Genomic profiling–guided evaluation of metabolic correction with tirzepatide in patients with HFpEF: results from a prospective controlled study in Kazakhstan

Background The dual GIP/GLP-1 receptor agonist tirzepatide has demonstrated significant metabolic and cardiometabolic benefits in patients with heart failure with preserved ejection fraction (HFpEF). However, molecular mechanisms underlying its cardiovascular effects and determinants of individual therapeutic response remain insufficiently characterized. Purpose To evaluate the clinical efficacy of tirzepatide in patients with HFpEF with and without type 2 diabetes (T2D), integrating whole-genome profiling and molecular biomarker analysis to identify predictors of response and support precision treatment strategies. Methods This prospective, open-label, controlled implementation study was conducted in collaboration with a university medical center, and a research institute of cardiology and internal diseases. Adults with HFpEF, with or without T2D, were enrolled after informed consent. All participants received once-weekly subcutaneous tirzepatide (up to 10 mg) in addition to guideline-directed therapy for 40 weeks. Comprehensive phenotyping included echocardiography, cardiopulmonary testing, metabolic profiling, and circulating biomarker assessment. Whole-genome sequencing evaluated mutational burden, structural variants, and cardiometabolic genomic signatures. The primary endpoint was change in functional capacity and HF-related clinical parameters. Secondary endpoints included metabolic indices, biomarker modulation, and safety. Genotype–phenotype associations were assessed using multivariable and bioinformatic analyses. Results A total of 120 patients were enrolled (mean age 61±9 years; 64% women; 52% with T2D). At 24 weeks, preliminary analyses demonstrated significant reductions in body weight and improvement in metabolic parameters and functional capacity, accompanied by favorable modulation of inflammatory and cardiometabolic biomarkers. Genomic analysis identified a subgroup with variants in metabolic and inflammatory pathways associated with greater improvement in 6-minute walk distance (+62 m vs +28 m, p=0.01), along with superior metabolic and inflammatory response. Treatment was generally well tolerated; gastrointestinal events were the most common adverse effects. Conclusions Tirzepatide improved functional capacity, weight, and cardiometabolic markers in patients with HFpEF. Integration of whole-genome profiling identified molecular subgroups with differential therapeutic response, supporting a precision cardiometabolic approach. Further analyses will validate genomic predictors and assess long-term outcomes.