Cardiovascular Disease

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Frailty is common among older adults living with cardiovascular disease (CVD).  Across the spectrum of heart disease, prevalence estimates of physical frailty have been reported at 52% among those with systolic and diastolic heart failure, 42% in those with acute coronary syndrome , and 37% in those with valvular heart disease.

Introduction:

Frailty is common among older adults living with cardiovascular disease (CVD).  Across the spectrum of heart disease, prevalence estimates of physical frailty have been reported at 52% among those with systolic and diastolic heart failure (Sze et al., 2019), 42% in those with acute coronary syndrome (Núñez et al., 2020), and 37% in those with valvular heart disease (Afilalo et al., 2017).

A leading hypothesis suggests that the high levels of inflammation associated with aging – “inflammageing” – is a strong risk factor for both cardiovascular disease and frailty (Ferrucci et al., 2018). The relationship between frailty and CVD is therefore complex, and is likely to have mutual causality.  For example, it is likely that many common cardiovascular conditions drive inflammatory pathway activation, which in turn impacts skeletal muscle and other tissues that drive physical frailty.   In addition, chronic inflammatory pathway activation that may stem from biological aging changes and underlying frailty likely also accelerates/worsens clotting states, cardiovascular diseases, and related complications.

Impact of Frailty on Cardiovascular Disease:

Frail adults with CVD typically suffer with worse disease outcomes than those who are not frail (Afilalo, 2014; Veronese et al., 2017). For example, the presence of physical frailty was associated with longer hospital length of stay, increased re-hospitalization, and greater cardiovascular mortality in those with acute myocardial infarction (Erkstad et al., 2011). Similarly,  mortality risk was increased three-fold at one year in frail versus non-frail older adults with moderate heart failure (Lupon et al., 2008). Gait speed appears to be a particularly important marker for poor outcomes in cardiovascular disease patients, with risk of mortality increased more than 5-fold comparing gait speeds below versus above WHAT in one study of cardiac surgery patients (Afilalo et al., 2010).

Applying Knowledge of Frailty to Treatment of CVD:

Importantly, physical frailty is also associated with an increased susceptibility to harmful effects from standard therapies for CVD. For example, medical therapy for ischemic heart disease typically includes prolonged antiplatelet therapy, which increases bleeding risk disproportionately in those who are also frail (Alonso et al., 2016).

Current practice reflects concerns by physicians about the tolerability of treatments for CVD in older adults and in particular those who are frail. Several studies have found that those with known frailty were less likely to receive the same extent of therapy as compared to adults without frailty. Physically frail patients were less likely to be admitted to coronary care units and to undergo cardiac catheterization or coronary artery bypass surgery (Damluji et al., 2019). In a 2013 study of patients with atrial fibrillation, frailty was associated with considerably less frequent receipt of evidence-based therapies (Hess et al., 2013). In addition, the use of guideline-directed medical therapy with ACE inhibitor and beta-blockers was lower when frailty was encountered (Sze et al., 2019). It is not known whether medications are tried and not tolerated or never considered because of concern over physical function. For example, fatigue could limit the clinical ability to use beta-blockers to achieve a reduced work-load of the heart as is otherwise indicated. However, denying therapy to older adults is also inappropriate, as early revascularization results in improved clinical outcomes and better symptom control after myocardial infarction regardless of age (Forman et al., 2016).

Research is needed to determine whether the accelerated decline in health among frail older patients with cardiovascular disease could be mitigated by early mobility after procedures, incentive spirometry, physical therapy, and nutritional enrichment. This is an active area with ongoing research trials (Bendayan et al. , 2014; Stammers et al, 2015; NCT03522454).

This reference list supports the text above and provides additional references related to frailty in cardiovascular disease:   

HIV and Frailty

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With the widespread availability of effective antiretroviral therapy (ART) beginning in the late 1990’s, HIV infection has been transformed into a chronic disease. Survival among people living with HIV (PLWH) is now approaching that of the general population. However, there appears to be an acceleration of aging processes in PLWH. Aging-related comorbidities, such as cardiovascular disease, pulmonary disease, diabetes, heart failure, and kidney disease are more frequent and tend to occur at an earlier age in those living with HIV (Schouten et al., 2014; Guaraldi et al., 2011; Gonciulea et al., 2017; Drozd et al., 2017).  Markers of biologic aging, such as epigenetic alterations in cellular DNA – a “clock” for cellular aging – are similar to persons without HIV who are over five years older (Fülöp et al., 2017; Horvath et al., 2015).

