The incretin pipeline in 2026: dual and triple agonists, amylin combinations and oral agents

Two earlier pieces on this site cover how GLP-1 drugs came about (a short history of GLP-1 drugs) and how single, dual and triple agonists compare (from single to dual to triple agonists). This one is a status map: which hormone pathways each molecule uses, which molecules had reached approval by 22 October 2026, and where the evidence still has gaps.

Four hormone pathways

GLP-1 is an intestinal hormone whose main actions are to stimulate insulin secretion and inhibit glucagon secretion; it also slows gastrointestinal motility and appears to be a physiological regulator of appetite and food intake ¹. GIP is the second incretin, and the tirzepatide label states that nonclinical studies suggest adding GIP receptor activity may further contribute to the regulation of food intake ². Developers of glucagon-containing molecules describe glucagon receptor agonists as acting directly on the liver to stimulate fatty acid oxidation and inhibit lipogenesis ³. Amylin is a pancreatic hormone; the older amylin analogue pramlintide needs three daily injections because of its short half-life, and cagrilintide was developed as a stable, lipidated, long-acting amylin analogue ⁴.

Approved as of 22 October 2026

Semaglutide (GLP-1). Drugs@FDA lists an original approval date of 4 June 2021 for Wegovy (NDA 215256) ⁶. Its current label adds indications to reduce the risk of major adverse cardiovascular events in adults with established cardiovascular disease and either obesity or overweight, and an accelerated approval for noncirrhotic MASH with F2 to F3 fibrosis ⁵.

Tirzepatide (GIP and GLP-1). Drugs@FDA lists an original approval date of 8 November 2023 for Zepbound (NDA 217806) ⁷. The label covers long-term weight management and moderate to severe obstructive sleep apnoea in adults with obesity ².

Orforglipron (GLP-1, non-peptide). Drugs@FDA lists approval of Foundayo (NDA 220934) on 1 April 2026 as a new molecular entity ⁹. Its label describes a once-daily oral GLP-1 receptor agonist for long-term weight management in adults with obesity, or overweight with at least one weight-related comorbid condition ⁸. It is the only molecule in this list that is not a peptide ²².

Mazdutide (GLP-1 and glucagon), China only. Mazdutide received its first approval, in China, in June 2025, for long-term weight management in adults with a BMI of 28 kg/m2 or more, or 24 kg/m2 or more with at least one weight-related comorbidity ¹⁰. No Drugs@FDA application record for mazdutide was returned on 22 October 2026 ¹².

Still investigational

An openFDA search of Drugs@FDA on 22 October 2026 returned no application record for retatrutide, survodutide, mazdutide, pemvidutide, VK2735 or cagrilintide ¹². Absence from that database means no approved US application, not that no application has been filed. CagriSema, the cagrilintide/semaglutide combination, was likewise not FDA-approved as of 22 October 2026 ¹².

• Retatrutide (GIP, GLP-1 and glucagon). In the 80-week TRIUMPH-1 phase 3 trial, mean body-weight change was -17.6% to -25.0% across three doses versus -3.9% with placebo ¹³.
• Survodutide (glucagon and GLP-1). In the 76-week SYNCHRONIZE-1 phase 3 trial, the phase 3 report describes it as investigational and gives mean changes of -12.2% and -13.0% versus -5.4% with placebo ¹⁴.
• Pemvidutide (GLP-1 and glucagon). Its programme has focused on the liver: in the 24-week IMPACT phase 2b analysis in biopsy-confirmed MASH, MASH resolution without fibrosis worsening occurred in 58% and 52% of the two pemvidutide groups versus 20% with placebo ¹⁵. A phase 3 MASH trial with clinical outcome events as a primary endpoint is registered as recruiting ¹⁶.
• VK2735 (GLP-1 and GIP). In the 13-week VENTURE phase 2 trial, mean body-weight change ranged from -9.1% to -14.7% across four doses versus -1.7% with placebo ¹⁷. A 78-week phase 3 trial with an estimated 4,500 participants is registered as active ¹⁸.
• CagriSema (amylin plus GLP-1). This is a co-administration of two separate peptides, cagrilintide and semaglutide, rather than one molecule ¹⁹. In the 68-week REDEFINE 1 trial in adults without diabetes, mean body-weight change was -20.4% versus -3.0% with placebo ¹⁹. In REDEFINE 2, in adults with type 2 diabetes, it was -13.7% versus -3.4% ²⁰.

