Body Composition Changes After Initiation of GLP-1 Receptor Agonists in Adults With Obesity or Type 2 Diabetes

Type 2 diabetes affects more than 500 million people worldwide, and in Mexico it affects about 17% of adults, often together with obesity, which affects around 37.1% of adults. This combination substantially increases the risk of cardiometabolic complications. GLP-1 receptor agonists (GLP-1RAs), also known as GLP-1 analogs or incretin mimetics, have changed the treatment of type 2 diabetes and obesity by producing clinically meaningful weight loss and improving metabolic outcomes. These medications mimic the body's incretin hormones, activating specific receptors that increase glucose-dependent insulin release and reduce glucagon release, helping control blood sugar. Their safety profile is well characterized. The most common side effects are gastrointestinal, mainly nausea, vomiting, and diarrhea, which tend to be dose dependent, occur mostly during dose titration, and are usually mild to moderate and temporary, though they are the main reason some people stop treatment.

Although these medications are effective for weight loss, most research so far has focused on total body weight rather than how different parts of the body change, particularly the balance between fat and muscle. This matters because the quality of weight loss, meaning how much comes from fat versus from muscle, can affect strength and physical function over time. The research question this study addresses is what the size and pattern of changes in body composition, specifically appendicular lean mass and fat mass measured by DXA, after adults with obesity and/or type 2 diabetes start a GLP-1 receptor agonist under real world clinical conditions. The working hypothesis is that after starting GLP-1RA therapy, participants will show longitudinal changes in body composition characterized by a reduction in fat mass along with a simultaneous decrease in appendicular lean mass, with different patterns of change across individuals, under real world conditions.

The main objective of the study is to evaluate the size and trajectory of changes in appendicular lean mass and fat mass, measured by DXA, over 12 months after starting or adjusting a GLP-1RA in adults with obesity and/or type 2 diabetes treated under real world conditions.

The study also has several secondary objectives. These include identifying patterns that link the loss of appendicular lean mass with the regain of body fat during follow-up; assessing changes in grip strength and how they relate to changes in appendicular muscle mass; and evaluating whether treatment adherence, dose reduction, or stopping treatment is associated with a higher likelihood of losing muscle mass or regaining fat. The study will also assess changes in physical performance and functional mobility, using usual walking speed and the Timed Up and Go test in adults, and the Short Physical Performance Battery in older adults specifically, and it will assess changes in metabolic and biochemical parameters during follow-up, including HbA1c, fasting glucose, lipid profile, and C-reactive protein. Other secondary aims are to develop a predictive model for appendicular lean mass loss and fat regain based on clinical and body composition variables, and to explore the association between changes in appendicular muscle mass and glycemic control. At one of the two study sites only, the study will evaluate changes in resting energy expenditure measured by indirect calorimetry and their relationship with changes in body composition. The study will also evaluate sarcopenia risk using the SARC-F questionnaire, comparing scores of 0 to 10 and a threshold of 4 or higher, and how this evolves at 24 and 52 weeks, exploring its association with appendicular lean mass and the appendicular skeletal muscle index. Finally, as an exploratory analysis, and only among participants who choose to provide an optional blood sample described below, the study will look at whether a specific genetic variant, rs10305420 in the GLP1R gene, is associated with the size and pattern of longitudinal changes in body weight, body mass index, and appendicular lean mass.

This is a prospective, observational, multicenter cohort study conducted under routine clinical practice conditions, sometimes called a real world study. It is not a drug trial. The research team will not assign, adjust, or withhold any medication. Each participant's treating physician makes all treatment decisions, including which GLP-1 receptor agonist to prescribe, dosing, and any changes over time, based on clinical indication, current treatment guidelines, medication availability, coexisting conditions, and the patient's preferences. There is a single study group and no comparator or control group, and treatment assignment is not randomized.

