Comment on Kutz et al. Comparative Cardiovascular Effectiveness and Safety of SGLT-2 Inhibitors, GLP-1 Receptor Agonists, and DPP-4 Inhibitors According to Frailty in Type 2 Diabetes. Diabetes Care 2023;46:2004–2014

Findings from a recent cohort study published in Diabetes Care (1), which included >740,000 individuals with type 2 diabetes (T2D) aged ≥65 years, demonstrated that both sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) were associated with smaller numbers of cardiovascular events and death than dipeptidyl peptidase 4 inhibitors (DPP-4i), with the largest benefits being seen among frail people. Adverse events that affected frailer individuals were not more common with SGLT2i or GLP-1RAs than with DPP-4i (1).

We wish to highlight that despite this robust evidence, there is still diffuse hesitancy to prescribe SGLT2i and/or GLP-1RAs to frail subjects, possibly due to the fear of side effects and the lack of guidance on their use.

In a cross-sectional study that evaluated 103,790 people with T2D and cardiovascular disease and a median age of 71 years (range 64–79), divided in three groups according to the frailty status (nonfrail, moderately frail, and severely frail) and followed up for a median time of 4.5 years, most frail individuals were less likely to receive SGLT2i and GLP-1RAs than nonfrail ones despite having a high risk of cardiovascular and diabetes-related events and no documented contraindications (2).

Is this excess of cautiousness driven by lack of safety data on SGLT2i and GLP-1RAs in older people? Indeed, compared with other noninsulin glucose–lowering agents, SGLT2i are associated with a higher rate of several side effects, including diabetic ketoacidosis, genitourinary infections, and dehydration; however, none of these adverse events was reported more frequently among older adults (3). Likewise, the incidence of side effects associated with GLP-1RA therapy, in clinical trials recruiting patients aged ≥65 years, was found to be similar between randomized treatment groups (4). We acknowledge that there is still a paucity of evidence on the effects of GLP-1RAs and SGLT2i on muscle mass.

In clinical practice, can we be selective when using both classes of these drugs? We previously described, in older people with T2D, an anorexic malnourished (AM) phenotype characterized by low body weight, malnutrition, low HbA_1c, and increased risk of hypoglycemia and a sarcopenic obese (SO) phenotype characterized by an elevated body weight and high HbA_1c (5). Based on this distinction, in the SO phenotype, SGLT2i and/or GLP-1RAs represent a reasonable option, as they are associated with weight loss and confer cardiorenal protection. In the AM phenotype, the use of long-acting insulin analogs may be a better choice due to their anabolic effects and the advantage of being administered once daily (5).

In light of the existing literature, the underuse of SGLT2i and GLP-1RAs in frail older people does not seem to be justifiable. We believe that the implementation of frailty assessment in routine diabetes care would help to identify those individuals who might benefit from a close monitoring for adverse reactions.

Future randomized clinical trials will need to evaluate the efficacy of these drugs and their influence on muscle mass in populations with T2D phenotypic heterogeneity and a broad spectrum of frailty.