Introduction

Glucagon-like peptide-1 (GLP-1) is a hormone rapidly released by intestinal L-cells following food intake that stimulates pancreatic insulin secretion. Later, it was observed that GLP-1 also inhibits pancreatic glucagon secretion and gastric emptying. These findings collectively drove the development of a new class of GLP-1-based drugs as hypoglycemic therapies for type 2 diabetes (T2D). Subsequent preclinical studies in rats and mice demonstrated that GLP-1 also reduces food intake by affecting brain regions involved in feeding regulation, thereby achieving weight loss.

The first human GLP-1 receptor agonist (GLP-1RA), liraglutide, contains a 16-carbon lipid side chain that can non-covalently bind to albumin. This modification extends the circulating half-life (t1/2), confers partial resistance to DPP-4, and delays renal clearance. Liraglutide was approved for type 2 diabetes in 2010, with once-daily administration. Subsequently, a once-weekly T2D drug, the extended-release form of exenatide, was approved in 2012. Then in 2014, dulaglutide, an immunoglobulin-based GLP-1RA, received approval for once-weekly dosing. The latest GLP-1 drugs, such as semaglutide (which has a C18 octadecanedioic acid moiety linked to Lys26) and tirzepatide (a GIPR-GLP-1R co-agonist with a C20 eicosanedioic acid lipid moiety), have also been approved for T2D and obesity.

Current GLP-1 drug development for obesity and related complications focuses on molecules that can provide greater weight loss, improved tolerability, reduced dosing frequency, and ideally lower manufacturing costs. The GLP-1 drugs under development include small molecules, peptides, and antibody-based GLP-1RAs. In addition, there is a concentrated effort to develop GLP-1-based multi-agonists, including GIPR–GLP-1R dual agonists, GCGR–GLP-1R dual agonists, GCGR–GIPR–GLP-1R triple agonists, amylin receptor (AMLNR)–GLP-1R co-agonists, and GIPR antagonist–GLP-1RAs.

I. Approved GLP-1-Based Therapies

The field of GLP-1-based drugs has evolved from the initially approved short-acting agents, such as twice-daily exenatide and lixisenatide, to long-acting therapies like once-daily liraglutide and once-weekly agents including once-weekly exenatide and dulaglutide. Modern GLP-1-based drugs, such as semaglutide and tirzepatide, enhance glucose control and deliver greater weight loss, and are approved for the treatment of T2D and overweight with one or more weight-related comorbidities or obesity.

Exenatide, the first GLP-1 drug approved in 2005, has a very short t1/2 of approximately 2.4 hours and requires twice-daily administration to reduce HbA1c by 0.6-0.8% and achieve modest weight loss of 1-2%. Lixisenatide is an exenatide derivative with amino acid modifications at the carboxy terminus to improve stability, and its circulating t1/2 is 3 hours, used for blood glucose control in T2D patients. Once-weekly exenatide is administered as a subcutaneous injection of microsphere-encapsulated exenatide-poly(d,l-lactide-co-glycolide) mixture; its extended release provides higher efficacy in glucose control with comparable weight loss effects to twice-daily dosing.

Liraglutide, a human GLP-1 analog administered once daily at doses of 1.2 mg or 1.8 mg, was approved for T2D in 2010, with a circulating t1/2 of 13-15 hours through non-covalent binding to albumin. Compared with exenatide, once-daily liraglutide significantly reduces HbA1c and body weight, though gastrointestinal adverse events are more frequent in liraglutide-treated subjects. Dulaglutide is an immunoglobulin Fc-based molecule containing two modified GLP-1 peptides, with pharmacokinetic properties suitable for once-weekly administration. Dulaglutide 1.5 mg once weekly is non-inferior to liraglutide 1.8 mg once daily.

Next-generation GLP-1 drugs, such as semaglutide and tirzepatide, are long-acting peptides administered once weekly, with more effective glucose control and weight loss than older molecules, which may reflect enhanced receptor engagement and optimized pharmacokinetics. The superior efficacy of tirzepatide may reflect the contribution of biased receptor signaling at GIPR and GLP-1R, favoring cAMP production over β-arrestin recruitment.

