Clinical implications for practice, with particular relevance to older adults

The observed association between GLP-1-RA therapy and decreased skeletal muscle mass in several studies has important implications for clinical practice, particularly for older adults. Older adults face unique vulnerabilities, such as substantial risk for functional decline, falls and fall-related complications, and loss of independence, all of which demand attention to GLP-1-RA therapies in these populations [85]. Despite these risks, existing literature suggests that adverse outcomes of GLP-1-RA treatment among older adults may be mitigated with four key strategies: monitoring muscle health, nutritional interventions, exercise interventions, and adjunct pharmacotherapies. Critically, these strategies should not be interpreted as prescriptive clinical protocols, but rather, provisional considerations that should be individualized for each patient’s unique clinical context (i.e. renal function, nutritional status, comorbidities, contraindications).

First, measuring and monitoring muscle health during GLP-1-RA therapy can help identify potential declines and allow providers to intervene early. Grip strength is traditionally the preferred standard to measure muscle health in older adults, but because the studies in this review rarely observed significant changes in grip strength during GLP-1-RA therapy, other methods could also be considered [86]. Regular evaluations of 6-minute walking distance and gait speed may be beneficial in older adults at risk of frailty and falls, which the loss of skeletal muscle mass could exacerbate [[87], [88], [89]]. While no studies have yet shown that GLP-1-RA treatment directly increases sarcopenia risk in older adults specifically, it remains a significant concern [90]. While DXA remains the reference standard for body composition assessment in the sarcopenia literature, routine DXA monitoring during GLP-1-RA therapy has not been validated and may not be practical in most clinical settings.

A second strategy for preserving muscle health during treatment is adequate nutrition. Consensus guidelines for older adults recommend consuming at least 1.0–1.2 g of protein per kilogram of body weight daily for healthy older adults [91,92]. However, in the specific context of GLP-1-RA therapy for obesity, a recent joint advisory recommends 1.2–1.6 g of protein per kilogram body weight daily to preserve muscle mass [55]. Protein source is another important consideration. Complete proteins should be prioritized, and a recent study found that the dietary requirement of leucine in older adults was roughly 78 mg/kg/day, which is higher than most current recommendations [93]. Critically, this leucine threshold is taken from the general nutrition and aging literature and, to our knowledge, has not been studied specifically in the context of GLP-1-RA therapy. Plant-based protein, dairy, lean poultry, seafood, and eggs tend to be encouraged in comparison to red and processed meats [55]. Older adults should also ensure adequate levels of vitamin D, which is essential for maintaining high bone mineral density in a population at risk of osteoporosis and fractures, although this recommendation is taken from the general nutrition and aging literature as opposed to being specific for GLP-1-RA therapy [15]. Vitamin D deficiencies are common worldwide, especially among older adults, and may independently represent another risk factor for sarcopenia [94]. A recent consensus statement recommends combining vitamin D supplementation with calcium in order to reduce fracture risk in older adults [95]. Some studies also suggest that omega-3 fatty acids (such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) are beneficial at reducing sarcopenia risk, supporting the potential use of fish oil supplementation in older adults receiving GLP-1-RA therapy, although these recommendations also come from the general literature and future studies need to examine them in the context of GLP-1-RA therapy [15].

Third, exercise interventions are essential during treatment because protein intake alone is not sufficient to preserve muscle mass without resistance training [55]. An important consideration for starting an exercise regimen in patients receiving GLP-1-RA therapy is potential fatigue during treatment (a commonly reported side effect) often resulting from sedentary lifestyles, especially older adults. This may require slowly building up over time to a goal of 60 to 90 min of resistance training per week [14]. Incorporating aerobic exercise alongside resistance training is also beneficial, but no studies to our knowledge have examined the effects of exercise in the specific context of GLP-1-RA therapy. Weight regain after the completion of GLP-1-RA treatment is common, and continuing aerobic exercise and overall increased energy expenditure may help mitigate this risk [14]. Among older adults, it is essential that physical activity recommendations are patient-specific, as this population can have widely different fitness levels and comorbidities that influence their ability to exercise [15]. Some older adults may not be able to attain standard exercise recommendations, which can cause decreased motivation and reduced adherence. Therefore, incorporating short sessions of exercise and intermittent forms of physical activity is a promising approach for older adults [96].

Finally, adjunct pharmacotherapies may be considered in cases of significant muscle loss unresponsive to lifestyle interventions, although no such drugs are currently approved by the FDA for the treatment of sarcopenia [97,98]. These pharmacological interventions must be used with caution in older adults due to the potential of adverse side effects, comorbidities and polypharmacy; few studies evaluate their clinical efficacy specifically on older adults [99]. Investigational agents targeting muscle preservation are discussed in Section IV (“Future Directions”).

Provisional considerations for preserving muscle health during GLP-1-RA therapy are summarized in Fig. 1, and a proposed monitoring framework is presented in Table 4. In this framework, three crucial clinical domains that warrant careful monitoring for older adults receiving GLP-1-RA treatment (muscle health and fall risk; nutritional status; functional capacity) are highlighted. Clinicians can reference the guidelines in this framework to perform baseline assessments, monitor status during GLP-1-RA therapy, and remain vigilant for potential red flags (see Table 4). These recommendations were not directly tested in the studies included in this review, and are instead derived from indirect evidence and general principles of sarcopenia prevention. Therefore, they should be regarded as hypothesis-generating rather than prescriptive clinical guidance. The individual medical context of each patient (i.e. renal function, nutritional status, comorbidities, contraindications) should always be considered when applying these suggestions. The specific thresholds and recommendations cited in Table 4 are drawn from the referenced literature in the table and are intended to serve as starting points for clinical decision-making as opposed to strict protocols.

Fig. 1: Provisional Multimodal Strategy for Preserving Muscle Health During GLP-1-RA Therapy in Older Adults.

Clinical Domain | Baseline Assessment | Monitoring During Therapy | Red Flags | References
Muscle Health and Fall Risk [59,100] | - fall history- SARC-F questionnaire | - fall diary- repeat SARC-F questionnaire each visit | - new difficulty with ADLs | - Marassi & Fadini, 2026- Prokopidis, 2026
Nutritional Status [12,55] | - body weight- dietary protein intake- Vitamin D | - weight trajectory- protein intake logs- micronutrient levels every 6 months | - weight loss >2% per month- protein intake consistently <0.8 g/kg/day- Vitamin D deficiency | - LeRoith et al., 2019- Mozaffarian et al., 2025
Functional Capacity [30,101,102] | - handgrip strength (HGS)- gait speed- ADL assessment | - repeat HGS every 3–6 months- repeat gait speed every 3–6 months | - large decline in HGS, HGS<16 kg in women, or HGS<27 kg in men⁎⁎- gait speed decline >0.1 m/s in 12 months⁎⁎⁎- new ADL dependence | - Adam et al., 2023- Artaud et al., 2015- Cruz-Jentoft et al., 2019

Fig. 1 Caption: Provisional considerations for preserving muscle health during GLP-1-RA therapy, with particular relevance to older adults. Monitoring and assessing muscle mass and/or function, nutritional optimization, and exercise integration may be considered, while adjunct pharmacotherapies remain investigational. A legend indicates where evidence for muscle-preserving strategies is strong and where it is weak or mixed. These considerations are provisional and performance-based, grounded primarily in indirect evidence from the literature on frailty, sarcopenia, nutrition, and general aging, as opposed to being derived from the GLP-1-RA trials themselves. They should not be interpreted as ready-to-implement clinical guidelines.