Frailty can be defined as a situation of extreme vulnerability to the effects of low-intensity stressors. It results from difficulty maintaining homeostasis due to loss of functional reserve.3 Two conceptual frameworks have been used to explain frailty.

• (1)

  The ‘frailty phenotype’ was described by Fried et al.4 in 2001 using data obtained from the Cardiovascular Health Study. According to this phenotype, frailty represents an alteration in different physiological systems that causes the aforementioned drop in functional reserve and is expressed clinically through the five criteria shown in Table 1.4 According to this definition, a person is considered frail if they meet at least three of the five criteria and pre-frail if they meet one or two of these criteria. Those who do not meet any of the criteria are classified as robust.4

  Table 1.

  Operational criteria of the frailty phenotype.

  Characteristic	Measure
  Unintended weight loss (in the past year)	>4.5kg (communicated) or ≥5% in the past year (objectified)
  Weakness	Grip strength (adjusted for sex and BMI) in the lowest quintile
  Self-reported exhaustion	Communicated by means of two statements of the CES-Da depression scale: “I felt that everything I did was an effort” and “I could not get going” The individual would report always or almost always (3–4 days/week or greater)
  Slowness	Walking time 4.57m (adjusted for sex and height) in the lowest quintile
  Low physical activity	Energy expenditure: – Men: <383kcal/week – Women: <270kcal/week
  Presence of frailty Frail: at least three criteria are met Pre-frail: one or two criteria are met Not frail: no criteria are met

  a

  Center for Epidemiologic Studies-Depression Scale (CES-D) is a 20-item instrument that assesses symptoms of depression in DSM-IV.

  BMI, body mass index; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders (fourth edition).

  Adapted from Fried et al.,4 2001.
• (2)

  In the ‘cumulative deficit model’ created by Rockwood et al.,5 frailty is defined by the presence of deficits that accumulate over time and progress to a level of vulnerability that becomes incompatible with independent living and survival. The operational translation of this conceptual framework is embodied in the Frailty Index, which quantitatively describes the health status of the patient and the progression of their frailty over time and evaluates potential deficits the patient may have in the following categories: disease, cognitive status, health conditions, nutritional status, ability to communicate, independence for activities of daily living, motivation, perception of health status, strength, balance, mobility, sleep, social aspects, geriatric syndromes, and disability.5–7 The value of this index for each individual is calculated as the ratio of observed deficits to the total number of possible deficits.

As noted by other authors, the Fried phenotype and Frailty Index have significant differences that may influence their use; these are discussed in detail elsewhere.3,8 The Frailty phenotype can be used at the patient's first visit; in contrast, the Frailty Index requires a thorough initial geriatric assessment.8 It should be highlighted that the modified Frailty Index has a potentially superior ability to discriminate between patients with moderate frailty and those with severe frailty3 and is more sensitive to change.8 Therefore, it is theoretically more useful for assessing the outcome of interventions or describing the evolution of the health status of the patient. However, it should be noted that both models have demonstrated convergent validity with respect to health outcomes and are therefore helpful in identifying frailty.3,8

Attempts to arrive at an operative and universal definition of frailty have not yet been successful. Experts from different disciplines collaborating on the “Frailty Operative definition – Consensus Conference” project (2012) concluded that frailty is a multidimensional syndrome that affects physical function (i.e., gait and mobility), nutritional status, and mental health and cognition, and is the result of a decrease in physiological reserve and resistance to stressors.9 In a similar sense, representatives from six international societies (the International Association of Gerontology and Geriatrics; Society on Sarcopenia, Cachexia and Wasting Diseases; the International Academy of Nutrition and Aging; the European Union Geriatric Medicine Society; the American Medical Directors Association; and the American Federation for Aging Research) have defined frailty as “a medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and reduced physiologic function that increases an individual's vulnerability for developing increased dependency and/or death.”10

A systematic review showed that, if psychosocial components are included in the definition of frailty, the prevalence of frailty in the population aged ≥65 years is 13.6%; if the definition of frailty is limited to a physical condition, the prevalence is only 9.9%.11 Overall, the average prevalence of frailty is 10.7%; this prevalence increases with age and is higher in women than in men.11 In another systematic review that included 24 studies conducted in individuals aged ≥65 years, the prevalence of frailty was 14% when the Fried phenotype was used and 24% when the cumulative deficit model was used.12 These authors also found that the prevalence of frailty increases with age and is more prevalent in women. It is also noteworthy that Black individuals are four times more likely to develop frailty than are White individuals.13

