A Narrative Review on GLP-1 Receptor Agonists for Obesity in Older Women: Maximizing Weight Loss While Preserving Lean Mass

The efficacy of GLP-1 receptor agonists (GLP-1 RAs) in older adults has been robustly demonstrated in randomized controlled trials (RCTs) [34], providing strong evidence for their use in managing obesity and related comorbidities in individuals aged over 65. Two major trial programs, the STEP program for semaglutide [35,36,37,38,39] and the SURMOUNT trials [40,41,42,43] for tirzepatide, offer critical insights into the benefits of these therapies in older populations.

In the STEP program [35,36,37,38,39], which assessed the effects of semaglutide, two key studies—STEP 1 [35] and STEP 5 [39]—examined the weight loss effects in older adults. In both trials, subanalyses specifically focusing on women aged 65 years and older showed that these individuals experienced significant reductions in body weight, comparable to those seen in younger cohorts. On average, weight loss in this age group ranged from 10–15%, with a slight attenuation of this effect in participants aged over 70 years. This attenuation may be attributed to age-related metabolic changes, including reduced caloric expenditure, muscle mass, and hormonal shifts that influence weight regulation. Despite this attenuation, the improvements observed in metabolic parameters, such as HbA1c (glycated hemoglobin), blood pressure, and lipid profiles, were significant. Notably, STEP 5 [39] confirmed that these weight loss effects were durable, with sustained reductions in body weight and improvements in metabolic outcomes over a two-year period, which is particularly relevant for the management of chronic obesity in aging populations. The long-term efficacy observed in these trials reinforces the potential for GLP-1 RAs to manage obesity as a chronic condition in older women [Table 1]. In other words, weight reduction was observed during active treatment, while post-discontinuation follow-up indicated relative weight stability after treatment cessation, rather than further weight loss or rebound.

Similarly, the SURMOUNT-1 [40] and 2 [41] trials, which evaluated the effects of tirzepatide, revealed even greater weight loss efficacy, with mean reductions in body weight ranging from 15% to 21%. These trials also included older adults, showing that tirzepatide’s dual agonism (activating both GLP-1 and GIP receptors) may offer superior efficacy compared to single-agonist GLP-1 therapies. The sustained effects of tirzepatide were confirmed up to 72 weeks, highlighting its potential for long-term use in older adults managing obesity. In addition to weight loss, participants in these trials showed improvements in insulin sensitivity, greater reductions in fat mass, and modest improvements in physical functioning metrics, such as mobility and endurance. While the data on women over 75 years of age remains limited, the overall findings from these trials support the efficacy of tirzepatide in older women, particularly those with obesity and type 2 diabetes, a common comorbidity in this population [Table 1].

Across trials, approximately 25–40% of total weight loss has been attributed to lean mass reduction, underscoring the importance of muscle-preserving strategies in older women.

Real-world evidence from observational studies has further corroborated the findings from randomized controlled trials, demonstrating that GLP-1 RAs are effective in achieving clinically meaningful weight loss in older women, particularly those with type 2 diabetes or cardiovascular comorbidities [44]. These studies highlight that older patients can achieve significant weight reduction, with many experiencing reductions in HbA1c, improved blood pressure, and better lipid profiles. In addition to metabolic improvements, real-world data indicate that older adults treated with GLP-1 RAs show reductions in healthcare utilization, such as fewer hospital admissions and a decrease in the need for medication adjustments, which ultimately enhances their health-related quality of life [45,46]. The ability of GLP-1 RAs to reduce the burden of chronic disease, improve glycemic control, and decrease healthcare costs presents a compelling case for their integration into clinical practice for older women, especially those with comorbid conditions like diabetes and hypertension [47].

However, the generalizability of trial data to multimorbid elderly patients remains a critical point of concern. While GLP-1 RAs have shown positive outcomes in controlled trial settings, real-world applications must consider the unique challenges that frail older adults face. For example, individuals with cognitive impairments, mobility limitations, or on polypharmacy regimens may experience difficulties with injectable therapies, which are a common form of administration for GLP-1 Ras [48]. The act of self-injecting, combined with the possible side effects of the medications, such as nausea and gastrointestinal discomfort, could pose significant barriers to adherence in these patients. Furthermore, appetite suppression, while beneficial for weight loss, may be less well-tolerated in frail older adults, particularly those at risk for malnutrition or those with low body mass.

