PREVENTION and MANAGEMENT of FRAILTY SYNDROME in OLDER ADULTS with DIABETES Author

LITHUANIAN UNIVERSITY OF HEALTH SCIENCES

FACULTY OF MEDICINE

DEPARTMENT OF GERIATRICS

PREVENTION AND MANAGEMENT OF FRAILTY SYNDROME IN OLDER ADULTS WITH DIABETES

Author: Akhila Haroon Supervisor: Prof. Jūratė Macijauskienė

Kaunas, 2021

1 TABLE OF CONTENTS

1. SUMMARY ...... 3

2. ACKNOWLEDGMENTS ...... 4

3. CONFLICTS OF INTEREST ...... 4

4. ABBREVIATIONS ...... 5

5. INTRODUCTION ...... 6

6. AIM AND OBJECTIVES ...... 8

7. RESEARCH METHODOLOGY AND METHODS ...... 9

7.1. Search Strategy ...... 9 7.2. Data Sources ...... 9 7.3. Search Terms ...... 9 7.4. Search Outcomes ...... 10 8. RESULTS AND THEIR DISCUSSION ...... 11

8.1. Frailty Syndrome Concept ...... 11 8.2. Pathophysiological Factors Linked to Frailty ...... 11 8.3. Clinical Aspects of Frailty ...... 13 8.4. Biological Markers ...... 15 8.5. Consequences of Frailty in the Elderly ...... 16 8.6. Frailty and Disability ...... 16 8.7. Frailty and Comorbidity ...... 17 8.8. Relationship between frailty and diabetes in older adults ...... 18 8.9. Risk of frailty syndrome in elder individuals with diabetes ...... 20 8.10. Management and prevention strategies of frailty in older adults with Diabetes ...... 23 9. CONCLUSIONS ...... 28

10. PRACTICAL RECOMMENDATIONS ...... 29

11. REFERENCES ...... 30

2 1. SUMMARY

Author: Akhila Haroon Research title: Prevention and Management of Frailty Syndrome in Older Adults with Diabetes Aim and Objectives: This study aims to review the prevention and management of frailty syndrome among the elderly with diabetes mellitus (DM). The objectives were to determine the relationship between diabetes and frailty, risk of frailty and the management and prevention strategies of frailty among elderly with DM.

Research Methodology: A literature search was conducted on PubMed, Google Scholar and Cochrane Library with the help of key terms and Boolean operators. Literature from the past ten years in the English language were included. After the screening of 167 studies, 84 studies were found to be relevant to the research aim and objectives that are included in the results section.

Results: There is a relationship between frailty and diabetes because diabetes increases the risk of frailty. Additionally, not diabetes but frailty is linked to long hospital stays and mortality. The risk of frailty and prevalence is higher among the older population with DM than non-diabetic adults. To delay or manage frailty, the combination of nutritional and exercise intervention can reduce the occurrence of frailty among the older population with DM. However, there is insufficient evidence and further research is needed to specifically design exercise and nutritional intervention for older people with DM.

Conclusion: Patients with diabetes are at high risk of frailty. Thus, they need to reduce its occurrence or manage the condition with the help of exercise and nutritional intervention. The physicians are recommended to develop in collaboration with physiotherapist and dietician a management plan for patients with diabetes, which includes exercise and nutritional adjustments for frailty prevention.

3 2. ACKNOWLEDGMENTS

I would like to express my sincere gratitude to my supervisor, Prof. Jūratė Macijauskienė, for her continuous support and guidance throughout the completion of this master’s thesis. Her advice and dedicated involvement in every step of the journey have been invaluable.

I would like to thank all the staff in the Department of Geriatrics and the Medical Faculty for their exceptional work and continuous excellence.

My appreciation also goes out to my family for their tremendous understanding and encouragement.

3. CONFLICTS OF INTEREST

The author reports no conflicts of interest.

4 4. ABBREVIATIONS

ADL - Activities of daily living

BMI - Body Mass Index

CRP - C-reactive protein

DM - Diabetes Mellitus

DM1 - Diabetes Mellitus Type 1

DM2 - Diabetes Mellitus Type 2

FI - Frailty Index

IL-6 - Interleukin-6

RT - Resistance training

TNF-α - Tumour necrosis factor-alpha

UK - United Kingdom

5 5. INTRODUCTION

The accelerated process of population ageing and the increase in life expectancy [1] should draw society's attention to the health conditions, morbidity and functional limitations of the elderly. The changes observed in the demographic structure result in shifts in the epidemiological profile, with a reduction in infectious and contagious diseases and an increase in chronic degenerative diseases, which, for the most part, interfere with the quality of life and functional capacity of the ageing population [2,3].

In this context, the frailty syndrome of the elderly has been conceptualised as a clinically diagnosable condition, resulting from the decline in physiological and functional reserves in several systems, providing less physiological and psychological tolerance to stressors and exposure to high risk of adverse events to physical and mental health [4,5]. The frailty syndrome is a genetic condition and of neuroendocrine origin, which generates greater vulnerability to diseases or acute stresses in the elderly and is characterised by reduced muscle mass and strength and low energy for daily activities [5,6].

There are several consequences of frailty among the older population because its characteristics affect all the systems in the body and cause harm to the overall body of older adults [7]. Considering these consequences, the reduction in homeostatic reserves is prominent. On the other hand, certain diseases like diabetes affect the homeostasis of the body and increase the risk of frailty by inducing muscle mass loss or sarcopenia [8]. Ultimately, frailty leads to a decrease in physical functioning and higher risks of mortality and hypoglycaemia [9 -11].

Diabetes mellitus (DM) is a disease characterised by hyperglycaemia that adversely affects the cardiovascular system, kidneys and nervous system and causes insulin resistance [12]. In addition, it is linked to dyslipidaemia and possibly high blood pressure [12]. In some populations, prevalence can be as high as 30% in people over 65. In the United Kingdom (UK), it is anticipated that approximately half of the patients with diabetes are adults aged 65 or over [13]. The global prevalence of diabetes was approximately 9.3%, affecting 463 million people. It can reach up to 10.9% by 2045 accounting for 700 million people [14]. The consequences of diabetes include a reduction in functionality and frequent hospitalisations. This disease is linked to several complications including retinopathy, cardiovascular disease, peripheral vascular disease and renal failure [15,16].

6 Geriatric syndromes, particularly frailty, among older adults is an emerging complication of diabetes other than macrovascular or microvascular diseases resulting in potential disability [17]. Understanding the association between diabetes and frailty would help in the management and prevention of frailty among older adults with diabetes. The combination of the two chronic conditions makes treatment difficult. Considering this, the correct treatment of a condition is not certainly effective for another, inhibiting the desired response. Thus, this study aims to review the literature regarding the prevention and management of frailty syndrome among older adults with DM.

7 6. AIM AND OBJECTIVES

The aim is to perform a literature review regarding the prevention and management of frailty syndrome among older adults with diabetes. The objectives of the study are: • To determine the relationship between frailty and diabetes in older adults. • To determine the risk of frailty syndrome in older patients with diabetes. • To discuss the management and prevention strategies of frailty in the older population with diabetes.

8 7. RESEARCH METHODOLOGY AND METHODS

7.1. Search Strategy This is a literature review methodology, which means existing literature is searched, collected and reviewed for attaining the research aim. A proper search strategy has been developed and used for collecting the secondary data for this research.

7.2. Data Sources For searching the literature, electronic databases were used as they are easy to use and provide access to reliable literature [18]. For this research, journal articles from PubMed, Google Scholar and Cochrane Library were retrieved.

7.3. Search Terms For extensive and relevant searching, it is necessary to use pertinent key terms as they form the basis of a search strategy [19]. Hence, this study extracted key terms from the aims and objectives of the research. The key terms included “frailty prevention”, “frailty management”, “older diabetic adults”, “frailty risk”, and “frailty and diabetes relationship”. Moreover, the synonyms of these keywords are also identified and utilised when searching to assure inclusion of all relevant literature. These keywords are used in combination with Boolean operators for getting relevant results. In Table 1, the different combinations used for searching literature are presented.

Table 1: Combination of Search Terms Used Combination Search Terms with Boolean Operators No. 1. Frailty OR Frailty syndrome AND relationship OR association AND diabet* older adults OR diabet* elderly 2. Frailty OR Frailty syndrome AND Risk factors AND diabet* older adults OR diabet* elderly 3. Frailty OR Frailty syndrome AND management OR treatment OR therapy AND diabet* older adults OR diabet* elderly 4. Frailty OR Frailty syndrome AND prevention OR preventive strategy AND diabet* older adults OR diabet* elderly *used include all the combination of the words available, e.g., diabetes and diabetic

9 Inclusion and Exclusion Criteria Certain filters were used to get relevant and up-to-date literature in relation to the research aim and objectives. The inclusion criteria were: • Literature within the last 10 years (2012 to present). • Articles in the English Language. • Studies using qualitative, quantitative, systematic reviews, and meta-analysis methodologies. On the other hand, certain exclusion criteria were also developed to exclude irrelevant or useless information. • Studies available in other languages. • Literature published before 2012 (with the exception of original articles in which the concept or instrument described) • Opinion article or literature reviews. With the help of these criteria and the key terms, all the databases are searched to collect literature that can fulfil the research aim. The collected data from this process is reviewed for relevancy and then presented in the next section.