Introduction

With the widespread availability of effective antiretroviral therapy (ART) beginning in the late 1990’s, HIV infection has been transformed into a chronic disease. Survival among people living with HIV (PLWH) is now approaching that of the general population. However, there appears to be an acceleration of aging processes in PLWH. Aging-related comorbidities, such as cardiovascular disease, pulmonary disease, diabetes, heart failure, and kidney disease are more frequent and tend to occur at an earlier age in those living with HIV (Schouten et al., 2014; Guaraldi et al., 2011; Gonciulea et al., 2017; Drozd et al., 2017).  Markers of biologic aging, such as epigenetic alterations in cellular DNA – a “clock” for cellular aging – are similar to persons without HIV who are over five years older (Fülöp et al., 2017; Horvath et al., 2015).

Among PLWH, the clinical and public health significance of frailty has become more widely recognized (Piggott et al., 2016). Multiple studies have shown a high prevalence of physical frailty is this population. In the AGEhIV Cohort Study in Amsterdam, the prevalence of frailty, using the physical frailty phenotype, was 10.6% in PLWH compared to 2.7% in age, sex, and race-matched controls. The prevalence of pre-frailty was also significantly higher in PLHW (50.7% v 36.3%). Even after adjustment for demographic factors, smoking, hepatitis C infection, comorbidities and depression, HIV-infection was associated with a doubling of the odds of frailty and pre-frailty (Kooij et al., 2016). In the Multicenter AIDS Cohort Study, a study of men who have sex with men, the prevalence of frailty was also higher in PLWH compared to demographically similar HIV-uninfected men (12% vs 9%), particularly in those who had a past history of AIDS (Althoff et al., 2014).

The Impact of HIV Infection on Frailty

The etiology of the higher prevalence of frailty in PLWH is multifactorial, with both infection and treatment contributing to the problem. Chronic inflammation, which is present in PLWH even when HIV viral load is undetectable, leads to accelerated cellular senescence, mitochondrial dysfunction, and metabolic dysregulation (Erlandson et al., 2014).  These changes in physiology are known to develop during aging and are thought to play a role in the development of frailty in the general population. Infection with HIV therefore causes a premature onset of these processes.

Antiretroviral therapy (ART) for HIV infection is likely to have both direct and indirect effects on physical function. Nucleoside analogue reverse transcriptase inhibitors (NRTI) that are thymidine analogues, including AZT and d4T, were used extensively in PLWH when combination antiretroviral therapy became available and have direct effects on mitochondrial function.  These changes result in persistent body composition alterations (subcutaneous lipoatrophy and relative central lipohypertrophy), insulin resistance, and dyslipidemia, which in turn may predispose these individuals to more accelerated aging-related declines in physical function (Kooij et al., 2016). Although in the current HIV treatment era these medications are seldom used, their adverse effects may persist in those who were previously exposed. Efavirenz, a previously widely used non-NRTI, has been linked to frailty in a study the AIDS Clinical Trial Group, although it is unclear if this association is causal (Erlandson et al., 2017).  More recently, the integrase strand transfer inhibitors (InSTI or commonly “integrase inhibitors”), which are currently a key component of most ART regimens, have been linked to significant weight gain (Eckard & McComsey, 2020). Whether these changes in adiposity will predispose PLWH to faster declines in physical function as they age is an important area of inquiry.

Impact of Frailty on those living with HIV

An increased prevalence of frailty among PLWH at a relatively young age stands to have a major impact on both health and quality of life as the HIV population ages. By 2035, an estimated 70% of the HIV population in the US will be over 50 years old, with 25% over 65 years of age (Smit et al., 2017).

Frailty among PLWH, as in the general population, is associated with multiple adverse outcomes, including falls, fractures, and mortality (Kelly et al., 2019; Erlandson et al., 2019; Sharma et al., 2019).  Frailty is also related to decreased muscle mass (sarcopenia), which is associated with mortality in PLWH, especially when coupled with accumulation of visceral fat, in a phenotype reminiscent of sarcopenic obesity (Scherzer et al., 2011; Hawkins et al, 2018).  In the FRAM study, PLWH in the lowest tertile of skeletal muscle mass had twice the mortality of those in the highest tertile, an effect that was especially prominent in those with the most (i.e., highest tertile) of visceral fat (Scherzer et al., 2011).

