Diabetes therapy : research, treatment and education of diabetes and related disordersJan 5, 2026

How Changing Incretin Hormones is Improving Heart and Kidney Health in Diabetes Treatment

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 6, 2026

Abstract

Long-acting GLP-1 receptor agonists reduce major adverse cardiovascular events (MACE), with a significant impact on kidney outcomes in patients with type 2 diabetes mellitus (T2DM).

Long-acting GLP-1 receptor agonists have been shown to decrease all-cause and cardiovascular deaths, heart-failure hospitalizations, and kidney-related complications.
A pooled analysis from 2019 and a subsequent update in 2025 indicate consistent reductions in MACE and severe kidney outcomes, regardless of initial blood sugar levels.
In patients with obesity but without diabetes, semaglutide 2.4 mg has been associated with lower MACE rates in the SELECT trial.
The FLOW trial demonstrated that semaglutide reduced major kidney disease events and cardiovascular-related deaths in patients with chronic kidney disease and T2DM.
Oral semaglutide has been found to reduce three-point MACE compared to placebo in the SOUL cardiovascular outcome trial.
Tirzepatide was shown to be non-inferior to dulaglutide in terms of MACE while producing greater reductions in weight and blood sugar levels.

Simplified

INTRODUCTION: In patients with type 2 diabetes mellitus (T2DM), cardiovascular (CV) disease and chronic kidney disease (CKD) drive excess morbidity and mortality. Beyond glucose-lowering, incretin-based therapies may provide organ protection across the cardiorenal axis.

METHODS: Narrative review of mechanistic pathways and randomized trials of GLP-1 receptor agonists (GLP-1RA), DPP-4 inhibitors, and newer dual/triple agonists, with targeted updates from recent pivotal programs (SELECT, FLOW, SOUL, SURPASS-CVOT) and emerging oral small-molecule GLP-1R agonists.

RESULTS: Long-acting GLP-1RA reduces major adverse CV events (MACE), all-cause and CV death, heart-failure hospitalization, and kidney composites across CV outcome trials and meta-analyses. A 2019 pooled analysis and a 2025 update confirm consistent reductions in MACE and hard kidney outcomes independent of baseline HbA1c. In obesity without diabetes, semaglutide 2.4 mg lowered MACE in SELECT, expanding prevention beyond glycemia. In CKD with T2DM, FLOW showed that semaglutide reduced major kidney disease events and death from CV/kidney causes. In T2DM with ASCVD and/or CKD, the SOUL cardiovascular outcome trial (CVOT) demonstrated that oral semaglutide reduced three-point MACE versus placebo. In head-to-head CVOT, tirzepatide was non-inferior to dulaglutide on MACE while achieving greater weight and HbA1c reductions. Mechanistically, GLP-1R signaling spans Gs-cAMP/PKA, β-arrestin-dependent pathways, and additional routes (including Gq contexts), aligning with anti-inflammatory, natriuretic, and antifibrotic effects observed preclinically and clinically. Oral non-peptide GLP-1R agonists (e.g., orforglipron) show phase 2 efficacy but lack long-term CV/renal outcome data.

CONCLUSIONS: Incretin-based therapy has shifted care from glucose-centric targets to cardiorenal risk reduction. GLP-1RA are guideline-endorsed for patients with T2DM and high CV/renal risk irrespective of HbA1c; dual agonists and oral small-molecule agents may broaden indications pending definitive outcome evidence.

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Competing interests

Declarations. Conflict of interest: All authors (José Pablo Miramontes-González, Álvaro Rodrigo-Alaíz, Miriam Gabella-Martín, David González-Calle, Juana Carretero-Gómez and Luis Corral-Gudino) have nothing to disclose. Ethical Approval: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

PubMed

How Changing Incretin Hormones is Improving Heart and Kidney Health in Diabetes Treatment

Abstract

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Competing interests

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