Future directions

While the available evidence suggests that GLP-1-RA therapy is frequently associated with some degree of skeletal muscle mass loss in general populations, studies specifically examining older adults are minimal, and the current evidence base is drawn predominantly from general adult populations. Specifically, age-specific guidelines on GLP-1-RA dosing, nutritional intake, and exercise habits during therapy would greatly aid clinicians prescribing GLP-1-RAs for older adults. Further, given that higher GLP-1-RA doses are associated with greater lean mass loss [74], future studies should investigate whether modified dose titration schedules or lower maintenance doses in older adults can balance therapeutic efficiency with muscle preservation. More studies examining functional outcomes (i.e. grip strength, gait speed) are especially important given the risk of falls and frailty in older adults. Furthermore, more longitudinal evidence is needed to determine the impact of GLP-1-RA therapy on performance-based trajectories of aging, such as physical function, resilience, and recovery. Future reviews on GLP-1-RAs and skeletal muscle should aim to stratify studies by methodological characteristics to minimize confounders. Alternatively, future studies can stratify by population characteristics, such as the presence or absence of T2DM and gender balance. Standardized muscle assessment methodologies are needed to allow for direct comparison between studies, given that results from BIA may not be comparable to results from MRI, CT, or DXA. The extent to which GLP-1-RA treatment may increase the risk of sarcopenia in older adults remains unknown.

Importantly, future studies can help determine whether nutritional and exercise interventions can preserve muscle mass in older adults receiving GLP-1-RAs, or if other strategies (i.e. adjunct pharmacotherapies) are needed. Several investigational pharmacological approaches may eventually complement lifestyle interventions for muscle preservation during GLP-1-RA therapy, although none are currently approved for this indication and none were examined in the studies included in this review. Notably, antimyostatins such as bimagrumab, landogrozumab, apitegromab, and taldefgrobep are an investigational class of drugs that function by blocking myostatin and other negative growth regulators of muscle. Early-phase trials suggest that these agents may preserve lean mass during GLP-1-RA-induced weight loss. For instance, results from the COURAGE trial suggest that the addition of the antimyostatin trevogrumab to semaglutide preserved 50–51% of lean mass compared with semaglutide alone [1]. However, these agents remain investigational, and larger and longer trials in the context of GLP-1-RA associated muscle loss are necessary to confirm efficacy and safety before they can be recommended for clinical use. Studies may also investigate combination therapy of GLP-1-RAs and muscle-preserving pharmacotherapies.