Response rates and associated factors after a multicomponent intervention in frail older adults with diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and frailty are associated with functional decline in older population. OBJECTIVE: To explore the individual response to a multimodal intervention on functional performance. DESIGN: A cluster-randomised multicentre clinical trial. SETTING: Outpatients in hospital or primary care. SUBJECTS: 843 (77.83 years, 50.65% men) prefrail and frail individuals ≥70 years with T2DM. METHODS: Participants were allocated to usual care group (UCG) or a multicomponent intervention group (IG): 16-week progressive resistance training, seven nutritional and diabetological educational sessions and achievement of glycated haemoglobin (7-8%) and blood pressure (<150 mmHg) targets. Functional performance was assessed with the Short Physical Performance Battery (SPPB) at 1 year. We used multivariate binomial and multinomial logistic regression models to explore the effect of the IG, and adherence on the outcomes studied, in several adjusted models. RESULTS: 53.7% in the IG versus 38.0% in the UCG improved by at least 1 point in their SPPB score [OR (95% CI): 2.07 (1.43, 2.98), P value <0.001]. Age, SPPB score and number of frailty criteria met decreased the probability of improving the SPPB score. Factors associated with worsening were pertaining to IG (decreased), age, SPPB score and the number of frailty criteria (increased). An adherence ≥84% was needed to achieve benefits, reaching the peak in the probability of improving SPPB when this was ≥85% [OR(95%CI): 2.38 (1.29, 4.79), P value 0.014]. CONCLUSIONS: Factors predicting the likelihood of improvement in a multimodal programme in pre-frail and frail older adults with diabetes are age, basal SPPB score, the number of frailty criteria and adherence.

Impact of deintensifying hypoglycaemic drugs in older adults with type 2 diabetes: protocol for an emulation of a target trial.

INTRODUCTION: In older adults with type 2 diabetes (T2D), overtreatment with hypoglycaemic drugs (HDs: sulfonylureas, glinides and/or insulins) is frequent and associated with increased 1-year mortality. Deintensification of HD is thus a key issue, for which evidence is though limited. The primary objective of this study will be to estimate the effect of deintensifying HD on clinical outcomes (hospital admission or death) within 3 months in older adults (≥75 years) with T2D. METHODS: We will emulate with real-world data a target trial, within The Health Improvement Network cohort, a large-scale database of data collected from electronic medical records of 2000 general practitioners in France. From 1 January 2010 to 28 February 2019, we will include eligible patients ≥75 years who will have T2D, a stable dose of HDs, glycated haemoglobin A1c (HbA1c) value <75 mmol/mol (9.0%) and no deintensification in the past year. The target trial will be sequentially emulated (ie, eligibility assessed) every month in the database. Patients will be classified at baseline of each sequential trial in the intervention arm (deintensification of HDs: decrease of ≥50% in the total dose of HDs, including complete cessation) or control arm (no deintensification of HDs). The pooled dataset for all sequential emulated trials will be analysed. The primary outcome will be time to first occurrence of hospital admission or death, within 3 months. Secondary outcomes will be hospitalisation, death, appropriateness of glycaemic control and occurrence of HbA1c >75 mmol/mol within 1 year. Participants will be followed from baseline to 12 months after randomisation, administrative censoring, or death, whichever occurs first. A pooled logistic regression will be used to estimate the treatment effect on the incidence of the outcomes. DISSEMINATION AND ETHICS: No ethical approval is needed for using retrospectively this fully anonymised database. The results will be disseminated during conferences and through publications in scientific journals.

Metabolic Characteristics of Frail Older People with Diabetes Mellitus-A Systematic Search for Phenotypes.

