Unravelling the frailty syndrome in diabetes
Authors: Alan J Sinclair, Ahmed H Abdelhafiz
Journal: The Lancet Healthy Longevity (2021)

Worldwide, the prevalence of diabetes is increasing, particularly in older people due to increased life expectancy.1Sinclair A Saeedi P Kaundal A Karuranga S Malanda B Williams R Diabetes and global ageing among 65-99-year-old adults: findings from the International Diabetes Federation Diabetes Atlas, 9th edition.Diabetes Res Clin Pract. 2020; 162108078Summary Full Text Full Text PDF PubMed Scopus (126) Google Scholar In older people, frailty is an emerging and high impact complication of diabetes.2Sinclair AJ Abdelhafiz AH Rodríguez-Mañas L Frailty and sarcopenia—newly emerging and high impact complications of diabetes.J Diabetes Complications. 2017; 31: 1465-1473Crossref PubMed Scopus (123) Google Scholar Frailty is a dynamic state of reduced physiological reserve that increases vulnerability to adverse health outcomes including mortality.3Hanlon P Fauré I Corcoran N et al.Frailty measurement, prevalence, incidence, and clinical implications in people with diabetes: a systematic review and study-level meta-analysis.Lancet Healthy Longev. 2020; 1: e106-e116Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar Therefore, the importance of frailty is increasingly recognised in the clinical guidelines of diabetes management in older people, but recommendations are broad and non-specific because they do not distinguish sufficiently between frailty severity or other key features that might influence clinical benefit.4Sinclair AJ Abdelhafiz A Dunning T et al.An international position statement on the management of frailty in diabetes mellitus: summary of recommendations 2017.J Frailty Aging. 2018; 7: 10-20PubMed Google Scholar, 5LeRoith D Biessels GJ Braithwaite SS et al.Treatment of diabetes in older adults: an Endocrine Society* clinical practice guideline.J Clin Endocrinol Metab. 2019; 104: 1520-1574Crossref PubMed Scopus (178) Google ScholarThe interaction between dysglycaemia (out of range blood glucose concentrations) and frailty is complex and unclear.3Hanlon P Fauré I Corcoran N et al.Frailty measurement, prevalence, incidence, and clinical implications in people with diabetes: a systematic review and study-level meta-analysis.Lancet Healthy Longev. 2020; 1: e106-e116Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar This is partially as a consequence of a paucity of literature investigating the relationship between dysglycaemia as a risk factor and frailty as an outcome. In The Lancet Healthy Longevity, Erik Fung and colleagues6Fung E Lui L-T Huang L et al.Characterising frailty, metrics of continuous glucose monitoring, and mortality hazards in older adults with type 2 diabetes on insulin therapy (HARE): a prospective, observational study.Lancet Healthy Longev. 2021; 2: e724-e735Summary Full Text Full Text PDF Scopus (2) Google Scholar have published a timely observational study that examined the interrelationship between dysglycaemia, frailty, and mortality among 215 community-living older adults with type 2 diabetes on insulin therapy and using continuous glucose monitoring (CGM). Fung and colleagues found that incremental frailty was associated with increased dysglycaemia, particularly hyperglycaemia rather than hypoglycaemia. In addition, severe hyperglycaemia, defined as level 2 time above range (TAR) of blood glucose concentration more than 13·9 mmol/L, increased the risk of mortality (although when adjusting for frailty, this relationship was weakened). After 28·0 months (IQR 25·3–30·4) of follow-up, the adjusted hazard ratio for mortality associated with level 2 TAR was 1·019 (95% CI 1·002–1·037). According to the authors, these findings position level 2 TAR as a clinically actionable and prognostic marker in the management of frail older adults with type 2 diabetes. However, it should be acknowledged that setting up CGM in routine, community-based clinical practice in older, frail individuals, particularly in care-home residents, is fraught with practical and logistical difficulties. Nevertheless, this work adds to the current literature in this area and reinforces the important conclusion that it is not just episodes of hyperglycaemia, but the increased proportion of time in severe hyperglycaemia that also increases the risk of frailty.Fung and colleagues6Fung E Lui L-T Huang L et al.Characterising frailty, metrics of continuous glucose monitoring, and mortality hazards in older adults with type 2 diabetes on insulin therapy (HARE): a prospective, observational study.Lancet Healthy Longev. 