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Diabetes increases the risk of physical dysfunction and disability. Diabetes-related complications and coexisting morbidities partially explain the deterioration in physical function. The decline in muscle mass, strength and function associated with diabetes leads to sarcopenia, frailty and eventually disability. Frailty acts as a mediator in the pathogenesis of disability in older people with diabetes and its measurement in routine daily practice is recommended. Frailty is a dynamic process which progresses from a robust condition to a pre-frail stage then frailty and eventually disability. Therefore, a multimodal intervention which includes adequate nutrition, exercise training, good glycaemic control and the use of appropriate hypoglycemic medications may help delay or prevent the progression to disability. •This review addresses two key emerging complications in diabetes – frailty and sarcopenia. We know that diabetes increases the risk of physical dysfunction and disability but up to now, many have considered these outcomes due to the combined effects of micro- and macro-vascular complications. It is now becoming increasingly clear that such traditional diabetes-related complications and coexisting morbidities only partially explain the deterioration in physical function, and that frailty and underlying sarcopenia may be important in this decline in performance.•We provide an up to date and innovative approach to examining these issues and provide practical clinical guidance on assessment and management of these complications in a setting of diabetes in older adults.

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.

Background: Frailty is an increasingly recognised complication of diabetes in older people and should be taken into consideration in management plans, including the use of the new therapies of sodium glucose cotransporter-2 (SGLT-2) inhibitors and glucagon like peptide-1 receptor agonists (GLP-1RA). The frailty syndrome appears to span across a spectrum, from a sarcopenic obese phenotype at one end, characterised by obesity, insulin resistance, and prevalent cardiovascular risk factors, to an anorexic malnourished phenotype at the other end, characterised by significant weight loss, reduced insulin resistance, and less prevalent cardiovascular risk factors. Therefore, the use of the new therapies may not be suitable for every frail older individual with diabetes. Objectives: To review the characteristics and phenotype of frail older people with diabetes who should benefit from the use of SGLT-2 inhibitors or GLP-1RA. Methods: A narrative review of the studies investigating the benefits of SGLT-2 inhibitors and GLP-1RA in frail older people with diabetes. Results: The current evidence is indirect, and the literature suggests that the new therapies are effective in frail older people with diabetes and the benefit appears to be proportional with the severity of frailty. However, frail patients described in the literature who benefited from such therapy appeared to be either overweight or obese, and to have a higher prevalence of unfavourable metabolism and cardiovascular risk factors such as dyslipidaemia, gout, and hypertension compared to non-frail subjects. They also have a higher prevalence of established cardiovascular disease compared with non-frail individuals. In absolute terms, their higher cardiovascular baseline risk meant that they benefited the most from such therapy. The characteristics of this group of frail patients fulfil the criteria of the sarcopenic obese frailty phenotype, which is likely to benefit most from the new therapies due to the unfavourable metabolic profile of this phenotype. There is no current evidence to suggest the benefit of the new therapies in the anorexic malnourished phenotype, which is underrepresented or totally excluded from these studies, such as in patients living in care homes. This phenotype is likely to be intolerant to such therapy due to its associated risk of inducing further weight loss, dehydration, and hypotension. Conclusions: Clinicians should consider the early use of the new therapies in frail older people with diabetes who are either of normal weight, overweight, or obese with prevalent cardiovascular risk factors, and avoid their use in those frail subjects who ae underweight, anorexic, and malnourished.

Advancing age is associated with albuminuria and vascular changes. This review will explore the putative links between the two. Vascular ageing involves endothelial dysfunction as well as increased arterial diameter, wall thickness and stiffness, ultimately leading to arterial sclerosis. This process is accelerated by a defective vascular repair process. Endothelial dysfunction is likely to be involved in the initiation and development of microalbuminuria. It is often followed by the development and progression of atherosclerosis. Initially, microalbuminuria is reversible but becomes fixed with the progression of vascular structural changes including glomerulosclerosis. The prevalence of microalbuminuria increases with age and has been shown to be a marker of widespread microvasculopathy at various levels including cerebral, cardiac and renal microcirculations. This has been linked to endpoint clinical events, with microalbuminuria increasing the risk of cognitive impairment and strokes, cardiovascular disease outcomes, and progression to end-stage renal failure. Evidence of microvascular damage such as microalbuminuria associated with increased cardiovascular risk may suggest that microvascular damage and dysfunction predate overt macrovascular disease. Microalbuminuria and reduced glomerular filtration rate (GFR) may be markers of different pathologic processes. It is likely that microalbuminuria and reduced GFR simply represent, respectively, the spectrum of renal vascular manifestations from systemic endothelial dysfunction (microvascular disease) to systemic atherosclerosis (macrovascular disease). Copyright © 2011 S. Karger AG, Basel [PUBLICATION ABSTRACT]

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.

