Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are currently at the forefront of type 2 diabetes mellitus (T2DM) and obesity treatment development and usage. However, recent focus on multi-receptor agonism with glucose-dependent insulinotropic polypeptide (GIP) and glucagon (Gcg) receptors has been investigated to assess for improved glycemic control, weight loss, and safety profile.
Several dual GLP-1/GIP RAs are currently in development, with the GIP receptor assisting GLP-1 in modulating central and peripheral pathways to prompt weight loss by increasing lipolysis and fat oxidation. Dual GLP-1/Gcg is another novel combination that utilizes the Gcg receptor which increases energy expenditure by stimulating glucose production, fat oxidation, and mobilization of energy stores to promote weight loss. Triple agonism of GLP-1/GIP/Gcg is still mainly being investigated in clinical trials, but preliminary results show similar if not improved glycemic control and weight loss. However, despite the multi-agonist approach, gastrointestinal adverse events do not seem to be mitigated compared to traditional GLP-1 RAs.
The current literature shows promising results for the efficacy of dual and triple agonism of GLP-1/GIP/Gcg receptors. Further research should focus on direct comparative studies between current GLP-1 RAs against these multi-receptor agonist agents.
Obesity and type 2 diabetes mellitus (T2DM) incidence have continued to drastically increase and currently affect approximately 650 million adults and 537 million adults, respectively [1,2]. Glucagon-like peptide-1 receptor agonists (GLP-1) RAs were originally developed as antidiabetic agents, with weight reduction later recognized as an additional benefit [3,4].
Dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP), dual GLP-1/glucagon (Gcg), and triple GLP-1/GIP/Gcg agonists have recently emerged and have the potential to transform an already rapidly changing therapeutic landscape. Despite the efficacy of single-target GLP-1 RAs, the glycemic control or weight reduction effects were not universally effective or optimal for all patients. Thus, the next-generation agents aim to harness multiple receptors' physiological effects to produce greater effects potentially [5]. Preliminary findings with the complementarity action of dual and triple incretins have shown greater efficacy in reducing hemoglobin A1c (HbA1c) and weight loss than placebo (PLCB) or active comparators [[5], [6], [7], [8]]. Another important consideration for developing these agents is the optimal receptor agonism. While progress has been made in characterizing ligand-receptor interactions, the specific structural and sequence features that govern selective or balanced activation of GLP-1R, GIPR, and GCGR remain partially understood. A deeper understanding of these mechanisms is essential to inform rational design and enhance therapeutic efficacy [5].
Incretins have demonstrated additional indications, including cardiovascular risk mitigation, substance abuse control, chronic kidney disease benefits, and conditions that benefit from weight loss, such as Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and obstructive sleep apnea [9]. This review aims to synthesize the available literature on these agents and their clinical outcomes and rates of complications compared to PLCB or active comparators. Additionally, this review highlights the current and future possibilities of these medications.
Check access to the full text by signing in through your organization.
GLP-1 receptors are Class B G-protein-coupled receptor protein (GPCRs) when activated by their ligand (GLP-1), which activates Gs and Gq proteins, increasing the intracellular levels of cyclic adenosine monophosphate (cAMP) [10], [11], [12]. The increase in cAMP subsequently leads to activation of protein kinase A (PKA), leading to insulin (INS) secretion and Gcg inhibition. INS secretion is also regulated through cAMP activation of Rap1 through the Exchange Protein directly activated by cAMP
GLP-1 and GIP are two key incretin hormones secreted postprandially that play crucial roles in glucose metabolism and energy homeostasis [9]. The use of dual GLP-1/GIP RAs seeks to harness the complementary actions of these hormones, addressing some of the limitations seen with monotherapy [19,20].
Among the dual GLP-1/GIP agonists under development, tirzepatide (TZP) demonstrates substantial reduction of HbA1c and body weight. TZP is evaluated extensively in the SURPASS clinical trials
Dual GLP-1/Gcg RAs can enhance the weight loss effects of GLP-1 RAs and counteract the potential hyperglycemic effects of Gcg receptor stimulation alone [30,31]. While GLP-1 and Gcg receptor activation may exert opposing effects on blood glucose, clinical trials have shown encouraging results in weight loss and metabolic improvements with dual agonism [15]. These therapies are still in the early stages of clinical development and less frequently used, but several compounds, including
Drug development strategies undertaking triple GLP-1/GIP/Ggr agonists have introduced the potential avenue of a superior drug class in the realm of currently available dual options. Three novel triple agonists are under investigation: LY3437943 (retatrutide), HM15211 (efocipegtrutide), and SAR441255.
Beyond its indications for glycemic control and weight reduction, GLP-1 RAs have demonstrated pleiotropic effects, expanding towards cardiovsacular risk reduction, improvements in MASLD, and potential neuroprotective effects. These effects are mediated through direct and indirect receptor activation that mediates metabolic, anti-inflammatory, and anti-atherogenic pathways. Emerging data with multi-receptor agonism may potentiate these effects. Gcg activation can enhance lipid oxidation while
With the persistently high prevalence of obesity and T2DM and the growing popularity of GLP-1RAs, newer medications that target and activate a combination of GLP-1, GIP, and Gcg receptors have gained significant attention due to their potential to synergistically enhance weight loss and maintain glycemic control while maintaining a similar if not improved safety profile. These studies are important for understanding how these RAs compare to existing therapies and their role in managing obesity
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
All authors declare that no funding was received.
All authors declare that there are no potential conflicts of interest.
No financial or material support was provided.
© 2025 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
