Introduction

Background

Glucagon-like peptide-1 receptor agonists (GLP-1-RAs) are a class of medications that exert their effects by activating GLP-1 receptors and mimic endogenous GLP-1. Their effects include stimulating insulin release, inhibiting glucagon release, delaying gastric emptying, and suppressing appetite. These effects led to their initial approval for the treatment of type 2 diabetes mellitus (T2DM) in 2005 [1,2]. Given their ability to promote weight loss, GLP-1-RAs have increasingly been approved and used for chronic weight management since 2015 [3].

Beyond glycemic control and weight loss, there are expanding indications suggesting that GLP-1-RAs have potential pleiotropic effects, including treatment of cardiovascular disease (CVD), heart failure with preserved ejection fraction (HFpEF), chronic kidney disease (CKD), metabolic dysfunction-associated steatohepatitis (MASH), obstructive sleep apnea (OSA), and peripheral artery disease (PAD), among others [1,3]. Emerging data further suggest that GLP-1-RA usage is associated with a lower risk of all-cause dementia and current research is examining whether it slows cognitive decline [1]. As of October 2025, twelve GLP-1-RA therapies have been approved for treatment of T2DM or obesity by the United States Food and Drug Administration (FDA), with >40 agents currently in development [3].

The older adult and GLP-1-RA

A population of interest for the use of GLP-1-RA therapy is older adults, typically defined as aged ≥65. This group represents the fastest-growing demographic in the world, but also the most sedentary, spending an estimated 9.7 h per day engaged in sedentary behavior [[4], [5], [6]]. Sedentary behavior is robustly associated with T2DM and weight gain, which may partly explain why half of the individuals with T2DM are older adults and 38.9% of older adults are obese [[7], [8], [9], [10], [11]]. Furthermore, the prevalence of T2DM is expected to dramatically increase over the next few decades due to the aging population and increasing numbers of higher-risk groups [12]. Concurrently, GLP-1-RA use rose from 3.4% to 13.8% in older adults with T2DM from 2017 to 2022 [13].

Despite the expanding indications for GLP-1-RAs, some studies report concerns that GLP-1-RA therapy is associated with the loss of skeletal muscle [14,15]. This is hypothesized to occur through appetite suppression, leading to reduced caloric (including protein) intake and triggering of catabolic hormones utilizing muscle mass for energy [16]. These concerns are most relevant for older adults at the highest risk of sarcopenia, estimated to affect 18.8% of community-dwelling older adults [17]. In older adults with diabetes, sarcopenia prevalence increases to 28.5%, with a threefold higher risk of sarcopenia compared with non-diabetics [18,19]. Sarcopenia can lead to major clinical morbidity and mortality due to weakness, poor balance, and difficulty with daily tasks, a 1.6-fold increase in fall risk and a 1.7–1.8-fold increase in fracture risk [20,21]. These effects can be devastating for older adults, especially in cases of hip fracture. For instance, hip fractures in older adults often lead to significant and permanent declines in physical and psychological quality of life, with most patients never returning to pre-fracture levels of independence [22].

There are additional considerations that make older adults a group of significant interest for GLP-1-RA treatment. Notably, older adults are more likely to have concurrent comorbidities that can complicate treatment. Approximately 30% of older adults with diabetes have coronary heart disease, twice the rate observed in non-diabetics [12]. Older adults also have a high prevalence of hypertension (HTN), CVD, heart failure, and CKD, many of which are emerging indications of GLP-1-RA treatment [12,23]. In fact, early research shows GLP-1-RAs can provide both cardiovascular and renal benefits, with studies estimating a 14% reduction in major adverse cardiovascular events (MACE) and a 14% reduction in kidney events [24,25]. This suggests multiple use cases for GLP-1-RA in this population. However, due to the likelihood of having multiple comorbidities, polypharmacy can be widespread in older adults, with one study estimating that 46% of older adults with diabetes have polypharmacy (defined as the use of ≥ 5 medications) [26]. Importantly, polypharmacy is associated with increased adverse drug events, hypoglycemia, drug-drug interactions, and reduced adherence [26,27]. One study estimates that 55% of older adults with diabetes are prescribed at least one potentially inappropriate medication [27]. As GLP-1-RA’s potential downstream effects and polypharmacy’s negative effects are not commonly discussed in the literature, such considerations should be important to physicians balancing the benefits and risks of GLP-1-RA treatment in older adults.

A recent meta-analysis of randomized controlled trials found that GLP-1-RA therapy led to, on average, roughly 28% of total weight loss being attributable to muscle-based indices [28]. While this suggests an emerging pattern of GLP-1-RA-induced muscle loss, direct evidence in older adults remains minimal, and the functional consequences of this muscle loss (i.e. effects on strength, gait, falls, frailty, and independence) are largely unknown in this population. Critically, the endpoints most commonly reported in GLP-1-RA trials (i.e. total weight loss, change in body mass index (BMI), single time-point lean mass estimation) are insufficient to capture dimensions of performance which are most relevant for older adults. For instance, BMI may misclassify body composition in older adults due to age-related shifts in body fat and muscle distribution, while total weight loss cannot distinguish between the loss of fat and lean mass [29]. Additionally, single time-point estimations of lean mass do not capture the trajectories of muscle quality or performance (e.g. strength, gait, frailty), which are the outcomes that most directly determine functional independence and survival in older populations [30,31]. This gap between the available evidence and clinical needs of older adults serves as the rationale for the present review and its performance-based framing.