GLP-1, GIP and Glucagon: Triple Agonists in Peptide Research Explained

Peptide research has evolved over recent years from single receptor agonists like semaglutide, through dual concepts like tirzepatide, toward triple agonists. These molecules simultaneously activate three receptors relevant to energy and glucose metabolism: GLP-1, GIP and glucagon. For this reason, they are being intensively studied as a multi-target approach in metabolic research.

The questions are straightforward: what functions do these three signalling pathways serve, why might their combination be useful, and how robust is the clinical evidence so far? The following sections outline the scientific foundations and the key studies.

The Three Receptors in Detail

Understanding the approach requires an overview of the three receptor systems involved and their physiological functions.

GLP-1 Receptor

Glucagon-like peptide-1 (GLP-1) is an incretin hormone released in the small intestine after food intake. Activation of the GLP-1 receptor triggers several metabolically relevant effects:

• Glucose-dependent insulin secretion: GLP-1 stimulates the beta cells of the pancreas to release insulin, but only when blood glucose is elevated. This reduces the risk of hypoglycaemia.
• Appetite suppression: Central mechanisms in the hypothalamus and brainstem enhance satiety and reduce food intake.
• Slowed gastric emptying: The passage of food through the stomach is slowed, which blunts postprandial blood glucose peaks.

GLP-1 receptor agonists such as semaglutide and liraglutide form the foundation of current incretin therapy and are the most thoroughly studied class in this area.

GIP Receptor

Glucose-dependent insulinotropic peptide (GIP) is the second major incretin hormone. Its role was long debated, and it was at times even considered unfavourable in obesity. More recent research has produced a more nuanced picture:

• Insulin response: GIP can augment glucose-dependent insulin secretion and, in combination with GLP-1, improve glucose control.
• Fat metabolism: The GIP receptor is also expressed on adipocytes. Its activation influences lipid storage and fat turnover. The precise mechanisms remain an active area of research.
• Bone health: Osteoprotective effects have been proposed for GIP. Whether and to what extent this is clinically relevant is still under investigation.

Clinical data from tirzepatide, a dual GLP-1/GIP agonist, demonstrate that GIP can be pharmacologically relevant. In pivotal studies, the combination achieved stronger effects on weight and glycaemic control than several previously established GLP-1-based comparator arms.

Glucagon Receptor

Glucagon is traditionally regarded as the counterpart to insulin because it raises blood glucose. Its inclusion in metabolic agents therefore seems counterintuitive at first. The research rationale rests on the fact that glucagon can trigger metabolic effects beyond its glycaemic action:

• Energy expenditure: Preclinical and early clinical data suggest that glucagon signalling may increase energy expenditure.
• Hepatic metabolism: Glucagon influences hepatic glucose production, glycogenolysis and lipid metabolism.
• Fat breakdown: Enhanced lipid mobilisation and lipid oxidation are discussed as possible contributions to weight reduction.

Why Combine? The Logic of Complementary Effects

The idea behind multi-agonists is not simply "more receptors = more effect". At the core are complementary mechanisms that address different aspects of metabolism simultaneously.

GLP-1 + GIP: Dual incretin activation can augment the insulin response and improve glucose control. Whether GIP reliably attenuates gastrointestinal side effects is not universally established and depends on the compound, dose and study design.

GLP-1 + Glucagon: GLP-1 can partially offset the blood-glucose-raising effects of glucagon, while glucagon may contribute to higher energy expenditure.

GIP + Glucagon: Complementary effects on fat metabolism and glycaemic homeostasis are discussed for this combination. Claims about preservation of muscle mass should be stated cautiously for now, as the human data remain limited.

The triple combination aims to unite these principles in a single molecule:

• Appetite reduction, primarily via GLP-1
• Improved glucose-dependent insulin response via GLP-1 and GIP
• A possible additional contribution to energy expenditure via glucagon
• Simultaneous control of weight, glucose and further metabolic parameters

Generations at a Glance: Mono -> Dual -> Triple

Development can be broadly divided into three generations:

Generation 1, mono-agonists (GLP-1)

• Examples: semaglutide, liraglutide
• Weight reduction in studies: approximately 15 to 17% (semaglutide 2.4 mg, STEP programme)
• Strength: well characterised, broad evidence base
• Limitation: gastrointestinal side effects, plateau effect on weight reduction

Generation 2, dual agonists (GLP-1/GIP)

• Example: tirzepatide
• Weight reduction in studies: approximately 21 to 23% (tirzepatide 15 mg, SURMOUNT-1)
• Strength: greater efficacy than mono-GLP-1 on key endpoints
• Limitation: no direct glucagon signalling pathway

