Evolution of incretin-based therapies: From GLP-1 monotherapy to dual and triple agonists: A new era in metabolic therapy

Incretin physiology and pathophysiology

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are the two primary incretin hormones responsible for postprandial glucose regulation. GLP-1 is secreted from enteroendocrine L-cells in the distal ileum and colon, while GIP is secreted by K-cells in the proximal small intestine in response to nutrient ingestion, particularly carbohydrates and lipids.^3-5 These hormones act via specific G protein–coupled receptors—GLP-1R and GIPR—expressed in various tissues, including pancreatic β-cells, adipose tissue, gastrointestinal tract, kidney, and the central nervous system.^6-8

GLP-1 enhances glucose-dependent insulin secretion, suppresses glucagon release, delays gastric emptying, and promotes satiety via hypothalamic signalling.^6,9,10 GIP primarily stimulates insulin secretion and plays a significant role in lipid metabolism by enhancing triglyceride storage in adipose tissue, promoting lipogenesis, and possibly contributing to obesity in insulin-resistant states.^11-13

Glucagon, secreted by pancreatic α-cells, counterbalances insulin by promoting hepatic gluconeogenesis, glycogenolysis, and ketogenesis during fasting.^14,15 Recent research has elucidated glucagon’s role in increasing energy expenditure and promoting weight loss when co-activated with GLP-1 and/or GIP, forming the mechanistic basis for emerging dual and triple receptor agonists.^16-18 A comparative summary of the key physiological functions and receptor expression of incretin hormones is presented in Table I.

The ‘incretin effect’—wherein oral glucose elicits a stronger insulin response than intravenous glucose—is well-preserved in healthy individuals and accounts for approximately 60–70% of postprandial insulin secretion.^2,4,19 However, this effect is significantly blunted in individuals with type 2 diabetes mellitus (T2DM), due to both impaired incretin secretion and reduced receptor responsiveness.^19-21 GIP, in particular, exhibits markedly reduced insulinotropic activity at physiological concentrations in T2DM—described as GIP resistance.²²

This ‘incretin resistance’ has important clinical implications. While endogenous GLP-1 activity is reduced, pharmacological doses of GLP-1 receptor agonists can overcome this resistance and restore glycaemic control.²³ In contrast, native GIP monotherapy has shown limited benefit; however, its co-activation with GLP-1R in dual or triple agonists (e.g., tirzepatide, retatrutide) has shown synergistic effects—including enhanced insulin sensitivity, appetite suppression, and significant weight loss.^8,24,25

Emerging insights into the molecular basis of incretin resistance, including β-cell dedifferentiation, receptor downregulation, and inflammatory signalling, continue to guide development of next-generation metabolic therapies.²⁶

Historical evolution of incretin-based therapies:

Next-generation incretin-based therapies

The therapeutic landscape of metabolic disease has expanded rapidly with the advent of dual and triple incretin receptor agonists, which aim to synergise the beneficial effects of multiple gut hormones.

Dual agonists: GIP + GLP-1

Tirzepatide represents the first-in-class dual agonist targeting both GIP and GLP-1 receptors. It enhances glucose-dependent insulin secretion, delays gastric emptying, suppresses appetite, and improves adipose tissue insulin sensitivity through GIP receptor activation, while maintaining the glycaemic and satiety benefits of GLP-1 agonism.^14,17,20 The SURPASS clinical program (SURPASS-1 to -6) demonstrated robust reductions in HbA1c (up to 2.5%) and body weight (up to 22.5%), with greater efficacy than both GLP-1 RAs and basal insulin comparators.^14,15,42 Additionally, tirzepatide significantly improves lipid profiles and inflammatory markers, making it a promising agent for comprehensive cardiometabolic risk reduction.^15,30,43 Real-world data support these findings, with consistent efficacy across diverse populations, including in early-phase Asian subgroup analyses, although India-specific data remain limited.^14,42,44 Regulatory bodies such as the US FDA and EMA have approved tirzepatide for T2DM (as Mounjaro in 2022) and for chronic weight management (as Zepbound in 2023), and most recently for obstructive sleep apnoea in patients with obesity (approved in December 2024), with ongoing studies exploring expanded indications.^33,45,46

Dual agonists: GLP-1+glucagon

Another approach harnesses the energy-expenditure and lipolytic effects of glucagon alongside the glucose-lowering and satiety-inducing actions of GLP-1. Survodutide, a GLP-1/glucagon dual agonist, has shown promising results in reducing visceral fat and hepatic steatosis, partly by increasing thermogenesis and mitochondrial uncoupling.^37,47 Recent trials have demonstrated significant improvements in liver enzymes, insulin resistance, and weight loss, particularly in individuals with MASLD (formerly NAFLD) and metabolic dysfunction-associated steatohepatitis (MASH).^37,48,49 These findings support the repositioning of dual agonists as potential agents for the treatment of both obesity and fatty liver diseases.^49-51