Applying Knowledge of Frailty in HIV

Understanding the pathogenesis of frailty in PLWH is the first step towards robust interventions.  One important research question is whether the mechanisms underlying frailty and impaired physical function are similar or different from frailty in the general population.  Are there molecular pathways that are more or less activated?  Are the physical manifestations of frailty pathways, such as immunosenescence, mitochondrial dysfunction, and hormonal dysregulation, the same as the general population in PLWH?  If differences exist between PLWH and the general population, this would suggest that the strategies to alter the physical function trajectory may also differ.

Over the past 30 years, the health of PLWH has been radically transformed with advances in our understanding of HIV, improved antiretroviral treatments, and their more widespread availability.  Advances in frailty science will help improve the health and well-being for PLWH in the next 30 years.

Primary Care

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Performing Frailty Assessment in Primary Care

Primary care doctors frequently need to help older patients make decisions in situations where knowing about frailty could, and should, influence medical choices. For example, frailty status changes risk prediction for elective surgery and alters the tolerability of side effects from aggressive cancer treatments.  Interventions to mediate such risks can only be initiated when frailty has been identified. Thus, frailty screening, followed by more comprehensive assessment when appropriate, can provide primary care physicians with important clinical information to optimize the care of older adults.

Consensus statements by both American and international leaders in aging research advocate for broad-based frailty screening in older adults for these reasons (Cesari et al., 2016; Morley et al., 2013; Turner and Clegg, 2014; Walston et al., 2019). However, individual providers seeking to implement screening in their own primary care practice often find it difficult to identify the time and the appropriate tools to measure frailty.  In addition, the limited number of interventional studies that identify effective strategies to mitigate frailty or that demonstrate benefits of frailty assessment for subsequent surgical or medical outcomes may lead care providers to consider the screening to be futile.

Clinics which have successfully implemented frailty assessment into routine, consultative or primary care, such as the Successful Aging and Frailty Evaluation clinic at the University of Chicago (Huisingh-Scheetz et al., 2019) or the Gerontopole Geriatric Frailty Clinic (Tavassoli et al., 2014), provide experience which can offer a framework for incorporating frailty into primary care.

Targeting Screening

Current expert consensus suggests that all adults age ≥70 or experiencing weight loss >5% over a year should be screened for frailty (Morley et al., 2013). This very broad approach facilitates early frailty detection. Relying on an “eyeball” test to trigger screening may identify individuals fairly late in the frailty trajectory when frailty interventions may have less impact. Providers implementing frailty screening to aid in surgical or medical treatment decision making may wish to consider screening early enough to allow frailty reduction strategies prior to the surgical or medical treatment

Choosing a Screening Method

Selecting a frailty screening method depends on the clinical or research goals.  Caution in selection of tools for clinical practice is recommended as agreement between frailty tools vary widely (Aguayo et al., 2017). A overview of screening instruments that can be utilized are provided here.  There are many validated instruments that identify a high-risk subset of older adults so that their subsequent care can be tailored effectively.  For most busy primary care physicians, selection of a quick, highly sensitive screening method may be most practical for implementation. Some assessments can be calculated using largely electronic medical record data, while others are more easily administered over the phone.   Shorter frailty screening instrument options include the FRAIL scale (Morley et al., 2012) and the Edmonton Frail Scale (Rolfson et al., 2006), but many alternatives are available.  After such high-risk frail adults are identified, they could then be referred for more complete physical frailty testing and a comprehensive geriatric assessment, conducted by either a geriatrician or a trained primary care physician.  Those screening positive on a shorter frailty instrument may be referred for a more thorough evaluation of frailty. Deficit accumulation scales with between 30 and 70 items are available, as is the physical frailty assessment instrument. This consists of gait speed (e.g., 4-meter timed walk), grip strength, weight loss calculation, physical activity energy expenditure, and self-reported exhaustion (Fried et al., 2001).

For the practitioner interested in frailty intervention, careful choice of frailty measurement methods is particularly important, because this choice determines the target of intervention. The majority of frailty intervention studies to date have assessed and targeted physical frailty, which can allow for quantified changes in function and targeting of functionality (Puts et al., 2017). Physical frailty is an appropriate endpoint for interventions that manipulate underlying biology and physiology, as it arose from a model of physiological determinants (Fried et al, 2001) having a considerable evidence base (Fried et al, 2009; Szanton et al., 2009) . The Edmonton Frail Scale highlights frailty-related domains such as cognition or medical issues, thus can be helpful in intervention strategy development in addressing and potentially treating such issues after an initial screen.  The Gerontopole Frailty Screening Tool includes measures of mobility difficulties and fatigue, and can be useful if one seeks to identify persons at risk for incident disability (Vellas et al., 2013).