In older women, the clinical issue is not “low body mass” as a contraindication, but rather reduced muscle reserves and/or low muscle function, particularly in the context of sarcopenic obesity, where excess adiposity coexists with impaired muscle strength and unfavorable body composition. This phenotype is especially relevant in women ≥65 years due to menopausal body-fat redistribution, anabolic resistance, and higher baseline risk of functional decline. To improve clinical applicability, a structured phenotyping and monitoring approach may be adopted using the ESPEN–EASO diagnostic algorithm, which prioritizes the assessment of muscle strength followed by confirmation of sarcopenic obesity through body-composition evaluation (e.g., DXA/BIA) with muscle mass normalized to body weight and concurrent evidence of excess adiposity, with subsequent staging according to functional and cardiometabolic complications [49].

As a result, clinicians must exercise caution when prescribing GLP-1 RAs to elderly patients, especially those with cognitive impairments or those who are frail, as the benefits must be carefully weighed against the potential risks [50].

Despite these challenges, the real-world evidence underscores the promise of GLP-1 RAs in managing obesity and its comorbidities in older women. With proper patient selection, monitoring, and adjustment of treatment plans, GLP-1 RAs can provide significant improvements in weight, glycemic control, and overall health outcomes. Future research should focus on identifying specific subgroups of older patients who are most likely to benefit from these therapies, as well as strategies to mitigate potential risks and optimize adherence in frail, multimorbid individuals. In sum, while GLP-1 RAs represent an important therapeutic option for managing obesity in older women, further evidence is needed to refine treatment approaches and ensure the safety and efficacy of these agents in the most vulnerable populations.

Aging is characterized by a progressive decline in skeletal muscle mass and function, a condition known as sarcopenia. This condition significantly increases the risk of falls, fractures, disability, and mortality [51]. Sarcopenia is considered a distinct geriatric syndrome and is particularly prevalent in older women, largely due to menopause-related hormonal changes, reduced physical activity levels, and the cumulative burden of chronic diseases [52]. The loss of muscle mass in this population is further exacerbated by anabolic resistance and low-grade chronic inflammation, often referred to as “inflammaging” [9]. These factors impair the muscle’s ability to respond effectively to anabolic stimuli, thus contributing to the progressive deterioration of muscle tissue.

Although sarcopenia has classically been regarded as a manifestation of undernutrition, in recent decades—and especially in both industrialized and developing countries—it has become increasingly linked to obesity, establishing a self-sustaining vicious cycle between these two interrelated conditions [19]. The effect of adiposity amplifies all the pathophysiological mechanism of the inflammaging sustaining the lean mass loss [9,19].

Clinical trials have demonstrated that approximately 25–40% of the total weight loss observed with GLP-1 receptor agonists (GLP-1 RAs) is attributable to the loss of lean mass, including muscle. This proportion of lean mass loss is of particular clinical concern in older women, particularly those with pre-existing sarcopenia or low baseline muscle reserves [53]. The use of tirzepatide, which induces greater total weight reduction, may be associated with even higher absolute losses in lean mass. Although some studies suggest that GLP-1 RAs preferentially reduce visceral fat, the risk of functional decline remains significant, as muscle loss may impair overall physical function [54].