Potential participants are identified through institutional clinical databases, electronic medical records, clinic appointment schedules, and institutional social media at each participating site. Adults 18 years of age or older with a documented diagnosis of obesity and/or type 2 diabetes are eligible if their treating physician has indicated, as part of routine care, a therapy with activity on the GLP-1 receptor. This includes GLP-1 receptor monoagonists, dual GIP/GLP-1 coagonists, or other multiple coagonists with activity on the GLP-1 receptor that hold current health authorization for clinical use in Mexico. This study excludes experimental products, unauthorized medications, and formulations intended solely for research. Participants can enter the study in one of two ways: by starting an eligible therapy during the recruitment period, or by being in an active dose titration phase, meaning they have had at least four weeks of prior exposure to an eligible therapy, their treating physician has indicated a dose escalation, and they have not yet reached a stable maintenance dose, defined for this study as a dose that has remained unchanged for at least eight consecutive weeks. For participants with prior treatment exposure, the study will document the original treatment start date, the medication used, previous doses, any dose escalations, duration of exposure, weight recorded before starting treatment when available, and the dose corresponding to the index date. Participants must also be willing and able to attend follow-up evaluations at 24 weeks (plus or minus 3 weeks) and 52 weeks (plus or minus 6 weeks), and must sign informed consent to take part.

Participants will not be included, or will be excluded, if they have a diagnosis of type 1 diabetes or other specific forms of diabetes; if they are pregnant or breastfeeding at the time of recruitment; if they have conditions that limit an adequate DXA body composition measurement, such as body weight above the equipment's technical limit of 159 kg, the presence of metallic devices or materials that interfere with the scan, or having had a radiologic contrast study within the 7 days before the evaluation; if they have an acute illness at recruitment that could interfere with study evaluations or longitudinal follow-up, including hospitalization in the 4 weeks before the baseline visit, active pneumonia, acute COVID-19 infection, diabetic ketoacidosis, or major surgery in the 6 weeks before recruitment; if they have chronic diseases or conditions associated with severe alterations in body composition, such as active cancer, active systemic inflammatory disease, advanced heart failure, or kidney disease requiring replacement therapy; if they have current or recent, meaning within 3 months, use of systemic corticosteroids at chronic pharmacologic doses or medications with a direct effect on muscle mass; if they have current or recent, meaning within 3 months before the index date, use of weight loss medications other than GLP-1RA, such as phentermine, topiramate, or naltrexone/bupropion; or if they are simultaneously enrolled in a double blind randomized clinical trial. During follow-up, a participant may be withdrawn from the study if they withdraw their consent, or if they develop a clinical condition that, in the judgment of the investigators, makes it unfeasible or unsafe to continue, such as a prolonged hospitalization, a major acute event, or severe functional decline.

Recruitment will rely on institutional clinical databases from the Unidad de Investigación de Enfermedades Metabólicas (UIEM) and the Instituto de Diabetes, Obesidad y Nutrición S.C. Phone numbers and contact information used by the research team will come exclusively from information already on file in the clinical record or institutional databases. Authorized research staff will make first contact by phone, explaining the study in general terms, including the procedures involved, estimated duration, and possible benefits and risks of participating. If a person expresses interest and meets the inclusion and exclusion criteria, staff will schedule a baseline visit. Informational materials about the study will also be shared through institutional social media and displayed in visible areas at participating sites for informational purposes only, and participation is voluntary. Interested individuals who see these materials may contact the research team by phone or email, and the team will carry out an initial eligibility screening before giving detailed study information or scheduling any related procedure. People already enrolled in a double blind randomized clinical trial will not be included. Based on the sample size calculation and anticipated losses during follow-up, of up to about 20% at 52 weeks, the study plans to recruit a total of approximately 168 participants across both centers, 84 at the main site (UIEM, INCMNSZ) and 84 at the collaborating site (IDON SC). No incentives, in kind or otherwise, will be offered to participants.

For participants who begin a new therapy, the index date is the start date of that therapy. For participants who join during the active titration phase, the index date is the date of the documented dose escalation that led to their enrollment. Participants will be followed for 52 weeks to evaluate the study outcomes. Concomitant use of other glucose lowering medications, including metformin, SGLT2 inhibitors, DPP-4 inhibitors, sulfonylureas, or insulin, is permitted and will be documented systematically at each follow-up visit. If GLP-1RA treatment is permanently discontinued during follow-up, the participant will be censored at the date of discontinuation for the longitudinal analyses.