7.4. Search Outcomes In the initial research, thousands of results were obtained in all the three databases. Thus, filters and inclusion criteria were applied that reduced the number of results to a total of 167, from which duplicate studies were removed leaving 162 articles. The title and abstract of these 162 articles were reviewed and 102 were found to be relevant. The complete screening results in 84 articles to be relevant. From these 84 articles, 61 formed background to the topic and 23 addressed the research objectives. The articles were analysed and presented thematically.

10 8. RESULTS AND THEIR DISCUSSION

8.1. Frailty Syndrome Concept

The state of frailty is a clinical-biological syndrome characterised by a decrease in the resistance and physiological reserves of the elderly in stressful situations, as a consequence of the cumulative wear and tear of the physiological systems, causing a greater risk of suffering adverse health effects such as disability, falls, hospitalisation, institutionalisation and death [4,9,10]. The definition of frailty has two aspects. Firstly, there is a decrease in physiological reserves in multiple areas or domains such as endurance, flexibility and muscular strength, balance or equilibrium, reaction time, coordination, cardiovascular function, hearing, vision, nutrition and cognitive functioning [5]. Secondly, there is a predisposition to suffer adverse health effects in stressful situations in daily life, where the magnitude of the situation is not always in correspondence with the impairment that it causes in health, producing great functional deterioration [5].

Brivio et al. have suggested that alterations of various physiological systems, including dysfunction of the musculoskeletal system, neurological control and energy metabolism, in the presence of a physiological stimulus, influence the development of this disorder [20]. Several researchers identified that the common clinical symptoms of frailty are an involuntary reduction in muscle strength, endurance, body weight, and gait and balance disturbances, and a reduction in physical mobility [4,5,7,11].

8.2. Pathophysiological Factors Linked to Frailty Frailty is a consequence of alterations in multiple physiological, cellular, and molecular systems, so it can be said that its origin is multifactorial. Among the systems involved are the cardiovascular, neuroendocrine, metabolic and immune systems [21,22]. The disorders related to ageing as well as the lifestyle factors as a pathophysiological basis of frailty include sarcopenia, osteopenia, neuroendocrine dysfunction, immune dysfunction, physical activity and nutritional status.

The term sarcopenia describes the loss of skeletal muscle mass related to the ageing process and can be considered as a sign of frailty syndrome [23]. Its etiopathogenesis includes various mechanisms both intrinsic to the muscle itself and changes in the nervous system, hormonal factors and lifestyle (sedentary lifestyle). Intrinsic muscle changes include a reduction in fast muscle fibres (type II) and 11 mitochondrial DNA damage, while the loss of alpha motor units in the spinal cord occurs in the nervous system [24]. The cellular changes that occur in the sarcopenic process involve a decrease in factors that promote muscle anabolism, an increase in inflammatory factors like cytokines, clotting factors, and oxidative stress. Additionally, other factors include immobility or decreased physical activity that contribute to muscle catabolism [25]. Sarcopenia can be diagnosed by associating height, body weight, pelvic circumference, handshake strength and skin folds [23,24]. Besides, Osteopenia can be defined as the decrease in bone mass in the range of -1.0 to -2.5 standard deviations in bone densitometry [26]. It is an important component of frailty, especially in postmenopausal women, where there is an increase in low bone density, risk of fractures, and other associated adverse outcomes, for instance, immobility, disability, institutionalisation and death [27]. Factors such as decreased oestrogen levels, low calcium intake and low vitamin D levels are major causes of osteopenia [28]. It has been shown that in ageing there is dysfunction in the hypothalamic-pituitary gland-adrenal gland axis (neuroendocrine dysfunction), expressed by:

• Increased cortisol: Cortisol secretion increases with age in both sexes. High levels of cortisol are related to sarcopenia and decreased resistance to infectious diseases [29]. Women tend to have higher levels than men, making them more susceptible to frailty [30]. • Decreased growth hormone: This hormone plays a vital role in the development and maintenance of muscle mass at all ages. In both sexes, its secretion decreases as people age, thus favouring the development of sarcopenia [31]. • Decreased testosterone: In males, there is a progressive decline in testosterone secretion with advancing age, due to dysfunction of the hypothalamic-pituitary axis and testicular failure [32]. Testosterone helps maintain muscle mass and decreased secretion contributes to sarcopenia [33]. • A decrease in oestrogen: Oestrogen levels decrease abruptly with menopause accelerating the loss of muscle mass [34].

Ageing is associated with increased levels of catabolic cytokines such as interleukins and tumour necrosis factor-alpha (TNF-α) and with a decline in humoral immunity [35]. Testosterone in men limits the production of catabolic cytokines while oestrogens can increase them, contributing to a higher incidence of frailty in women [36,37]. Additionally, lifestyle factors such as low physical activity and poor calorie intake 12 among older adults make them more vulnerable to frailty syndrome [38,39]. The inflammatory system has been identified as one of the most significant factors in the etiological pathway of frailty. Therefore, Puzianowska-Kuźnicka et al. [40] proposed that C-reactive protein (CRP), interleukin-6 (IL-6), and TNF-α increase significantly as the patient's frailty increases. High uric acid levels are also linked to an increased risk of frailty syndrome [41], and insulin resistance might also be linked to the aetiology of frailty syndrome. Several studies were examining the effects of different exercises on certain markers of frailty. It has been shown that exercise can decrease levels of uric acid (42), muscle protein TNF-α [43] and IL-6 [44] in the elderly. Regular exercise can also lower CRP levels [45] and improve insulin action in older adults [46]. This indicates that exercise can suppress mild systemic inflammation that leads to delay or slow the progression of frailty development. Thus, it can be said that an exercise is a significant tool for preventing frailty incidence. Several researches show that physical activity can prevent frailty and its consequences, for example, disability [47,48]. On the other hand, it has been stated that nutritional status and frailty have an association. The low serum nutrients level, protein intake, and energy are positively linked to frailty because it decreases muscle mass [49]. Malnutrition plays a major role in the pathogenesis of frailty [50]. In general, it is recommended that a person should consume enough calories and protein to prevent prolonged malnutrition while offering antioxidant activity for micronutrients (vitamins A, C, D, E, lutein, lycopene, alpha and beta carotene) and elements, for example, zinc and selenium [51]. The majority of these elements are found in vegetables and fruits, and older adults often lack the right amount (5 servings per day) in their diets [52,53].

8.3. Clinical Aspects of Frailty The signs and symptoms of frailty vary and based on the model utilised for defining it. According to the phenotype model, the clinical manifestations are associated with loss of strength whereas the psychosocial symptoms are also included as per multiple domains. An important point to be considered is that all frail patients does not present with the same symptoms [6]. The main sign of physical weakness is a state of physical and/or mental instability, as well as a decrease in physiological reserves [54], while the accumulation of deficits at different systemic levels is depleted [4]. As people age, each person's physiological system reacts differently to changes. Researchers believe that the human body's response to stress has a limit [54]. When the physiological reserve falls

13 below the stress threshold, the failure of the systems occurs and the subclinical multi- failure causes frailty and increases vulnerability [55]. Fried et al. (2001) [56] developed a hypothesis of frailty considering that the clinical manifestations present in the syndrome are related to each other, and theoretically can be unified within a cycle where the massive presence of the elements that make it up to define it, as presented in Figure 1.

Fig. 1. The cycle of frailty by Fried [57]

Individuals can initiate the syndrome at any part of the cycle, but mainly in two ways. 1. As a result of age-associated physiological changes, for example, anorexia associated with ageing, musculoskeletal changes, and sarcopenia [4]. 2. As a result of the effect of other diseases [6].

Fried et al. validated a phenotype based on the following criteria [56,58].

1. Involuntary loss of over 10 pounds of body weight or a decrease greater than or equal to 5%.

14 2. 20% decrease in the strength of the handgrip, measured with a dynamometer and adjusted according to sex and the body mass index (BMI). 3. Poor energy and endurance, as a sign of exhaustion, explored by means of 2 questions obtained from a scale from the Centre for the Epidemiological Study of Depression. 4. Speed when walking a distance of 15 feet (4.6 m) greater than or equal to 6 or 7s, depending on sex and height. 5. Low physical activity according to a version of a questionnaire that collects the time spent in the practice of physical exercises and recreational activities [56,58].

The Fried criteria have served as a model for the assessment of frailty in clinical settings where an accurate, easy and fast diagnosis is needed, including first contact consultation for outpatients.