Applying Knowledge of Frailty in Primary Care 

The information provided by a frailty assessment may impact clinical management of older adults in several key ways.

Risk Stratification

The prevalence of frailty is high among older adults seeking consultation for surgery and primary care physicians are often asked to medically clear these patients for procedures (Beckert et al, 2017). Knowing a patient’s frailty status can improve the pre-operative or pre-procedural risk assessment can aid in surgical risk / benefit conversations with patients. It can also support tailored education and counseling to patients and families on peri-operative and post-operative care and recovery expectations. Identifying frailty sufficiently early in the pre-operative period can provide an opportunity for more intense and time-limited frailty mitigation strategies implemented prior to procedures to reduce risk. There is limited experience, but at least one such study has shown promise in the setting of renal transplantation.

Preventative Interventions

Frailty identification should trigger frailty interventions. Such interventions aim to reverse physiologic vulnerability, improve functional status, expand the “health-span,” improve resilience to stressors of all kinds, and reduce the consequences of frailty such as falls. Although more work is needed (Walston et al., 2018), some evidence-based interventions include:

  • Strength training, general exercise, and physical activity
  • Nutrition support to prevent or reverse weight loss and micronutrient deficiencies or to aid in muscle building
  • Reduction of polypharmacy

Furthermore, those with physical frailty often have concomitant social and cognitive deficiencies which can be simultaneously addressed using multidisciplinary teams.

Framing Care Plans

Research has suggested frailty status can help frame overall care planning. For example, more aggressive medical management for chronic medical conditions might be pursued in non-frail patients, or earlier referrals for palliative care and hospice services that help optimize quality of life might be made for patients with advanced frailty (Espinoza and Walston, 2005).

Summary

Frailty assessments are increasingly relevant to the care of older adults in primary practice as care providers seek methods to better identify the most vulnerable subset of older adults.  A wide variety of instruments can be utilized, depending on the purpose in mind, to measure frailty and design potential intervention strategies.

Emergency Medicine

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Introduction

The prevalence of frailty among older adults presenting to emergency departments (ED) appears to be significantly enriched compared to background rate estimates (of around 10%) found in studies of community dwelling older adults in high-income countries. A study in Dublin of almost 200 consecutive patients older than 70 reported that 47% were classified as frail using a deficit accumulation index (DAI) frailty assessment (Fallon et al., 2018). Among a sample of U.S. older adults discharged home after their ED visit, 20% were found to be frail using the physical frailty phenotype (Stiffler et al., 2013).

Impact of Frailty on Emergency Medicine 

Frail older adults in the ED present significant challenges to emergency medicine providers. The first occurs at the beginning of every interaction–with triage–because the differences in response to illness and injury in older adults may result in a lower severity score than is warranted by the condition. 

Under-diagnosis at triage has been documented in studies of older adults presenting to EDs across the United States (Platts-Mills et al., 2010; Kodadek et al., 2015). The failure to accurately triage acute illness in older adults results, in part, from the blunted responses to illness in this population, arising from changes in the immune system and reaction to both endogenous and exogenous pyrogens (see Research Topics). This can lead to less dramatic clinical findings on exam–lack of fever and other inappropriately normal vital signs and more subtle laboratory value abnormalities than in younger patients with similar disease (Katz and Carpenter; Heffernan et al., 2010).  In addition, medication side effects and communication challenges, including vision and hearing deficits, can create further barriers for emergency medicine providers evaluating older adults for serious illness or traumatic injury. 

Frailty also increases the risk of poor outcomes following an ED visit. Hospital admission, death, and nursing home admission among older adults within 30 days of ED discharge have all been linked to a higher DAI. After adjusting for demographics, insurance status and previous health service use, only repeat ED visits were not significantly associated with an elevated DAI (Hastings et al, 2008). Functional decline has even been noted in study of vulnerable older adults who were seen in the ED for what were thought to be minor injuries (Sirois et al., 2017).