Previous studies conducted in Spain indicated that frailty has a significant impact on the older population. In these studies, the prevalence of frailty ranges from 8.4% to 16.9%, and the prevalence of pre-frailty ranges from 41.8% to 48.5% when the Fried Frailty Phenotype is applied.14–18 Although the variables analyzed in different studies varied, the factors most commonly associated with frailty were age, comorbidity, depression, and cognitive disorders. Variability in these prevalences may be due to differences in the age of the studied populations, the use of modified Fried criteria in certain studies, and the use of different cut-off values for some of the items.

Frailty is the manifestation of disorders in different physiological systems of the body, including the central nervous, endocrine, immune, musculo-skeletal, cardiovascular, respiratory, and renal systems. Frailty becomes apparent when a (currently not accurately defined) level of decline in physiological reserves occurs.19,20

Several longitudinal studies conducted in older populations have demonstrated an association between frailty and a deterioration in quality of life, a risk of falls, new or increased disability, hospitalizations, nursing home entry, and mortality.4,21–27 Subjects who are moderately or severely frail have a relative risk (RR) for institutionalization of 8.6 (95% confidence interval [CI], 4.9–15.2) when compared with subjects who are physically active.21 Frail subjects are more likely to have an impaired quality of life and/or to have been hospitalized.26 As compared to non-frail patients, frail patients have a greater likelihood of losing basic activities of daily life (hazard ratio [HR] 2.5, 95% CI 1.3–4.8), mobility (HR 2.7, 95% CI 1.5–5.0), and instrumental activities of daily life (HR 1.9, 95% CI 1.1–3.3).27 It has also been reported that frail women have a higher age-adjusted likelihood of presenting with recurrent falls (odds ratio [OR], 2.4), disability (OR 2.2–2.8), and death (HR 2.4–2.7).23 In another study, both women and men showed an increased likelihood of death with almost identical effect sizes compared with the previous study: a HR of 2.8 (95% CI 1.5–5.3) for women, and a HR of 2.4 (95% CI 1.0–5.9) for men.24 The effect of frailty on survival has also been studied in a systematic review of studies conducted in randomly sampled older individuals.12 In this systematic review, the existence of a gradient between frailty and mortality was found, with reduced survival associated with increasing numbers of frailty criteria.12

An estimated 382 million people have diabetes worldwide (46% undiagnosed), and this figure is expected to grow by 55% to 592 million in 2035.36 As is the case with frailty, the incidence and prevalence of diabetes increases with age, and more than 25% of the people aged ≥65 years has diabetes.37 The International Diabetes Federation (IDF) estimates that 18.6% of people aged between 60 and 79 years have diabetes, and more than 35% of all diabetes cases are in this age group.36 In Spain, the Di@betes study showed that at least 30% of people aged between 61 and 75 years and more than 35% of people aged >76 years have diabetes.38

The prevalence of diabetes increases with the presence of frailty. The Cardiovascular Health Study showed that the prevalence of diabetes was 18.8% in individuals without frailty, 24.5% in individuals with pre-frailty, and 32.4% in individuals with frailty.39 Likewise, the presence of frailty is higher in patients with diabetes. Data from this study indicate that frailty is present in 25% of individuals with diabetes and pre-frailty is present in 18.2% compared with a prevalence of frailty of 6.9% in the whole sample who were aged ≥65 years.4 However, in Spain, the Toledo study showed that frailty is present in only 10.2% of individuals with diabetes and in 7.8% of individuals without diabetes; moreover, this study found no association between these two factors in a multivariate analysis.15 A study that evaluated the progression of frailty and pre-frailty in an older cohort living in the community found that the presence of diabetes in women with pre-frailty reduced by 50% the likelihood of their frailty improving.40