Frailty in older people with diabetes is viewed as one homogeneous category. We previously suggested that frailty is not homogeneous and spans across a metabolic spectrum that starts with an anorexic malnourished (AM) frail phenotype and ends with a sarcopenic obese (SO) phenotype. We aimed to investigate the metabolic characteristics of frail older people with diabetes reported in the current literature to explore whether they fit into two distinctive metabolic phenotypes. We performed systematic review of studies published over the last 10 years and reported characteristics of frail older people with diabetes mellitus. A total of 25 studies were included in this systematic review. Fifteen studies reported frail patients' characteristics that could fit into an AM phenotype. This phenotype is characterised by low body weight, increased prevalence of malnutrition markers such as low serum albumin, low serum cholesterol, low Hb, low HbA1c, and increased risk of hypoglycaemia. Ten studies reported frail patients' characteristics that describe a SO phenotype. This phenotype is characterised by increased body weight, increased serum cholesterol, high HbA1c, and increased blood glucose levels. Due to significant weight loss in the AM phenotype, insulin resistance decreases, leading to a decelerated diabetes trajectory and reduced hypoglycaemic agent use or deintensification of therapy. On the other hand, in the SO phenotype, insulin resistance increases leading to accelerated diabetes trajectory and increased hypoglycaemic agent use or intensification of therapy. Current literature suggests that frailty is a metabolically heterogeneous condition that includes AM and SO phenotypes. Both phenotypes have metabolically distinctive features, which will have a different effect on diabetes trajectory. Therefore, clinical decision-making and future clinical studies should consider the metabolic heterogeneity of frailty.

Amino Acid Profiles in Older Adults with Frailty: Secondary Analysis from MetaboFrail and BIOSPHERE Studies.

An altered amino acid metabolism has been described in frail older adults which may contribute to muscle loss and functional decline associated with frailty. In the present investigation, we compared circulating amino acid profiles of older adults with physical frailty and sarcopenia (PF&S, n = 94), frail/pre-frail older adults with type 2 diabetes mellitus (F-T2DM, n = 66), and robust non-diabetic controls (n = 40). Partial least squares discriminant analysis (PLS-DA) models were built to define the amino acid signatures associated with the different frailty phenotypes. PLS-DA allowed correct classification of participants with 78.2 ± 1.9% accuracy. Older adults with F-T2DM showed an amino acid profile characterized by higher levels of 3-methylhistidine, alanine, arginine, ethanolamine, and glutamic acid. PF&S and control participants were discriminated based on serum concentrations of aminoadipic acid, aspartate, citrulline, cystine, taurine, and tryptophan. These findings suggest that different types of frailty may be characterized by distinct metabolic perturbations. Amino acid profiling may therefore serve as a valuable tool for frailty biomarker discovery.

Metabolic Impact of Frailty Changes Diabetes Trajectory.

Diabetes mellitus prevalence increases with increasing age. In older people with diabetes, frailty is a newly emerging and significant complication. Frailty induces body composition changes that influence the metabolic state and affect diabetes trajectory. Frailty appears to have a wide metabolic spectrum, which can present with an anorexic malnourished phenotype and a sarcopenic obese phenotype. The sarcopenic obese phenotype individuals have significant loss of muscle mass and increased visceral fat. This phenotype is characterised by increased insulin resistance and a synergistic increase in the cardiovascular risk more than that induced by obesity or sarcopenia alone. Therefore, in this phenotype, the trajectory of diabetes is accelerated, which needs further intensification of hypoglycaemic therapy and a focus on cardiovascular risk reduction. Anorexic malnourished individuals have significant weight loss and reduced insulin resistance. In this phenotype, the trajectory of diabetes is decelerated, which needs deintensification of hypoglycaemic therapy and a focus on symptom control and quality of life. In the sarcopenic obese phenotype, the early use of sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists is reasonable due to their weight loss and cardio-renal protection properties. In the malnourished anorexic phenotype, the early use of long-acting insulin analogues is reasonable due to their weight gain and anabolic properties, regimen simplicity and the convenience of once-daily administration.

Overtreatment of older people with type 2 diabetes-a high impact frequent occurrence in need of a new definition.