Oral agents: a peptide tablet and a small molecule

Oral GLP-1 therapy is not new: Drugs@FDA lists an original approval date of 20 September 2019 for the oral semaglutide tablet application (NDA 213051) ²¹, and oral semaglutide for chronic weight management was approved as Wegovy tablets under NDA 218316 on 22 December 2025 ^5,28. Orforglipron is different in kind: it is a synthetic nonpeptide agonist that binds the human GLP-1 receptor with high affinity, shows low intrinsic efficacy for effector activation and negligible beta-arrestin recruitment, yet gave a full biological response at low receptor occupancy in mouse experiments ²². Its label gives a geometric mean absolute bioavailability of 77% after a 0.8 mg dose and an elimination half-life of approximately 29 to 49 hours, and notes that orforglipron is not pharmacologically active in rats or mice ⁸. In the 72-week ATTAIN-1 trial in adults with obesity without diabetes, mean body-weight change was -7.5% to -11.2% across three doses versus -2.1% with placebo, and adverse events led to discontinuation in 5.3% to 10.3% of orforglipron recipients versus 2.7% with placebo ²³. In ATTAIN-2, in adults with type 2 diabetes, the corresponding changes were -5.1% to -9.6% versus -2.5% ²⁴. A drug profile reports that orforglipron has also been submitted for review in the EU, Japan and Canada ²⁵. VK2735 is also being developed in an oral form, but its registry record describes that form as the same peptide dual agonist given daily ²⁶.

What the trials have shown

Across these programmes, randomized placebo-controlled trials have consistently reported larger body-weight reductions than placebo ^{11,13,14,17,19,23}. Gastrointestinal adverse events were the most common class in every trial summarised here; for example, they affected 79.6% of the CagriSema group versus 39.9% of the placebo group in REDEFINE 1 ¹⁹, and 80.9% to 89.7% of survodutide recipients versus 47.9% with placebo in SYNCHRONIZE-1 ¹⁴. Glucagon-containing molecules have reported liver-specific results, including a 68.5% relative liver-fat reduction at one pemvidutide dose after 12 weeks ³.

What the trials have not shown

• Head-to-head data are scarce. Most trials summarised here compare a drug with placebo; REDEFINE 1 included semaglutide and cagrilintide monotherapy arms, but its primary comparison was with placebo ¹⁹.
• Not every primary endpoint was met. IMPACT did not meet its second primary endpoint, fibrosis improvement without worsening of MASH, at 24 weeks ¹⁵.
• Some evidence is short or narrow. VENTURE lasted 13 weeks and was not powered for most between-group comparisons ¹⁷. The mazdutide phase 3 trials enrolled Chinese adults ¹¹, and the main US data come from a 179-participant phase 2 trial ²⁷.
• Tolerability varies by dose. In the US mazdutide phase 2 trial, 20% of the 16 mg group stopped treatment because of adverse events, mainly gastrointestinal ²⁷.
• Outcome trials are still running. For the investigational molecules, hard clinical outcomes have not yet been reported; the pemvidutide phase 3 registration lists clinical outcome events through approximately month 60 ¹⁶.

Key points

• As of 22 October 2026, semaglutide, tirzepatide and orforglipron have FDA approvals for weight management, and mazdutide is approved in China but not the United States ^6,7,9,10,12.
• Retatrutide, survodutide, pemvidutide, VK2735 and CagriSema had no Drugs@FDA application record on that date ¹².
• Orforglipron is a non-peptide small molecule; oral semaglutide and oral VK2735 are peptides ^21,22,26.
• Gastrointestinal events dominate the safety data, and long-term outcome results for the newer molecules are still pending ^14,16,19.