Age-related metabolic and renal changes predispose older people to an increased risk of diabetes mellitus and diabetic kidney disease, respectively. As the prevalence of the ageing population is increasing, because of increased life expectancy, the prevalence of older people with diabetic kidney disease is likely to increase. Diabetic kidney disease is associated with an increased risk of adverse outcomes and increased costs to healthcare systems. The management includes promotion of a healthy lifestyle and control of cardiovascular risk factors such as hyperglycaemia, hypertension and dyslipidaemia. Older people are a heterogeneous group of people from a community-living fit and independent person to a fully dependent individual residing in a care home. Therefore, management in this age group should be based on a patient’s functional level adopting tight metabolic control in the fit individual and relaxed targets in the frail person. However, despite the maximum available therapy, a significant number of patients with diabetic kidney disease still progress to renal failure and experience adverse cardiac outcomes. Therefore, future research is required to explore methods of early detection of diabetic kidney disease and to investigate novel therapeutic interventions to further improve the outcomes.

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.

The prevalence of diabetes is increasing particularly in the older age group due to the increased life expectancy. Ageing is associated with vascular and renal changes that predispose older people with diabetes to an increased risk of cardio-renal complications. This manuscript is set to review the use of the sodium glucose transporter-2 (SGLT-2) inhibitors and the glucagon like peptide-1 receptor agonists (GLP1-RA) in older population with diabetes especially in those with comorbidities and frailty. The recently introduced (SGLT-2) inhibitors and the GLP1-RA have shown promising cardio-renal protective outcomes. In addition to the favourable effect of glycaemic control on cardio-renal complications, these new agents seem to add additional benefits independent of their hypoglycaemic properties. The favourable outcomes have been shown in the older age group (>65 years) who were reasonably represented in the randomised controlled clinical trials. However, the evidence for those ≥75 years old is limited due to the small number of the included participants and the few clinical events. Data from both real world and post-hoc analyses of clinical trials is assuring about the use of these new agents in older people. However, it remains reasonable to express caution in using these agents in frail older people with diabetes due to high risk of adverse events in this group. •Ageing is associated with vascular and renal changes that predispose older people with diabetes to adverse events.•The new hypoglycaemic therapy has a favourable effect in those >65 years old that may also include those >75years.•In early to moderate frailty and/or raised comorbidity profile, the new therapy still can be considered.•The new therapy is better avoided in severely frail comorbid older people with diabetes due to high risk of side effects.

The global population is aging due to a reduction in youthful deaths and an extension of the later stages of life. With aging comes a decline in the physiologic functions of various organs and systems. Vascular aging is associated with structural and functional changes of the arterial wall leading to loss of elasticity and compliance. Renal vasculature is not spared as aging is associated with arterial, arteriolar and capillary, glomerular changes (glomerulosclerosis). It is likely that age-related vascular changes are linked to the decline in renal function observed with aging. These changes occur at varying stages of aging depending on predisposing genetic factors and associated life course exposure to cardiovascular risk factors including hypertension and diabetes. The decline in renal function with 'normal' aging in the absence of associated progressive cardiovascular disease is slow and does not seem to be of major clinical significance. The current definition of chronic kidney disease (CKD), including microalbuminuria, and the method of estimation of glomerular filtration rate have inadvertently resulted in an exaggerated prevalence of CKD in the elderly. This is combined with the fact that most of the studies showing decline in renal function with aging are limited by the absence of a correction for associated comorbid confounding factors, resulting in difficulty separating the effect of physiological aging on kidney function from pathological aging due to comorbidities. Such a correction is difficult, if not impossible, to objectively construct. We suggest that only those fractions of older patients with underlying progressive vascular pathology likely to involve the kidneys will, in the future, warrant attention to reduce vascular risk and the associated kidney damage. Copyright © 2010 S. Karger AG, Basel [PUBLICATION ABSTRACT]

The relationships between hypoglycemia, frailty and dementia appear to be reciprocal and can lead to a vicious circle. Frailty appears to be a crucial factor increasing the risk for both hypoglycemia and dementia, initiating the reciprocal relationships. Weight loss is likely to be the underlying risk factor for frailty. Many frail older people with diabetes seem to have unnecessarily tight glycemic control, being treated with hypoglycemic medications that likely increase the risk of hypoglycemia. As patients get older with significant weight loss their glycemic targets should be reviewed, and reduction or even withdrawal of their hypoglycemic medications should be considered.