GLP-1 Receptor Agonists in Clinical Development: The Emerging Pipeline and Recent FDA and EMA Decisions
The GLP-1 receptor agonist class is evolving faster than almost any other therapeutic area, with development programs extending beyond type 2 diabetes and obesity into cardiovascular, renal, hepatic, and respiratory indications. For regulatory and clinical teams, tracking which candidates are advancing, which mechanisms are gaining traction, and how the FDA and EMA are responding to expanding indication claims is essential context for trial design, submission planning, and competitive positioning.
The analysis below draws on clinical trial records and recent FDA and EMA regulatory decisions to map the current GLP-1 landscape: the approved agents that anchor the class, the oral small-molecule and multi-receptor agonist candidates in active development, and the indication expansions reflected in recent agency actions.
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GLP-1 receptor agonists in clinical development: the emerging pipeline and recent FDA/EMA decisions
The GLP-1 receptor agonist (GLP-1 RA) field has moved well past the first generation of injectable peptides. The commercial backbone remains semaglutide and tirzepatide, but the active development frontier now runs in three directions at once: oral small-molecule agonists, multi-receptor "incretin-plus" agonists (adding GIP, glucagon, or amylin activity), and a rapid push into indications far beyond glycaemic control, including heart failure, metabolic liver disease, chronic kidney disease, and obstructive sleep apnea. This overview summarizes what current clinical trial records and recent FDA and EMA decisions show.
The approved backbone
Three molecules anchor the class in the US and EU:
- Tirzepatide (a GLP-1/GIP dual agonist), marketed by Eli Lilly as Mounjaro for type 2 diabetes and Zepbound for chronic weight management. Mounjaro was approved by FDA as a new molecular entity on 13 May 2022 179180181. In the EU, Mounjaro is authorised for both type 2 diabetes (pivotal SURPASS-1 to -5 programme) and weight management (pivotal SURMOUNT-1, supported by SURMOUNT-4 and SURPASS subgroup analyses) 304312313322.
- Semaglutide (a GLP-1 RA), marketed by Novo Nordisk as Ozempic and oral Rybelsus for type 2 diabetes and Wegovy for weight management. Wegovy's original weight-management approval dates to 4 June 2021 777879.
- Liraglutide (a GLP-1 RA), the earlier Novo Nordisk agent, authorised as Saxenda for weight management as an adjunct to diet and physical activity 217225.
The near-term competitive picture is also shifting on the generic side: an ANDA referencing semaglutide from Apotex appears in Drugs@FDA, signalling the beginning of generic entry pressure on the older semaglutide franchise 80.
Recent FDA decisions (2024 to 2026): indication expansion and an oral formulation
The most consequential recent FDA activity is not new molecules but the expansion of the two incumbent products into cardiometabolic and sleep indications, plus the first oral formulation for weight loss.
- Zepbound (tirzepatide), obstructive sleep apnea. FDA approved moderate-to-severe OSA in adults with obesity on 20 December 2024, based on the SURMOUNT-OSA master protocol (NCT05412004), comprising two randomized, double-blind, placebo-controlled studies (Study 5/GPI1 in patients not on PAP therapy and Study 6/GPI2 in patients on PAP therapy); the primary endpoint was change from baseline in the apnea-hypopnea index at Week 52 345356361363.
- Wegovy (semaglutide), MASH. FDA labeling now supports non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with stage 2 to 3 fibrosis, based on Study 8/9/11 under NCT04822181. At Week 72, resolution of steatohepatitis without worsening of fibrosis occurred in 63% versus 34% on placebo (difference 29 points, 95% CI 21 to 36), and fibrosis improvement without worsening steatohepatitis in 37% versus 22% 289290293294295.
- Wegovy oral tablet (application 218316). FDA approved an oral tablet formulation of semaglutide for chronic weight management on 22 December 2025. The tablet is co-formulated with SNAC to aid gastric absorption (oral bioavailability roughly 1% to 2%), and the 25 mg once-daily exposure was predicted to be comparable to Wegovy 2.4 mg once-weekly injection 3323393427576.