To our best knowledge to the date, there is only one clinical study investigating the impact of GLP-1RAs on sarcopenic obesity. The SEMALEAN study, conducted in 106 patients, predominantly female, demonstrated a significant reduction in the prevalence of sarcopenic obesity, decreasing from 49% at baseline to 33% after 12 months of semaglutide treatment [55]. Moreover, the reduction in sarcopenic obesity prevalence occurred despite an initial decline in absolute lean mass during the early phase of semaglutide treatment (approximately −3 kg), which subsequently stabilized over follow-up, while indicators of muscle function showed improvement. This improvement was accompanied by favorable changes in body composition assessed by dual-energy X-ray absorptiometry (DEXA), including a significant reduction in total and visceral fat mass, while absolute lean mass loss was relatively limited and proportionally lower than fat mass reduction. Consequently, appendicular lean mass indexed to body weight and fat-free mass percentage showed stabilization or relative improvement over follow-up. In addition, preclinical data suggest that GLP-1 receptor agonists not only mitigate weight gain but also attenuate muscular atrophy and improve mitochondrial function in skeletal muscle, potentially disrupting the vicious cycle linking adiposity and sarcopenia [56]. These effects appear to be mediated, at least in part, by reductions in systemic and local low-grade inflammation and improvements in metabolic and mitochondrial efficiency [56,57,58].

The loss of muscle mass has profound functional implications, translating into decreased strength, endurance, and overall physical capacity. Studies utilizing dual-energy X-ray absorptiometry (DEXA) and physical performance tests—such as the Short Physical Performance Battery (SPPB) and handgrip strength assessments—have documented declines in functional status in a subset of patients receiving GLP-1 RAs, particularly in those who do not engage in concurrent physical activity interventions [57]. A decline in physical function undermines the benefits of weight loss and may lead to increased dependency, institutionalization, and elevated mortality risk. Therefore, it is crucial to consider the potential adverse effects of muscle loss when prescribing GLP-1 RAs to older adults, particularly in those with pre-existing sarcopenia or who are at risk of functional decline [33].

A comprehensive approach to managing muscle loss in older women requires regular and systematic monitoring of nutritional status, muscle strength, and physical performance. Routine assessments, such as handgrip strength and gait speed, are essential indicators of muscle function and overall physical health. These tests provide valuable insights into an individual’s ability to perform daily activities and their risk for functional decline, frailty, and falls. Incorporating these assessments into clinical practice ensures that interventions are tailored to the individual’s specific needs, which is especially important for the aging population, where baseline health conditions can vary significantly [58].

According to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), the identification of potential cases should begin when an individual shows symptoms or signs suggestive of sarcopenia—such as frequent falls, general weakness, slowed walking speed, difficulty standing up from a chair, or unintentional weight and muscle loss. In these situations, EWGSOP2 advises using the SARC-F questionnaire to gather patients’ self-reported information on typical sarcopenia-related issues [59]. If the SARC-F score suggests “probable sarcopenia,” EWGSOP2 recommends proceeding with a stepwise diagnostic pathway. This involves assessing muscle strength, confirming the condition through imaging techniques, and determining its severity. This structured approach follows the FACS model: Find cases, Assess, Confirm, and determine Severity [59].

However, certain studies have shown that SARC-F performs less reliably in individuals with sarcopenic obesity [60]. As a result, some authors recommend using adapted screening approaches that incorporate additional measures such as mid-arm circumference (MAC) and/or calf circumference (CC) to improve detection accuracy.

In our view, it could be reasonable to perform preliminary screening before initiating GLP-1 receptor agonist therapy for obesity in older women. Using modified versions of the SARC-F or directly assessing muscle strength—such as through handgrip testing—may be appropriate. This approach is justified by the differing risk–benefit profile of GLP-1 RA treatment in patients with obesity depending on whether sarcopenia is present [60].

Use of advanced techniques, such as DEXA scans or bioelectrical impedance analysis (BIA), may be appropriate for high-risk patients, particularly those with pre-existing sarcopenia or those undergoing aggressive weight loss interventions. DEXA scans provide precise measurements of body composition, including lean mass and fat mass, allowing clinicians to track changes over time and make informed decisions about treatment adjustments. BIA, while less precise than DEXA, is a more accessible and cost-effective tool for evaluating body composition and monitoring changes in muscle mass [18].

The implementation of a comprehensive geriatric assessment (CGA) is also recommended for older patients undergoing weight loss interventions. The CGA involves a multidisciplinary evaluation that includes medical, nutritional, functional, and psychological assessments, which help to identify risk factors for frailty and guide individualized treatment plans. This holistic approach ensures that any potential issues, such as malnutrition, depression, or cognitive decline, are addressed early and appropriately [61]. It also optimizes interdisciplinary interventions, which may involve dietitians, physiotherapists, and geriatricians working collaboratively to ensure the patient’s nutritional, physical, and emotional needs are met.