BACKGROUND: Diabetes overtreatment is a frequent and major issue in older people with type 2 diabetes but its definition is often inconsistent and may be misleading. This critical review has aimed at examining the definitions of diabetes overtreatment in older people used in research studies. METHODS: Studies addressing diabetes overtreatment in people aged 65 or older were identified by searching the PubMed database according to an extensive search equation. RESULTS: Twenty-two research studies providing a definition of diabetes overtreatment in people aged were found. Overall, 12 different definitions of diabetes overtreatment were used. All studies defined overtreatment according to a HbA1c threshold (varying from <42 mmol/mol [<6.0%] to <64 mmol/mol [<8%]). Amongst them, 2 definitions had no consideration about glucose-lowering (GL) treatment, 6 required the prescribing of ≥1 GL agent(s), and 4 the prescribing of ≥1 GL agent(s) inducing the high risk of hypoglycaemia (i.e., sulfonylurea(s) or insulin(s)). Only 4 definitions (four studies) were individualised, using varying HbA1c thresholds according to patients' age or health status. CONCLUSIONS: Definitions of diabetes overtreatment are heterogeneous across research studies, which is confusing. A standardised definition, based on the individual risk of hypoglycaemia and/or its complications must be promoted in order to bring clarity and greater insight into this field, as well as to improve the quality of management of diabetes in older patients.

Multimorbidity, Frailty and Diabetes in Older People-Identifying Interrelationships and Outcomes.

Multimorbidity and frailty are highly prevalent in older people with diabetes. This high prevalence is likely due to a combination of ageing and diabetes-related complications and other diabetes-associated comorbidities. Both multimorbidity and frailty are associated with a wide range of adverse outcomes in older people with diabetes, which are proportionally related to the number of morbidities and to the severity of frailty. Although, the multimorbidity pattern or cluster of morbidities that have the most adverse effect are not yet well defined, it appears that mental health disorders enhance the multimorbidity-related adverse outcomes. Therefore, comprehensive diabetes guidelines that incorporate a holistic approach that includes screening and management of mental health disorders such as depression is required. The adverse outcomes predicted by multimorbidity and frailty appear to be similar and include an increased risk of health care utilisation, disability and mortality. The differential effect of one condition on outcomes, independent of the other, still needs future exploration. In addition, prospective clinical trials are required to investigate whether interventions to reduce multimorbidity and frailty both separately and in combination would improve clinical outcomes.

Hypoglycaemic therapy in frail older people with type 2 diabetes mellitus-a choice determined by metabolic phenotype.

Frailty is a newly emerging complication of diabetes in older people and increasingly recognised in national and international clinical guidelines. However, frailty remains less clearly defined and frail older people with diabetes are rarely characterised. The general recommendation of clinical guidelines is to aim for a relaxed glycaemic control, mainly to avoid hypoglycaemia, in this often-vulnerable group of patients. With increasing age and development of frailty, body composition changes are characterised by an increase in visceral adipose tissue and a decrease in body muscle mass. Depending on the overall body weight, differential loss of muscle fibre types and body adipose/muscle tissue ratio, the presence of any associated frailty can be seen as a spectrum of metabolic phenotypes that vary in insulin resistance of which we have defined two specific phenotypes. The sarcopenic obese (SO) frail phenotype with increased visceral fat and increased insulin resistance on one side of spectrum and the anorexic malnourished (AM) frail phenotype with significant muscle loss and reduced insulin resistance on the other. In view of these varying metabolic phenotypes, the choice of hypoglycaemic therapy, glycaemic targets and overall goals of therapy are likely to be different. In the SO phenotype, weight-limiting hypoglycaemic agents, especially the new agents of GLP-1RA and SGLT-2 inhibitors, should be considered early on in therapy due to their benefits on weight reduction and ability to achieve tight glycaemic control where the focus will be on the reduction of cardiovascular risk. In the AM phenotype, weight-neutral agents or insulin therapy should be considered early on due to their benefits of limiting further weight loss and the possible anabolic effects of insulin. Here, the goals of therapy will be a combination of relaxed glycaemic control and avoidance of hypoglycaemia; and the focus will be on maintenance of a good quality of life. Future research is still required to develop novel hypoglycaemic agents with a positive effect on body composition in frailty and improvements in clinical outcomes.

Multicomponent intervention to prevent mobility disability in frail older adults: randomised controlled trial (SPRINTT project).