Generation 3, triple agonists (GLP-1/GIP/glucagon)

• Example: retatrutide
• Weight reduction in studies: the published phase 2 study of retatrutide reported up to 24.2% after 48 weeks. For TRIUMPH-4, Lilly communicated topline data in December 2025 with a mean absolute weight loss of up to 32.3 kg. This figure is not directly comparable to percentage values from other studies owing to the different endpoint.
• Strength: combination of weight, glycaemic and further metabolic effects
• Limitation: phase 3 programme still ongoing, long-term safety data not yet available

Evidence for Retatrutide

Retatrutide (LY3437943) is a clinically advanced triple agonist from Eli Lilly. The peptide activates the receptors for GIP, GLP-1 and glucagon.

Key results of the phase 2 study:

• Dose-dependent weight reduction from -8.7% (1 mg) to -24.2% (12 mg) after 48 weeks
• Improvements across several cardiometabolic parameters, including fasting glucose and HbA1c
• Indications of reductions in liver fat in examined subgroups
• Side effect profile similar to other incretin-based agents, predominantly gastrointestinal

The phase 3 programme TRIUMPH encompasses, according to Lilly and ClinicalTrials.gov, several indications and designs. These include studies in obesity or overweight, type 2 diabetes, knee osteoarthritis, obstructive sleep apnoea, and cardiovascular and renal outcomes. The Lilly overview page updated in December 2025 also lists studies in chronic low back pain and MASLD.

A central registration protocol is TRIUMPH-1 (NCT05929066) in obesity or overweight without type 2 diabetes. For cardiovascular and renal events, TRIUMPH-Outcomes (NCT06383390) is additionally running. Lilly lists further results from the development programme for 2026 on its retatrutide overview page; later time points depend on study progress and data analysis.

Retatrutidemetabolic

First-ever triple-action weight management peptide targeting three receptors at once: GIP, GLP-1, and glucagon. Shown exceptional results in Phase 2 trials - up to 24% weight reduction. The most advanced metabolic peptide available.

Further Multi-Agonists in Research

Retatrutide is not the only approach. The pipeline of multi-receptor agonists continues to grow:

Survodutide (BI 456906)

Survodutide from Boehringer Ingelheim is a dual GLP-1/glucagon agonist. This distinguishes it from tirzepatide, which combines GLP-1 and GIP.

• In the published phase 2 study, mean weight changes after 46 weeks ranged up to 14.9% depending on dose, compared with 2.8% under placebo
• Particular interest exists in MASH and MASLD, as glucagon signalling may influence hepatic fat metabolism
• Phase 3 studies for weight management are ongoing in the SYNCHRONIZE programme

Mazdutide (LY3305677)

Mazdutide, developed by Innovent Biologics in collaboration with Eli Lilly, is likewise a dual GLP-1/glucagon agonist. Clinical development has been documented primarily in China so far.

• In the phase 3 study GLORY-1, mean weight changes of 11.0% with 4 mg and 14.0% with 6 mg were reported after 48 weeks
• The study population is also relevant, as many obesity studies to date have come from Western cohorts
• According to Innovent, mazdutide was already approved in China in 2025 for weight management and glycaemic control in type 2 diabetes

CagriSema (cagrilintide + semaglutide)

A conceptually different approach from Novo Nordisk: instead of a single multi-agonist, the GLP-1 agonist semaglutide is combined with the amylin analogue cagrilintide.

• Amylin enhances satiety via signalling pathways distinct from GLP-1
• In the phase 3 studies published in the New England Journal of Medicine in 2025, REDEFINE-1 reported approximately 22.7% and REDEFINE-2 approximately 15.7% weight reduction in obesity or overweight with type 2 diabetes
• No glucagon agonism, but an alternative multi-target approach
• Demonstrates that multi-target concepts are not confined to incretin receptors

Outlook: What Comes After Triple Agonists?

Research is not stopping at three receptors. Several directions are emerging:

Quad-agonists and beyond: In theory, further receptors such as amylin or FGF21 signalling pathways could be integrated. With each additional target, however, the complexity of dose-finding and the risk of unexpected interactions also increases.

Oral formulations: Most current peptide agonists are administered subcutaneously. Oral dosage forms could broaden practical applicability, but are pharmacologically demanding for more complex peptides.

Personalised combinations: Rather than a single multi-agonist for everyone, different metabolic phenotypes could be addressed more specifically in the longer term.

Tissue-selective agonists: Peptides acting preferentially in certain tissues, for example more strongly in the liver and less systemically, could reduce side effects further.

Frequently Asked Questions