Triple agonists: GLP-1+GIP+glucagon

The most recent innovation involves triple agonists, such as retatrutide, which combine the insulinotropic action of GLP-1 and GIP with the thermogenic effects of glucagon. This multi-receptor approach aims to replicate the hormonal synergy observed after bariatric surgery.^44,52,53 Early-phase studies of retatrutide show unprecedented weight reductions of up to 24% and reductions in liver fat content by ⁓82%, surpassing all currently approved monotherapy or dual agonist regimens.^52-54 In addition to weight and glycaemic control, triple agonists may improve hepatic steatosis, lipid metabolism, and systemic inflammation, with implications for the comprehensive management of metabolic syndrome and MASH.^55-57 Several triple agonists are now in Phase 2 and 3 trials, with retatrutide anticipated to gain FDA approval by 2026.^52,54

Dual and triple incretin-based co-agonists represent a significant leap in metabolic therapy by targeting multiple pathways involved in glucose and energy homeostasis. As reviewed by Gutgesell et al,⁵¹ agents like tirzepatide (GIP/GLP-1) and retatrutide (GIP/GLP-1/glucagon) exhibit synergistic effects—improving glycaemic control, promoting substantial weight loss, and enhancing hepatic lipid metabolism beyond what is seen with GLP-1 monotherapy.⁵⁸ Notably, triple agonists have demonstrated up to 24% body weight reduction while preserving lean mass, a potential advantage in advanced metabolic disease.¹ Table III provides a detailed pharmacologic comparison across mono-, dual-, and triple incretin receptor agonists. The authors further highlight the importance of receptor selectivity and partial agonism, especially at the glucagon receptor, to balance efficacy and safety. Such tailored approaches are driving the development of next-generation agents like HM15211 and LY3437943, designed for obesity and MASLD/MASH.⁴³

Beyond survodutide, other GLP-1 and glucagon receptor dual agonists such as cotadutide and efinopegdutide have shown therapeutic potential in targeting both metabolic and hepatic endpoints. Cotadutide (MEDI0382) was developed to harness the complementary mechanisms of GLP-1-induced insulinotropic and anorectic effects alongside glucagon-mediated enhancement of energy expenditure and hepatic lipid oxidation. Clinical trials have demonstrated its ability to reduce hepatic fat content, improve insulin sensitivity, and promote moderate weight loss in individuals with type 2 diabetes mellitus (T2DM) and obesity, particularly those with metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH)^49,53,59-61 Notably, cotadutide showed superior effects in reducing liver fat compared to GLP-1 monotherapy, making it a promising candidate for dual-targeting liver and metabolic dysfunction. However, its glycaemic efficacy was somewhat lower, and gastrointestinal tolerability remained a concern.

Similarly, efinopegdutide is a long-acting PEGylated GLP-1/glucagon receptor co-agonist that has shown promise in reducing hepatic steatosis and modulating lipid metabolism. Phase 2 data indicate its potential for treating MASLD/MASH, especially in patients with coexisting T2DM, with added benefits on satiety and fat oxidation^49,59 To compare mechanistic actions, clinical endpoints, and safety profiles across the incretin-based agent spectrum, refer to Table III, and the Figure, which details pharmacologic attributes from GLP-1 monotherapy to dual and triple receptor co-agonists. While its weight reduction capacity is not as pronounced as newer triple agonists, efinopegdutide’s hepatic specificity and safety profile suggest a potential role as a niche therapy for metabolic liver diseases. Together, these incretins represent a growing class of next-generation incretin-based co-agonists with hepatocentric and metabolic benefits.

Close

Figure. Comparative efficacy of GLP-1 RA (e.g., Semaglutide), GIP/GLP-1 dual agonist (Tirzepatide), GLP-1/Glucagon dual agonist (Survodutide), and triple agonist (Retatrutide) on HbA1c reduction, weight loss, appetite suppression (scale of 1–5), and hepatic fat reduction. Data compiled from key trials and peer-reviewed literature (2020–2025).

Export to PPT

Expanding therapeutic horizons

Incretin co-agonists are increasingly recognised for their broad-spectrum metabolic benefits that extend well beyond glycaemic control. Emerging evidence has underscored their effectiveness in obesity without diabetes, with agents such as tirzepatide and retatrutide achieving unprecedented weight reductions exceeding 20%, rivalling bariatric surgery outcomes in select patient populations.^44,51,56 This has ushered in a new era of pharmacotherapy targeting non-diabetic obesity—an area previously underserved.