Participants will be assessed at three time points. A baseline visit will include the full set of evaluations described below. A phone contact at 12 weeks will be used to document treatment continuity, current dose, any titration, interruptions, or discontinuation. In person follow-up visits will take place at 24 and 52 weeks. At the site UIEM, vital signs, including blood pressure, heart rate, and oxygen saturation, are measured after a 5 minute rest, with the participant seated, feet flat on the floor, back against the chair, and the left arm resting, using a Welch Allyn Connex vital signs monitor. Height is measured with a Seca 360 degree stadiometer, with the participant barefoot, heels together, toes apart, legs straight, shoulders relaxed, and the head positioned in the Frankfort plane, and is recorded to the nearest 0.1 cm. Waist circumference is measured at the midpoint between the last rib and the top of the iliac crest, at the end of a normal exhalation without compressing the skin with the tape, and is recorded to the nearest 0.1 cm using a Lufkin W606PMMX tape measure; hip circumference is measured with the participant standing with legs together, at the most prominent point of the buttocks. Grip strength is assessed with a TAKEI TKK5401 dynamometer, with three trials on the dominant arm separated by 1 minute rest between each. Body weight is measured on a Seca 515/514 bioimpedance scale, with the participant having an empty bladder, having not eaten, wearing light clothing, with no metal objects, and without socks or shoes; once weight is obtained, the participant places feet and palms on the corresponding electrodes for the bioimpedance measurement. Body composition is measured with a GE Healthcare Lunar Prodigy Advance (Encore version 16) DXA densitometer, with the participant lying face up at the center of the scanning table, arms within the scan area, and velcro bands used to secure the knees and feet to prevent movement during the scan. At the UIEM site only, indirect calorimetry using a Schiller Cardiovit CS-20 device measures resting energy expenditure.

The study uses several questionnaires. A standardized clinical history and pharmacologic treatment questionnaire, developed and standardized by the UIEM and applied consistently at both sites, is administered through a direct interview lasting about 30 minutes to collect sociodemographic and clinical information. The IPAQ, or International Physical Activity Questionnaire, is a widely used tool that evaluates a person's level of physical activity through questions about the amount and intensity of activity performed at work, at home, during transport, and in leisure time. A 24 hour dietary recall is used to gather detailed information about a person's diet, including nutrients consumed, portion sizes, and food choices. A 7 day semiquantitative food frequency questionnaire, covering 140 foods and beverages and previously validated for estimating energy and nutrient intake in the Mexican population, is also used to collect dietary information. The SARC-F questionnaire is a brief clinical screening tool designed to identify sarcopenia risk in older adults, evaluating five domains related to muscle function and physical performance: strength, meaning difficulty lifting or carrying weight; need for assistance walking; difficulty rising from a chair; difficulty climbing stairs; and the number of falls in the past year, with each item scored from 0 to 2. In addition to these questionnaires, functional assessments include usual gait speed and the Timed Up and Go test in adults, and the Short Physical Performance Battery specifically in older adults.

During the study, venous blood samples will be collected from each participant at the three follow-up visits, for clinical chemistry analysis, a lipid panel, HbA1c, glucose, total cholesterol, HDL, LDL, non-HDL cholesterol, triglycerides, serum creatinine, ALT, AST, GGT, uric acid, insulin, C-reactive protein, and, at baseline, apolipoprotein B. Participants who accept an optional pharmacogenetic component will have an additional blood sample of about 4 mL collected in an EDTA tube during the same baseline blood draw. This sample will be used to extract genomic DNA and determine the rs10305420 variant of the GLP1R gene, as well as ancestry informative markers included in the protocol. Declining to provide this additional sample will not prevent participation in the main cohort. Biological samples will not be used to create permanent or immortalized cell lines, nor will they be stored for purposes unrelated to the study.

The variables followed throughout the study include changes in appendicular lean mass, changes in the appendicular skeletal muscle index, changes in resting energy expenditure, changes in total fat mass, changes in body fat percentage, changes in visceral fat, changes in body weight, changes in body mass index, changes in muscle strength, changes in physical performance, changes in sarcopenia risk, and changes in bone mineral density at the lumbar spine and at the hip. Biochemical variables followed include HbA1c, glucose, blood urea nitrogen, total cholesterol, HDL, LDL, non-HDL cholesterol, triglycerides, serum creatinine, ALT, AST, GGT, uric acid, insulin, and C-reactive protein. Vital signs included blood pressure, heart rate, and oxygen saturation, and anthropometric measurements included weight, height, waist circumference, and hip circumference.