Sarcopenia, defined as a reduction in muscular mass and function (strength or performance),41 is considered a key component of frailty and may represent the pathophysiological link between diabetes and frailty.28 Data from several studies reviewed by other authors28,30,42,43 show a close relationship between diabetes, insulin resistance, the chronic low-grade inflammation characteristic of diabetes and sarcopenia, and/or muscle deterioration. Many studies have shown that muscle strength and quality decrease in patients with diabetes, and this decline becomes more pronounced the longer the patient is affected with diabetes and the poorer their glycemic control. Insulin resistance is associated with a decrease in muscle strength, most likely due to a decrease in protein synthesis, increased degradation, and a resultant loss of muscle mass. At the same time, insulin resistance in aging patients can lead to mitochondrial alterations that result in a decrease in production of the energy required for muscle contraction and an increase in oxidative stress.

Insulin-like growth factor type 1 plays an important role in protein synthesis, and levels of this molecule decrease with age and in patients with diabetes.44,45 This decrease is related to the development of frailty, functional decline, and disability in the older patient. Research on markers related to inflammation in frail and non-frail individuals indicates that the frailest subjects have elevated levels of high sensitivity C-reactive protein, a soluble biomarker of inflammation,46,47 and other procoagulant factors. Patients with diabetes also have elevated levels of cytokines, such as tumor necrosis factor alpha and interleukin-6, that stimulate proteolysis and apoptosis in muscle cells. Additionally, different studies describe a dysregulation of the levels of various hormones, such as testosterone and cortisol, and nutrients, such as vitamin D, in patients with insulin resistance, sarcopenia, and functional decline.28–30,42

These mechanisms provide a direct association between diabetes and functional sarcopenia/impairment, and explain most of the attributable risk of disability in older patients with diabetes. However, other factors can explain the relationship between these two entities, including atherosclerosis, depressive illness, and cognitive decline.29,48 Patients with diabetes develop atherosclerosis at an accelerated rate.29 Atherosclerosis can be related to sarcopenia and frailty through processes that affect muscle performance (i.e., peripheral vascular disease and peripheral neuropathy) or chronic kidney disease, which can result in inactivity, loss of muscle mass, and a decline in physical and cognitive function.28,29 Diabetes and depression are interrelated, and depression has been linked to a progressive decline in strength. It has also been shown that diabetes and impaired glucose tolerance are associated with a worsening of cognitive function.29 Patients with type 2 diabetes are at an increased risk of developing mild cognitive impairment, vascular dementia, and Alzheimer's disease. Additionally, elevated glucose levels have been associated with an increased risk of developing dementia in patients without diabetes.48 The inter-relations among these factors are summarized in Fig. 2.

Figure 2.

Pathophysiology of the relationship between diabetes and frailty (based on Refs. 29 and 74). GH, growth hormone; IGF, insulin-like growth factor; IL, interleukin; TNF, tumor necrosis factor; Vit., vitamin.

(0.15MB).

According to the international consensus on frailty (Frailty Consensus: A Call to Action) and the Consensus Document on Prevention of Frailty and Falls in the Older Person, which was approved by the Interterritorial Council of the Spanish National Health System and is scheduled to be implemented between 2015 and 2025 all persons aged 70 years or older, should be screened for frailty.10 Given the significant repercussions that frailty has on older individuals (especially patients with diabetes), and the implications for the management of diabetes, the IDF also recommends screening patients with diabetes who are aged ≥70 years for frailty.

Functional status is an important prognostic factor in older patients. Consequently, a comprehensive functional assessment that quantitatively encompasses the physical, cognitive, and emotional status of the patient should be a critical part of the clinical evaluation of older patients with diabetes.37

The international consensus on frailty endorses validated instruments to assess the presence of frailty, including the FRAIL questionnaire, the CHS Frailty Screening Measure (corresponding to the Fried Phenotype), the Clinical Frailty Scale (a tool recommended by the IDF), and the Gérontopôle Frailty Screening Tool.10 These tools can identify people with frailty who need further evaluation by specialists. In Table 2, we list a number of instruments that can be used to assess frailty.