Simultaneously, dual and triple receptor agonists have demonstrated significant promise in metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). Agents like cotadutide and efinopegdutide have led to marked reductions in hepatic fat content, improved transaminase profiles, and potential histological improvement in fibrosis and inflammation.^{33,46,48-50,62}

Beyond hepatic and adipose tissues, incretin-based therapies have shown notable cardiorenal protective effects. GLP-1 receptor agonists are already established in reducing major adverse cardiovascular events (MACE), while newer agents—tirzepatide and survodutide—may further enhance these benefits through synergistic weight reduction, lipid modulation, and suppression of systemic inflammation.^27,29,37,58 Additionally, they are now being investigated for post-bariatric metabolic support, potentially helping stabilise weight trajectories and glycaemic parameters following surgery.^38,45

From a regulatory perspective, tirzepatide is now approved for both T2DM and obesity in the United States, Europe, and Japan, while retatrutide and survodutide are in late-stage clinical development with substantial global momentum.^44,56,63 Market uptake has been rapid, and real-world data have largely affirmed the efficacy and tolerability profiles observed in trials.^37,56

Meanwhile, next-generation incretin agents—particularly triple agonists and GLP-1/glucagonco-agonists—continue to expand into new clinical indications. These include heart failure with preserved ejection fraction (HFpEF), polycystic ovary syndrome, and neurodegenerative diseases, reflecting their central anti-inflammatory and neuroprotective properties.^41,64,65

Emerging pharmacogenomic data indicate considerable inter-ethnic variability in responsiveness to incretin-based therapies. Polymorphisms in genes such as GIPR, GLP1R, and TCF7L2 influence receptor activity and downstream signalling.⁶⁵ However, major clinical trials—SURPASS, SURMOUNT, and RETAKE—have largely excluded South Asian and LMIC cohorts, raising concerns about generalisability and pharmacogenomic equity.^3,4 Inclusion of these populations in Phase III and IV global trials is essential to tailor future therapy and policy decisions.

Lastly, cost-effectiveness remains a substantial implementation barrier. Despite robust metabolic benefits, high cost and restricted insurance coverage limit the uptake of these therapies in low- and middle-income countries. Health-economic models specific to resource-constrained settings are urgently needed to inform reimbursement strategies.^5,6,7 Integration of these agents into public health systems like India’s Ayushman Bharat scheme or the WHO Essential Medicines List could substantially widen access, provided local efficacy and safety data are generated through real-world studies.

Therefore, triple agonists (GLP-1 + GIP + glucagon) are designed to:

• Simultaneously target multiple metabolic pathways—enhancing insulin secretion (GLP-1, GIP), improving insulin sensitivity (GIP), and increasing energy expenditure and hepatic lipid oxidation (glucagon).⁴³

• Overcome the limitations of GLP-1 monotherapy, which primarily lowers glucose and body weight through appetite suppression but has modest effects on hepatic steatosis and thermogenesis.^52,55

• Leverage synergistic hormonal effects that mimic post-bariatric physiology, thereby delivering greater weight loss (up to 24%), profound hepatic fat reduction (∼82%), and robust glycaemic improvement compared with dual or single agonists.^36,41

• Expand indications beyond type 2 diabetes to obesity without diabetes, MASLD/MASH, cardiometabolic risk reduction, and potentially HFpEF and PCOS, based on emerging phase-2/3 evidence.^41,46,62

• Provide multi-system benefit, making them uniquely suited for complex metabolic disease where hyperglycaemia, adiposity, hepatic dysfunction, and inflammation coexist.^5,6,7,41,46

The incretin-based therapeutic landscape has witnessed a remarkable evolution—from the modest glycaemic effects of early DPP-4 inhibitors to the transformative metabolic benefits seen with dual and triple agonists.^29,32,44,52 This trajectory reflects a deeper understanding of incretin physiology, resistance mechanisms in type 2 diabetes mellitus (T2DM), and the multifaceted roles of gut-derived hormones in energy homeostasis.^35,44 GLP-1 receptor agonists have already established themselves as cornerstones in T2DM and obesity care, offering proven cardiovascular and renal protection.^29,37,39 Building on this foundation, multi-agonist therapies such as tirzepatide and retatrutide have demonstrated unprecedented efficacy in reducing HbA1c, body weight, hepatic steatosis, and other markers of metabolic dysfunction.^44,49,53,57

Beyond glycaemic control, these agents represent a new paradigm in holistic metabolic regulation, targeting interconnected pathways involved in obesity, MASLD, and cardiometabolic risk.^48,49,50 The integration of these pharmacotherapies with lifestyle interventions and digital health tools further enhances the potential for personalised, sustained outcomes.^5,16 As the therapeutic arsenal continues to expand, the future of metabolic disease management lies in tailoring co-agonist regimens to patient-specific profiles—bridging clinical efficacy with long-term safety, affordability, and equitable global accessibility.^41,56,65