Delirium is a second risk factor which complicates the ability to provide rapid disease identification and stabilization, as well as significantly delaying disposition, lengthening ED stays and triggering hospitalization. Importantly, these two risk factors are not fully independent as frailty measured by DAI has been linked to risk of delirium in the ED (Giroux et al., 2018). 

Applying Knowledge of Frailty in the Emergency Department 

Practical limitations to assessing frailty in the ED are significant. In particular, while the biology of physical frailty is likely to play a key role in the under-diagnosis and triage of older adults in the ED, current physical frailty assessment is not practical in the ED. Even if testing could be administered, grip strength and walking speed cannot be easily interpreted in those with acute illnesses which effect functional capacity. This is easily appreciated to be true for common presentations such as asthma or pneumonia. Some have started to look at using components of physical frailty measured in those being discharged from the ED as individual markers of outcomes(Afilalo et al., 2020), but research on frailty in the ED has generally used deficit accumulation scoring systems to categorize patients. Wider recognition of and screening for frailty among older adults prior to an ED visit, when these patients are well, may be of higher value than evaluating for frailty at the point of an ED visit. These pre-ED visit frailty results could be shared with the emergency medicine provider during an acute event, like allergy warnings or difficult airway alerts to help identify higher risk patients. Furthermore, such a flag could allow for the appropriate adjustment interpreting vital signs at triage, for example.

Appreciating that the vulnerability impacts not just the acute care but also the success of the disposition should direct the types of interventions studied to reduce the impact of frailty. Ancillary services that can facilitate communication beyond the ED visit, such as pharmacy consultation for medication reconciliation, social work or case management resources to support transitions in care, may allow emergency medicine providers to improve the long-term health of vulnerable adults who pass through their care. The foundations of emergency medicine, identification of time sensitive disease and injury as well as efficient and timely care of these patients, are unlikely to change. However, being able to identify vulnerable older adults who are at high risk of poor outcomes, should be recognized as equally as important. Innovative approaches in caring for these vulnerable older adults is likely to lead to changes that improve care for this population. 

The research to date has been done on descriptive cohort studies and the field is ready for randomized clinical trials comparing the use of DAI screening, or pre-determined physical frailty, to improve outcomes during and following ED visits (Jorgenson and Braband, 2017). 

References: 

  • Fallon et al, Screening for frailty in older emergency department patients: the utility of the Survey of Health, Ageing and Retirement in Europe Frailty Instrument. QJM, 2018; 111(3):151 
  • Stiffler et al 2013 Frailty assessment in the Emergency Department J Emerg Med 45(2): 291
  • Platts-Mills TF, Travers D, Biese K, et al. Accuracy of the emergency severity index triage instrument for identifying elder emergency department patients receiving an immediate life-saving intervention.  Acad Emerg Med. 2010;17(3):238-243. doi:10.1111/j.1553-2712.2010.00670.x 
  • Kodadek LM, Selvarajah S, Velopulos CG, Haut ER, Haider AH.  Undertriage of older trauma patients: Is this a national phenomenon? J Surg Res 2015. doi:10.1016/j.jss.2015.05.017
  • Katz ED, Carpenter CR. Fever and immune function in the elderly. In: Geriatric Emergency Medicine.  Meldon SW, Ma OJ, Woolard R (eds), McGraw-Hill, 55-69
  • Heffernan DS, Thakkar RK, Monaghan SF, et al. Normal presenting vital signs are unreliable in geriatric blunt trauma victims. J Trauma - Inj Infect Crit Care. 2010;69(4):813-818. doi:10.1097/TA.0b013e3181f41af8 
  • Hastings SN, Purser JL, Johnson KS, Sloane RJ, Whitson HE. Frailty predicts some but not all adverse outcomes in older adults discharged from the emergency department.  J Am Geriatr Soc. 2008;56(9):1651-1657. doi:10.1111/j.1532-5415.2008.01840.x 
  • Giroux M, Sirois MJ, Boucher V, et al. Frailty Assessment to Help Predict Patients at Risk of Delirium When Consulting the Emergency Department. J Emerg Med. 2018;55(2):157-164. doi:10.1016/j.jemermed.2018.02.032 
  • Sirois MJ, Griffith L, Perry J, et al. Measuring frailty can help emergency departments identify independent seniors at risk of functional decline after minor injuries.  J Gerontol - Ser A Biol Sci Med Sci. 2017;72(1):68-74. doi:10.1093/gerona/glv152 
  • Afilalo et al, 2020 Frailty and adverse outcomes in older adults being discharged from the emergency department: A prospective cohort study. CJEM. 2020 Jan;22(1):65-73
  • Jørgensen R, Brabrand M. Screening of the frail patient in the emergency department: A systematic review. Eur J Intern Med. 2017. doi:10.1016/j.ejim.2017.09.036 