As recommended by the IDF and treatment guides for older diabetics, multidimensional and, whenever possible, multidisciplinary assessments of older patients with diabetes should be performed to collect information about medical, functional, cognitive, emotional, and social functioning of the patient.50,51 A comprehensive geriatric assessment is likely the most complete way to assess a patient with frailty.49 This assessment is a dynamic and structured diagnostic process that detects and quantifies the problems, needs, and abilities of the older individual in four key areas: clinical, functional, mental, and social. This assessment can then be used to develop an interdisciplinary plan for intervention, treatment, and long-term monitoring, thereby enabling the patient to maintain a high degree of independence and an acceptable quality of life. During this evaluation, emphasis should be placed on managing these complex diseases and evaluating the patient's quality of life.49,50,52 At a minimum, the evaluation should assess the patient's functional capacity, cognitive function, and mental health.50Table 2 lists evaluations and instruments proposed by the IDF that can be used with minimal training in daily clinical practice.

Given the elevated prevalence of diabetes in older patients and because approximately 40% of cases of diabetes remain undiagnosed,38 all older patients should be periodically evaluated to detect diabetes. These evaluations are especially warranted in certain groups, including in all patients admitted to a nursing home.50 The IDF recommends using the same diagnostic criteria for diabetes that are used for the general population; however, only the simplest possible tests should be used in frail patients.

There is widespread consensus that the objectives of glycemic control in the frail older patient should be individualized and that the strict control of glycemia (for example, glycated hemoglobin [HbA1c] <7%) is associated with a risk of hypoglycemia and functional decline.35,50,51,53,54 Because the estimated time to achieve benefits from intensive glycemic control is at least 8 years (United Kingdom Prospective Diabetes Study), the available guidelines currently recommend less stringent control objectives (HbA1c <8.0–8.5%) in frail patients or patients with a limited life expectancy (<5 years). Table 3 describes the main recommendations of the American Diabetes Association (ADA), the IDF and other consensuses for achieving glycemic control and managing diabetes in the frail older patient.

Below, we summarize the limited information available for treating older patients with diabetes that considers the frailty of the patient.

Not all patients clearly fit into one category. Therefore, the preferences and characteristics of the patient and their caregivers are important factors to consider when developing individualized treatment plans. Treatment goals for the management of complications depend on the functional status of the patient, including their frailty, cognitive status, risk of hypoglycemia, and life expectancy.58

The recommendations of the IDF and ADA for the management of certain complications and comorbidities associated with diabetes are summarized in Table 3.

Interventions to address patients’ cardiovascular risks are necessary to prevent or delay cardiovascular disease in people with diabetes. In this context, the ADA recommends preventive measures in all patients aged ≥60 years to address some of the main risk factors for cardiovascular disease (tobacco use, blood pressure, dyslipidemia, renal function, glycemic control, obesity, periodontitis, sleep apnea, and peripheral vascular disease). However, the role of cardiovascular disease as a prognostic marker of death and functional impairment in older patients with diabetes is controversial, especially in patients aged >75 years.68

Hypoglycemia is the main side effect of diabetes treatment in general older patients, and hypoglycemia can have serious consequences, including cognitive impairment, falls, fractures, and cardiovascular events, that lead to frailty and disability, creating a vicious circle of hypoglycemia and frailty.67 Avoiding hypoglycemia should be one of the main goals of treatment. Thus, glycemic targets should be individualized, focusing on the short term to avoid hypoglycemia instead of having a long term strategy.67 In addition to drug treatment, under-nutrition plays an important role in the occurrence of hypoglycemia in frail patients. Therefore, the improvement of the energy intake is central to the management of these patients.67 Recommendations on the use of insulins have been made above. It is recommended that family members and caregivers be educated to recognize and treat hypoglycemia50 and that frail patients living in the community should be enrolled in an ‘SOS-call’ program.

The IDF also makes general recommendations for handling hyperglycemic emergencies.50 Glycemic goals should minimize severe hyperglycemia and reduce the risk of diabetic ketoacidosis or a hyperglycemic hyperosmolar state. Both medical and non-medical teams should be taught to recognize risk factors and manage hyperglycemic emergencies in older patients. Additional research on the consequences of frailty in diabetic patients and the development of intervention programs specifically designed for these patients could help improve their clinical care. In this context, the MID-FRAIL study, which was funded under the 7th Framework Programme of the European Union and led by Spain, provides an opportunity to explore the usefulness of a multidimensional intervention for frail and pre-frail patients aged >70 years with type 2 diabetes.69