Changes in Body Composition Following Pharmacological Treatment for Obesity.

Background and Rationale Obesity is a chronic, complex disease associated with an increased risk of type 2 diabetes, cardiovascular disease, metabolic dysfunction, and reduced quality of life. In recent years, the introduction of highly effective anti-obesity medications, particularly semaglutide and tirzepatide, has substantially improved the possibilities for achieving clinically meaningful and sustained weight loss.

However, weight loss involves changes not only in body fat but also in lean body mass, which includes skeletal muscle, organs, body water, and other non-fat tissues. Previous research suggests that approximately 10-30% of total weight lost during obesity treatment may consist of fat-free mass, although this proportion varies considerably depending on the intervention, patient characteristics, and measurement methods.

For example, a person losing 10 kg of body weight may also experience a reduction in fat-free mass of approximately 1-3 kg. Importantly, a reduction in fat-free mass does not necessarily correspond to an equivalent loss of skeletal muscle tissue or muscle function.

This distinction is particularly relevant because skeletal muscle plays a fundamental role in mobility, physical independence, glucose metabolism, energy expenditure, and long-term metabolic health.

Although clinical trials have demonstrated substantial reductions in body weight and fat mass with semaglutide and tirzepatide, important questions remain regarding their effects on skeletal muscle. In particular, relatively limited information is available about whether changes in muscle mass during treatment are accompanied by measurable reductions in muscle strength, physical performance, or the ability to carry out everyday activities.

Understanding these effects is essential for optimizing obesity treatment. The goal should not simply be to reduce body weight, but to improve body composition while preserving muscle strength, physical function, and overall health.

Study Objectives The main objective of this study is to investigate how treatment with semaglutide or tirzepatide affects body composition and muscle function in adults living with obesity.

Specifically, the study aims to:

Evaluate changes in body composition after more than six months of pharmacological treatment, including changes in total body weight, fat mass, fat-free mass, and estimated skeletal muscle mass.

Assess changes in muscle strength and physical performance, determining whether reductions in fat-free mass are associated with changes in functional capacity.

Explore factors associated with muscle preservation, including age, sex, degree of weight loss, dietary protein intake, and participation in structured physical activity.

Examine differences in body composition and functional outcomes according to the magnitude of weight loss and the medication received.

Investigate additional changes in abdominal adipose tissue and skeletal muscle morphology through optional ultrasound assessments at participating centers.

An additional objective is to generate clinically relevant evidence that may help healthcare professionals develop strategies to preserve muscle health during obesity treatment.

Study Design and Participants This is a prospective, observational, multicenter study coordinated by the Obesity Section of the Spanish Society of Endocrinology and Nutrition (SEEN).

The study will involve several Spanish healthcare centers with experience in the management of obesity.

Participants will be adults living with obesity, without diabetes, who are receiving semaglutide or tirzepatide as part of their routine clinical care.

The study will evaluate participants before treatment and after a treatment period exceeding six months, allowing researchers to examine changes in body composition and muscle function over time.

As an observational study, treatment decisions will remain under the responsibility of the attending physicians, following routine clinical practice. Participants will not be randomly assigned to either medication.

Study Assessments

1. Body Composition Body composition will be assessed using bioelectrical impedance analysis (BIA), a non-invasive technique that estimates the relative contributions of fat mass and fat-free mass to total body weight.

   Measurements will include:

   Total body weight and percentage weight loss. Fat mass, expressed in kilograms and as a percentage of body weight. Fat-free mass, expressed in kilograms and as a percentage of body weight. Estimated skeletal muscle mass. Estimated appendicular skeletal muscle mass, representing the muscle mass of the arms and legs.

   These assessments will help determine whether weight loss is predominantly attributable to reductions in body fat and how the relative contribution of fat-free mass changes during treatment.

   Because bioimpedance estimates depend on hydration status and other physiological factors, measurements will be performed under standardized conditions whenever possible.