Monitoring should be continuous, with therapy adjustments made based on the patient’s functional and nutritional trajectories. Regular follow-ups are crucial to assess the effectiveness of interventions and make necessary modifications. This approach ensures that weight loss interventions, particularly those involving GLP-1 RAs, do not result in unintended consequences, such as excessive muscle loss or functional decline, and that the overall health and quality of life of older women are preserved [18,62]. By combining resistance exercise, protein supplementation, and a comprehensive assessment and monitoring strategy, clinicians can help mitigate the risks of muscle loss during weight loss, thereby optimizing health outcomes for older women.

Resistance exercise, typically performed 2–3 times per week (150 min/week), is considered the most effective intervention to preserve and enhance muscle mass during weight loss, particularly in older adults. This form of exercise induces mechanical loading on muscles, which stimulates muscle protein synthesis and counteracts the catabolic effects of caloric restriction, a common concern in weight loss strategies [63]. Resistance training, when performed correctly, promotes muscle hypertrophy and strength by creating a stimulus for the muscle fibers to adapt and grow. Additionally, this form of exercise is crucial in preventing the muscle atrophy that often accompanies weight loss, especially when combined with GLP-1 RAs, which facilitate fat reduction but may also result in lean mass loss [64].

Programs that incorporate progressive overload—gradually increasing the resistance or intensity of exercises—are particularly effective in promoting long-term muscle preservation and functional improvements. Functional movements, such as squats, lunges, and liftings, not only preserve muscle mass but also improve overall physical performance, thereby enhancing the individual’s capacity to perform daily activities. Evidence suggests that combining resistance exercise with GLP-1 RAs not only helps preserve lean mass but also leads to improvements in physical performance metrics, such as mobility, balance and strength [65]. Furthermore, resistance exercise improves insulin sensitivity, which is essential for managing obesity, diabetes, and metabolic syndrome [66]. Additionally, resistance training enhances mitochondrial function by increasing the number and efficiency of mitochondria within muscle cells, which is particularly important in older adults, as mitochondrial dysfunction contributes to muscle loss and metabolic decline [67]. Regular exercise, therefore, supports long-term weight maintenance by improving metabolic flexibility, which is the body’s ability to switch between burning fat and carbohydrates depending on availability.

Adequate protein intake is critical in maintaining muscle mass, particularly in older adults who are undergoing weight loss interventions. The recommended protein intake for older women is generally 1.2–1.5 g of protein per kilogram of body weight per day. This higher protein requirement is due to age-related anabolic resistance, where muscle protein synthesis is impaired despite adequate dietary intake [68,69,70]. Leucine, a branched-chain amino acid, plays a pivotal role in stimulating muscle protein synthesis via the mTOR (mechanistic target of rapamycin) pathway. Leucine-enriched protein sources and essential amino acid supplements have been shown to enhance this anabolic response, further supporting muscle preservation during weight loss [71].

When combining GLP-1 RAs with protein supplementation, particularly in older women, optimal body composition outcomes can be achieved. This combined approach may mitigate the potential loss of muscle mass associated with GLP-1 RA therapy. Moreover, distributing protein intake evenly across meals has been found to be particularly effective, as it maximizes muscle protein synthesis throughout the day [72]. Consuming protein shortly after exercise has also been shown to enhance the anabolic response, facilitating muscle repair and growth. In clinical practice, it is essential to assess an individual’s dietary protein intake, especially during weight loss interventions, as deficiencies may exacerbate muscle loss and impair recovery [73]. Clinical guidelines recommend monitoring protein intake and providing supplementation or dietary adjustments as needed to ensure adequate protein consumption, particularly in older adults who may have decreased appetite or difficulty in obtaining sufficient protein from food alone [74].

All the abovementioned interventions are summarized in Table 2.

No new data were created.