GLP-1 Receptor Agonists and Incretin Therapies: Recent FDA and EMA Approvals and the Clinical Pipeline

GLP-1 receptor agonists and incretin therapies: recent FDA and EMA decisions and the clinical pipeline (September 2026)

Key takeaways

• Orforglipron is now approved by FDA. FDA approved FOUNDAYO (orforglipron) tablets under NDA 220934 on April 1, 2026, as a Type 1 new molecular entity ²⁰⁹⁶⁵⁵. It was reviewed under the Commissioner's National Priority Voucher (CNPV) pilot and approved 50 days after filing, the first new molecular entity approved under that program (FDA press release, April 1, 2026). It is the first small-molecule, non-peptide oral GLP-1 receptor agonist approved by FDA, and it carries no food or water dosing restrictions ^1171665. No EMA EPAR for orforglipron was found as of this review.
• Oral semaglutide for obesity came first in the US. FDA approved oral Wegovy (semaglutide 25 mg tablets) under NDA 218316 on December 22, 2025 ^1015480. The EU added Wegovy tablets as an extension of the existing marketing authorisation ⁶⁵¹.
• Established incretins keep adding indications and doses. Examples are Wegovy HD 7.2 mg (FDA, March 19, 2026) ¹²¹³, the Wegovy MASH accelerated approval (August 15, 2025) ⁷⁴⁴, and a cardiovascular risk-reduction indication for Mounjaro in type 2 diabetes (August 27, 2026) ⁹⁶¹. In the EU, the recent actions were Kayshild (semaglutide for MASH, March 26, 2026) ⁹⁰⁴, Kyinsu (insulin icodec/semaglutide, November 24, 2025) ⁷⁰⁷, and the first hybrid liraglutide products referencing Saxenda (July 2026) ³⁰⁰⁶⁰⁴.
• The late-stage pipeline has moved past single-agonist GLP-1. ClinicalTrials.gov shows large Phase 3 programs for retatrutide, CagriSema, maridebart cafraglutide, survodutide, NNC0487-0111, zenagamtide, eloralintide, VK2735 and AZD6234. Behind them is a broad group of Chinese and other ex-US GLP-1-based candidates, many of them oral.

1. Orforglipron (FOUNDAYO): the first approved non-peptide oral GLP-1 receptor agonist

Regulatory record

Indication and dosing

FOUNDAYO is indicated, together with a reduced-calorie diet and increased physical activity, "to reduce excess body weight and maintain weight reduction long term" in adults with obesity, or in adults with overweight and at least one weight-related comorbid condition ⁶⁵⁹. Concomitant use with another GLP-1 receptor agonist is not recommended ⁶⁵⁹.

• Tablet strengths are 0.8, 2.5, 5.5, 9, 14.5 and 17.2 mg, taken once daily. Treatment starts at 0.8 mg, and each step up follows at least 30 days on the current dose, to a maximum of 17.2 mg ⁶⁵⁹.
• It may be taken with or without food. FDA's review describes the product as having a "lack of food and water dosing restrictions" ⁶⁵⁹⁶⁶⁵. The US-approved oral semaglutide products do not share this feature.
• The label contains CYP3A4 interaction limits. The maximum dose is 9 mg with strong CYP3A4 inhibitors. Strong CYP3A4 inhibitors that also inhibit OATP1B, and strong CYP3A4 inducers, should be avoided ⁶⁵⁹.

Pivotal evidence

FDA based substantial evidence of effectiveness on two 72-week, randomized, double-blind, placebo-controlled Phase 3 trials ⁹²²⁹³⁵:

FDA's clinical interpretation depended on the population. In ATTAIN-1, all three doses met the 5% threshold for clinically meaningful placebo-adjusted weight loss. In ATTAIN-2, only 36 mg clearly met it. FDA judged 12 mg borderline and found that 6 mg did not meet the threshold ⁹²⁶⁹²⁷. The overall benefit-risk assessment was favorable ⁹³³⁶⁵⁸.

