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Florian Kahles¹, Andreas L Birkenfeld^2,3,4,5, Nikolaus Marx¹

¹Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen, Aachen, Germany.

The Journal of Clinical Investigation

|February 16, 2026

Summary

This summary is machine-generated.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve cardiovascular outcomes in high-risk patients. Oral GLP-1RAs and dual GIP/GLP-1 agonists offer further therapeutic advancements for managing diabetes and cardiovascular risk.

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Area of Science:

Endocrinology and Metabolism
Cardiovascular Disease Research
Pharmacology

Background:

Glucagon-like peptide-1 (GLP-1) is a key hormone regulating glucose metabolism.
GLP-1 receptor (GLP-1R) pathway activation is a therapeutic target for type 2 diabetes.
Incretin-based therapies include dipeptidyl peptidase 4 (DPP-4) inhibitors and GLP-1 receptor agonists (GLP-1RAs).

Purpose of the Study:

To review the cardiovascular effects of GLP-1 and GLP-1RAs.
To summarize clinical data on GLP-1RAs in patients with cardiovascular disease or high cardiovascular risk.
To discuss advancements in incretin-based therapies, including oral formulations and dual agonists.

Main Methods:

Review of existing literature on GLP-1, GLP-1RAs, and cardiovascular outcomes.
Analysis of data from large-scale cardiovascular outcomes trials (CVOTs) involving DPP-4 inhibitors and GLP-1RAs.
Examination of clinical trial results for tirzepatide, a dual GLP-1R/GIPR agonist.

Main Results:

DPP-4 inhibitors show CV safety but not CV event reduction.
Several GLP-1RAs (liraglutide, semaglutide, dulaglutide) have demonstrated significant reductions in CV outcomes in CVOTs.
Oral GLP-1RAs and dual GIP/GLP-1 agonists represent newer therapeutic strategies with enhanced efficacy in HbA1c reduction and weight loss.

Conclusions:

GLP-1RAs have a favorable cardiovascular profile and reduce CV events in high-risk populations.
Advancements in incretin-based therapies, including oral GLP-1RAs and dual agonists, offer improved glycemic control and weight management.
Ongoing CVOTs are crucial for evaluating the long-term cardiovascular impact of newer agents like tirzepatide.