2. Muscle Strength and Physical Function Muscle health involves more than the quantity of muscle tissue. Muscle strength and physical performance are particularly important because they directly influence mobility, independence, and the ability to perform daily activities.

   Two simple, validated clinical tests will be used. Handgrip strength: Participants will be asked to squeeze a handheld dynamometer, which measures the force generated by the hand and forearm muscles. Handgrip strength is widely used as an indicator of overall muscle strength and functional health.

   Chair-stand test: Participants will perform a standardized test involving repeated transitions from a seated to a standing position. This test provides information about lower-limb functional performance, which is particularly relevant for activities such as standing up, climbing stairs, and maintaining independence.

   By combining body composition measurements with functional assessments, researchers will investigate whether reductions in estimated muscle mass are accompanied by changes in muscle strength or performance.

3. Additional Ultrasound Assessments Participating centers with the necessary equipment and expertise may undertake optional ultrasound sub-studies.

   Abdominal ultrasound will be used to measure the thickness of subcutaneous and preperitoneal adipose tissue, providing additional information about regional fat distribution.

   Musculoskeletal ultrasound of the rectus femoris will allow researchers to examine muscle morphology and explore whether structural changes occur during weight loss.

   These complementary assessments may improve understanding of changes that cannot be fully characterized using bioimpedance alone.

4. Nutrition, Physical Activity, Treatment Tolerability, and Quality of Life The study will also collect information on several factors that may influence body composition and muscle health.

These include dietary habits, particularly protein intake; participation in physical exercise and resistance training; adverse effects associated with semaglutide or tirzepatide; and patient-reported quality of life.

This information will help researchers explore why some individuals preserve muscle mass and strength more effectively than others despite achieving similar reductions in body weight.

Statistical Analysis The principal analyses will examine changes in body composition, muscle strength, and physical performance between baseline and follow-up.

Participants will also be evaluated according to their percentage of weight loss and clinically relevant weight-loss categories.

Researchers will explore associations between changes in fat-free mass, estimated skeletal muscle mass, handgrip strength, and chair-stand performance.

Where appropriate, statistical models will account for potentially influential factors, including age, sex, baseline body composition, protein intake, and structured physical activity.

Exploratory univariable and multivariable regression analyses will be used to identify factors associated with clinically relevant changes in muscle mass or function.

Comparisons between semaglutide and tirzepatide may also be undertaken, while recognizing that treatment allocation is not randomized and that differences between patient groups may influence the observed results.

Expected Scientific and Clinical Relevance The increasing effectiveness of obesity medications has shifted attention toward an important clinical question: How can substantial weight loss be achieved while preserving muscle strength and physical function? This study seeks to address that question by examining both quantitative changes in body composition and their potential functional consequences.

Its findings may help clarify whether reductions in fat-free mass during treatment with semaglutide or tirzepatide are associated with meaningful changes in muscle strength and physical performance.

The study may also identify patient characteristics and lifestyle factors associated with better preservation of muscle health, potentially supporting more individualized nutritional and exercise recommendations.

For example, the results could contribute to determining which patients may benefit most from closer functional monitoring, adequate dietary protein intake, or structured resistance exercise during pharmacological obesity treatment.

Importantly, because the study is observational, it will primarily identify changes and associations rather than establish direct causal effects of either medication on skeletal muscle.

Potential Impact on Patient Care For individuals living with obesity, successful treatment involves more than achieving a lower number on the scale.

Preserving the ability to walk, climb stairs, carry out everyday tasks, and remain physically independent is an essential component of long-term health.

By integrating measurements of body composition, muscle strength, and physical performance, this multicenter Spanish study aims to provide a more comprehensive assessment of the benefits and potential limitations of modern pharmacological obesity treatments.

Ultimately, the findings could help guide a more personalized approach to obesity management, combining effective weight reduction with strategies designed to maintain muscle health, physical capacity, and quality of life.