Semaglutide (Novo Nordisk)

Weight loss drugs and bariatric surgery may work differently, but they lead to surprisingly similar results inside the body. Both significantly reduce fat while also causing a modest loss of muscle, reshaping overall body composition. Since muscle helps protect against early death, this balance matters more than the number on the scale. The study suggests these treatments improve health—but not without trade-offs.New research from Vanderbilt Health shows that both modern weight loss drugs and bariatric (weight loss) surgery can improve body composition in people with obesity. These treatments lead to a large drop in fat while also causing a smaller reduction in fat-free mass (including lean muscle). This balance matters because body composition plays a major role in long-term health. A higher proportion of fat mass (FM) is linked to a greater risk of death from obesity-related conditions, including cardiovascular problems. In contrast, a higher proportion of fat-free mass (FFM) is associated with a lower risk of death. Why Fat Loss and Muscle Preservation Matter The findings highlight an important tradeoff. While reducing fat is beneficial, maintaining lean mass is also critical for overall health and survival. Understanding how these two components change with different treatments remains an active area of research. The researchers noted that more studies are needed to better understand how FM and FFM shift after bariatric surgery or treatment with GLP-1 receptor agonist drugs in real-world clinical settings. Their findings were published in JAMA Network Open. Study Design and Patient Data The study was led by Danxia Yu, PhD, associate professor of Medicine in the Division of Epidemiology, and Jason Samuels, MD, assistant professor of Surgery. Researchers conducted a retrospective analysis using electronic health records. The study included 1,257 patients between the ages of 18 and 65 who underwent bariatric surgery at Vanderbilt Health from 2017 to 2022. It also included 1,809 patients treated with the drugs semaglutide or tirzepatide from 2018 to 2023. Individuals with a history of end-stage renal disease or congestive heart failure were excluded from the analysis. To evaluate changes in body composition, the researchers used bioelectrical impedance analysis. This method estimates FM and FFM based on individual characteristics such as height, weight, age, race, gender, history of diabetes, and duration of GLP-1 treatment. Key Findings Over 24 Months Over a 24-month period, both treatment approaches produced similar patterns. Patients experienced substantial reductions in FM along with modest decreases in FFM. At the same time, the ratio of FFM to FM increased, indicating an overall improvement in body composition. The study also found differences between men and women. Male patients tended to preserve fat-free mass more effectively over the long term compared to female patients. Research Team and Funding The first authors of the study were graduate student Zicheng Wang, MS, and postdoctoral fellow Lei Wang, PhD, both in Epidemiology. Additional contributors included Xinmeng Zhang and You Chen, PhD (Biomedical Informatics and Computer Science); Brandon Lowery (Vanderbilt Institute for Clinical and Translational Research); Lauren Lee Shaffer, MS, and Quinn Wells, MD (Cardiovascular Medicine); and Charles Flynn, PhD, Brandon Williams, MD, Matthew Spann, MD, and Gitanjali Srivastava, MD (Surgery). The research was supported in part by National Institutes of Health grants R01DK126721 and R01CA275864.

Researchers at 23andMe report that common variants in GLP1R and GIPR genes predict differential weight loss and gastrointestinal side effects among patients taking semaglutide or tirzepatide, according to a study published April 8, 2026 in Nature. The findings, drawn from a genome-wide association study of 27,885 GLP-1 receptor agonist users, identify the first potentially pharmacogenomically actionable loci for this drug class and lay groundwork for further research that could enable genotype-informed prescribing in obesity treatment. The study’s most statistically robust result centers on GLP-1-induced nausea, localized to the GLP1R locus, with genome-wide significant associations identified for nausea and vomiting. For efficacy, a missense variant in GLP1R (rs10305420, p.Pro7Leu) located in the receptor’s signal peptide was associated with approximately 0.76 kg additional weight loss per allele copy, with the effect attributed to enhanced receptor trafficking to the cell surface rather than altered ligand binding. No genome-wide significant loci for overall BMI loss were identified, consistent with a polygenic architecture for GLP-1 efficacy. The side-effect genetics yielded a mechanistically distinct finding specific to tirzepatide. A partial loss-of-function variant in GIPR (rs1800437, p.Glu354Gln) was associated with increased vomiting risk exclusively in tirzepatide users — not in those taking semaglutide, which lacks GIP receptor activity. The biological rationale is that GIP receptor co-activation in tirzepatide normally buffers GLP-1-induced nausea centrally; when GIPR function is impaired, that buffering is lost. Individuals homozygous for risk alleles at both GLP1R and GIPR loci showed 14.8-fold increased odds of tirzepatide-mediated vomiting, a finding that could have direct implications for drug selection prior to treatment initiation. The study was conducted entirely within 23andMe‘s consumer genetics infrastructure, with no academic university co-affiliations listed among the authors. Participants were recruited from the company’s customer base following a GLP-1 survey launched in August 2024. The primary GWAS for efficacy included 15,237 participants with percentage BMI loss as the outcome. Self-reported weight data showed strong correlation with electronic health record measurements in a 195-person overlap cohort (r ≈ 0.57), supporting the validity of the survey-based phenotyping approach. An independent replication cohort of 4,855 participants from the NIH’s All of Us program showed directional consistency with discovery findings. Predictive models incorporating both genetic and non-genetic variables — including baseline BMI, drug type, and treatment duration — outperformed genetics alone, though the genetic contribution was statistically detectable. Tirzepatide was associated with greater average BMI loss than semaglutide across the cohort, consistent with data from the SURMOUNT and STEP clinical trial programs. The pharmacogenomics of GLP-1 receptor agonists has attracted interest from multiple groups as prescriptions for semaglutide (Novo Nordisk’s Ozempic and Wegovy) and tirzepatide (Eli Lilly’s Mounjaro and Zepbound) have expanded. Academic programs at the Broad Institute, Lund University, and the MRC Epidemiology Unit in Cambridge have published on genetic modifiers of incretin response, including TCF7L2 variants affecting GLP-1 secretion. Population biobanks including FinnGen and deCODE Genetics (Amgen) have contributed GLP1R variant studies. The 23andMe dataset differs from these efforts in scale of self-reported pharmacological phenotyping and in its recruitment mechanism, though the reliance on self-reported outcomes and a predominantly European-ancestry cohort represents a limitation shared with much of the existing literature. The findings remain at the discovery and replication stage. The authors note that the work lays a foundation for precision medicine approaches in obesity treatment, though the path from GWAS discovery to clinical deployment involves substantial further work. Your email address will not be published. Required fields are marked * Comment * Name * Email * Website