8.4. Biological Markers Several studies have linked frailty syndrome to biomarkers [59,60]. Saedi et al. showed a positive relationship between frailty status and acute phase reactants, inflammation, metabolism, and coagulation [59]. They demonstrated that C-reactive protein is higher in frail patients than in those who are not, even after excluding diabetes and heart disease. They affirm that there is a significant relationship between the risk of being frail and the increase in C-reactive protein values [59]. It has also been reported that high levels of coagulation factor VIII and fibrinogen have been associated with the state of frailty [61]. Metabolic markers such as insulin, blood glucose, lipids and proteins have been studied. Lower levels of albumin and low-density lipoprotein cholesterol are also linked to the frail population [62]. The decrease in the risk of frailty is associated with an increase in cholesterol levels of low-density lipoproteins, high-density lipoproteins and total cholesterol [59,63,64]. Also, when diabetes and heart disease patients are excluded, those with higher levels of total cholesterol and low-density lipoprotein cholesterol are less likely to be frail [63]. Besides, coagulation pathway markers such as D-dimer and active factor XI alpha1 antitrypsin have been extensively studied in relation to frailty. Increased level of brittleness has been linked to high levels of D-dimer and active factor XI alpha1 antitrypsin [65]. High levels of D-dimer and to a lesser degree IL-6 are linked to a decline in functional status and increased mortality [66].

15 8.5. Consequences of Frailty in the Elderly The risk of falling and fractures are important consequences of frailty in the elderly, and the fall may be involved in reduced function, loss of independence and even in the death of the elderly [67]. Fear of falling may lead the elderly to assume cautious behaviours that help prevent falls, but these behaviours can reduce confidence and participation in activities, favouring functional decline (self-protective immobility) and, thus, increasing risk frailty or its aggravation [68]. It is worth noting that falls and the fear of falling can be both causative agents and outcomes of frailty. The fear of falling influences changes in the temporal-spatial parameters in the elderly, leading to a slower gait speed [69]. On the other hand, the reduction in gait speed - an attribute of frailty - constitutes an important risk of falls and the fear of falling becomes a consequence in this case. Limitations in the performance of activities of daily living or those related to mobility, necessary for an independent and autonomous life, comprise one of the consequences of frailty that has the greatest impact on the life of the elderly and their family [67]. Although functional disability is an outcome of frailty in the elderly in most cases, it can also be an antecedent event of a phenomenon, especially in circumstances in which it occurs abruptly, such as that resulting from a stroke. Functional disability, normally considered as the ultimate limit of frailty, results in greater demand for family care, greater consumption of health services, both outpatient and hospital, as well as higher rates of institutionalisation of the elderly, in addition to favouring urinary incontinence, pressure ulcers and anticipating death [5,68]. From a psychological point of view, incontinence is also a risk factor for decompensation in the elderly due to the social inconvenience caused by the inability to stay clean, causing a sense of rejection, depression, or aggravation. Thus, frailty has severe physical and psychological consequences, indicating the significance of its prevention and treatment.

8.6. Frailty and Disability Recent publications clearly define the state of frailty with that of disability, frequently used as synonyms [70,71]. Disability is the inability to perform at least one of the activities of daily living [71]. Both categories have in common that their prevalence increases in advanced ages and that they confer a risk of dependence and death, but they differ in 3 aspects: • Disability can arise from the dysfunction of one or several physiological systems, while frailty always arises from the dysfunction of multiple systems.

16 • Disability can remain stable for years, while frailty always progresses over time. • Frailty can occur in a significant number of older adults who are not disabled. The last two aspects justify describing frailty as a subclinical or preclinical disability [72]. Frailty can cause disability, regardless of the existence or non-existence of diseases. Perhaps, it is a physiological precursor and etiological factor of disability [73]. The state of frailty has a predictive value for the appearance of adverse health effects, since frail subjects have a higher percentage of hospitalisation, falls and death [4,9,10,19,20]. This value is maintained after adjusting for socioeconomic factors, depressive symptoms, and disability; therefore, frailty syndrome constitutes an independent risk factor. To establish prevention strategies, it is significant to diagnose the syndrome before disability and institutionalisation have appeared. It is evident that prevention programs should be aimed at maintaining physical activity and achieving an adequate and balanced intake of nutrients and micronutrients.

8.7. Frailty and Comorbidity There is a wide association between frailty and chronic diseases such as atherosclerosis, heart failure, diabetes mellitus, chronic obstructive pulmonary disease, anaemia, and depression [22,74–77]. Frailty can be a manifestation in the clinical course of these diseases or their complications and, in turn, can be a triggering factor and a poor prognosis.

In this study, frailty is being studied among patients with diabetes. Diabetes Mellitus (DM) is a metabolic disorder characterised by persistent hyperglycaemia, resulting from a deficiency in insulin production or its action, causing long-term systemic complications [78]. Diabetes has been prevailing in the UK, as the statistics from 2019 indicated that 3.9 million people have been living with diabetes [79]. DM is linked to higher rates of hospitalisation and a higher incidence of cardiovascular and cerebrovascular problems, blindness, renal failure and non-traumatic lower-limb amputations [15]. Thus, it is imperative to manage this problem as its complication can lead to several other diseases.

DM can be caused by two main mechanisms: deficiency in the production or action of insulin, being classified into two main groups according to the cause, type 1 and type 2 respectively [78]. The DM1 has classical clinical and early diagnosis due to its acute manifestations. This group is composed of children and adolescents being uncommon in adults [12]. On the other hand, DM2 affects adults and older people. DM2 has a very 17 important genetic component that would alter insulin secretion through poor beta cell regeneration, insulin resistance, or both. If environmental factors such as obesity, sedentary lifestyle, smoking and stress, among others, are added to the above, glucose intolerance or a prediabetic state will occur and DM2 will eventually develop. There is no cure for diabetes, but it can be managed with the help of several strategies such as dietary measures, physical activity, and glucose control [80].

The presence of two chronic conditions requires adequate and considerable management and treatment strategies to control both conditions. Hence, this literature review explores the relationship between DM and frailty and the strategies to manage frailty among patients with diabetes.

8.8. Relationship between frailty and diabetes in older adults The relationship between frailty and diabetes has been proved in several studies, as shown in Table 2. Kane et al. (2017) [81] investigated the relationship between metabolic syndrome and frailty. Metabolic syndrome increases the risk of diabetes. This secondary analysis showed that older adults aged 65+ had a higher prevalence of metabolic syndrome and frailty in contrast to young adults aged 20-65 years. However, the findings revealed an association between metabolic syndrome and frailty in younger adults not in older adults. Moreover, frailty is related to higher mortality risk among young and older adults both and predicted better mortality as compared to metabolic syndrome. Thus, the findings indicated that metabolic syndrome and frailty are both linked to poor outcomes, but frailty showed increased mortality risk among older adults. In contrast, Hanlon et al. (2018) [82] examined the association between multimorbidity and frailty among older individuals. Thus, the data was taken from 493,737 subjects aged 37 to 73 years from the UK data bank, from which 59% were not frail, 38% pre-frail, and 3% frail. The results suggested that frailty has an association with multimorbidity among people with long-term conditions. Diabetes is one of the long-term conditions linked to frailty. Additionally, frailty and pre- frailty had a significant relationship with mortality for all ages. Thus, management and prevention of frailty among middle-aged people having multimorbidity should be focused.

18 Table 2: Summary of Association between Diabetes and Frailty Study (author, Design Sample size and Findings year) characteristics Kane et al., Secondary 6403 younger individuals The findings showed a 2017 [81] analysis, and 2152 older adults relationship between correlational with metabolic syndrome metabolic syndrome and research and high frailty index (FI) frailty in younger adults not in older adults. Moreover, frailty is related to higher mortality risk among older and young individuals both and predicted better mortality as compared to metabolic syndrome. Hanlon et al., Correlational 493,737 subjects aged Diabetes is one of the long- 2018 [82] research 37 to 73 years from UK term conditions linked to data bank, from which frailty. Additionally, frailty 59% were not frail, 38% and pre-frailty had a pre-frail, and 3% frail significant relationship with mortality for all ages. Howrey et al., Correlational 1327 subjects aged 65 The statistical results 2018 [83] Study and older indicated a large effect of diabetes on the probability of frailty, indicating that diabetes is a major contributor to higher frailty in older adults. MacKenzie et Correlational 400 patients with means Frailty syndrome is more al., 2020 [84] Study age of 81.4 years, 35.3% likely to occur in a patient had diabetes and 79.3% with diabetes than non- were frail diabetic ones. Frailty was linked to increased mortality and hospital length of stay. Castrejón- Cross-sectional 7,164 older individuals An association between Pérez et al., study with a mean FI score of diabetes and frailty was 2016 [85] 0.175 and an average found and the prevalence of age of 70.6 years diabetes was 22.2%. The presence of any diabetic complication was strongly linked to frailty. Li et al., 2019 Prospective 3,149 subjects, one-third Higher FI and bone mineral [86] cohort study were women and 4.4% density were found in had diabetes either type patients with diabetes. The 1 or type 2 risk of fracture was higher in individuals with higher FI, implying that people with diabetes are at greater risk of fractures.

