GIP in Cardiovascular and Kidney Disease: From Physiology to Pharmacology.

AIMS: To provide a comprehensive overview of the cardiovascular and renal effects of glucose-dependent insulinotropic polypeptide (GIP) by integrating its physiological role with recent human trial data on tirzepatide, the first dual GIP and glucagon-like peptide-1 (GLP-1) receptor agonist. MATERIALS AND METHODS: This narrative review synthesizes key physiological data of native GIP across tissues-especially the heart, vessels, kidney, and adipose tissue-and summarizes clinical evidence from the SUMMIT and the SURPASS programmes. Central to this review is the analysis of the SURPASS-CVOT trial, which compared the cardiovascular protective effects of tirzepatide versus dulaglutide in individuals with type 2 diabetes and established atherosclerotic CV disease. RESULTS: Preclinical data regarding GIP receptor modulation in the cardiorenal district remains controversial, a contention partially reflected in recent clinical evidence. Within the innovative framework of SURPASS-CVOT, tirzepatide established non-inferiority to dulaglutide for 3-point MACE while slowing eGFR decline in participants with high-risk chronic kidney disease. Furthermore, the SUMMIT trial demonstrated that in individuals with obesity and heart failure (HF) with preserved ejection fraction, tirzepatide reduced the composite endpoint of CV death or worsening HF events, regardless of baseline kidney function. Despite these advancements, knowledge gaps persist regarding the potential synergistic cardiorenal benefits of combining dual incretin agonism with sodium-glucose cotransporter-2 inhibitors. CONCLUSION: While adding GIP receptor agonism to GLP-1 receptor agonism clearly improves cardiometabolic risk factors, its precise and independent contribution to long-term CV and renal protection remains to be fully elucidated. Ongoing outcome trials, such as SURMOUNT-MMO and TREASURE-CKD, will provide additional insights into these effects. Furthermore, emerging strategies-including combining GIP receptor antagonism with GLP-1 receptor agonism or moving toward triple agonism-represent promising alternatives to favorably modify the multiple determinants of cardiometabolic risk.