Diabetes

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Introduction

Diabetes increases in prevalence in older populations. One quarter of adults aged 65 years and over in the United States has diabetes (CDC). Further, approximately half of the older adult population has prediabetes (CDC). Large population studies also suggest that many older adults have undiagnosed diabetes (Cowie et al., 2009). Diabetes prevalence is also increased among older adults with physical frailty (Walston et al., 2002). In fact, there is evidence of an association between insulin resistance and physical frailty even in those without diabetes (Barzilay et al., 2007).  

Impact of Glucose Metabolism on Frailty 

Frailty alters glucose-insulin dynamics in a manner that suggests the presence of increased insulin resistance in frail individuals. Such a mechanism would impact dynamic handling of nutrients more than stable baseline conditions. Both insulin levels and peak glucose levels were higher in physically frail women after a 2-hour oral glucose tolerance test, although the fasting levels had not been different (Kalyani et al., 2012; Goulet et al., 2009). Similarly, frail older adults who underwent a mixed meal test had a more exaggerated and prolonged glucose response than non-frail controls (Serra-Prat et al., 2009).  Although weight loss is associated with the development of physical frailty, in cross sectional studies, those with physical frailty are more like to be obese than non-frail individuals (Hubbard et al., 2010).

Insulin resistance may in fact be a risk factor for frailty. In the Women’s Health and Aging Study, older women who at baseline were in the highest A1C category (≥8%) had a 3-fold greater risk of developing frailty during follow up compared to otherwise similar women the lowest A1C category (<5.5%) (Blaum et al., 2009).   

Research should consider the potential for bidirectional interactions between insulin resistance and frailty. For example, frail older adults have a higher burden of inflammatory markers that may impact glucose metabolism by changing adipose function. High blood glucose levels may, in turn, further activate pathways that cause muscle catabolism, worsening the declines in grip strength and gait speed which are key features of physical frailty. 

Applying Knowledge of Frailty to Treatment of Diabetes  

The multifactorial nature of this relationship suggests that interventions on either side may improve both. Future studies are needed to investigate whether interventions that improve frailty status may also reduce the burden of diabetes and, conversely, whether glucose-lowering treatments may prevent frailty in older adults.

References:

  • Center for Disease Control. National Diabetes Statistics Report 2020: Estimates of Diabetes and Its Burdens in the United States
  • Cowie CC, et al Full accounting of diabetes and pre-diabetes in the U.S. population in 1988–1994 and 2005–2006 Diabetes Care 2009: 32:287–294
  • J. Walston, M.A. McBurnie, A. Newman, et al., Cardiovascular Health Study. Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study. Arch Intern Med, 162 (2002), pp. 2333-2341
  • J.I. Barzilay, C. Blaum, T. Moore, et al. Insulin resistance and inflammation as precursors of frailty: the Cardiovascular Health Study. Arch Intern Med, 167 (2007), pp. 635-641
  • R.R. Kalyani, R. Varadhan, C.O. Weiss, et al. Frailty Status and Altered Glucose-Insulin Dynamics. J Gerontol A Biol Sci Med Sci. 2012 Dec;67(12):1300-6. doi: 10.1093/gerona/glr141
  • E.D. Goulet, A. Hassaine, I.J. Dionne, et al. Frailty in the elderly is associated with insulin resistance of glucose metabolism in the postabsorptive state only in the presence of increased abdominal fat. Exp Gerontol, 44 (2009), pp. 740-744
  • M. Serra-Prat, E. Palomera, P. Clave, et al. Effect of age and frailty on ghrelin and cholecystokinin responses to a meal test. Am J Clin Nutr, 89 (2009), pp. 1410-1417
  • R.E. Hubbard, I.A. Lang, D.J. Llewellyn, et al. Frailty, body mass index, and abdominal obesity in older people. J Gerontol A Biol Sci Med Sci, 65 (2010), pp. 377-381
  • C.S. Blaum, Q.L. Xue, J. Tian, et al. Is hyperglycemia associated with frailty status in older women? J Am Geriatr Soc, 57 (2009), pp. 840-847.