19 Howrey et al. (2018) [83] investigated the association of diabetes with frailty in older individuals. The data was taken from an epidemiological study and included frail adults. The statistical results indicated a large effect of diabetes on the probability of frailty, indicating that diabetes is a major contributor to higher frailty in older adults. Diabetes was linked to a 32% rise in the likelihood of high-level frailty. Similarly, the study of MacKenzie et al. (2020) [84] recruited 400 older adults, from which 35.3% had diabetes and 79.3% had frailty syndrome. MacKenzie et al. (2020) found that frailty syndrome is more likely to occur in a patient with diabetes than non-diabetic ones [84]. This showed that diabetes and frailty had a relationship with each other. Likewise, Castrejón-Pérez et al. (2016) [85] explored the relationship between frailty and diabetes in older adults due to their unclear association. A total of 7,164 older adults participated in the study having a mean FI score of 0.175 and a mean age of 70.6 years. An association between diabetes and frailty was found and the prevalence of diabetes was 22.2%. The presence of any diabetic complication was strongly linked to frailty. Thus, frailty syndrome must be a specific concern among the population with diabetes. Li et al. (2019) [86] explored the association of frailty with fracture risk and increased risk of fracture in DM2 patients. Of the total 3,149 subjects, one-third were women and 4.4% had diabetes either type 1 or type 2. In contrast, to control participants, higher FI and bone mineral density was found in patients with DM. The risk of fracture was higher in people with higher FI, implying that people with diabetes are at higher risk of fractures. Hence, patients with DM are more frail than non-diabetic patients.

8.9. Risk of frailty syndrome in older individuals with diabetes The risk of frailty and its associated factors in older patients with diabetes has been highlighted by several researchers, as given in Table 3. Castro-Rodríguez et al. (2016) [87] in a prospective cohort study examined the role of frailty to predict mortality and disability in individuals with diabetes. The researcher enrolled 1,825 adults aged 65 and over, from which 363 had diabetes. Patients with diabetes who were fail died more frequently than the other older adults. Thus, the findings proposed that frailty is a risk factor for disability and death in older individuals with diabetes. Hence, it is recommended to assess the status of frailty regularly in population with diabetes.

20 Table 3: Summary of Risk of Frailty in Patients with Diabetes Study Design Sample size and Findings (author, year) characteristics Castro- Prospective 1825 individuals Patients with DM who were frail died Rodríguez et cohort study ≥65 years old more frequently than other older adults. al., 2016 [87] with 363 people Thus, the findings proposed that frailty is having diabetes a risk factor for disability and death in older individuals with diabetes. Li et al. 2015 Cross- 146 DM2 patients Prefrail and frail individuals are at high [88] sectional ≥ 60 and above risk of diabetic nephropathy, mobility study impairment, and ADL disability. Liccini et al., Observational 198 persons ≥ 50 The risk of frailty and sarcopenia 2016 [89] study years old with increased among DM patients. diabetes Additionally, the further risk factors associated with frailty and sarcopenia included higher hospitalisation rate and ADL disability. Inoguchi et al., Cross- 158 older adults ≥ ADL disability is an adverse result of 2019 [90] sectional 70 years old frailty, which was found to be associated study without ADL with low serum bilirubin level. disability and diabetes and ≥ 40 older adults with ADL disability and diabetes Casals et al., Cross- 288 patients ≥ 65 DM increases the risk of frailty among 2018 [91] sectional years old with older individuals. The risk factors that study DM2 promote frailty are poorer nutritional status, higher triglycerides concentrations, lower systolic blood pressure, poorer balance and lower independence in ADL. Yanagita et al. Descriptive 132 DM2 patients In patients DM, low body weight, total 2017 [92] study ≥ 65 years old cholesterol, glycated haemoglobin, systolic blood pressure, high-density lipoprotein cholesterol and albumin levels are independent and strong risk factors for frailty. Bouillon et al., Prospective 2,707 participants 37.5% of participants were categorised 2013 [93] cohort study aged 45-69 years as prefrail and 2.8% as frail. The results without diabetes affirmed that the risk of frailty increases with diabetic risk factors. García- Prospective 1750 individuals The risk of frailty increased among Esquinas et cohort study ≥60 years old patients with DM. al., 2015 [94] (346 with DM and 1404 non-DM) Wang et al., Multicity 2049 participants Frailty in patients with DM increased the 2020 [95] observational ≥45 years old risk of falls. Moreover, poor health status study with DM2 and poor balance performance are also linked to a higher risk of falls. Chhetri et al. Prospective 10,039 The incidence and prevalence of frailty is 2017 [96] cohort study participants with higher in DM individuals in comparison to 70.51 years non-DM elderly. mean age ADL – activities of daily living, DM – diabetes mellitus

21 MacKenzie et al. (2020) [84] proposed that diabetes did not increase the risk of mortality or hospital stay but frailty in patients with diabetes increases this risk of increased length of hospital stay and mortality. Moreover, Li et al. (2015) [88] enrolled 146 DM2 patients aged 60 and above to study the influence of frailty in older people with diabetes. Initially, 15.1% of participants were frail, 37.7% were prefrail, and 47.2% were robust at the baseline. The adjustment of gender, age, and diabetes severity showed that prefrail and frail individuals are at high risk of diabetic nephropathy, mobility impairment and ADL disability. Moreover, the risk of hospitalisation and mortality among older population with diabetes increased with frailty. Thus, frailty is a significant risk factor for unfavourable health consequences in older adults with DM2. Liccini et al. (2016) [89] evaluated the risk of frailty and sarcopenia among patients with diabetes in six months after screening. As a sample, 198 persons with diabetes aged 50-90 years were enrolled. After 6 months, it was found that 29.3% had sarcopenia, 28.8% had frailty, 38.9% were prefrail, and 32.3% were non-frail. This indicated that the risk of frailty and sarcopenia increased among diabetes patients. Additionally, the further risk factors associated with frailty and sarcopenia included higher hospitalisation rate and ADL disability. In the study of Chhetri et al. (2017) [96], the incidence of frailty in people with DM and pre-diabetic community-dwelling elder adults. From 10,039 subjects, the follow-up of 6,293 elderly was done at 12 months. According to the results, the incidence and prevalence of frailty are higher in individuals with diabetes in comparison to non- diabetic elderly. To decrease the risk of frailty, older people should control their blood glucose level. Additionally, Inoguchi et al. (2019) [90] explored the risk of disability in ADL among older individuals with DM. For this purpose, 158 older adults aged 70 and over without ADL disability and diabetes and 40 older adults with ADL disability and diabetes were recruited. ADL disability is an adverse result of frailty, which was found to be associated with a low level of serum bilirubin. The risk of frailty in patients with DM is higher who had a low level of serum bilirubin. Casals et al. (2018) [91] determined the prevalence of frailty in older adults having DM2 and identify the factors that promote frailty among them. A total of 288 subjects participated aged over 65 with DM2. The prevalence of frailty among patients with diabetes is higher in contrast to the general population aged 65 above. This signifies that diabetes heightens the risk of frailty among older people. Moreover, the risk factors that promote frailty are poorer nutritional status, higher triglycerides concentrations, lower systolic blood pressure, poorer balance and lower independence for ADL. In contrast, Yanagita et al. (2017) [92] explored the risk factors of frailty in aged patients with diabetes.

22 The 132 DM2 patients aged 65 and above were divided into groups of frail and non-frail. In patients with diabetes, low body weight, total cholesterol, glycated haemoglobin, systolic blood pressure, high-density lipoprotein cholesterol, and albumin levels are independent and strong risk factors for frailty. These factors suggested that reverse metabolism associated with malnutrition in older population with DM increase the frailty risk. The results also indicated that good glycaemic control is more significant for frailty than diabetes. The cohort study of Bouillon et al. (2013) [93] investigated the risk of future frailty in the elderly with established diabetes risk factors. For this purpose, Bouillon et al. (2013) [93] enrolled 2,707 participants aged 45-69 years with no diabetes. After 10.5 years of follow-up, 37.5% of participants were categorised as prefrail and 2.8% as frail. The results affirmed that the risk of frailty increases with diabetic risk factors including no consumption of vegetables and fruits, low physical activity, smoking cessation, female gender, and increased age. Moreover, García-Esquinas et al. (2015) [94] examined the role of diabetes as a risk factor for frailty. A large sample of 1,750 people aged 60 and over were recruited, from which 346 were diabetic and 1404 were free of diabetes. After the follow- up of three and a half years, the risk of frailty increased among patients with diabetes. This association might be linked to altered serum lipid profile, poor glucose control, obesity and unhealthy behaviours. Additionally, an observational study by Wang et al. (2020) [95] recruited 2,049 people with DM2 aged 45 and above to analyse the relationship between risk of falls and frailty in patients with DM. The findings showed that frailty in patients with diabetes further increased the risk of falls. Moreover, poor health status and poor balance performance are also linked to a higher risk of falls. This implies that more attention must be given to the prevention of falls in frail people with diabetes.

8.10. Management and prevention strategies of frailty in older adults with Diabetes

As highlighted earlier, people with DM are at higher risk of becoming frail. Hence, they need to prevent or manage frailty through nutritional or physical activity strategies, as shown in Table 4.

23 Table 4: Summary of Management of Frailty in Patients with Diabetes Study Design Sample size and Findings (author, year) characteristics Lopez-Garcia et Prospective 8970 women aged ≥60 Adherence to a al., 2018 [97] cohort study years with DM2 Mediterranean diet can prevent or facilitate the management of frailty among patients with diabetes. This diet promotes protein intake.