The main adverse events caused by all GLP-1 drugs are nausea, diarrhea, constipation, and vomiting, reflecting the activation of central nervous system GLP-1R+ neurons associated with the emetic response and reduced gastric emptying. Compared with current GLP-1 drugs, optimized pharmacokinetics and slower CMax time may achieve greater efficacy and tolerability, which is an important goal for novel GLP-1 drugs including oral small-molecule GLP-1RAs.

II. Novel GLP-1R Small-Molecule Agonists

Currently approved GLP-1RAs are all peptides delivered by subcutaneous injection; although oral semaglutide is available, its bioavailability remains low and the tablets must be taken on an empty stomach. A variety of oral small-molecule GLP-1RAs are under development. Oral GLP-1RAs do not require injection pen supplies or cold chain for distribution. Existing data indicate that these investigational oral GLP-1RAs exhibit pharmacokinetic and pharmacodynamic profiles suitable for once-daily oral administration, and the most promising molecules may achieve at least 15-20% weight loss in obese populations.

ASC30

ASC30 is a small-molecule GLP-1RA developed by Ascletis Pharma, which has been studied in two Phase I 28-day multiple ascending dose (MAD) trials in obese subjects, with doses escalating from 2 mg to 40 mg weekly. At the maximum tolerated dose, body weight was reduced by 4.3% to 6.3% from baseline. Ascletis also intends to develop a once-monthly subcutaneous formulation of ASC30.

AZD5004

ECC5004, now co-developed with AstraZeneca and named AZD5004, is a biased small-molecule GLP-1RA that favors cAMP accumulation without requiring β-arrestin recruitment or receptor internalization. AZD5004 has been explored in single ascending dose and MAD studies in T2D patients at doses ranging from 10 mg to 50 mg once daily for 4 weeks. Within 28 days, subjects taking 50 mg daily achieved a 5.8% weight loss. The Phase IIb SOLSTICE trial is evaluating a range of doses of AZD5004 over 26 weeks in T2D patients with HbA1c of 7-10.5%.

CT-996

CT-996, initially developed by Carmot Therapeutics, is an once-daily oral small-molecule GLP-1RA with biased signaling, currently being developed by Roche for T2D and obesity. In a 4-week Phase I trial, once-daily CT-996 at a final dose of 120 μg achieved weight loss of up to 6.1% compared with placebo, and Phase II studies are planned for 2025.

Danuglipron

Danuglipron, a small-molecule GLP-1RA, was obtained through medicinal chemistry research, focusing primarily on optimizing cAMP accumulation with a subtle bias toward cAMP relative to βArr1 recruitment. Danuglipron has been studied at a range of doses from 2.5 mg to 120 mg in T2D patients. Over 16 weeks, the highest dose of danuglipron reduced HbA1c by 0.47% to 1.14%, but its clinical development was halted in April 2025 due to adverse events, including one case of drug-induced liver injury.

GSBR-1290

Structure Therapeutics is developing GSBR-1290 (aleniglipron), an once-daily oral small-molecule GLP-1RA that is biased toward cAMP activation with minimal binding to β-arrestin. In overweight and obese populations, subjects treated with GSBR-1290 achieved an average weight loss of 6.2%; however, a considerable proportion of subjects reduced the dose of GSBR-1290 (40.5%) or discontinued treatment (18.9%) due to adverse reactions.

KAI-7535

KAI-7535 is an oral small-molecule GLP-1RA developed by Kailera Therapeutics, which has been evaluated in single ascending dose and MAD human studies in healthy volunteers. In the 28-day MAD study, body weight was reduced by an average of 4.38 kg compared with the baseline weight of 67.9 kg.

Orforglipron

LY3502970 (now known as orforglipron) is a small-molecule GLP-1RA initially discovered by Chugai Pharmaceutical as a partial agonist of GLP-1R, biased toward G protein activation. In Phase II studies, orforglipron demonstrated significant efficacy in T2D and obese patients, with HbA1c reductions of up to 1.67% and weight loss of up to 7.9 kg at the highest dose, and is currently being studied in separate Phase III trials for T2D and obesity.

RGT-075

RGT-075 is a small-molecule GLP-1RA developed by Regor Therapeutics Group. In studies of overweight or obese patients over 12 years old, its weight loss effect reached up to 5%, and a Phase IIb trial is underway to explore the effect of higher doses.

