The Next Wave of GLP‑1 Treatments

Introduction

The therapeutic approach to obesity and type 2 diabetes mellitus (T2DM) is evolving in a similar way to how clinicians use antibiotics: targeting several pathways that often produce stronger and more durable effects than acting on a single pathway.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) laid the foundation, but the complexity of fat mass regulation quickly revealed the limits of one hormonal signal ¹.  This has led to multi-hormonal agents that act simultaneously on glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, and/or peptide YY (PYY), better replicating the physiological and coordinated post-prandial response.

By engaging these pathways, the new therapies achieve broader and more synergistic metabolic improvements, marking a shift from single target drugs to integrated hormone-based treatment ¹.

GLP-1–Based Therapies

GLP-1 is secreted by intestinal endocrine cells after nutrient ingestion.  It enhances glucose-dependent insulin secretion, slows gastric emptying, reduces appetite, and promotes weight loss ^1–5.  Central nervous system GLP-1 signalling within the hypothalamus and brainstem is central to regulating fat mass ⁶.

Beyond glycaemia, GLP-1 exerts anti-inflammatory, endothelial, and lipid-modulating effects ¹.  Long-acting GLP-1RAs on their own such as semaglutide achieve substantial weight loss and glycaemic improvement, aided by gradual dose escalation strategies that improve tolerability ¹.

Oral semaglutide represents a significant advancement, using SNAC (sodium N-(8-[2-hydroxybenzoyl] amino) caprylate) to overcome gastrointestinal degradation and enable systemic absorption, despite low bioavailability (~1%) and strict fasting administration requirements ⁷.

Further innovations include small-molecule oral GLP-1RAs, such as orforglipron, which activate the GLP-1 receptor (GLP-1R) without peptide structures and offer simpler administration but without the same weight loss range ^1,8-9.

GIP-Related Therapies

GIP is also released by different endocrine cells in the small intestine.  It stimulates insulin secretion during normoglycemia and influences lipid storage, though its metabolic effects are highly context-dependent ¹.

Importantly, both GIP receptor (GIPR) agonism and GIPR antagonism have been shown to reduce body weight; an unexpected therapeutic paradox ¹.  Central GIPR signalling suppresses appetite in rodents, while peripheral GIP actions vary with insulin sensitivity ^1,10.  In humans, exogenous GIP shows limited appetite loss (anorectic) effects, suggesting species-specific physiological differences ¹¹.

GLP-1/GIP Dual Agonists

Dual agonism of the GLP-1R and GIPR aims to capitalise on complementary hormonal effects.  Tirzepatide is the first approved dual GLP-1/GIP agonist and achieves greater weight loss and glycaemic improvement than semaglutide alone, suggesting synergistic incretin modulation ¹².  Additional co-agonists, including SCO-094, VK2735, CT-388, and DR10627, are under development to refine receptor balance and broaden metabolic benefits ¹.

Unimolecular GLP-1RAs/GIPR Antagonists

In contrast to co-agonists, unimolecular agents combining GLP-1R activation with GIPR blockade exploit evidence that GIPR antagonism enhances weight loss by disrupting adipogenic GIP signalling and amplifying GLP-1 driven satiety pathways ¹.

Maridebart cafraglutide (formerly AMG-133) exemplifies this approach by merging GLP-1 agonism with a monoclonal GIPR-blocking antibody.  Monthly dosing produces meaningful body weight reductions (12–16%) and improves glycaemia in people with obesity and T2DM ^1,13.  Pre-clinical work with the GIPR antagonist AT-7687 shows similar synergy when paired with GLP-1RAs ¹.

Oxyntomodulin Physiology and Oxyntomodulin-Based Therapies

Oxyntomodulin (OXM) is also secreted by the endocrine cells in the intestine but does not have a dedicated receptor.  Instead OXM binds to both the glucagon and GLP-1R ¹⁴.  Glucagon as a standalone peptide is secreted by pancreatic alpha-cells.  It increases hepatic glycogenolysis and gluconeogenesis during fasting but also regulates satiety, enhances hepatic β-oxidation, reduces liver fat, and increases energy expenditure ^1,15.

OXM mimics many of these same effects when it binds the glucagon receptors ¹⁴.  These metabolic properties support OXM use within multi-agonist therapies, without the risk of pure glucagon’s inherent hyperglycaemic potential.

OXM analogues (GLP-1/Glucagon Co-agonists)

Co-activation of GLP-1R and glucagon receptors leverages the anorectic and insulinotropic actions of GLP-1 with glucagon-driven increases in energy expenditure.  Survodutide and mazdutide are leading examples.  Survodutide has demonstrated up to 13–15% weight loss, alongside significant improvement in metabolic dysfunction–associated steatohepatitis (MASH) ^1,16-17.  Mazdutide produces dose-dependent weight reduction and glycaemic improvement with good tolerability ¹⁸.

Triple GIP/GLP-1/Glucagon Co-agonists

Retatrutide is a triple agonist that simultaneously activates GLP-1Rs, GIPRs, and glucagon receptors.  This design aims to maximise appetite suppression and thermogenesis.  In phase 2 trials, retatrutide achieved approximately 17–18% weight loss in individuals with obesity without T2DM, surpassing most available pharmacotherapies ^1,19.

Amylin Physiology and Amylin-Based Therapies 

Amylin is co-secreted with insulin and slows gastric emptying, suppresses glucagon, and increases satiety through pathways distinct from other anorectic hormones ^1,20.  Long-acting analogues such as cagrilintide produce clinically significant weight loss ²¹.

Amylin/GLP-1 Dual Agents

CagriSema, a fixed combination of semaglutide and cagrilintide that integrates GLP-1–mediated appetite suppression with amylin driven satiety and gastric emptying effects.  Recent trials show approximately 23% weight loss, exceeding either monotherapy or approaching metabolic surgery efficacy ^1,21.

Peptide YY Physiology and Related Medicines

Peptide YY (PYY) is co-secreted with GLP-1 by endocrine cells in the intestine and converted to its active form PYY 3-36, which acts via Y2 receptors to inhibit neuropeptide Y (NPY) neurons and promote satiety ^1,22.   After bariatric surgery, postprandial PYY, GLP-1, and OXM rises sharply and contributes to improved adipocyte mass regulation.  Early PYY analogues show reduced food intake and modest weight loss in short-term studies ^1,22.

Table 1.  Comparison Table of Novel GLP-1–Based Medications

Conclusion

Together, these advances mark a decisive shift in obesity and T2DM therapeutics from a single pathway modulation toward integrated, multimodal hormone-based interventions.

GLP-1 remains the backbone, but layering complementary signals from GIP, glucagon, amylin, and PYY allows for unprecedented degrees of weight reduction and metabolic restoration, as summarised for comparison in Table 1.

As uni-, dual-, and triple-molecular agents continue to refine receptor balance, the field is rapidly approaching the efficacy once achievable only through metabolic surgery.

The emerging challenge is no longer whether we can produce profound metabolic benefits, but rather how to optimise durability, individualise receptor targeting, and translate these complex pharmacologic innovations into long term clinical decision making.

This therapeutic evolution represents not merely incremental drug development, but a redefinition of how we conceptualise and treat the chronic diseases of obesity and type 2 diabetes.

• References
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