García- Prospective 1750 individuals aged Diabetes nutritional therapy Esquinas et al., cohort study 60 years and above from has the ability to lessen the 2015 [94] which 346 were diabetic risk of frailty in older and 1404 were free of individuals with DM. diabetes

Serra-Prat et Randomised, 172 pre-frail older people 15.3% of the control group al., 2017 [98] open-label, (≥70 years) participants and 4.9% of the controlled trial nutritional and physical intervention group (coordination, balance, strengthening and aerobic exercises) evolved frailty. Rodriguez- Cluster- 964 participants aged The physical performance of Mañas et al., randomized ≥70 years pre-frail and the intervention group was 2019 [99] multicentre frail adults having DM2 better than the control group. clinical trial Thus, the deterioration in the physical functioning of frail and pre-frail patients with diabetes can be managed via multimodal intervention.

De Labra et al., Systematic Nine clinical trials Exercise interventions 2015 [100] review improve mobility, balance, functional ability and muscle strength for frail older adults. Espinoza et al. Review - Metformin targets (2019) [62] inflammation and insulin resistance. Thus, it can be a promising pharmacological intervention to prevent frailty.

Sumantri et al. Case-control 236 older adults aged Metformin had shown a (2014) [101] study ≥60 years significant protective effect among aged patients with early diabetes. Hazuda et al. Prospective 2289 from Diabetes Metformin might be (2021) [102] cohort study Prevention Program ineffective for the reduction (DPP) at 10 years and of frailty prevalence. Early 2385 at 8 years intensive lifestyle among prediabetic people is effective to reduce the frailty prevalence in later life.

24 In this regard, Lopez-Garcia et al. (2018) [97] examined the influence of a Mediterranean diet on the risk of frailty among older patients with diabetes. Mediterranean diet includes plenty of fruits and vegetables, whole grains, nuts, beans and fish. In this study, 8,970 women aged 60 and over with DM2 were included. The adherence to a Mediterranean diet was followed up for four years. A total of 569 frailty cases were identified during follow-up. The diet showed a 28% reduction in the risk of frailty, which further increased when vegetables and fruits are highly consumed. Thus, a Mediterranean diet might prevent or facilitate the management of frailty among patients with diabetes. Similarly, García-Esquinas et al. (2015) [94] claimed that diabetes nutritional therapy has the ability to lessen the risk of frailty in older individuals with DM. Serra-Prat et al. (2017) [98] conducted a randomised controlled trial recruiting 172 pre-frail older people aged 70 years and above. The intervention group received nutritional and physical intervention including coordination, balance, strengthening and aerobic exercises, whereas the control group received usual care. After 12 months of follow-up, 15.3% of the control group participants and 4.9% of the intervention group evolved frailty. Hence, the intervention focused on nutritional and physical activity can reduce frailty risk in older adults with DM. Rodriguez-Mañas et al., 2019 [99] analysed the efficiency of a multimodal programme in the frail and pre-frail elderly with DM. The trial included a total of 964 participants aged ≥70 years, who were frail and pre-frail individuals with DM2. The multimodal intervention included supervised training to assure optimal diabetes care, a structured nutritional and diabetes educational programme in 7 sessions and a progressive and individualised resistance training programme of sixteen weeks. On the other hand, the control group got the usual care. At 12 months, the physical performance of the intervention group was better than the control group. Thus, the deterioration in the physical functioning of frail and pre-frail diabetic patients can be reduced and managed through a structured multimodal intervention. Moreover, a systematic review by De Labra et al. (2015) [100] proposed that exercise interventions are advantageous in terms of mobility, balance, functional ability and muscle strength for frail older adults. However, the evidence is unclear about the optimal exercise type and intensity. With regard to pharmacological intervention, the review by Espinoza et al. (2019) [62] proposed that several studies have shown the relationship between inflammation, insulin resistance, obesity, diabetes and frailty. Since metformin targets inflammation and insulin resistance, it can be a promising pharmacological intervention to prevent frailty. The case- control study by Sumantri et al. (2014) [101] investigated 236 older adults aged ≥60 years,

25 from which 59 were frail and 177 controls were non-frail. Metformin had shown a significant protective effect among aged patients with early diabetes. Contrastingly, Hazuda et al. (2021) [102] showed that an early intensive lifestyle in individuals at high risk of DM at an average age of fifty years, is effective to reduce the frailty prevalence in later life. However, metformin might be ineffective for the reduction of frailty prevalence. The discussed results showed that diabetes and frailty have found to be associated with one another among older adults. Moreover, frailty increases the risk of falls, fractures, mortality and hospital stay among older adults with DM. For the prevention and management of frailty, physical and nutritional interventions have found to be effective for patients with diabetes. Considering pharmacological interventions, metformin has shown mixed results about its protective effects among early older adults with DM.

For frail elderly adults with DM, specific guidelines have been made for the frequency, intensity, and repetition of resistance and endurance training [103,104]. However, the percentage of older people who continue to participate in the recommended exercise programmes has not yet been determined and the attrition can be high. Exercise programmes for older frail adults show that exercise can improve physical functioning [99,100]. Moreover, older people with DM2 were found to have improved lower body strength due to exercise [100]. The low level of physical activity in older people produces a decrease in muscle strength, giving them a greater risk for falls, fractures, frailty, and disability. The reported incidence of frailty is lower in the nutrition and exercise intervention group of older individuals who are frail or prefrail living in the community [98]. There are limited randomised controlled trials using exercise for elderly frail people with DM2. Therefore, further research is required to understand the influence of exercise on frail elderly with diabetes.

Besides exercise, diet can also contribute to the reduction of the frailty risk; nevertheless, nutritional programmes have not been investigated as measures to prevent frailty. Behaviourally focused exercise and nutrition education programme improved the physical functioning of older adults [98,99]. A review highlighted that there is scarce evidence to make dietary recommendations or guidelines specifically for frail elderly with DM2. The available limited evidence indicated that a diet rich in calories and protein can be used for the prevention of malnutrition and weight loss. Dietary recommendations for frail people include adequate energy (calories/day on the basis of sex, age, BMI and physical activity) and nutritional quality that contain more nutritional food than high-calorie

26 foods [97]. Nutritionists and medical professionals together can develop a personalised diet plan for frail older people with DM2.

A limitation of this review is that it included published trials and evidence and did not consider the trials in Clinicaltrials.gov and the European Union Registry that have not been published. Moreover, the data was collected and reviewed by a single person, which increases the risk of subjective biases in the study. In addition, the filter to include English language studies only and three databases might have limited the search outcomes in the literature search. Nonetheless, the strength of the review is that it addressed all the research objectives and aim and provided implications for practice.

27 9. CONCLUSIONS

1. The results indicated that there is a relationship between diabetes and frailty because diabetes increases the risk of frailty. Additionally, not diabetes but frailty is linked to long hospital stays and mortality. 2. There is a high risk of frailty in older adults with diabetes due to poor nutritional status, high triglycerides concentrations, low systolic blood pressure, low glycated haemoglobin, low albumin levels, poor balance, and low independence for ADL. The risk of frailty and prevalence is higher among older adults with diabetes than non-diabetic adults. Furthermore, there is a higher risk of fractures and falls among older adults with diabetes who are frail. 3. Non-pharmacological interventions including exercise and nutrition can reduce the risk of frailty. A Mediterranean diet has the potential to prevent frailty among older adults with diabetes. The combination of nutritional and exercise intervention including coordination, balance, strengthening, and aerobic exercises reduce the occurrence of frailty in older individuals. Mixed evidence has been found regarding the protective effect of metformin among the elderly with diabetes.

28 10. PRACTICAL RECOMMENDATIONS

Considering the findings of this study, it is recommended that:

• Frailty must be regularly evaluated among all patients with diabetes because diabetes is related to frailty and it is a significant risk factor for disability and death among them. The evaluation of these individuals with the help of a frailty scale would help in identifying the people who are pre-frail or at high risk of becoming frail. • For effective avoidance or delay of frailty, the elderly must be advised to take adequate control of blood glucose and reduce the related risk factors. • Exercise and adequate nutritional status have been identified as promising intervention to reduce frailty risk in adults with DM. • The physician and dietitian must work together for the development of a nutritional plan for such patients. • More research is needed to know which exercise and nutritional therapy are most favourable for frail adults with diabetes in order to manage frailty.

