Cardiovascular protection beyond glucose lowering: GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonism in contemporary cardiology

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  Figure 1. Evidence-graded mechanistic framework for cardiovascular effects of GLP-1-based therapies. This author-generated conceptual model integrates clinical, translational and preclinical evidence concerning the potential cardiovascular effects of GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonism. Randomised human studies directly demonstrate reductions in body weight, glycaemia, blood pressure, albuminuria and inflammatory biomarkers, together with improvements in selected cardiovascular and kidney outcomes. Human imaging and physiological studies provide supportive evidence for changes in cardiac loading, ectopic adiposity, vascular function and myocardial perfusion. Direct cardiomyocyte receptor signalling, plaque-cell biology, apoptosis, ferroptosis and specific intracellular pathways remain supported predominantly by preclinical or ex vivo studies. Solid arrows indicate treatment effects demonstrated in randomised human studies; dotted arrows indicate supportive human imaging, biomarker or physiological evidence; and dashed arrows indicate predominantly preclinical or ex vivo hypotheses. The diagram illustrates potential biological relationships and does not establish…

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  Figure 2. Author-generated evidence map for GLP-1-based therapies across major cardiovascular–kidney–metabolic phenotypes. This author-generated evidence map summarises the strength and nature of the available clinical evidence across major cardiovascular–kidney–metabolic phenotypes. In high-risk type 2 diabetes, several long-acting GLP-1 receptor agonists reduce three-point MACE. In adults with established ASCVD and overweight or obesity without diabetes, semaglutide reduces major cardiovascular events. In obesity-related HFpEF, semaglutide improves symptoms and physical function, whereas tirzepatide additionally reduces worsening heart failure events. Dedicated randomised evidence remains limited or absent for HFrEF, atrial-fibrillation-specific treatment, coronary microvascular dysfunction and low-risk primary prevention. Categories identified as established are based primarily on direct randomised outcome evidence. Supportive or emerging categories are based on secondary analyses, observational studies, imaging studies or mechanistic data and should not be interpreted as established treatment indications. This figure is an author-generated summary and does not represent a formal GRADE…

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  Figure 3. Author-generated practical phenotype-directed algorithm for GLP-1-based therapy in cardiovascular practice. This author-generated algorithm integrates current clinical evidence and patient-specific considerations to illustrate phenotype-directed use of GLP-1-based therapies across major cardiovascular–kidney–metabolic phenotypes. When heart failure or chronic kidney disease is prominent, SGLT2 inhibitor therapy remains foundational when indicated, while GLP-1-based therapy is considered according to phenotype-specific evidence, treatment goals, and individual characteristics, including tolerability, frailty, sarcopenia, nutritional status, kidney function, cost, and treatment persistence. Evidence categories are author-generated and do not represent a formal grading system. Dark solid borders indicate direct randomised cardiovascular outcome evidence, light solid borders indicate emerging clinical evidence with evolving guideline incorporation, dashed borders indicate author-integrated or hypothesis-generating frameworks, and grey dashed borders indicate insufficient cardiovascular outcome evidence. This algorithm is conceptual and should not replace clinical guidelines or…

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  Figure 4. Integrated heart–kidney–metabolic axis and the rationale for combination therapy. This author-generated conceptual synthesis illustrates the partially distinct and potentially complementary roles of GLP-1-based therapies and SGLT2 inhibitors. Cardiovascular disease, kidney dysfunction and metabolic abnormalities interact bidirectionally through shared mechanisms including insulin resistance, visceral adiposity, systemic inflammation, lipotoxicity, haemodynamic stress and neurohormonal activation. Within this interconnected axis, GLP-1-based therapies preferentially address weight excess, residual atherosclerotic risk, inflammatory-metabolic dysfunction and symptoms associated with obesity-related heart failure with preserved ejection fraction. By contrast, sodium-glucose cotransporter-2 inhibitors provide particularly strong benefits for heart failure hospitalization, kidney protection and haemodynamic regulation. Their overlapping but complementary actions provide a biological and clinical rationale for combination treatment in selected patients with cardiovascular–kidney–metabolic syndrome. CKM, cardiovascular–kidney–metabolic; eGFR, estimated glomerular filtration rate; GIP,…