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.