29 11. REFERENCES 1. Spijker J, MacInnes J. Population ageing: The timebomb that isn’t? BMJ [Internet]. 2013;347. Available from: https://www.bmj.com/content/347/bmj.f6598 2. Jin K, Simpkins JW, Ji X, Leis M, Stambler I. The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging Dis [Internet]. 2015;6(1):1–5. Available from: /pmc/articles/PMC4306469/ 3. Chang AY, Skirbekk VF, Tyrovolas S, Kassebaum NJ, Dieleman JL. Measuring population ageing: an analysis of the Global Burden of Disease Study 2017. Lancet Public Heal. 2019;4(3):e159–67. 4. Ruiz M, Cefalu C, Reske T. Frailty syndrome in geriatric medicine. Am J Med Sci. 2012;344(5):395–8. 5. Leng S, Chen X, Mao G. Frailty syndrome: an overview. Clin Interv Aging [Internet]. 2014;9:433. Available from: /pmc/articles/PMC3964027/ 6. Wou F, Conroy S. The frailty syndrome. Med (United Kingdom). 2013;41(1):13–5. 7. Yeolekar ME, Sukumaran S. Frailty Syndrome : A Review. J Assoc physicians india. 2014;62(11):34–8. 8. Stout MB, Justice JN, Nicklas BJ, Kirkland JL. Physiological Aging: Links Among Adipose Tissue Dysfunction, Diabetes, and Frailty. Physiology [Internet]. 2017 [cited 2021 Mar 18];32(1):9–19. Available from: https://www.physiology.org/doi/10.1152/physiol.00012.2016 9. Garre-Olmo J, Calvó-Perxas L, López-Pousa S, de Gracia Blanco M, Vilalta- Franch J. Prevalence of frailty phenotypes and risk of mortality in a community- dwelling elderly cohort. Age Ageing [Internet]. 2013;42(1):46–51. Available from: https://academic.oup.com/ageing/article-lookup/doi/10.1093/ageing/afs047 10. Abdelhafiz AH, Rodríguez-Mañas L, Morley JE, Sinclair AJ. Hypoglycemia in older people - A less well recognized risk factor for frailty. Aging Dis [Internet]. 2015;6(2):156–67. Available from: /pmc/articles/PMC4365959/ 11. Mohler MJ, Fain MJ, Wertheimer AM, Najafi B, Nikolich-Žugich J. The Frailty Syndrome: Clinical measurements and basic underpinnings in humans and animals. Exp Gerontol. 2014;54:6–13. 12. Zimmet PZ, Magliano DJ, Herman WH, Shaw JE. Diabetes: A 21st century challenge. Lancet Diabetes Endocrinol. 2014;2(1):56–64. 13. British Geriatrics Society. Diabetes [Internet]. 2018 [cited 2021 Mar 18]. Available from: https://www.bgs.org.uk/resources/diabetes 30 14. Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843. 15. Gregg EW, Sattar N, Ali MK. The changing face of diabetes complications. Lancet Diabetes Endocrinol. 2016;4(6):537–47. 16. Mauricio D, Alonso N, Gratacòs M. Chronic Diabetes Complications: The Need to Move beyond Classical Concepts. Trends Endocrinol Metab. 2020;31(4):287–95. 17. Yoon SJ, Kim K Il. Frailty and disability in diabetes. Ann Geriatr Med Res [Internet]. 2019;23(4):165–9. Available from: /pmc/articles/PMC7370756/ 18. Asghari S, Mahdavian M. Secondary analysis of electronic databases: Potentials and limitations. Diabetologia. 2013;56(9):2096–7. 19. Aromataris E, Riitano D. Constructing a search strategy and searching for evidence. Am J Nurs. 2014;114(5):49–56. 20. Brivio P, Paladini MS, Racagni G, Riva MA, Calabrese F, Molteni R. From Healthy Aging to Frailty: In Search of the Underlying Mechanisms. Curr Med Chem. 2019;26(20):3685–701. 21. Fulop T, McElhaney J, Pawelec G, Cohen AA, Morais JA, Dupuis G, et al. Frailty, Inflammation and Immunosenescence. Interdiscip Top Gerontol Geriatr [Internet]. 2015;41:26–40. Available from: https://www.karger.com/Article/FullText/381134 22. Clegg A, Hassan-Smith Z. Frailty and the endocrine system. Lancet Diabetes Endocrinol. 2018;6(9):743–52. 23. Cruz-Jentoft AJ, Sayer AA. Sarcopenia. Lancet. 2019;393(10191):2636–46. 24. Tournadre A, Vial G, Capel F, Soubrier M, Boirie Y. Sarcopenia. Jt Bone Spine. 2019;86(3):309–14. 25. Marzetti E, Calvani R, Tosato M, Cesari M, Di Bari M, Cherubini A, et al. Sarcopenia: an overview. Aging Clin Exp Res [Internet]. 2017;29(1):11–7. Available from: https://link.springer.com/article/10.1007/s40520-016-0704-5 26. Drey M, Sieber CC, Bertsch T, Bauer JM, Schmidmaier R, The FiAT intervention group. Osteosarcopenia is more than sarcopenia and osteopenia alone. Aging Clin Exp Res [Internet]. 2016;28(5):895–9. Available from: https://link.springer.com/article/10.1007/s40520-015-0494-1 27. Kaplan SJ, Pham TN, Arbabi S, Gross JA, Damodarasamy M, Bentov I, et al. Association of radiologic indicators of frailty with 1-year mortality in older trauma patients: Opportunistic screening for sarcopenia and osteopenia. JAMA Surg

31 [Internet]. 2017;152(2):164604. Available from: https://jamanetwork.com/ 28. Elam ML, Johnson SA, Hooshmand S, Feresin RG, Payton ME, Gu J, et al. A calcium-collagen chelate dietary supplement attenuates bone loss in postmenopausal women with osteopenia: A randomized controlled trial. J Med Food [Internet]. 2015;18(3):324–31. Available from: https://www.liebertpub.com/doi/abs/10.1089/jmf.2014.0100 29. Phillips AC, Upton J, Duggal NA, Carroll D, Lord JM. Depression following hip fracture is associated with increased physical frailty in older adults: The role of the cortisol: Dehydroepiandrosterone sulphate ratio. BMC Geriatr [Internet]. 2013;13(1):1–9. Available from: https://link.springer.com/articles/10.1186/1471- 2318-13-60 30. Le NP, Varadhan R, Fried LP, Cappola AR. Cortisol and Dehydroepiandrosterone Response to Adrenocorticotropic Hormone and Frailty in Older Women. Newman A, editor. Journals Gerontol Ser A [Internet]. 2020; Available from: https://academic.oup.com/biomedgerontology/advance- article/doi/10.1093/gerona/glaa134/5851918 31. Palmer J, Pandit V, Zeeshan M, Kulvatunyou N, Hamidi M, Hanna K, et al. The acute inflammatory response after trauma is heightened by frailty: A prospective evaluation of inflammatory and endocrine system alterations in frailty. J Trauma Acute Care Surg [Internet]. 2019;87(1):54–60. Available from: https://journals.lww.com/01586154-201907000-00008 32. Chiang JM, Kaysen GA, Segal M, Chertow GM, Delgado C, Johansen KL. Low testosterone is associated with frailty, muscle wasting and physical dysfunction among men receiving hemodialysis: A longitudinal analysis. Nephrol Dial Transplant [Internet]. 2019;34(5):802–10. Available from: https://academic.oup.com/ndt/article/34/5/802/5063538 33. Shin MJ, Jeon YK, Kim IJ. Testosterone and Sarcopenia. World J Mens Health [Internet]. 2018;36(3):192–8. Available from: https://synapse.koreamed.org/upload/SynapseData/PDFData/2074wjmh/wjmh- 36-192.pdf 34. Nedergaard A, Henriksen K, Karsdal MA, Christiansen C. Menopause, estrogens and frailty. Gynecol Endocrinol [Internet]. 2013;29(5):418–23. Available from: https://www.tandfonline.com/doi/abs/10.3109/09513590.2012.754879 35. Vatic M, von Haehling S, Ebner N. Inflammatory biomarkers of frailty. Exp Gerontol. 2020;133:110858.

32 36. Gordon EH, Hubbard RE. Physiological basis for sex differences in frailty. Curr Opin Physiol. 2018;6:10–5. 37. Greco EA, Pietschmann P, Migliaccio S. Osteoporosis and Sarcopenia Increase Frailty Syndrome in the Elderly. Front Endocrinol (Lausanne) [Internet]. 2019;10(APR):255. Available from: https://www.frontiersin.org/article/10.3389/fendo.2019.00255/full 38. Da Silva VD, Tribess S, Meneguci J, Sasaki JE, Garcia-Meneguci CA, Carneiro JAO, et al. Association between frailty and the combination of physical activity level and sedentary behavior in older adults. BMC Public Health [Internet]. 2019;19(1):709. Available from: https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-019-7062-0 39. Otsuka R, Tange C, Tomida M, Nishita Y, Kato Y, Yuki A, et al. Dietary Factors Associated with the Development of Physical Frailty in Community-Dwelling Older Adults. J Nutr Heal Aging [Internet]. 2019;23(1):89–95. Available from: https://link.springer.com/article/10.1007/s12603-018-1124-3 40. Puzianowska-Kuźnicka M, Owczarz M, Wieczorowska-Tobis K, Nadrowski P, Chudek J, Slusarczyk P, et al. Interleukin-6 and C-reactive protein, successful aging, and mortality: The PolSenior study. Immun Ageing [Internet]. 2016;13(1):1– 12. Available from: https://link.springer.com/articles/10.1186/s12979-016-0076-x 41. García-Esquinas E, Guallar-Castillón P, Carnicero JA, Buño A, García-García FJ, Rodríguez-Mañas L, et al. Serum uric acid concentrations and risk of frailty in older adults. Exp Gerontol. 2016;82:160–5. 42. Chen JH, Wen CP, Wu SB, Lan JL, Tsai MK, Tai YP, et al. Attenuating the mortality risk of High serum uric acid: The role of physical activity underused. Ann Rheum Dis [Internet]. 2015;74(11):2034–42. Available from: https://ard.bmj.com/content/74/11/2034 43. Wang J, Leung KS, Chow SKH, Cheung WH. Inflammation and age-associated skeletal muscle deterioration (sarcopaenia). J Orthop Transl. 2017;10:94–101. 44. Reihmane D, Dela F. Interleukin-6: Possible biological roles during exercise. Eur J Sport Sci [Internet]. 2014;14(3):242–50. Available from: https://www.tandfonline.com/doi/abs/10.1080/17461391.2013.776640 45. Fedewa M V., Hathaway ED, Ward-Ritacco CL. Effect of exercise training on C reactive protein: A systematic review and meta-Analysis of randomised and non- randomised controlled trials. Br J Sports Med [Internet]. 2017;51(8):670–6. Available from: https://bjsm.bmj.com/content/51/8/670

