This study examines how two different weight-loss strategies affect heart and metabolic health, as well as changes at the molecular level in the body. One group includes adults who are starting a GLP-1 receptor agonist medication (i.e., semaglutide or tirzepatide) prescribed by their own doctor for weight loss. The other group includes adults who will participate in a structured lifestyle program combining a reduced-calorie diet with increased physical activity. Both groups complete assessments at the start of the study and again after three months.
At each visit, participants have their weight, body composition, blood pressure, and resting metabolic rate measured. A blood draw is collected to evaluate cholesterol, blood sugar, insulin, appetite hormones, and liver and kidney function markers, and to analyze gene activity (RNA sequencing) and metabolites, which are small molecules that reflect how the body is using energy and nutrients. Participants also complete online questionnaires about diet, disordered eating, stress, mental health, and quality of life. Those in the lifestyle group attend three individual nutrition and physical activity counseling sessions over the course of the study.
The main goals of the study are (1) to determine whether GLP-1 receptor agonist medication or lifestyle changes produce greater improvements in heart and metabolic health markers over three months; (2) to examine if GLP-1 receptor agonist medication or lifestyle changes produce greater improvement in disordered eating, stress, mental health, and quality of life; (3) to investigate if GLP-1 receptor agonist medication or lifestyle changes produce greater improvement in appetite-related hormones (i.e., ghrelin, GLP-1, insulin, leptin, and peptide YY); and (4) to explore whether the two approaches cause different changes in gene expression and metabolic profiles. This is a pilot study conducted at Texas Tech University's Nutrition and Metabolic Health Initiative clinic in Lubbock, Texas.
Who can participate: Adults aged 18 years and older with a BMI of 27.5 or higher who are either starting semaglutide or tirzepatide therapy for weight management or who are seeking weight management without the use of weight-loss medications.
Who cannot participate: Individuals who are pregnant or lactating, have a pacemaker or internal medical device, have certain serious medical conditions (such as active cancer, uncontrolled hypertension, or severe kidney disease), have type 1 diabetes, or use insulin for type 2 diabetes.
Age 18 years or older
BMI of 27.5 kg/m2 or higher
For GLP-1 RA arm: initiating semaglutide or tirzepatide for weight loss as prescribed by their own medical provider
For LS comparator arm: not currently taking a GLP-1 receptor agonist or other weight-loss medication, and no use of weight-loss medication within the past 3 months
Pregnant
Breastfeeding
Wears a pacemaker or other internal medical device
Chronic kidney disease in the past 2 years
Parallel
GLP-1 Receptor Agonist Therapy
DrugParticipants receive semaglutide or tirzepatide as prescribed by their own medical provider prior to study enrollment. Dosing and titration followed the prescribing provider's clinical judgment and are not controlled by the study team. Both medications are GLP-1 receptor agonists approved for weight management and glycemic control; tirzepatide additionally acts on the glucose-dependent insulinotropic polypeptide (GIP) receptor.
Structured Lifestyle Intervention
BehavioralA reduced-calorie diet providing a 500 kcal daily deficit from individually calculated total energy expenditure, combined with a goal of 150 to 300 minutes of moderate-intensity physical activity per week. Total energy expenditure is estimated by multiplying each participant's measured resting metabolic rate (MedGem indirect calorimetry) by a standard physical activity factor. Meal plans are based on the Academy of Nutrition and Dietetics Nutrition Care Manual. Three individual counseling sessions are delivered over three months in person or via a HIPAA-secured video platform.
Change in Fasting Blood Glucose
Fasting serum blood glucose measured from venipuncture sample and analyzed as part of the basal metabolic panel. Used as the reference outcome for power estimation; a between-group difference of 4.71 mg/dL was the minimum detectable effect based on a prior semaglutide meta-analysis (SD = 9.9 mg/dL).
Change in LDL Cholesterol
Serum LDL cholesterol measured from a fasting venipuncture sample. A decrease of 10% or more from baseline is considered clinically meaningful.
Change in Triglycerides
Serum triglycerides measured from fasting venipuncture sample. A decrease of 30% or more from baseline is considered clinically meaningful.
Change in Fasting Insulin
Serum fasting insulin measured from venipuncture sample. Used alongside fasting glucose to characterize insulin resistance.
Differential Gene Expression Profiles
Whole-blood RNA sequencing analyzed using DESeq2 to identify differentially expressed genes from baseline to 3 months within each arm and between arms. Gene Set Enrichment Analysis used to identify enriched biological pathways.
Change in Plasma Metabolomic Signatures
Untargeted metabolomics conducted on plasma samples. Univariate and multivariate analyses including principal component analysis and partial least squares discriminant analysis performed using the MetaboAnalyst R package.
Association Between Gene Expression Changes and Cardiometabolic Outcome Changes
Pearson or Spearman correlations and partial least squares regression used to examine associations between transcriptomic change scores and changes in lipid panel, blood glucose, insulin, and blood pressure within and between arms.
Change in Dietary Intake
Dietary intake patterns assessed using the Short Food Frequency Questionnaire administered via Qualtrics.
Change in Body Weight and Body Mass Index (BMI)
Body weight measured using a calibrated scale. BMI calculated from measured height and weight.
Change in Body Composition
Lean mass and fat mass assessed via bioelectrical impedance analysis (BIA).
Change in Resting Metabolic Rate
Resting metabolic rate measured using the MedGem indirect calorimetry device following standard protocol.
Change in Appetite-Related Hormones
Serum concentrations of ghrelin, GLP-1, insulin, leptin, and peptide YY measured from fasting venipuncture samples.
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