Safety and postmarketing obligations

• Boxed warning for thyroid C-cell tumors. FDA applied the boxed warning even though orforglipron is not pharmacologically active in rats or mice and did not cause tumors in rodent studies. FDA treats C-cell findings as an on-target GLP-1 receptor class effect whose human relevance is unknown ^659864875.
• Gastrointestinal tolerability. In the pooled pivotal trials, GI adverse events occurred in about 66% of orforglipron patients versus 37% on placebo. Discontinuations due to adverse events were 8.1% versus 3.5% ⁹³³. The label restarts titration at a lower dose after 7 or more missed doses ⁸⁷⁰.
• Hepatic. FDA found no substantial evidence of increased idiosyncratic liver-injury risk ⁹³³. It nonetheless requested 5 years of enhanced pharmacovigilance, with serious DILI cases (jaundice, liver failure, transplant, death) submitted as 15-day Alert reports ⁸⁸¹. This is a small-molecule-specific obligation not seen with the peptide agonists.
• 505(o) PMRs. The PMRs include a class-wide medullary thyroid carcinoma registry case series running at least 15 years ⁸⁶³⁸⁶⁴ and a pediatric obesity registry cohort study of at least 10 years (PMR 4977-3) ⁸⁸². FDA also identified pregnancy exposure as a risk requiring further assessment ⁸⁸².
• No REMS was required ⁸⁶³.

What the orforglipron trial registry signals next

The ClinicalTrials.gov portfolio suggests Lilly is building toward label expansion well beyond chronic weight management:

• Type 2 diabetes (ACHIEVE program). ACHIEVE-1 (completed) ²⁹, ACHIEVE-2 versus dapagliflozin ²⁷, ACHIEVE-3 versus semaglutide ²¹, ACHIEVE-4 versus insulin glargine ²³, ACHIEVE-5 ³⁰, ACHIEVE-J long-term safety (completed) ¹⁹, ACHIEVE-RAM in Ramadan fasting ¹⁵, and ACHIEVE-PEDS versus dulaglutide in pediatric T2D ⁹. The approved label is limited to weight reduction ⁶⁵⁹, so a T2D indication remains a prospective filing.
• Obesity comorbidities and outcomes. A cardiovascular outcomes trial in ASCVD ²⁴, peripheral artery disease (ATTAIN-PAD) ⁴¹, obstructive sleep apnea (ATTAIN-OSA) ⁴⁹, hypertension master protocols ¹⁰¹¹¹⁶, knee osteoarthritis pain ¹³, stress urinary incontinence ⁴⁷, and weight-maintenance after prior therapy ⁴⁸.
• Special populations and regions. Adolescents ⁸, Japan (ATTAIN-J) ⁶, China (ATTAIN-CN) ¹⁷, and overweight individuals at risk of obesity complications (ATTAIN-NOW) ⁴⁵.

2. Other recent FDA actions in the incretin class

The oral Wegovy review shows how far FDA would bridge. OASIS 4 (64 weeks, placebo-controlled) was the only pivotal adequate and well-controlled trial ^10321036. The cardiovascular indication was extended to the tablet by pharmacokinetic bridging to the subcutaneous SELECT trial, without a dedicated outcomes trial ¹⁰³³.

Class-wide labeling activity also continues. The Drugs@FDA record shows coordinated labeling supplements across GLP-1 products (Ozempic, Rybelsus, Victoza, Saxenda, Trulicity, Byetta, Bydureon, Adlyxin, Soliqua, Xultophy) on shared action dates in November 2024, May 2025 and October 2025 ^{477483486495504506513522472531}.

3. Recent EMA decisions

Where EMA and FDA diverge

• Cardiovascular claims. CHMP did not grant Wegovy a separate MACE-reduction indication. SELECT results were placed in SmPC section 5.1 and cross-referenced from the weight-management indication ⁶³⁷. For the tablets, EMA concluded that cardiovascular benefit could not be assumed from subcutaneous data and removed the section 4.1 cardiovascular reference ⁶³⁹. FDA took the opposite position and granted the tablet a MACE indication by PK bridging ¹⁰³³.
• Comorbidity indications. For Mounjaro, CHMP concluded that a standalone OSA indication was unnecessary because the population is already covered by the weight-management indication. SURMOUNT-OSA data went into SmPC sections 4.1, 4.8 and 5.1 instead ^897889884.
• Pediatric scope. Mounjaro's EU T2D indication extends to children aged 10 years and older ⁸⁸⁴.

For sponsors, this means EU labeling strategy for new incretins should plan on comorbidity and outcomes data appearing in section 5.1 rather than as discrete indications.

No EPARs were found for orforglipron, cagrilintide/CagriSema, survodutide or retatrutide as of this review.