33 46. McGarrah RW, Slentz CA, Kraus WE. The Effect of Vigorous- Versus Moderate- Intensity Aerobic Exercise on Insulin Action. Curr Cardiol Rep [Internet]. 2016;18(12):1–6. Available from: https://link.springer.com/article/10.1007/s11886- 016-0797-7 47. Marzetti E, Calvani R, Tosato M, Cesari M, Di Bari M, Cherubini A, et al. Physical activity and exercise as countermeasures to physical frailty and sarcopenia. Aging Clin Exp Res [Internet]. 2017;29(1):35–42. Available from: https://link.springer.com/article/10.1007/s40520-016-0705-4 48. McPhee JS, French DP, Jackson D, Nazroo J, Pendleton N, Degens H. Physical activity in older age: perspectives for healthy ageing and frailty. Biogerontology [Internet]. 2016;17(3):567–80. Available from: https://link.springer.com/article/10.1007/s10522-016-9641-0 49. Kim J, Lee Y, Won CW, Lee KE, Chon D. Nutritional Status and Frailty in Community-Dwelling Older Korean Adults: The Korean Frailty and Aging Cohort Study. J Nutr Heal Aging [Internet]. 2018;22(7):774–8. Available from: https://link.springer.com/article/10.1007/s12603-018-1005-9 50. Kurkcu M, Meijer RI, Lonterman S, Muller M, de van der Schueren MAE. The association between nutritional status and frailty characteristics among geriatric outpatients. Clin Nutr ESPEN. 2018;23:112–6. 51. Freeland-Graves JH, Nitzke S. Position of the Academy of Nutrition and Dietetics: Total Diet Approach to Healthy Eating. J Acad Nutr Diet. 2013;113(2):307–17. 52. Nicklett EJ, Kadell AR. Fruit and vegetable intake among older adults: A scoping review. Maturitas. 2013;75(4):305–12. 53. Bollwein J, Diekmann R, Kaiser MJ, Bauer JM, Uter W, Sieber CC, et al. Dietary Quality Is Related to Frailty in Community-Dwelling Older Adults. Journals Gerontol Ser A Biol Sci Med Sci [Internet]. 2013;68(4):483–9. Available from: https://academic.oup.com/biomedgerontology/article- lookup/doi/10.1093/gerona/gls204 54. Malaguarnera M, Vacante M, Frazzetto PM, Motta M. What is the frailty in elderly? Value and significance of the multidimensional assessments. Arch Gerontol Geriatr. 2013;56(1):23–6. 55. Dent E, Kowal P, Hoogendijk EO. Frailty measurement in research and clinical practice: A review. Eur J Intern Med. 2016;31:3–10. 56. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. academic.oup.com [Internet].

34 Available from: https://academic.oup.com/biomedgerontology/article- abstract/56/3/M146/545770 57. Walston JD. Connecting Age-Related Biological Decline to Frailty and Late-Life Vulnerability. Nestle Nutr Inst Workshop Ser [Internet]. 2015;83:1–10. Available from: https://europepmc.org/articles/PMC4871248 58. Bieniek J, Wilczyński K, Szewieczek J. Fried frailty phenotype assessment components as applied to geriatric inpatients. Clin Interv Aging [Internet]. 2016;11:453–9. Available from: /pmc/articles/PMC4853008/ 59. Al Saedi A, Feehan J, Phu S, Duque G. Current and emerging biomarkers of frailty in the elderly [Internet]. Vol. 14, Clinical Interventions in Aging. Dove Medical Press Ltd.; 2019. p. 389–98. Available from: /pmc/articles/PMC6388773/ 60. Teixeira-Gomes A, Lage B, Esteves F, Sousa AC, Pastorinho MR, Valdiglesias V, et al. Frailty syndrome, biomarkers and environmental factors – A pilot study. Toxicol Lett. 2020;330:14–22. 61. Gale CR, Baylis D, Cooper C, Sayer AA. Inflammatory markers and incident frailty in men and women: The english longitudinal study of ageing. Age (Omaha) [Internet]. 2013;35(6):2493–501. Available from: https://link.springer.com/article/10.1007/s11357-013-9528-9 62. Espinoza SE, Jiwani R, Wang J, Wang C pin. Review of Interventions for the Frailty Syndrome and the Role of Metformin as a Potential Pharmacologic Agent for Frailty Prevention. Clin Ther. 2019;41(3):376–86. 63. Wang Q, Wang Y, Lehto K, Pedersen NL, Williams DM, Hägg S. Genetically- predicted life-long lowering of low-density lipoprotein cholesterol is associated with decreased frailty: A Mendelian randomization study in UK biobank. EBioMedicine. 2019;45:487–94. 64. Osugi Y, Asai K, Kobayashi D. MALIGNANCIES DEVELOPMENT AFTER PMR AND GCA: PROPENSITY SCORE MATCHED COHORT STUDY. Innov Aging [Internet]. 2018;2(suppl_1):885–6. Available from: https://academic.oup.com/innovateage/article/2/suppl_1/885/5183945 65. Xu L, Zhang J, Shen S, Liu Z, Zeng X, Yang Y, et al. Clinical Frailty Scale and Biomarkers for Assessing Frailty in Elder Inpatients in China. J Nutr Heal Aging [Internet]. 2021;25(1):77–83. Available from: https://link.springer.com/article/10.1007/s12603-020-1455-8 66. Wannamethee SG, Whincup PH, Lennon L, Papacosta O, Lowe GD. Associations Between Fibrin D -Dimer, Markers of Inflammation, Incident Self-

35 Reported Mobility Limitation, and All-Cause Mortality in Older Men. J Am Geriatr Soc [Internet]. 2014;62(12):2357–62. Available from: https://onlinelibrary.wiley.com/doi/10.1111/jgs.13133 67. Buckinx F, Rolland Y, Reginster JY, Ricour C, Petermans J, Bruyère O. Burden of frailty in the elderly population: Perspectives for a public health challenge. Arch Public Heal [Internet]. 2015;73(1):19. Available from: https://archpublichealth.biomedcentral.com/articles/10.1186/s13690-015-0068-x 68. Jürschik P, Nunin C, Botigué T, Escobar MA, Lavedán A, Viladrosa M. Prevalence of frailty and factors associated with frailty in the elderly population of Lleida, Spain: The FRALLE survey. Arch Gerontol Geriatr. 2012;55(3):625–31. 69. Donoghue OA, Cronin H, Savva GM, O’Regan C, Kenny RA. Effects of fear of falling and activity restriction on normal and dual task walking in community dwelling older adults. Gait Posture. 2013;38(1):120–4. 70. Espinoza SE, Quiben M, Hazuda HP. Distinguishing Comorbidity, Disability, and Frailty. Curr Geriatr Reports [Internet]. 2018;7(4):201–9. Available from: https://link.springer.com/article/10.1007/s13670-018-0254-0 71. Kojima G. Frailty as a predictor of disabilities among community-dwelling older people: a systematic review and meta-analysis. Disabil Rehabil [Internet]. 2017;39(19):1897–908. Available from: https://www.tandfonline.com/doi/abs/10.1080/09638288.2016.1212282 72. Azzopardi RV, Vermeiren S, Gorus E, Habbig AK, Petrovic M, Van Den Noortgate N, et al. Linking Frailty Instruments to the International Classification of Functioning, Disability, and Health: A Systematic Review. J Am Med Dir Assoc. 2016;17(11):1066.e1. 73. Theou O, Rockwood MRH, Mitnitski A, Rockwood K. Disability and co-morbidity in relation to frailty: How much do they overlap? Arch Gerontol Geriatr. 2012;55(2):e1. 74. Holland AE, Harrison SL, Brooks D. Multimorbidity, frailty and chronic obstructive pulmonary disease: Are the challenges for pulmonary rehabilitation in the name? Chron Respir Dis [Internet]. 2016;13(4):372–82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30209972 75. Korada SKC, Zhao D, Tibuakuu M, Brown TT, Jacobson LP, Guallar E, et al. Frailty and subclinical coronary atherosclerosis: The Multicenter AIDS Cohort Study (MACS). Atherosclerosis. 2017;266:240–7. 76. Vitale C, Spoletini I, Rosano GM. Frailty in Heart Failure: Implications for

