for the early detection and management of DAC to boost the level of self-care among elderly diabetic patients. Figure 2 is a schematic interpretation of our synthesis of the literature associated with diabetesrelated complications in the older adult. The schema demonstrates in a visual form the association of DAC with glycemic control, and how these linkages are connected to self-care abilities, potentially forming a vicious cycle. Impaired glycemic control (hyperglycemia or hypoglycemia) leads to the development of DAC that again results in poor glycemic control. If it continues, such a mechanism may result in worse health outcomes, and subsequent high societal burden. The aim of developing this schema is to pictorially represent the complexity associated with diabetes management, and to draw the literature together around diabetes-associated complications (DAC) whilst thinking about how the relationships between the various complications might manifest. Of course, outcomes for patients and wider society are ultimately thought about and implicated.  Diabetes complications (microvascular and macrovascular) are not considered in the proposed vicious cycle, despite the fact that these complications can also affect glycemic control. It is suggested that future studies should attempt to address this complex paradigm. Another limitation of this systematic review is that only the elderly group of diabetic patients was considered. We included this subgroup of diabetes patients because this is the most vulnerable group for the development of DAC, as compared to other age groups. The association between DAC and glycemic control needs to be better understood through modelling the literature within this context. Future studies should also investigate this relationship empirically, based on patient characteristics such as gender, education level etc.

Conclusions
A thorough review of literature has revealed that DACs that are associated with diabetes is a complex area, and in the elderly the literature can be formulated into a schema demonstrating its interconnectedness. Impaired glycemic control aggravates DAC, and as a result, patients' self-care abilities are compromised. This not only affects patients' therapeutic goals, but also their HRQoL.
Improved HRQoL and increased life expectancy are major health intentions for elderly diabetic patients, which can be achieved by setting glycemic targets and maintaining good glycemic control. This calls for a collaborative effort by healthcare professionals (physicians, nurses, and pharmacists), patients' families and caregivers, and the patients themselves. All efforts performed by the caregivers and the healthcare professionals may fail if patients show a reluctance to perform self-care activities to manage the disease. Healthcare professionals should consider the management of DAC while making treatment decisions, rather than simply following conventional drug therapy strategies. Prioritizing DAC can not only help to break the vicious cycle, but it can also help to improve patients' HRQoL.