OBJECTIVE: To determine whether a multicomponent intervention based on physical activity with technological support and nutritional counselling prevents mobility disability in older adults with physical frailty and sarcopenia. DESIGN: Evaluator blinded, randomised controlled trial. SETTING: 16 clinical sites across 11 European countries, January 2016 to 31 October 2019. PARTICIPANTS: 1519 community dwelling men and women aged 70 years or older with physical frailty and sarcopenia, operationalised as the co-occurrence of low functional status, defined as a short physical performance battery (SPPB) score of 3 to 9, low appendicular lean mass, and ability to independently walk 400 m. 760 participants were randomised to a multicomponent intervention and 759 received education on healthy ageing (controls). INTERVENTIONS: The multicomponent intervention comprised moderate intensity physical activity twice weekly at a centre and up to four times weekly at home. Actimetry data were used to tailor the intervention. Participants also received personalised nutritional counselling. Control participants received education on healthy ageing once a month. Interventions and follow-up lasted for up to 36 months. MAIN OUTCOME MEASURES: The primary outcome was mobility disability (inability to independently walk 400 m in <15 minutes). Persistent mobility disability (inability to walk 400 m on two consecutive occasions) and changes from baseline to 24 and 36 months in physical performance, muscle strength, and appendicular lean mass were analysed as pre-planned secondary outcomes. Primary comparisons were conducted in participants with baseline SPPB scores of 3-7 (n=1205). Those with SPPB scores of 8 or 9 (n=314) were analysed separately for exploratory purposes. RESULTS: Mean age of the 1519 participants (1088 women) was 78.9 (standard deviation 5.8) years. The average follow-up was 26.4 (SD 9.5) months. Among participants with SPPB scores of 3-7, mobility disability occurred in 283/605 (46.8%) assigned to the multicomponent intervention and 316/600 (52.7%) controls (hazard ratio 0.78, 95% confidence interval 0.67 to 0.92; P=0.005). Persistent mobility disability occurred in 127/605 (21.0%) participants assigned to the multicomponent intervention and 150/600 (25.0%) controls (0.79, 0.62 to 1.01; P=0.06). The between group difference in SPPB score was 0.8 points (95% confidence interval 0.5 to 1.1 points; P<0.001) and 1.0 point (95% confidence interval 0.5 to 1.6 points; P<0.001) in favour of the multicomponent intervention at 24 and 36 months, respectively. The decline in handgrip strength at 24 months was smaller in women assigned to the multicomponent intervention than to control (0.9 kg, 95% confidence interval 0.1 to 1.6 kg; P=0.028). Women in the multicomponent intervention arm lost 0.24 kg and 0.49 kg less appendicular lean mass than controls at 24 months (95% confidence interval 0.10 to 0.39 kg; P<0.001) and 36 months (0.26 to 0.73 kg; P<0.001), respectively. Serious adverse events occurred in 237/605 (39.2%) participants assigned to the multicomponent intervention and 216/600 (36.0%) controls (risk ratio 1.09, 95% confidence interval 0.94 to 1.26). In participants with SPPB scores of 8 or 9, mobility disability occurred in 46/155 (29.7%) in the multicomponent intervention and 38/159 (23.9%) controls (hazard ratio 1.25, 95% confidence interval 0.79 to 1.95; P=0.34). CONCLUSIONS: A multicomponent intervention was associated with a reduction in the incidence of mobility disability in older adults with physical frailty and sarcopenia and SPPB scores of 3-7. Physical frailty and sarcopenia may be targeted to preserve mobility in vulnerable older people. TRIAL REGISTRATION: ClinicalTrials.gov NCT02582138.

The ability of eight frailty instruments to identify adverse outcomes across different settings: the FRAILTOOLS project.