- Rybelsus (oral semaglutide), cardiovascular risk reduction. FDA approved a MACE risk-reduction indication on 17 October 2025, based on the SOUL trial (NCT03914326), which randomized 9,650 patients with type 2 diabetes plus established cardiovascular disease and/or chronic kidney disease to oral semaglutide 14 mg or placebo, showing a MACE hazard ratio of 0.86 (95% CI 0.77 to 0.96). This contrasts with the original 2020 review, where PIONEER 6 supported cardiovascular safety but not a risk-reduction claim 366367364365.
Recent EMA decisions
On the EU side, the CHMP and PRAC records show parallel movement plus the first class-wide safety signal:
- Oral Wegovy (semaglutide) recommended in the EU. The CHMP recommended extending the marketing authorisation to add an oral tablet formulation for weight management in adults with obesity or overweight with at least one weight-related comorbidity, describing it as the first GLP-1 receptor agonist for weight management developed for oral use 222228.
- Cardiovascular indication treated as already covered. For Wegovy, the CHMP concluded that a separate indication for reducing major cardiovascular events in adults with established cardiovascular disease and BMI ≥27 kg/m² was not needed because this use is already covered by the approved weight-management indication 271.
- NAION safety signal. PRAC concluded that non-arteritic anterior ischaemic optic neuropathy (NAION) is a very rare side effect of semaglutide and recommended updating the product information across semaglutide products, with treatment discontinuation if NAION is confirmed 223.
- Supply. EMA, the HMA and the MSSG issued recommendations to address class-wide GLP-1 shortages (Ozempic, Saxenda, Trulicity, Victoza, Wegovy, Rybelsus, Bydureon, Byetta, Lyxumia, Mounjaro), including optimising distribution, expanding manufacturing capacity, and discouraging off-label cosmetic use 219.
The emerging pipeline
Clinical trial registries (CTIS under EU CTR 536/2014, and the legacy EU Clinical Trials Register) show a dense late-stage pipeline dominated by next-generation incretin agents. The table below summarizes the principal investigational agents surfacing in EU trial records.
| Agent (code) | Sponsor | Mechanism | Furthest phase in EU records | Conditions studied |
|---|---|---|---|---|
| Orforglipron | Eli Lilly | Oral, non-peptide small-molecule GLP-1 RA | Phase III | Obesity/overweight, type 2 diabetes, hypertension, osteoarthritis, ASCVD/CKD, paediatric obesity 2302312322372352436 |
| Elecoglipron (AZD5004) | AstraZeneca | Oral GLP-1 RA | Phase III | HFpEF/HFmrEF on background SGLT2i 7 |
| Retatrutide | Eli Lilly | Triple GLP-1/GIP/glucagon agonist | Phase III (MASLD); Phase II | Type 2 diabetes, obesity, MASH/MASLD 207213 |
| Survodutide | Boehringer Ingelheim | GLP-1/glucagon dual agonist | Phase III (obesity); Phase II (CKD) | Obesity, type 2 diabetes, MASH/MASLD with fibrosis, chronic kidney disease 202203204205208 |
| RO7795068 (CT-388) | Roche | GLP-1/GIP dual (biased) agonist | Phase III | Obesity/overweight with and without type 2 diabetes 257258266267 |
| KAI-9531 | Kailera Therapeutics | GLP-1/GIP dual agonist | Phase III | Obesity, with and without diabetes 18263264270 |
| CagriSema (cagrilintide + semaglutide) | Novo Nordisk | Amylin analogue + GLP-1 RA combination | Phase III | Obesity, type 2 diabetes, cardiovascular disease; Phase II in CKD and diabetic peripheral neuropathy 114124126129112 |
| Petrelintide | Zealand Pharma | Long-acting amylin analogue (amylin/calcitonin receptor agonist) | Phase II | Obesity/overweight with hypertension or dyslipidaemia 296297299300 |
| Maridebart cafraglutide (AMG 133) | Amgen | Long-acting incretin obesity agent | Phase III | Chronic weight management; HFpEF/HFmrEF with obesity 1620 |
| NNC0487-0111 | Novo Nordisk | Investigational incretin agent | Phase III | HFpEF/HFmrEF with obesity 182 |
Several themes stand out:
Oral small molecules are the next battleground. Lilly's orforglipron is the most advanced oral, non-peptide GLP-1 RA, with a broad Phase III programme (ATTAIN in obesity, plus dedicated studies in type 2 diabetes, hypertension, osteoarthritis, atherosclerotic cardiovascular disease/CKD, and a paediatric obesity trial) 2302312322372352436. AstraZeneca's oral elecoglipron (AZD5004) has entered Phase III, notably in HFpEF/HFmrEF on background SGLT2 inhibitor therapy 7. An oral peptide (Wegovy tablet) is already approved in the US and recommended in the EU, so the oral-versus-injectable dynamic is now central to the class 332222.
