Glucose intolerance affects many older adults in the United States with 49% having prediabetes and an additional 29% having type 2 diabetes mellitus (T2DM) [1]. The mechanisms that lead to age-related glucose intolerance and T2DM are unknown, but age-dependent decreases in β-cell function and insulin sensitivity are thought to be important in the deterioration of glucose homeostasis with age [2]. Unfavorable changes in body composition observed with aging can contribute to insulin resistance, including redistribution of fat from peripheral subcutaneous areas to a central location [3] and loss of lean muscle mass [4]. Overall, changes observed with aging appear to lead to glucose intolerance and T2DM.

Although T2DM complications are primarily thought of as nephropathy, neuropathy, and retinopathy, T2DM is associated with detrimental changes in physical function and body composition, and biomarkers of aging. A recent meta-analysis reports a 50%-80% increased risk of mobility disability; defined as walking speed, chair stand time, and balance test; for those with T2DM compared to people without T2DM [5]. In multiple longitudinal studies, older adults with T2DM have a greater decline in lean mass compared to those without T2DM [6-8]. Additionally, those with prediabetes compared to normoglycemia appear at increased functional risk [9]. These data suggest that insulin resistance, even in the early stages, is associated with adverse changes in body composition and physical function.

Historically, glycemic control has been the focus of T2DM management but the nonglycemic cardiovascular, renal, and weight benefits of some classes of antihyperglycemic agents lead to increased individualization of T2DM therapy regimen based on a patient’s co-morbidities even after glycemic goals are reached. Semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist. GLP-1 receptor agonists use the physiologic action of the incretin GLP-1 to increase insulin secretion and suppress glucagon release in response to meals. These drugs reduce hemoglobin A_1c (HbA_1c) by 1.45%-1.55%, depending on dose [10,11]. Semaglutide additionally has nonglycemic benefits, including chronic weight management and reduction of cardiovascular events. A recent meta-analysis determined that semaglutide has an average weight loss of 12% with 54% of participants achieving at least 15% weight loss [12]. Currently, semaglutide is approved by the Food and Drug Administration not only for T2DM management, to decrease cardiovascular events in adults with T2DM, and for chronic weight management for those with a BMI of ≥30 kg/m² or ≥27 kg/m² with at least 1 weight-related comorbidity Therefore, a significant portion of older adults may be prescribed GLP-1 receptor agonists considering that 29% of them have T2DM and 42.8% of them have a BMI of ≥30 kg/m² [1,13].

With significant weight loss resulting from semaglutide use, concomitant lean body mass losses may occur. However, the results on lean mass appear mixed, with most trials indicating that semaglutide results in reductions in total fat mass and lean mass with most of the weight loss resulting from fat mass loss [14-17], while others revealed that lean body mass remained stable [18-20]. The effect of semaglutide on physical function has been infrequently studied in older adults. One study found the preservation of grip strength [14] but have not evaluated other validated measures of function in older adults such as short physical performance battery and 6-minute walk distance. Additional measures of muscle quality such as histology and mitochondrial respiration have not been completed in humans. Of note, these trials have an average studied population younger than 65 years, limiting the ability to extrapolate the results to older adults. These data suggest a gap in the literature related to the effects of semaglutide on body composition and physical function in older adults.

Since semaglutide has positive changes in glycemic control, cardiovascular system, and weight management; there are possible changes to the aging process as well. Although there is no standard set of biomarkers to obtain for evaluation of aging, systemic interleukin (IL)-6, tumor necrosis factors α (TNFα), C-reactive protein (CRP), and GDF15 are proposed biomarkers that are used in geroscience guided clinical trials [21]. A process that contributes to aging is cellular senescence, which is a stable cell cycle arrest triggered in normal cells that can lead to impaired tissue regeneration and chronic age-associated disease [22]. Cellular senescence can be detected by staining tissues for senescence-associated β-galactosidase and senescence-associated secretory phenotype [22]. Although semaglutide has not been widely studied, the class of GLP-1 receptor agonists shows evidence of improvement in CRP and TNFα [23] with 1 study indicating that CRP has a significant decline following 68 weeks of treatment with semaglutide [24]. Therefore, this underscores the necessity for further research in this field.