BACKGROUND: To compare the performance of eight frailty instruments to identify relevant adverse outcomes for older people across different settings over a 12 month follow-up. METHODS: Observational longitudinal prospective study of people aged 75 + years enrolled in different settings (acute geriatric wards, geriatric clinic, primary care clinics, and nursing homes) across five European cities. Frailty was assessed using the following: Frailty Phenotype, SHARE-FI, 5-item Frailty Trait Scale (FTS-5), 3-item FTS (FTS-3), FRAIL scale, 35-item Frailty Index (FI-35), Gérontopôle Frailty Screening Tool, and Clinical Frailty Scale. Adverse outcomes ascertained at follow-up were as follows: falls, hospitalization, increase in limitation in basic (BADL) and instrumental activities of daily living (IADL), and mortality. Sensitivity, specificity, and capacity to predict adverse outcomes in logistic regressions by each instrument above age, gender, and multimorbidity were calculated. RESULTS: A total of 996 individuals were followed (mean age 82.2 SD 5.5 years, 61.3% female). In geriatric wards, the FI-35 (69.1%) and the FTS-5 (67.9%) showed good sensitivity to predict death and good specificity to predict BADL worsening (70.3% and 69.8%, respectively). The FI-35 also showed good sensitivity to predict BADL worsening (74.6%). In nursing homes, the FI-35 and the FTSs predicted mortality and BADL worsening with a sensitivity > 73.9%. In geriatric clinic, the FI-35, the FTS-5, and the FRAIL scale obtained specificities > 85% to predict BADL worsening. No instrument achieved high enough sensitivity nor specificity in primary care. All the instruments predict the risk for all the outcomes in the whole sample after adjusting for age, gender, and multimorbidity. The associations of these instruments that remained significant by setting were for BADL worsening in geriatric wards [FI-35 OR = 5.94 (2.69-13.14), FTS-3 = 3.87 (1.76-8.48)], nursing homes [FI-35 = 4.88 (1.54-15.44), FTS-5 = 3.20 (1.61-6.38), FTS-3 = 2.31 (1.27-4.21), FRAIL scale = 1.91 (1.05-3.48)], and geriatric clinic [FRAIL scale = 4.48 (1.73-11.58), FI-35 = 3.30 (1.55-7.00)]; for IADL worsening in primary care [FTS-5 = 3.99 (1.14-13.89)] and geriatric clinic [FI-35 = 3.42 (1.56-7.49), FRAIL scale = 3.27 (1.21-8.86)]; for hospitalizations in primary care [FI-35 = 3.04 (1.25-7.39)]; and for falls in geriatric clinic [FI-35 = 2.21 (1.01-4.84)]. CONCLUSIONS: No single assessment instrument performs the best for all settings and outcomes. While in inpatients several commonly used frailty instruments showed good sensitivities (mainly for mortality and BADL worsening) but usually poor specificities, the contrary happened in geriatric clinic. None of the instruments showed a good performance in primary care. The FI-35 and the FTS-5 showed the best profile among the instruments assessed.

A Therapeutic Vibrating Insole Device for Postural Instability in Older People with Type 2 Diabetes: A Randomized Control Study.

INTRODUCTION: Frail older people with diabetes often present with or develop walking impairments, in part due to lower-limb sensory-motor neuropathy. Several studies suggest a possible improvement of balance control using somatosensory stimulation. We undertook a novel randomized control trial, the aim of which was to observe whether use of this device for 1 month improves walking speed as measured in the 10-m fast walking speed test standardized to body size at month 1 (M1) (FWS). Secondary outcomes were the differences between intervention (VS) and control (C) in the 10-m normal walking speed test, step length, short physical performance battery, timed up and go test, and posturographic measures. METHODS: Subjects were aged ≥ 70 years and had had type 2 diabetes for at least 2 years. The intervention (VS) at home consisted of 22-min daily vibrating sequences with noise intensity set at 90% of the tactile threshold for each foot. The same device was used in group C but noise was set to 0. Compliance was retrieved from the device. RESULTS: Among 56 subjects, 27 were in the VS group and 29 in the C group; 35 subjects were frail, 15 were prefrail ,and 6 were non-frail. Bilateral neuropathy was present in 17 subjects. More than half of sessions were done in 36 subjects with no discernible difference according to intervention. At M1 there were no discernible differences in FWS between the groups [VS: 0.96 (0.53) cm s-1 cm-1, C: 0.94 (0.47) cm s-1 cm-1]. There were also no discernible differences in other outcomes, irrespective of the presence of bilateral neuropathy. CONCLUSION: In a cohort of frail, prefrail, or non-frail older subjects with diabetes, a 1-month intervention using a vibrating insole device did not alter measures of walking speed and related measures. Larger studies with longer term and different stimulation protocols are required to test this hypothesis more fully.