2021; 2: e724-e735Summary Full Text Full Text PDF Scopus (2) Google Scholar did not find an association between hypoglycaemia or time below range of blood glucose concentrations and frailty, but it can be speculated that this might be due in part to patients in the study being relatively young (median age 74 years [IQR 71–78]) and having a mild degree of frailty (based on their frailty index score), leaving a need for further exploration in those with severe frailty and older age. A previous longitudinal, population-based cohort study of people with new-onset type 2 diabetes (mean age 66 years) showed that hypoglycaemic episodes increase the risk of frailty by 44% (HR 1·443 [95% CI 1·01–2·05]),7Chao CT Wang J Huang JW Chan DC Chien KL Hypoglycemic episodes are associated with an increased risk of incident frailty among new onset diabetic patients.J Diabetes Complications. 2020; 34107492Crossref PubMed Scopus (12) Google Scholar and another study showed that glycated haemoglobin A1c (HbA1c) was inversely correlated with the clinical frailty scale (r=–0·31, p<0·01).8Yanagita I Fujihara Y Eda T et al.Low glycated hemoglobin level is associated with severity of frailty in Japanese elderly diabetes patients.J Diabetes Investig. 2018; 9: 419-425Crossref PubMed Scopus (24) Google Scholar Therefore, dysglycaemia in both directions (either low or high blood glucose) is likely to be a risk factor for frailty. A previous study by Zaslavsky and colleagues9Zaslavsky O Walker RL Crane PK Gray SL Larson EB Glucose levels and risk of frailty.J Gerontol A Biol Sci Med Sci. 2016; 71: 1223-1229Crossref PubMed Scopus (58) Google Scholar found a U-shaped relationship between blood glucose and frailty, with HbA1c of 7·6% associated with the lowest risk. Therefore, a glycaemic target of this range needs to be confirmed in future studies.Other challenges are associated with the definition of frailty syndrome itself and the complexity of its metabolic profile. Frailty is not a single homogeneous concept and the current tools or measures of assessment are not standardised and do not consider the metabolic side of frailty, which might have a substantial effect on how these patients are managed, particularly in regards to what type of glucose-lowering agent is best suited to optimise glycaemia and reduce cardiorenal risk. We have already hypothesised that frailty is a spectrum of different metabolic phenotypes, two of which seem to stand out.10Abdelhafiz AH Emmerton D Sinclair AJ Impact of frailty metabolic phenotypes on the management of older people with type 2 diabetes mellitus.Geriatr Gerontol Int. 2021; 21: 614-622Crossref PubMed Scopus (5) Google Scholar The first is a sarcopenic obese frail phenotype that is associated with hyperglycaemia (in which insulin resistance is high and GLP-1 receptor agonists and SGLT-2 inhibitors are likely to have benefits, and insulin treatment might not be desirable). The second is an anorexic malnourished frail phenotype that is associated with hypoglycaemia (in which GLP-1 receptor agonists and SGLT-2 inhibitors should be avoided because of further weight loss and dehydration, and any decision to use insulin would be a balance between its anabolic actions and the increased risk of hypoglycaemia).10Abdelhafiz AH Emmerton D Sinclair AJ Impact of frailty metabolic phenotypes on the management of older people with type 2 diabetes mellitus.Geriatr Gerontol Int. 2021; 21: 614-622Crossref PubMed Scopus (5) Google Scholar If our work on frailty metabolic phenotypes can be confirmed, it will partially explain why both dysglycaemic states (hyperglycaemia and hypoglycaemia) can be risk factors for frailty in general.Therefore, in future clinical intervention trials, more older people need to be included. However, inclusion should not just be based on age alone, but also on the presence and severity of frailty and its associated characteristics. This will allow a move away from recommendations for treatment based on expert opinion only and towards precision medicine. Worldwide, the prevalence of diabetes is increasing, particularly in older people due to increased life expectancy.1Sinclair A Saeedi P Kaundal A Karuranga S Malanda B Williams R Diabetes and global ageing among 65-99-year-old adults: findings from the International Diabetes Federation Diabetes Atlas, 9th edition.Diabetes Res Clin Pract. 