The Next Wave of Weight Loss and Diabetes Drugs: Multi-Target Peptide Agonists Beyond GLP-1

What the researchers found

The review synthesizes evidence for several emerging multi-agonist peptide drug classes:

- GLP-1/GIP dual agonists (e.g., tirzepatide) have already demonstrated superior efficacy over GLP-1 monotherapy

- GLP-1/glucagon dual agonists leverage glucagon's energy-expenditure effects while offsetting its glucose-raising activity with GLP-1's insulin-promoting action

- GLP-1/GIP/glucagon triple agonists (e.g., retatrutide) target all three receptors for potentially maximal metabolic benefit

- GDF15-based approaches represent a newer pathway that reduces appetite through brainstem signaling

- Beyond metabolic effects, these agents may offer cardioprotective and anti-inflammatory benefits

Why it matters

The obesity and diabetes drug market is undergoing its most transformative period in history. Understanding the pipeline of multi-agonist peptides is essential for clinicians, researchers, and patients alike. Each additional receptor target adds efficacy but also complexity — knowing which combinations are most promising and what safety trade-offs exist will guide the next decade of metabolic pharmacotherapy.

How the study worked

Narrative review of published preclinical and clinical evidence for novel dual and triple peptide agonists targeting GLP-1, GIP, glucagon, and GDF15 receptors. The review focuses on mechanisms of action, clinical efficacy data, and safety profiles.

What this study cannot tell us

As a review, no original data are presented. Many of the dual and triple agonists discussed are in early to mid-stage clinical development, and long-term efficacy and safety data are limited. The review explicitly excludes amylin analogs and other peptide approaches, so it does not cover the full landscape. The safety profiles of multi-agonist peptides are still being established, particularly for cardiovascular and gastrointestinal endpoints.

How to read the evidence

This is a narrative review synthesizing clinical and preclinical evidence for emerging drug classes. The evidence ranges from Phase III trial data (for some dual agonists) to early preclinical work (for some GDF15 approaches).

When this study was published

Published in 2025, this review captures the state of the art in a rapidly evolving field where new clinical trial results are emerging regularly.

The bigger picture

The evolution from single-target GLP-1 agonists to multi-receptor peptides mirrors a broader trend in drug development toward polypharmacology — using one molecule to hit multiple targets. Tirzepatide (GLP-1/GIP) was the first approved dual agonist, and triple agonists like retatrutide are in Phase III trials. The addition of GDF15 as a target introduces a completely different appetite-regulation pathway, potentially addressing patients who don't respond well to incretin-based approaches alone.

Questions still open

• Will triple agonists prove to be meaningfully more effective than dual agonists in Phase III trials, or will the added complexity not justify the incremental benefit?
• How does targeting GDF15 differ from incretin-based appetite suppression in terms of patient experience and side effects?
• Can multi-agonist peptides eventually replace bariatric surgery for severe obesity?

Common questions

Read the original research

Novel Dual and Triple Agonists Targeting GLP-1, GIP, Glucagon, and GDF15 for Type 2 Diabetes and Obesity Management.

Endocrinology, 166(11)

Citation

Zhang, Jiudan; Sanan, Shriya; Csanalosi, Marta; Zheng, Chao; Pfeiffer, Andreas F H. (2025). Novel Dual and Triple Agonists Targeting GLP-1, GIP, Glucagon, and GDF15 for Type 2 Diabetes and Obesity Management.. Endocrinology, 166(11). https://doi.org/10.1210/endocr/bqaf130