Dual effects of insulin resistance on mortality and function in non-diabetic older adults: findings from the Toledo Study of Healthy Aging.

Insulin signalling declines with increasing age and impacts skeletal muscle function and longevity in animal models. Our aim was to assess the relationships between insulin resistance (IR) and frailty and mortality in a unique community-dwelling cohort of older people. 991 non-diabetic subjects from the Toledo Study of Healthy Ageing (TSHA) cohort were included. IR was estimated by the homeostasis model assessment index (HOMA-IR) at baseline while frailty was determined by frailty phenotype (FP) and Frailty Trait Scale (FTS) at baseline and after 5-year follow-up. Deaths were also determined. Multivariate regression models were used to analyze the effects of HOMA-IR on outcomes. Age, gender, BMI, education level, cardio- and cerebro-vascular disease, glomerular filtration rate, and disability were included as potential confounding variables in progressive adjustment models. IR determined as increasing log HOMA-IR was inversely associated with risk of mortality. The association remained significant for all adjustment models (HR: 0.64-0.69). When we analyzed survival curves, the higher the HOMA-IR tertile, the lower the mortality rate (highest vs lowest tertile, p = 0.0082). In contrast, IR increased the risk of incident frailty determined by FP (OR 1.81 [1.14-2.87]) as well as deterioration of frailty status determined by worsening in FTS score (OR 1.28 [1.01-1.63]) at 5-year follow-up. In non-diabetic older subjects, IR significantly increases the risk for frailty and functional decline but decreased the risk of death at 5-year follow-up. This finding raises the need of assessing the effect of biomarkers on different outcomes before establishing their role as biomarkers of aging.

Two-Year Follow-up of a Multimodal Intervention on Functional Capacity and Muscle Power in Frail Patients With Type 2 Diabetes.

OBJECTIVES: To analyze the effects of a program composed of resistance training and nutritional interventions on functional capacity, maximal strength, and power output after 2 years of follow-up, including 2 periods of 16 weeks of intervention followed by several weeks of intervention cessation in frail patients with type 2 diabetes. DESIGN: MIDPOW is a substudy of a multicenter, multimodal intervention composed of resistance training combined with a structured diabetes and nutritional education program in frail and prefrail older people with type 2 diabetes (MID-Frail). SETTING AND PARTICIPANTS: This study recruited 52 participants (mean age: 79 ± 5.6, 63% women), with type 2 diabetes mellitus, frail or prefrail using Fried's frailty phenotype. METHODS: Primary outcomes of this substudy were Short Physical Performance Battery (SPPB) and maximal power output at 30% and 80% of 1RM. RESULTS: Each set of 16 weeks of intervention resulted in significant improvements in SPPB performance by a mean of 36.1% at week 18 (P < .001) and 10.2% at week 68 (P < .05). Maximal power output improvements at 30% and 80% of the 1RM ranged from 45.2% to 57.2% at week 18 (P < .01-.001); and no significant changes were observed after the second period of intervention. After 2 years of follow-up, the SPPB and maximal power values observed remained significantly higher than the baseline. CONCLUSIONS AND IMPLICATIONS: Resistance training combined with nutritional program improved SPPB, maximal strength, and power output in older frail patients with diabetes. These improvements were maintained above the basal levels after several weeks of intervention cessation during a 2-year follow-up.

Impact of frailty metabolic phenotypes on the management of older people with type 2 diabetes mellitus.

AIMS: To provide a pathophysiological basis for distinguishing metabolic variants of the frailty phenotype in older adults with type 2 diabetes. METHODS: We have made an in-depth review of the possible mechanisms in diabetes, ageing and frailty that will alter allow us to describe phenotypic changes which might assist in predicting responses to particular glucose-lowering therapy. RESULTS: Our review has enable us to describe with some confidence a sarcopenic obese phenotype and an anorexic malnourished phenotype. CONCLUSIONS: By identifying these two phenotypes we can predict which would be most responsive to certain classes of therapy and where therapies may be ill-advised. This represents the first novel approach in this area. Further work is being planned to develop this hypothesis. Geriatr Gerontol Int 2021; 21: 614-622.