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

Aging Clinical and Experimental Research https://doi.org/10.1007/s40520-022-02142-8 REVIEW Hypoglycaemic therapy in frail older people with type 2 diabetes mellitus—a choice determined by metabolic phenotype Alan J. Sinclair1,2 · Daniel Pennells3 · Ahmed H. Abdelhafiz3 Received: 27 December 2021 / Accepted: 21 April 2022 © The Author(s) 2022 Abstract 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. Keywords Older people · Type 2 diabetes mellitus · Body composition · Hypoglycaemic therapy · Frailty · Phenotype · Management Introduction Worldwide, the prevalence of diabetes is increasing particularity in those above the age of 65 years and peaks (22%) at the age of 75–79 years [1]. In addition to the known diabetes-related vascular complications, diabetes appears to * Alan J. Sinclair 1 King’s College, London, UK 2 Foundation for Diabetes Research in Older People (fDROP), Droitwich Spa WR9 0QH, UK 3 Department of Geriatric Medicine, Rotherham General Hospital, Moorgate Road, Rotherham S60 2UD, UK accelerate the emergence of frailty [2] Frailty is a dynamic state that increases vulnerability to adverse health outcomes including mortality [3]. As a result, the importance of frailty has been recognised in a number of important international clinical guidelines of diabetes management for older people [4, 5]. Clinical guidelines categorically divide older people as either robust, where tight glycaemic control is recommended, or frail where relaxed targets are preferred due to the side effects associated with hypoglycaemic therapy or where improved clinical outcomes may be considered to be less of a priority in this group of patients. For example, the recommendations for the use of the new anti-diabetes therapy of glucagon like peptide-1 receptor agonists (GLP1RA) and sodium glucose transporter-2 (SGLT-2) inhibitors are to be only carefully considered in frail individuals due to 13 Vol.:(0123456789) Aging Clinical and Experimental Research the risk of weight loss, dehydration and hypotension [4, 5]. Also, insulin is considered as a last treatment resort, after diet and oral hypoglycaemic medications, due to the fear of hypoglycaemia in these vulnerable patients. However, up to now, clinical guidelines have been generally non-specific about frailty and are not explicit about the characterisation of these frail patients. It should be appreciated that frailty is not a single homogeneous concept and the current diagnostic tools or measures are multiple, not standardised and do not consider the metabolic side of frailty [6]. It is likely that frailty has a spectrum of different metabolic phenotypes, which may have a significant impact on the choice of the most suitable hypoglycaemic agent as well as the optimum glycaemic target [7]. The aim of this manuscript was to review the commonly used frailty measures, the characteristics of frail older people with diabetes according to their metabolic phenotype, and explore the most appropriate and suitable hypoglycaemic agents to employ to achieve optimum glycaemic targets in this group of patients. Methods We undertook a detailed literature search with full assessment of relevant articles by searching the following databases: Google Scholar, Medline and Embase. We used the following Medical Subject Heading (MeSH) terms: older people, old age, elderly, diabetes mellitus, frailty, management, treatment, insulin, hypoglycaemic therapy and glucose-lowering therapy individually and in combinations. Articles were reviewed for relevance by abstract independently by the three authors. A manual search of citations in retrieved articles was performed in addition to an in-depth electronic literature search. Hand searching of relevant articles was limited by covid-19 measures and restricted access to medical libraries. We limited our selection to studies published in English language. Any disagreement between authors was resolved by consensus. Frailty Frailty is defined as a state of increased vulnerability to physical or psychological stressors because of decreased physiological reserve in multiple organ systems that cause limited capacity to maintain homeostasis [8]. Frailty is neither an inevitable part of growing old nor synonymous with ageing; however, it is highly prevalent among older people [9, 10]. The prevalence of frailty increases with increasing age reaching up to 7% in people > 65 years and up to 40% in those > 80 years [11]. Frailty has significant clinical consequences that affect both older people and health care systems. For example, frail older people are at increased risk of falls, fractures and dementia that lead to disability, 13 poor quality of life and early mortality [12–17]. These consequences are associated with an increased use of health care resources such as emergency department visits, hospitalisation and eventually institutionalisation [18]. Therefor (...truncated)