2020; 162108078Summary Full Text Full Text PDF PubMed Scopus (126) Google Scholar In older people, frailty is an emerging and high impact complication of diabetes.2Sinclair AJ Abdelhafiz AH Rodríguez-Mañas L Frailty and sarcopenia—newly emerging and high impact complications of diabetes.J Diabetes Complications. 2017; 31: 1465-1473Crossref PubMed Scopus (123) Google Scholar Frailty is a dynamic state of reduced physiological reserve that increases vulnerability to adverse health outcomes including mortality.3Hanlon P Fauré I Corcoran N et al.Frailty measurement, prevalence, incidence, and clinical implications in people with diabetes: a systematic review and study-level meta-analysis.Lancet Healthy Longev. 2020; 1: e106-e116Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar Therefore, the importance of frailty is increasingly recognised in the clinical guidelines of diabetes management in older people, but recommendations are broad and non-specific because they do not distinguish sufficiently between frailty severity or other key features that might influence clinical benefit.4Sinclair AJ Abdelhafiz A Dunning T et al.An international position statement on the management of frailty in diabetes mellitus: summary of recommendations 2017.J Frailty Aging. 2018; 7: 10-20PubMed Google Scholar, 5LeRoith D Biessels GJ Braithwaite SS et al.Treatment of diabetes in older adults: an Endocrine Society* clinical practice guideline.J Clin Endocrinol Metab. 2019; 104: 1520-1574Crossref PubMed Scopus (178) Google Scholar The interaction between dysglycaemia (out of range blood glucose concentrations) and frailty is complex and unclear.3Hanlon P Fauré I Corcoran N et al.Frailty measurement, prevalence, incidence, and clinical implications in people with diabetes: a systematic review and study-level meta-analysis.Lancet Healthy Longev. 2020; 1: e106-e116Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar This is partially as a consequence of a paucity of literature investigating the relationship between dysglycaemia as a risk factor and frailty as an outcome. In The Lancet Healthy Longevity, Erik Fung and colleagues6Fung E Lui L-T Huang L et al.Characterising frailty, metrics of continuous glucose monitoring, and mortality hazards in older adults with type 2 diabetes on insulin therapy (HARE): a prospective, observational study.Lancet Healthy Longev. 2021; 2: e724-e735Summary Full Text Full Text PDF Scopus (2) Google Scholar have published a timely observational study that examined the interrelationship between dysglycaemia, frailty, and mortality among 215 community-living older adults with type 2 diabetes on insulin therapy and using continuous glucose monitoring (CGM). Fung and colleagues found that incremental frailty was associated with increased dysglycaemia, particularly hyperglycaemia rather than hypoglycaemia. In addition, severe hyperglycaemia, defined as level 2 time above range (TAR) of blood glucose concentration more than 13·9 mmol/L, increased the risk of mortality (although when adjusting for frailty, this relationship was weakened). After 28·0 months (IQR 25·3–30·4) of follow-up, the adjusted hazard ratio for mortality associated with level 2 TAR was 1·019 (95% CI 1·002–1·037). According to the authors, these findings position level 2 TAR as a clinically actionable and prognostic marker in the management of frail older adults with type 2 diabetes. However, it should be acknowledged that setting up CGM in routine, community-based clinical practice in older, frail individuals, particularly in care-home residents, is fraught with practical and logistical difficulties. Nevertheless, this work adds to the current literature in this area and reinforces the important conclusion that it is not just episodes of hyperglycaemia, but the increased proportion of time in severe hyperglycaemia that also increases the risk of frailty. Fung and colleagues6Fung E Lui L-T Huang L et al.Characterising frailty, metrics of continuous glucose monitoring, and mortality hazards in older adults with type 2 diabetes on insulin therapy (HARE): a prospective, observational study.Lancet Healthy Longev. 