4. The emerging pipeline in trial registries

Late-stage programs (Phase 3 registered)

Patterns across the registry

1. Head-to-head designs against approved incretins are now common. Examples are retatrutide versus tirzepatide ⁶⁸⁹, CagriSema versus tirzepatide ⁹⁹⁷, zenagamtide versus semaglutide ⁷¹, NNC0487-0111 versus semaglutide ⁹⁴, KAI-9531 versus semaglutide ⁸³, and GZR18 versus Wegovy ⁹¹. This reflects an active-comparator environment in which placebo-only data may not be enough for payers or for differentiation claims.
2. Outcomes and comorbidity trials start alongside registration trials. CV outcomes trials are registered for orforglipron ²⁴, retatrutide ⁶⁹⁷, maridebart cafraglutide ⁹⁹ and survodutide ⁷⁴. HFpEF, OSA, MASH, CKD and osteoarthritis are repeated targets ^{101858734692784}.
3. Amylin-based agents are the next competitive tier. Candidates include CagriSema, NNC0487-0111, eloralintide, and petrelintide combined with enicepatide (ZYNERGY) ¹⁴⁷. Lilly is also combining eloralintide with macupatide ¹⁴⁰ and with tirzepatide ⁷⁷⁷. AstraZeneca's SELENE 3 tests AZD6234 as an adjunct to existing incretin therapy ⁸⁰.
4. More oral candidates are following orforglipron. Beyond oral Wegovy and FOUNDAYO, the registry lists zenagamtide tablets ⁶⁹, oral NNC0487-0111 ¹²⁸⁴, oral VK2735 ¹¹⁹⁶, and weekly oral ecnoglutide (EVOLVE-2) ¹⁴⁵. Other oral candidates are once-daily RGT001-075 (COMO-1) ¹³⁸, BGM0504 tablets ¹⁷⁶, MWN109 tablets ¹⁸², CX11 tablets ¹⁶⁷, DA-302168S tablets ¹⁶³, and a GZR18 tablet in Phase 1 ⁶⁷⁰.
5. Chinese sponsors are a substantial share of the pipeline. Phase 3 programs include VCT220 ⁶⁰, HDM1005 ⁸⁶, BGM0504 ⁹⁰, RAY1225 ⁹³, MWN109 ¹⁰⁹, MDR-001 ⁹², UBT251 (OSA) ⁹⁷ and ecnoglutide ⁹⁸⁰⁹⁸⁵. Semaglutide copies from CSPC and Jiuyuan are in comparative Phase 3 trials against Wegovy ⁹⁶⁹⁵. Mazdutide, a dual GLP-1R/GCGR agonist ⁸⁰⁴, appears in the registry mainly in investigator-initiated Phase 4 studies in China ⁷⁶³⁷⁶⁶, which indicates post-approval use in that market.
6. Mechanism transparency varies. Several sponsors, notably for retatrutide, survodutide, maridebart cafraglutide, eloralintide and AZD6234, do not state receptor targets in the retrieved registry records. RA teams building competitive landscapes should confirm mechanism from FDA or EMA documents or peer-reviewed sources, not from CT.gov alone.

5. Regulatory considerations for sponsors

• Small-molecule GLP-1 RAs bring a different safety review focus. For orforglipron, FDA added hepatic enhanced pharmacovigilance ⁸⁸¹ and CYP3A4/OATP1B dose limits ⁶⁵⁹ on top of the class-wide boxed warning and MTC registry PMR ⁶⁵⁹⁸⁶³. Sponsors of other non-peptide oral agents should expect the same DILI and DDI scrutiny.
• The class-wide PMR package now applies by default. New entrants should budget for a 15-year MTC registry and a pediatric obesity registry ⁸⁶³⁸⁸².
• FDA and EMA handle outcomes claims differently. FDA grants discrete MACE indications and accepts PK bridging across formulations ^1033961. CHMP tends to place outcomes data in SmPC section 5.1 and would not assume cardiovascular benefit transfers from subcutaneous to oral formulations ⁶³⁷⁶³⁹.
• The FDA effect-size threshold is applied separately in T2D. FDA's reading of ATTAIN-2 shows that the ≥5% placebo-adjusted threshold is assessed within the T2D population, where weight loss is smaller ⁹²⁶⁹²⁷. This matters for dose selection in programs that enrol obesity with and without diabetes.
• Generic and hybrid entry has started in the EU. Liraglutide hybrids referencing Saxenda were authorised in July 2026 via Article 10(3), reflecting the synthetic versus recombinant pro-peptide distinction ⁶⁰⁴.

Open questions to explore further

Several points could not be resolved from the retrieved records and warrant targeted follow-up. They are the substantive change in the August 2026 FOUNDAYO labeling supplement ⁶⁶³, the specific pregnancy PMR for orforglipron ⁸⁸², the EU regulatory status and timing for orforglipron, and Phase 3 readouts for retatrutide, CagriSema and maridebart cafraglutide as they reach FDA and EMA filing.