TERN-601

TERN-601 is a small-molecule GLP-1RA with pharmacokinetic properties suitable for once-daily administration. At the highest tested dose, a 4.9% weight loss was observed. The pharmacodynamic activity of TERN-601 is thought to partially reflect its prolonged exposure within the intestinal mucosa, which may trigger local GLP-1Rs, thereby activating the gut-brain axis that promotes satiety and enabling 24-hour drug coverage.

MET-097

MET-097 is a long-acting lipidated fully biased GLP-1RA with a t1/2 of 380 hours, potentially suitable for once-monthly administration. In a Phase I study, MET-097 was evaluated in 125 healthy, non-diabetic, overweight or obese adult participants; MET-097 1.2 mg once weekly resulted in a 7.5% weight loss at 36 days and 8.1% at 57 days. Adverse events, mainly gastrointestinal adverse events, were reported as mild to moderate and transient, consistent with data reported for the GLP-1 class. Future trials plan to explore the feasibility of once-monthly administration.

Ecnoglude

Ecnoglude is a high-affinity, cAMP-biased, DPP-4-resistant acylated GLP-1RA with reduced GLP-1R internalization and a t1/2 of 124-138 hours, suitable for once-weekly administration. An oral form of ecnoglude, named XW004, is being evaluated in a Phase I clinical trial. Results showed that 1.2 mg once weekly for several weeks reduced HbA1c by 2.39% from a baseline of 8.67%. Two Phase III trials are investigating ecnoglude as monotherapy or as an add-on to metformin in T2D patients.

GZR18

GZR18 (Bofanglutide) is a long-acting lipidated investigational GLP-1RA being evaluated in China for the treatment of obesity and T2D. In a 30-week Phase IIb trial evaluating once-weekly and once-every-two-weeks dosing in overweight or obese subjects, weight loss of up to 17.29% and 17.78% was observed, with the maximum effective doses being 48 mg once every two weeks and 24 mg once weekly. A Phase III trial in Chinese overweight or obese patients is under evaluation.

NPM-115

NPM-115 is a long-acting exenatide formulation delivered via a NanoPortal subcutaneous implant, and a 17-week trial is underway to assess its safety, tolerability, and pharmacokinetic profile.

III. GLP-1-Based Multi-Agonists

Some next-generation GLP-1 therapies are based on co-formulations with other peptide receptor agonists, such as the combination of cagrilintide (an amylin analog) and semaglutide (Cagri-Sema), or more commonly, single-molecule designs of GLP-1 drugs, like tirzepatide, which carry one or more additional metabolically active peptide epitopes to achieve simultaneous activation of multiple receptors and superior metabolic outcomes.

Tirzepatide

Tirzepatide is the first GIPR-GLP-1R co-agonist, with better glucose control and weight loss effects compared with semaglutide. Notably, tirzepatide is also being evaluated in a separate trial in combination with the MC4R agonist bremelanotide for weight loss in obese populations (NCT06565611).

In addition to tirzepatide, a variety of GIPR-GLP-1R drugs are under development. Some are injectable once-weekly or once-monthly formulations, while others are synthesized/formulated as small molecules or peptides for once-daily oral administration. GIP stimulates glucose-dependent insulin secretion, reduces appetite leading to weight loss with continuous administration, and enhances insulin sensitivity through non-weight loss mechanisms.

VK2735

VK2735 is another GIPR-GLP-1R co-agonist. The Phase II VENTURE trial studied 176 overweight or obese adults, and up to 88% of VK2735-treated subjects achieved at least 10% weight loss. An oral formulation of VK2735 is also under development; in a 28-day MAD study, the oral formulation produced weight loss of up to 3.3%, and 57% of subjects reported weight loss >5%. Phase III trials of the injectable formulation of VK2735 are planned for 2025.

KAI-9531

Kailera Therapeutics is developing HRS-9531, now renamed KAI-9531. This molecule is a dual GIPR–GLP-1R co-agonist with an average t1/2 of approximately 1 week. HRS-9531 has been studied in separate Phase II trials in T2D and obese patients; in T2D patients with a body mass index of 22-40, HbA1c was reduced by up to 2.2% from a baseline of 8.2%, and 90% of study subjects achieved HbA1c <6.5%. Adverse events were mild to moderate, mainly gastrointestinal adverse events, consistent with the GLP-1 class.