2021; 2: e724-e735Summary Full Text Full Text PDF Scopus (2) Google Scholar did not find an association between hypoglycaemia or time below range of blood glucose concentrations and frailty, but it can be speculated that this might be due in part to patients in the study being relatively young (median age 74 years [IQR 71–78]) and having a mild degree of frailty (based on their frailty index score), leaving a need for further exploration in those with severe frailty and older age. A previous longitudinal, population-based cohort study of people with new-onset type 2 diabetes (mean age 66 years) showed that hypoglycaemic episodes increase the risk of frailty by 44% (HR 1·443 [95% CI 1·01–2·05]),7Chao CT Wang J Huang JW Chan DC Chien KL Hypoglycemic episodes are associated with an increased risk of incident frailty among new onset diabetic patients.J Diabetes Complications. 2020; 34107492Crossref PubMed Scopus (12) Google Scholar and another study showed that glycated haemoglobin A1c (HbA1c) was inversely correlated with the clinical frailty scale (r=–0·31, p<0·01).8Yanagita I Fujihara Y Eda T et al.Low glycated hemoglobin level is associated with severity of frailty in Japanese elderly diabetes patients.J Diabetes Investig. 2018; 9: 419-425Crossref PubMed Scopus (24) Google Scholar Therefore, dysglycaemia in both directions (either low or high blood glucose) is likely to be a risk factor for frailty. A previous study by Zaslavsky and colleagues9Zaslavsky O Walker RL Crane PK Gray SL Larson EB Glucose levels and risk of frailty.J Gerontol A Biol Sci Med Sci. 2016; 71: 1223-1229Crossref PubMed Scopus (58) Google Scholar found a U-shaped relationship between blood glucose and frailty, with HbA1c of 7·6% associated with the lowest risk. Therefore, a glycaemic target of this range needs to be confirmed in future studies. Other challenges are associated with the definition of frailty syndrome itself and the complexity of its metabolic profile. Frailty is not a single homogeneous concept and the current tools or measures of assessment are not standardised and do not consider the metabolic side of frailty, which might have a substantial effect on how these patients are managed, particularly in regards to what type of glucose-lowering agent is best suited to optimise glycaemia and reduce cardiorenal risk. We have already hypothesised that frailty is a spectrum of different metabolic phenotypes, two of which seem to stand out.10Abdelhafiz AH Emmerton D Sinclair AJ Impact of frailty metabolic phenotypes on the management of older people with type 2 diabetes mellitus.Geriatr Gerontol Int. 2021; 21: 614-622Crossref PubMed Scopus (5) Google Scholar The first is a sarcopenic obese frail phenotype that is associated with hyperglycaemia (in which insulin resistance is high and GLP-1 receptor agonists and SGLT-2 inhibitors are likely to have benefits, and insulin treatment might not be desirable). The second is an anorexic malnourished frail phenotype that is associated with hypoglycaemia (in which GLP-1 receptor agonists and SGLT-2 inhibitors should be avoided because of further weight loss and dehydration, and any decision to use insulin would be a balance between its anabolic actions and the increased risk of hypoglycaemia).10Abdelhafiz AH Emmerton D Sinclair AJ Impact of frailty metabolic phenotypes on the management of older people with type 2 diabetes mellitus.Geriatr Gerontol Int. 2021; 21: 614-622Crossref PubMed Scopus (5) Google Scholar If our work on frailty metabolic phenotypes can be confirmed, it will partially explain why both dysglycaemic states (hyperglycaemia and hypoglycaemia) can be risk factors for frailty in general. Therefore, in future clinical intervention trials, more older people need to be included. However, inclusion should not just be based on age alone, but also on the presence and severity of frailty and its associated characteristics. This will allow a move away from recommendations for treatment based on expert opinion only and towards precision medicine. We declare no competing interests in the preparation of this work and received no funding to undertake it. Characterising frailty, metrics of continuous glucose monitoring, and mortality hazards in older adults with type 2 diabetes on insulin therapy (HARE): a prospective, observational cohort studyIn older adults with type 2 diabetes who are on insulin therapy, incremental frailty was associated with increased dysglycaemia and hyperglycaemia rather than hypoglycaemia. Mortality hazard was increased with severe hyperglycaemia. Future clinical studies and trials targeting actionable CGM metrics highlighted in this study could translate into improved care and outcomes. Full-Text PDF Open Access