The sample size was calculated using a paired means comparison, designed to detect a minimum clinically relevant difference of 0.5 kg in the change in appendicular lean mass, roughly equivalent to 5% of the average baseline value reported in adults treated with GLP-1 receptor agonists. A standard deviation of 2.0 kg for this change was assumed, based on body composition studies in adults treated with GLP-1RA that report a variability in muscle change of between 1.5 and 2.5 kg, adopting a conservative assumption within that range. The calculation used a two sided alpha of 0.05 and a power of 80%. Accounting for an anticipated 20% loss to follow-up, this results in a target sample size of 168 participants. Baseline characteristics will be described by group using means with standard deviation, or medians with interquartile range, for continuous variables, and frequencies with percentages for categorical variables. A two sided significance level of 0.05 will be used, and estimates will be reported with 95% confidence intervals. For the main objective, changes in body composition after starting GLP-1RA will be evaluated using linear mixed models for repeated measures. The outcomes analyzed will be the DXA derived body composition variables, namely appendicular lean mass, the appendicular skeletal muscle index, total fat mass, body fat percentage, and visceral fat. The models will include fixed effects for time, meaning baseline, 24 weeks, and 52 weeks, along with adjustment for relevant clinical, pharmacological, and ancestry related covariates, and a random intercept for each participant.

Data will be captured at the main site using the REDCap platform, and at the Cuernavaca site using an electronic form built in Google Forms with the same structure and content, so that data collection is equivalent across sites. To protect confidentiality, the electronic forms will not record direct identifying information; each participant will be assigned a unique code. Authorized research personnel will have access to the forms, and information will later be integrated into a central, anonymized database for analysis. The analysis database will not include direct identifiers such as name, phone number, or other personal data, and only the responsible investigator at each site will safeguard participant identity. Trained personnel will enter all collected data and validate it through double verification to ensure accuracy and consistency; records will be stored electronically with restricted access, in accordance with institutional confidentiality policies and Good Clinical Practice.

Any modification to the protocol, data collection instruments, or study procedures must be reported to and approved by the Research Ethics Committee before implementation, and will be evaluated based on its impact on participant safety, the study's methodological design, and the validity of the results. Overall follow-up and data management for the study will be carried out by the principal investigator, with support from a co-investigator, who will supervise protocol compliance, data quality, and regulatory aspects of the study. Periodic review sessions will take place bimonthly by remote meeting, with additional reviews held as needed to resolve specific discrepancies or issues. During these sessions, the team will verify that informed consent was properly obtained and documented, review the completeness, consistency, and traceability of the data collected, supervise compliance with inclusion and exclusion criteria, and confirm adherence to the protocol. Because this is an observational, minimal risk study, an independent Data Safety Monitoring Board will not be established; however, participant safety will be continuously monitored by the principal investigator and the clinical team.

The study will be considered successful if it reaches the estimated sample size, or at least 80% of the planned total, within the established period, and produces a database sufficient to evaluate the stated objectives. It could be considered unsuccessful if recruitment falls below 60% of the planned sample size, if losses to follow-up exceed 30%, if there is a systematic absence of key measurements that prevents evaluation of the main outcome, if there are significant ethical or regulatory noncompliance issues, or if the study is suspended by institutional decision or by the Ethics Committee due to unforeseen risks to participants.

Because participants continue to receive only the treatment prescribed by their own treating physician as part of routine clinical care, the study does not involve any research assigned medication, and no procedures for managing an overdose are contemplated within the protocol; any such situation would be handled through standard medical care. As this is an observational study conducted under real world clinical practice conditions, no risks beyond those associated with standard medical care are anticipated, and any adverse event that may occur will be addressed according to the standard institutional procedures at each participating site.