CT-868

Roche is developing CT-868, a biased GIPR-GLP-1R agonist, as an once-weekly treatment for T1D and overweight/obese patients, along with a related molecule CT-388 for obese patients with or without T2D. In a Phase Ib trial, CT-388 22 mg resulted in a 19% weight loss in obese patients.

BGM0504

BGM0504 is a long-acting dual GLP-1R-GIPR co-agonist with C-terminal acylation of C18 aliphatic diacid lipidation. In in vitro and preclinical studies, it exhibits greater potency at both receptors compared with tirzepatide. The safety, tolerability, and pharmacokinetic profile of BGM0504 were evaluated in Chinese healthy volunteers; a dose of 15 mg once weekly resulted in a 5.4 kg weight loss at 15 days.

Maridebart Cafraglutide

Interestingly, both gain-of-function and loss-of-function approaches for GIPR can be combined with GLP-1R agonism. MariTide (AMG-133 or maridebart cafraglutide) is a bispecific human GIPR-blocking antibody conjugated with two GLP-1RAs. MariTide demonstrated robust efficacy in preclinical and Phase I clinical trials, with a 14.6% weight loss after three once-monthly injections.

The Phase II trial of MariTide enrolled 592 obese and/or T2D patients; MariTide achieved a maximum weight loss of 20% in subjects, and 98% of trial subjects reported at least 5% weight loss. In overweight or obese and T2D patients, MariTide resulted in an average weight loss of 17% and reduced HbA1c by 2.2% from a baseline of 7.9%. Gastrointestinal side effects consistent with the GLP-1 class were the most commonly reported adverse events for MariTide. Antibodies and small-molecule antagonists or peptides that selectively block GIPR, such as AT-7687, are also in early clinical development.

Pemvidutide

Pemvidutide is a 29-amino acid balanced long-acting GCGR-GLP-1R co-agonist, suitable for once-weekly administration. The MOMENTUM trial explored the weight loss effect of pemvidutide; 2.4 mg once weekly achieved a 13.4% weight loss at 48 weeks. More than 30% of subjects achieved at least 20% weight loss at the highest tested dose, and adverse events reported in the MOMENTUM trial were consistent with the GLP-1 drug class.

Mazdutide

Mazdutide is an acylated GCGR-GLP-1R co-agonist suitable for once-weekly administration, mainly developed in China for the treatment of T2D and obesity. In Phase II testing in T2D patients, 3 mg, 4.5 mg, and 6.0 mg of mazdutide resulted in weight loss percentages of 0.9%, 5.0%, and 5.4% from baseline, respectively, compared with 0.9% for dulaglutide 1.5 mg once weekly and 1.1% for placebo. The safety of mazdutide was generally similar to that of dulaglutide-treated patients. In a 48-week Phase III study in overweight or obese populations, once-weekly mazdutide achieved a weight loss of up to 14.7% at the highest tested dose, with corresponding reductions in blood pressure, waist circumference, cholesterol, triglycerides, and transaminase levels.

Survodutide

Survodutide is a 29-amino acid acylated degradation-resistant GCGR-GLP-1R co-agonist suitable for once-weekly administration, with approximately tenfold lower in vitro potency at GCGR and GLP-1R compared with native peptides. In a 46-week Phase II study, the highest dose in the study produced a 12.1% weight loss. Currently, survodutide is undergoing Phase III trials to evaluate weight loss in people with (NCT06066528) or without (NCT0666515) T2D.

Retatrutide

Retatrutide is an investigational GCGR-GIPR-GLP-1R triple agonist drug being developed for the treatment of obesity, T2D, and metabolic liver disease. Retatrutide has weaker effects on human GCGR and GLP-1R but stronger effects on human GIPR. A Phase II trial evaluated multiple doses in 338 overweight or obese subjects over 48 weeks; results showed that at 48 weeks, the 8 mg group achieved a 22.8% weight loss, the 12 mg group a 24.2% weight loss, compared with a -2.1% weight change in the placebo-treated group.