This study aims to (1) ascertain the potential ramifications of semaglutide on the lean mass profiles and physical functionality of individuals with prediabetes or T2DM and (2) to assess the impact of semaglutide on molecular biomarkers of aging in blood, adipose, and skeletal muscle tissues. We hypothesize that semaglutide will induce favorable alterations in body composition, particularly for lean and adipose body mass quantified via dual-energy x-ray absorptiometry, and improve physical function, as assessed by metrics such as the short physical performance battery, handgrip strength, and walking speed. Additionally, clinical changes are associated with positive changes in systemic and tissue-specific biomarkers of aging.

This is a randomized, open-label pilot study. The institutional review board is notified of any deviations from the approved protocol or breaches of confidentiality.

As shown in Table 1, this study involves 8 visits, which include screening and baseline assessments (visit 1 and visit 2), randomization (visit 2), intervention follow-up (visits 3-5), end-of-study assessments (visits 6a and 6b), and a postintervention telemedicine follow-up visit (visit 7). The intervention phase occurs over 20 weeks. Participants are contacted before in-person visits to ensure they are able to attend or reschedule if needed. All in-person visits are conducted at the Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio.

The study is recruiting 20 older adults from San Antonio, Texas. Overall, for this pilot, our population is generally healthy older adults who are eligible to receive semaglutide for either indication of T2DM or chronic weight management. The inclusion criteria are as follows: (1) men and postmenopausal women; (2) aged 65 years and older; (3) BMI: 27-40 kg/m²; (4) HbA_1c 5.7%-7.5% or fasting blood glucose greater than 100 mg/dL; (5) community-dwelling; (6) willingness and ability to comply with protocol requirements. The exclusion criteria are as follows: (1) glomerular filtration rate≤29 mL/min/1.73 m² [25]; (2) hematocrit≤33%; (3) thyroid stimulating hormone>7 mIU/L with abnormal free thyroxine; (5) use of medications known to lower blood glucose besides metformin; (6) history of cardiovascular events; (7) systolic blood pressure≥170 mm Hg or diastolic blood pressure≥95 mm Hg; (8) active inflammatory, autoimmune, infectious, hepatic, gastrointestinal, malignant, or uncontrolled psychiatric disease; (9) ≥5% change in weight during the 3-month period prior to screening; (10) personal or family history of medullary thyroid cancer [26]; (11) personal or family history of multiple endocrine neoplasia syndrome type 2 [26]; (12) previous history of pancreatitis [26]; (13) electrocardiogram with QTc prolongation (QTc>470 ms in men or >480 ms in women) or evidence of ischemic changes; (14) personal history of diabetic retinopathy [26]; (15) allergy to semaglutide; and (16) type 1 diabetes or other insulin dependent diabetes. Individuals who initially fail their initial screening are eligible to be rescreened 12 weeks after their initial screening.

Recruitment methods include electronic medical records and Barshop Call Center Registry queries, community engagement activities, and web-based advertisements (including social media). Potential participants undergo a prescreening questionnaire to ensure they meet the inclusion and exclusion criteria for enrollment. Those who qualify from the prescreening questions are scheduled for a full in-clinic screening evaluation and sent an advance copy of the consent form.

We conduct an in-clinic evaluation consisting of medical and social history, current medications, vital signs, anthropometric measurements, and physical examination. Additionally, a fasting blood profile is collected to assess a complete metabolic panel, complete blood count, HbA_1c, thyroid stimulating hormone, and coagulation panel. Body composition analysis, evaluation of physical function, and completion of patient-reported measures, as detailed below, also are carried out during this visit.

Assessments are performed at baseline (screening or visit 1) and the end of the study (visits 6a and 6b) for both groups (Textbox 1).

The primary outcomes include changes in lean mass, 6-minute walk distance, grip strength, and short physical performance battery after the 20-week intervention between the semaglutide and lifestyle compared to lifestyle alone groups. We use intention-to-treat principles per the Consolidated Standard of Reporting Trials for analysis [39]. Experimental results are expressed as means (SEM). Comparisons of means between groups are performed by analysis of variance for repeated measures and general linear model are used to add covariates. Associations, within a group, between aging-related biomarkers versus body composition and physical function outcomes are determined by Pearson correlation. For tests of correlation coefficients between groups, we use Fisher Z transformation. Multiple regression analysis was used to determine the relationship between aging-related biomarkers and body composition and physical function outcomes. Covariates include age, sex, ethnicity, and BMI. Alpha equal to .05 is used to determine significance. We plan for 20 participants, 10 per group, to accomplish this pilot study within the funding mechanism timeframe. The data generated through this study are used to guide sample size and power calculations for further studies. The Biostatistics Core of the San Antonio Claude D Pepper Older Americans Independence Center is assisting with statistical analyses. Planned software analysis program is SAS (version 9.4; SAS Institute).