Direct benefits to participants include access to specialized body composition evaluation by DXA and, at one site, measurement of resting energy expenditure by indirect calorimetry, assessments that provide additional information beyond what is typically obtained in routine clinical practice. Routine clinical and laboratory studies, and usual medical care including the delivery of results, will continue according to institutional clinical practice and are not considered direct benefits of participating in the research protocol. Indirect benefits include generating precise information to better understand the role of GLP-1 receptor agonists in the development of changes in body composition; the information obtained may help identify clinical and biochemical predictors associated with therapeutic response, which could support the future development of more personalized therapies and more effective clinical strategies to prevent or reduce the loss of muscle mass and its metabolic and functional consequences in this population.

Although a participant is not required to explain the reason for withdrawing early from the study, the investigator will make a reasonable effort to determine the reason while fully respecting the participant's rights. When a reason is shared, it will be recorded specifically as the main reason for discontinuation, rather than simply as a withdrawal. No specific medication or treatment is planned to be provided at the end of the study; participants will continue with the usual therapy prescribed by their treating physician at their own health care facility.

The study's direct costs will be covered with institutional resources from the participating sites. At the main site, these will be financed by the Unidad de Investigación de Enfermedades Metabólicas (UIEM) at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, covering body composition assessments and materials needed for data collection. At the collaborating site, costs associated with recruiting and following participants, as well as clinical and laboratory studies, will be covered with the institution's own resources, in line with routine clinical practice and each institution's available resources. Most of the laboratory and imaging studies included in the protocol correspond to evaluations already performed as part of routine medical care, which supports the operational feasibility of the study. Participation will involve no cost to participants and no additional expenses related to their inclusion. Calibration and preventive maintenance of the DXA equipment will follow each participating site's standard institutional procedures and will be covered with each institution's operating resources. The study is conducted using existing infrastructure and administrative resources at each site, so no additional indirect costs are anticipated, and because it is an observational study performed under routine clinical practice conditions, no risks beyond those of standard medical care are expected; any adverse event will be managed according to each site's standard institutional procedures. The study is financed entirely through institutional resources at the participating sites and does not receive funding from the pharmaceutical industry or other commercial entities, and no financial compensation will be provided to participants.

Inclusion criteria

• Agrees to participate in the study by signing informed consent
• Age 18 years or older
• Diagnosis of obesity and/or type 2 diabetes mellitus, documented in the clinical record
• Receiving, on indication of the treating physician and as part of routine clinical care, a therapy with activity on the GLP-1 receptor, including a) GLP-1 receptor monoagonists, b) dual GIP/GLP-1 coagonists, or c) other multiple coagonists with activity on the GLP-1 receptor holding current health authorization for clinical use in Mexico
• Meeting one of the following conditions at the time of recruitment: a) starting an eligible therapy during the recruitment period, or b) being in an active dose titration phase, with an upward dose escalation documented by the treating physician, even if treatment started four or more weeks earlier, provided the participant has not yet reached a stable maintenance dose
• Willingness and ability to attend follow up evaluations at 24 weeks (plus or minus 3 weeks) and 52 weeks (plus or minus 6 weeks)

Exclusion criteria

• Diagnosis of type 1 diabetes or other specific forms of diabetes
• Pregnancy or breastfeeding at the time of recruitment
• Conditions that limit adequate measurement of body composition by DXA, including body weight above the equipment's technical limit of 159 kg, the presence of metallic devices or materials that interfere with the measurement, or having undergone a radiologic contrast study within the 7 days before the evaluation
• Acute illness at the time of recruitment that could interfere with the study evaluations or with longitudinal follow up, including hospitalization within the 4 weeks before the baseline visit, active pneumonia, acute COVID-19 infection, diabetic ketoacidosis, or major surgery within the 6 weeks before recruitment
• Chronic diseases or conditions associated with severe alterations in body composition, such as active cancer, active systemic inflammatory disease, advanced heart failure, or kidney disease on replacement therapy
• Current or recent use, within 3 months, of systemic corticosteroids at chronic pharmacologic doses or medications with a direct modulating effect on muscle mass
• Current or recent use, within 3 months before the index date, of weight loss medications other than GLP-1RA, such as phentermine, topiramate, or naltrexone/bupropion
• Simultaneous participation in a double blind randomized clinical trial