Obesity is a chronic, heterogeneous, and complex disease associated with increased morbidity, mortality, and health-care costs. By 2030, 1 in 2 people in the United States will have obesity. Lifestyle interventions are the cornerstone of obesity management. However, they often fail to achieve clinically significant weight loss, necessitating additional treatments involving pharmacotherapy or procedures. Advancements in obesity pharmacotherapy have improved weight-loss outcomes and reduced associated comorbidities. Despite these advances, variability in response to treatment between individuals is still considerable. This variability reflects limitations in the current “one-size-fits-all” approach to obesity management. A precision medicine approach aims to address this gap by incorporating genetic, physiological, and behavioral characteristics to guide treatment selection and improve outcomes. Advances in multi-omics technologies, such as genomics, proteomics, metabolomics, and microbiome profiling, offer new opportunities to refine patient stratification and identify novel therapeutic targets. These tools may help move obesity care toward a more individualized and mechanism-based approach.

Purpose: To evaluate the association of long-term, continuous tirzepatide use with cardiometabolic risk parameters and estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk in real-world practice. Methods: This multicenter retrospective observational study included 1028 adults with overweight or obesity who received weekly subcutaneous tirzepatide for at least 12 months within the Mayo Clinic Health System from June 2022 through May 2024. Atherosclerotic cardiovascular disease risk analyses included 275 individuals with complete baseline and 12-month follow-up data. Outcomes were changes in cardiometabolic parameters, estimated 10-year ASCVD risk, and ASCVD risk category. Results: At 12 months, median total body weight loss (TBWL) was 12.6%. Fasting glucose, HbA1c, triglycerides, and alanine aminotransferase decreased by 19.5%, 16.0%, 8.5%, and 10.6%, respectively, whereas HDL-cholesterol increased by 11.3% (all P < .001). Mean 10-year ASCVD risk did not change significantly overall (mean relative change, −3.7%; P = .18), but changes differed by TBWL category (analysis of variance, P < .001). Atherosclerotic cardiovascular disease risk decreased among individuals achieving 10% to 20% TBWL (−9.6%; P = .009) and >20% TBWL (−14.2%; P = .005), but not among those achieving <10% TBWL (+7.7%; P = .22). Low-risk prevalence increased from 38.3% to 46.4% (P < .001), with 11.7% transitioning from higher-risk categories to low risk. Main findings: Continuous tirzepatide use for at least 12 months was associated with clinically meaningful improvements in cardiometabolic parameters. Reductions in estimated 10-year ASCVD risk were observed among individuals achieving at least 10% TBWL, supporting greater weight loss as an important marker of cardiovascular risk improvement.

Background/Objectives: Individuals with type 2 diabetes (T2D) achieve less total body weight loss (TBWL) with obesity medications compared to those without T2D. The individualized metabolic surgery (IMS) score, originally developed to predict T2D remission after bariatric surgery, inversely correlates with TBWL response to semaglutide. IMS reflects T2D severity, incorporating HbA1c and T2D duration and medication use. This study aims to evaluate TBWL with tirzepatide across IMS severity categories and identify predictors of response in a real-world cohort. Methods: This retrospective analysis included 717 adults with T2D using tirzepatide for overweight or obesity within the Mayo Clinic Health System. Patients were stratified by IMS severity (mild, moderate, severe) and quartiles. Primary endpoint: TBWL% at 15 months. Secondary endpoints: categorical thresholds (≥5%, ≥10%, ≥15%, ≥20%) and predictors of TBWL%. Linear mixed-effects models and regression models were employed. Results: At 15 months, TBWL was greater in mild versus severe IMS groups (14.8% vs. 11.0%, p = 0.015), with similar trends across quartiles. The proportion achieving ≥ 20% TBWL was nearly two-fold higher in mild versus severe IMS (27% vs. 14%, p = 0.03). Female sex independently predicted greater TBWL, whereas insulin use, higher T2D medication burden (particularly weight-promoting agents), and HbA1c > 7% were associated with less TBWL. Conclusions: Tirzepatide produced clinically meaningful TBWL across all IMS categories, although TBWL declined with increasing IMS severity. Glycemic control and T2D medication use emerged as strong predictors of TBWL. The IMS score may serve as a practical tool to anticipate weight-loss trajectories, guide personalized treatment decisions, and inform patient counseling.