Multi-receptor agonism is maturing. Lilly's retatrutide (GLP-1/GIP/glucagon triple agonist) has advanced to Phase III in metabolic liver disease alongside Phase II work in diabetes and obesity 207213. Boehringer Ingelheim's survodutide (GLP-1/glucagon dual agonist) is in Phase III for obesity and Phase II for chronic kidney disease, with a MASH/fibrosis programme 202203204205208. Two GLP-1/GIP dual agonists directly challenging tirzepatide's mechanism, Roche's RO7795068 (CT-388) and Kailera's KAI-9531, are both in Phase III for obesity, including head-to-head-style designs against semaglutide 25725818270.
Amylin biology is the newest axis. Novo Nordisk's CagriSema pairs the amylin analogue cagrilintide with semaglutide and is in a wide Phase III programme spanning obesity, type 2 diabetes, and cardiovascular disease, with Phase II work in chronic kidney disease and diabetic peripheral neuropathy 114124126129112. Zealand Pharma's standalone amylin analogue petrelintide is in Phase II dose-finding for obesity 296297299300.
Expansion beyond diabetes and obesity
The registry data make clear that sponsors are testing incretin agents as broad cardiometabolic drugs, not just glucose- or weight-lowering agents. EU trial records show late-stage programmes in:
- Heart failure with preserved/mildly reduced ejection fraction (HFpEF/HFmrEF): Novo Nordisk (NNC0487-0111 and a Phase II Wegovy study in HFrEF), Amgen (maridebart cafraglutide), and AstraZeneca (elecoglipron) 182183167.
- Metabolic liver disease (MASH/MASLD): retatrutide (Phase III) and survodutide, plus the approved Wegovy MASH data 207202289.
- Chronic kidney disease: survodutide (Phase II) and CagriSema (Phase II), with orforglipron's combined ASCVD/CKD Phase III programme 205112186.
- Obstructive sleep apnea: now an approved Zepbound indication via SURMOUNT-OSA 345363.
- Adjacent indications: orforglipron is also being studied in hypertension and osteoarthritis in obese/overweight patients 237235.
What to watch
For regulatory-affairs teams, three developments deserve close tracking. First, the oral small-molecule agents (orforglipron, elecoglipron) will test how regulators handle small-molecule versus peptide comparability, CMC, and label positioning against injectables. Second, the multi-receptor and amylin combinations (retatrutide, survodutide, CT-388, KAI-9531, CagriSema, petrelintide) raise new benefit-risk and characterization questions as mechanisms diverge from the established GLP-1 template. Third, the class is being repositioned as cardiorenal and hepatic therapy: HFpEF, MASH, and CKD outcome trials are the pivotal studies that will define the next round of indications, while the emerging NAION safety signal shows that pharmacovigilance is scaling with the population exposure 223271.