Adverse events are assessed during set interactions with the participants. This includes in-person visits at the research facility and a telemedicine encounter during visit 7. They will also be provided with information on how to contact the research team if they have concerns about medication adverse reactions between visits. All adverse events are logged and reported to the institutional review board. Additionally, adverse events are reviewed by a medical doctor to determine the severity, the event’s relationship to the study intervention, and what action should be taken.

Each participant is assigned a study code not associated with their name. Data are saved and stored using REDCap (Research Electronic Data Capture; Vanderbilt University) electronic data management system, which is a secure, password-protected, local area network hosted at the University of Texas Health Science Center at San Antonio. Participants’ charts, which will include all the visits’ documents, are kept inside a locked cabinet located in the clinical research space.

The study is approved by the University of Texas Health Science Center San Antonio institutional review board (20220256HU) in accordance with the ethical standards of the responsible committees on humane experimentation and the Declaration of Helsinki. Eligible participants sign the informed consent after a research staff member has explained the study and answered all questions. Participants may choose to leave or opt out of the study at any time without penalty. Participants receive compensation for their time up to US $425 through a ClinCard if all visits are completed. Privacy and confidentiality are maintained by having only authorized research staff accessing patient health information, keeping participant files in a locked cabinet, and providing access to REDCap to the minimum authorized research staff. The study is registered with ClinicalTrials.gov (NCT05786521).

The purpose of this study is to investigate the effect of semaglutide in addition to lifestyle counseling compared to lifestyle alone on body composition, physical function, and systemic and local biomarkers of aging. We hypothesize that semaglutide therapy will improve body composition and physical function and that these clinical improvements are supported by positive changes to biomarkers of aging.

GLP-1 receptor agonists are a relatively novel group of antihyperglycemic agents that are prescribed in increasing frequency [40]. Thus far, glycemic control, cardiovascular benefits, and whole-body weight reduction have been observed in people treated with semaglutide [10,11,41]. The majority of studies on GLP-1 receptor agonist use suggest a loss of lean mass, though this is not universally observed [18,19]. With the popularity of these medications, the additional effects on health parameters especially important to older adults such as function and lean body mass need to be thoroughly evaluated.

Although there have been few studies examining the effect of semaglutide on measures of health span in older adults, several preclinical studies have been conducted. Semaglutide treatment in obese mice resulted in an increase of type I/II muscle fibers, muscle fiber density, mitochondrial mass, and decline of TNFα, IL6, and IL-1β compared to untreated obese mice, resulting in the semaglutide-treated mice having a muscle quality similar to the nonobese control group [42]. In a mouse model of sarcopenic obesity, where mice were fed a high-fat diet, treatment with semaglutide led to enhancements in muscle strength, muscle fiber characteristics, and markers of muscle atrophy when compared to mice that did not receive treatment. [43]. The improvements in muscle quality and strength seen with semaglutide may be through the SIRT1 pathway, which is a key regulator of skeletal muscle biology and function. SIRT1 has also been associated with the ability of GLP-1 receptor agonists to improve hepatic steatosis and skeletal muscle insulin resistance [44,45]. This study intends to add to this mechanistic research by providing an insight into the effects of semaglutide on biomarkers of aging. These findings may be especially relevant to older adults as clinical targets for future evaluation and potential intervention.

Although this is a randomized controlled trial, there are potential limitations. As this is an open-label trial, the lack of blinding can lead to ascertainment bias [46]. The small sample size for this pilot may lead to a type II error. Given the 5-month duration of the trial, it is possible that maximum weight loss may not be attained. Consequently, we lack a comprehensive understanding of the full impact of this class of medication under conditions of maximum weight loss.

Based upon the known glycemic, cardiovascular, and body weight loss effects of GLP-1 receptor agonists in the treatment of T2DM and chronic weight management, we are conducting a clinical trial to expand this work by examining the effects of semaglutide on body composition, physical function and biomarkers of aging in older adults with prediabetes and well-controlled T2DM. This study fills a significant gap by focusing on the effect of frequently used medication in older adults and infrequently studied outcomes of clinical significance in this population. The findings will serve as valuable insights for future research endeavors, potentially shaping the treatment approaches using GLP-1 receptor agonists among older adults.