Tirzepatide and SGLT2 Inhibitors for Heart Failure With Preserved Ejection Fraction and Obesity: Entering a New Cardiometabolic Therapeutic Era

Figures

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  FIGURE 1. Dual cardiovascular and metabolic outcomes of tirzepatide therapy. Tirzepatide administration drives complementary clinical benefits across two primary axes. The cardiovascular panel outlines reductions in heart failure events, enhanced exercise capacity and structural offloading via decreased left ventricular mass. The metabolic panel details systemic obesity management, driven by caloric reduction, profound visceral and total body weight loss and enhanced insulin sensitivity.

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  FIGURE 2. Pleiotropic mechanisms and clinical outcomes of SGLT2 inhibitors (Empagliflozin and Dapagliflozin). The schematic illustrates the primary cardiovascular, renal and metabolic pathways modulated by SGLT2 inhibition. These combined systemic effects directly translate into favourable ultimate clinical outcomes, including reduced heart failure hospitalizations, increased exercise capacity, targeted weight loss and an overall improved quality of life.

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  FIGURE 3. Potential synergistic mechanisms of tirzepatide and SGLT2i in the management of obesity‐related HFpEF. The diagram illustrates the distinct but complementary physiological axes of both therapies. The metabolic pathway of dual GIP/GLP‐1 agonism is characterized by central appetite suppression, multi‐organ fat reduction (including epicardial adipose tissue) and enhanced insulin sensitivity, while the haemodynamic and energetic pathway of SGLT2 inhibition features direct myocardial energetic improvements and systemic decongestion driven by rapid natriuresis. Together, these parallel pathways converge on the failing heart to reduce worsening heart failure events, decrease hospitalizations and improve patient quality of life.

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  FIGURE 4. Individual and potential compounded adverse effect profiles of tirzepatide and SGLT2 inhibitors. The outer sections delineate the established adverse events unique to each pharmacological class, including gastrointestinal disturbances and lean muscle reduction for tirzepatide, alongside genitourinary infections and euglycemic diabetic ketoacidosis (eDKA) for SGLT2 inhibitors. The intersecting centre highlights the theoretical, yet clinically significant, risks associated with their concurrent use. Because the safety profile of this specific combination is not yet definitively established in dedicated clinical trials, the overlap illustrates anticipated physiological interactions, namely exacerbated volume depletion, orthostatic hypotension, prerenal stress and hypoglycemia that necessitate vigilant clinical monitoring.