36 Management. Card Fail Rev [Internet]. 2018;4(2):104. Available from: /pmc/articles/PMC6125710/ 77. Brown PJ, Roose SP, Fieo R, Liu X, Rantanen T, Sneed JR, et al. Frailty and depression in older adults: A high-risk clinical population. Am J Geriatr Psychiatry. 2014;22(11):1083–95. 78. Kerner AW, Brückel J. Definition, Classification and Diagnosis of Diabetes Mellitus. Exp Clin Endocrinol Diabetes [Internet]. 2014;122:384–6. Available from: http://dx.doi.org/ 79. Diabetes UK. Diabetes Prevalence 2019 [Internet]. 2019 [cited 2021 Mar 18]. Available from: https://www.diabetes.org.uk/professionals/position-statements- reports/statistics/diabetes-prevalence-2019 80. Baynest HW. Classification, Pathophysiology, Diagnosis and Management of Diabetes Mellitus. J Diabetes Metab [Internet]. 2015;6(5):1–9. Available from: https://www.researchgate.net/publication/279274191 81. Kane AE, Gregson E, Theou O, Rockwood K, Howlett SE. The association between frailty, the metabolic syndrome, and mortality over the lifespan. GeroScience [Internet]. 2017;39(2):221–9. Available from: http://link.springer.com/10.1007/s11357-017-9967-9 82. Hanlon P, Nicholl BI, Jani BD, Lee D, McQueenie R, Mair FS. Frailty and pre- frailty in middle-aged and older adults and its association with multimorbidity and mortality: a prospective analysis of 493 737 UK Biobank participants. Lancet Public Heal [Internet]. 2018;3(7):e323–32. Available from: https://pubmed.ncbi.nlm.nih.gov/29908859/ 83. Howrey BT, Al Snih S, Markides KS, Ottenbacher KJ. Frailty and diabetes among Mexican American older adults. Ann Epidemiol [Internet]. 2018;28(7):421-426.e1. Available from: https://pubmed.ncbi.nlm.nih.gov/29778652/ 84. MacKenzie HT, Tugwell B, Rockwood K, Theou O. Frailty and Diabetes in Older Hospitalized Adults: The Case for Routine Frailty Assessment. Can J Diabetes [Internet]. 2020;44(3):241-245.e1. Available from: https://pubmed.ncbi.nlm.nih.gov/31466827/ 85. Castrejón-Pérez RC, Gutiérrez-Robledo LM, Cesari M, Pérez-Zepeda MU. Diabetes mellitus, hypertension and frailty: A population-based, cross-sectional study of Mexican older adults. Geriatr Gerontol Int [Internet]. 2017;17(6):925–30. Available from: http://doi.wiley.com/10.1111/ggi.12805 86. Li G, Prior JC, Leslie WD, Thabane L, Papaioannou A, Josse RG, et al. Frailty

37 and risk of fractures in patients with type 2 diabetes. Diabetes Care [Internet]. 2019;42(4):507–13. Available from: https://pubmed.ncbi.nlm.nih.gov/30692240/ 87. Castro-Rodríguez M, Carnicero JA, Garcia-Garcia FJ, Walter S, Morley JE, Rodríguez-Artalejo F, et al. Frailty as a Major Factor in the Increased Risk of Death and Disability in Older People With Diabetes. J Am Med Dir Assoc. 2016;17(10):949–55. 88. Li Y, Zou Y, Wang S, Li J, Jing X, Yang M, et al. A Pilot Study of the FRAIL Scale on Predicting Outcomes in Chinese Elderly People With Type 2 Diabetes. J Am Med Dir Assoc. 2015;16(8):714.e7-714.e12. 89. Liccini A, Malmstrom TK. Frailty and Sarcopenia as Predictors of Adverse Health Outcomes in Persons With Diabetes Mellitus. J Am Med Dir Assoc. 2016;17(9):846–51. 90. Inoguchi T, Fukuhara S, Yamato M, Nakai M, Etoh T, Masakado M, et al. Serum bilirubin level is a strong predictor for disability in activities in daily living (ADL) in Japanese elderly patients with diabetes. Sci Rep [Internet]. 2019;9(1):1–6. Available from: https://doi.org/10.1038/s41598-019-43543-6 91. Casals C, Sánchez JLC, Suárez-Cadenas E, Aguilar Trujillo MP, Estébanez Carvajal FM, Vázquez Sánchez MÁ. Frailty in older adults with type 2 diabetes mellitus and its relation with glucemic control, lipid profile, blood pressure, balance, disability grade and nutritional status. Nutr Hosp [Internet]. 2018;35(4):820–6. Available from: https://pubmed.ncbi.nlm.nih.gov/30070869/ 92. Yanagita I, Fujihara Y, Eda T, Tajima M, Yonemura K, Kawajiri T, et al. Low glycated hemoglobin level is associated with severity of frailty in Japanese elderly diabetes patients. J Diabetes Investig [Internet]. 2018;9(2):419–25. Available from: http://doi.wiley.com/10.1111/jdi.12698 93. Bouillon K, Kivimäki M, Hamer M, Shipley MJ, Akbaraly TN, Tabak A, et al. Diabetes risk factors, diabetes risk algorithms, and the prediction of future frailty: The whitehall II prospective cohort study. J Am Med Dir Assoc. 2013;14(11):851.e1-851.e6. 94. García-Esquinas E, Graciani A, Guallar-Castillón P, López-García E, Rodríguez- Mañas L, Rodríguez-Artalejo F. Diabetes and Risk of Frailty and Its Potential Mechanisms: A Prospective Cohort Study of Older Adults. J Am Med Dir Assoc. 2015;16(9):748–54. 95. Wang X, Chen Z, Li Z, Chen B, Qi Y, Li G, et al. Association between frailty and risk of fall among diabetic patients. Endocr Connect [Internet]. 2020;9(10):1057–

38 64. Available from: https://pubmed.ncbi.nlm.nih.gov/33112808/ 96. Chhetri JK, Zheng Z, Xu X, Ma C, Chan P. The prevalence and incidence of frailty in Pre-diabetic and diabetic community-dwelling older population: Results from Beijing longitudinal study of aging II (BLSA-II). BMC Geriatr [Internet]. 2017;17(1):47. Available from: http://bmcgeriatr.biomedcentral.com/articles/10.1186/s12877-017-0439-y 97. Lopez-Garcia E, Hagan KA, Fung TT, Hu FB, Rodríguez-Artalejo F. Mediterranean diet and risk of frailty syndrome among women with type 2 diabetes. Am J Clin Nutr [Internet]. 2018;107(5):763–71. Available from: https://academic.oup.com/ajcn/article/107/5/763/4990734 98. Serra-Prat M, Sist X, Domenich R, Jurado L, Saiz A, Roces A, et al. Effectiveness of an intervention to prevent frailty in pre-frail community-dwelling older people consulting in primary care: A randomised controlled trial. Age Ageing [Internet]. 2017;46(3):401–7. Available from: https://pubmed.ncbi.nlm.nih.gov/28064172/ 99. Rodriguez-Mañas L, Laosa O, Vellas B, Paolisso G, Topinkova E, Oliva-Moreno J, et al. Effectiveness of a multimodal intervention in functionally impaired older people with type 2 diabetes mellitus. J Cachexia Sarcopenia Muscle [Internet]. 2019;10(4). Available from: https://pubmed.ncbi.nlm.nih.gov/31016897/ 100. De Labra C, Guimaraes-Pinheiro C, Maseda A, Lorenzo T, Millán-Calenti JC. Effects of physical exercise interventions in frail older adults: A systematic review of randomized controlled trials Physical functioning, physical health and activity [Internet]. Vol. 15, BMC Geriatrics. BioMed Central Ltd.; 2015. p. 154. Available from: http://www.biomedcentral.com/1471-2318/15/154 101. Sumantri S, Setiati S, Purnamasari D, Dewiasty E. Relationship between Metformin and Frailty Syndrome in Elderly People with Type 2 Diabetes. Acta Med Indones [Internet]. 2016;46(3). Available from: www.inaactamedica.org/ 102. Hazuda HP, Pan Q, Florez H, Luchsinger JA, Crandall JP, Venditti EM, et al. Association of Intensive Lifestyle and Metformin Interventions With Frailty in the Diabetes Prevention Program Outcomes Study. J Gerontol A Biol Sci Med Sci [Internet]. 2021; Available from: https://academic.oup.com/biomedgerontology/advance- article/doi/10.1093/gerona/glaa295/6079760 103. Sinclair AJ, Sinclair H, Bellary S, Rodriguez-Manas L. The emergence of frailty and sarcopaenia in diabetes mellitus: Description of inter-relationships and clinical importance. Cardiovasc Endocrinol. 2016;5(2):40–50.

39 104. Sinclair AJ, Abdelhafiz A, Dunning T, Izquierdo M, Rodriguez Manas L, Bourdel- Marchasson I, et al. An International Position Statement on the Management of Frailty in Diabetes Mellitus: Summary of Recommendations 2017. J frailty aging [Internet]. 2018;7(1):10–20. Available from: https://pubmed.ncbi.nlm.nih.gov/29412437/