Other GCGR-GLP-1R Co-Agonists

AZD9550 is an early GCGR-GLP-1R co-agonist being studied in patients with metabolic liver disease and individuals with overweight and obesity with or without T2D (NCT06151964). UBT251 is a triple GCGR-GLP-1R-GIPR multi-agonist discovered by U.S. federal laboratories, currently being co-developed with Novo Nordisk. Bioglutide (NA-931) is an investigational quadruple receptor peptide agonist that activates GCG, GIP, GLP-1, and IGF-I receptors, developed as an once-daily oral formulation (capsule) for chronic weight management, with the potential to achieve meaningful weight loss and preferential reduction of adipose tissue mass.

IV. New Indications for GLP-1-Based Therapies

GLP-1-based therapy began with the approval of exenatide for T2D in 2005, followed by the first approval of such a drug for obesity (liraglutide) in 2014. Over the past decade, GLP-1-based therapies have been approved for a variety of new indications, expanding the clinical applications of GLP-1 therapy beyond blood glucose and weight control.

Cardiovascular Disease

In 2016, the LEADER trial established the first definitive evidence of cardioprotection in T2D patients treated with long-acting GLP-1 drugs such as liraglutide, specifically reducing non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. The cardioprotective effects of GLP-1 drugs were further demonstrated with oral and injectable semaglutide in the PIONEER-6 and SUSTAIN-6 CVOTs, respectively.

The SELECT trial explored the cardioprotective effect of semaglutide in 17,604 individuals with a history of atherosclerotic cardiovascular disease, overweight and one or more weight-related comorbidities or obesity, and without T2D. Subjects receiving semaglutide had a 20% reduction in non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, and a 19% reduction in all-cause mortality.

Nephropathy

The FLOW trial studied the effect of semaglutide in T2D and chronic kidney disease patients; the Data Safety Monitoring Board stopped the FLOW trial early because individuals receiving semaglutide had a 24% reduction in the primary composite outcome. Trial subjects randomized to semaglutide showed reductions in renal endpoints and cardiovascular mortality. Based on the results of the FLOW trial, regulatory authorities have now approved the use of semaglutide to prevent more severe chronic kidney disease and cardiovascular death in T2D patients with early evidence of chronic kidney disease.

Osteoarthritis

The STEP-9 trial examined the efficacy of semaglutide in 407 obese patients over 68 years old with knee osteoarthritis, with the primary endpoints being changes in body weight and pain scores. Results showed that semaglutide treatment improved pain and physical function scores, with weight reductions of 13.7% for semaglutide versus 3.2% for placebo. Subjects receiving semaglutide had greater reductions in analgesic use.

Sleep Apnea

Tirzepatide was studied in 469 patients with mild to moderate obstructive sleep apnea and obesity over several weeks. Results showed that patients receiving tirzepatide had reduced apnea-hypopnea index, decreased sleep disturbance and hypoxia burden, and lower levels of body weight, blood pressure, and circulating high-sensitivity CRP122. Based on the results of these two trials, the U.S. Food and Drug Administration (FDA) approved a new indication for tirzepatide as the first drug approved for the treatment of moderate to severe obstructive sleep apnea in obese adults, to be used in conjunction with exercise programs and a low-calorie diet.

Other Indications

Some of the cardiovascular benefits of GLP-1 drugs may be partially independent of observed weight loss and improved glucose control, along with preclinical data and reports of clinical improvement in multiple diseases, which has sparked interest in evaluating the therapeutic utility of GLP-1 drugs in a range of inflammatory, neurodegenerative, and neuropsychiatric diseases. Ongoing registrational trials are testing the efficacy of GLP-1 drugs in patients with metabolic dysfunction-associated steatohepatitis (MASH), peripheral artery disease, Parkinson's disease, and Alzheimer's disease.

Conclusion

GLP-1 receptor agonists have evolved from a single hypoglycemic drug to a "multipurpose agent" covering multiple fields such as metabolism, cardiovascular, and neurology. With the development of multi-agonists, oral formulations, and new indications, the clinical application boundaries of GLP-1 therapy continue to expand. In the future, GLP-1 therapy may become one of the core pillars of chronic disease management, truly realizing the vision of "one drug with multiple effects, benefiting multiple diseases".