Incretin Pipeline: Retatrutide and CagriSema

The tracker

Incretin drugs act on the receptors for gut hormones released after a meal, chiefly GLP-1 and GIP, and the newest candidates add the glucagon or amylin receptor. The table gives each molecule's United States position as of September 2026 and the latest milestone its sponsor or the FDA has dated. Approval is decided by the FDA record; a strong trial result, however large, does not change the status column.

Which are peptides, and why orforglipron is not

A peptide is a short chain of amino acids, and every injectable incretin drug in the table is one or is built from one. Tirzepatide is a peptide: its label describes a molecule based on the GIP sequence with a molecular weight of 4,813.53 Da ^[2]. Retatrutide is a peptide as well; its discovery paper calls it a triple agonist peptide at the glucagon, GIP and GLP-1 receptors ^[8]. Semaglutide and liraglutide are modified GLP-1 peptides ^[1][3], zenagamtide is described by its sponsor as a single peptide acting at two receptors ^[19], and survodutide is an acylated peptide ^[20].

Two approved drugs fall outside the peptide label from opposite directions. Dulaglutide joins a GLP-1 analogue to an antibody fragment, and its label describes a fusion protein of about 63 kilodaltons ^[5]; the index files it as a protein. Orforglipron is the non-peptide control row: the Foundayo label gives it a chemical formula and a molecular weight of 902.0 g/mol for its calcium salt, a small synthetic molecule taken as a daily tablet ^[7]. It activates the same GLP-1 receptor without being a peptide at all.

Being a peptide says nothing about legal status. The approved peptide drugs table lists the peptides with a US approval, and the GLP-1 receptor agonists page compares the class members this index covers.

Retatrutide

Retatrutide is investigational, and its phase 3 obesity program has now read out. TRIUMPH-1 randomized 2,339 adults with obesity, or overweight with a weight-related condition, and without diabetes; the earlier sponsor release reported average weight loss of 28.3 percent at 80 weeks at the highest dose tested against 2.2 percent on placebo ^[9]. The subsequently published treatment-regimen analysis reported 25.0 percent versus 3.9 percent; the body-composition review explains why analyses and endpoints must be kept distinct ^[25]. The registry lists that trial as completed, with primary completion in April 2026 ^[11]. TRIUMPH-2 and TRIUMPH-3 met their primary endpoints in July 2026, and Lilly plans to submit a biologics license application in the first quarter of 2027 ^[10]. No approval can come before that submission is reviewed.

Until then there is no lawful route to the drug outside a trial. Lilly's own release states that retatrutide is legally available only to participants in its clinical trials ^[9]. The FDA has stated that retatrutide cannot be used in compounding under federal law ^[12], and in March 2026 it issued warning letters to two firms selling retatrutide online as research-use-only material, finding the products to be unapproved new drugs intended for human use ^[13][14]. The retatrutide monograph carries the full record, and the registry files it as research-only.

Retatrutide versus tirzepatide

No head-to-head result exists yet, but a head-to-head trial does. TRIUMPH-5 is a phase 3, double-blind trial comparing retatrutide directly with tirzepatide in adults with obesity; its primary endpoint is percent change in body weight at week 80, and its estimated primary completion is November 2026 ^[15]. Until it reports, any claim that one drug beats the other is an inference across separate trials.

What can be compared now is mechanism and each drug's result against its own placebo. Tirzepatide acts at two receptors and retatrutide at three, adding glucagon ^[2][8]. In SURMOUNT-1, weight fell 20.9 percent at tirzepatide's highest dose against 3.1 percent on placebo over 72 weeks ^[24]; in TRIUMPH-1, 28.3 percent against 2.2 percent over 80 weeks ^[9]. Those trials differed in length, population and analysis, so the gap between the two numbers is not a measured difference between the drugs.

Tolerability cannot be ranked from the record either. In TRIUMPH-1, nausea affected up to 42.4 percent of retatrutide participants against 14.8 percent on placebo, and discontinuation for adverse events reached 11.3 percent at the highest dose against 4.9 percent ^[9]. Tirzepatide's approved label lists its own adverse reactions ^[2]. The legal difference is simpler: tirzepatide is approved and retatrutide is not.

CagriSema

CagriSema is Novo Nordisk's weekly injection combining cagrilintide, a long-acting amylin analogue, with semaglutide. The company submitted it to the FDA on December 18, 2025 for weight reduction in adults with obesity, or overweight with a weight-related condition ^[16]. The filing rests on REDEFINE 1, a 68-week trial in 3,417 adults, in which weight fell 20.4 percent with CagriSema against 3.0 percent on placebo when counted regardless of whether participants stayed on treatment ^[16]. The company lists a US decision among its milestones for the fourth quarter of 2026 ^[18].

The head-to-head trial went the other way. In REDEFINE 4, an open-label trial of 809 people, CagriSema produced 23.0 percent weight loss at 84 weeks against 25.5 percent with tirzepatide and did not meet its primary endpoint of non-inferiority ^[17]. Cagrilintide on its own is not approved, and the FDA has stated that it cannot be used in compounding under federal law ^[12].

The other candidates

Zenagamtide, also known as amycretin, is a single Novo Nordisk peptide acting at both the GLP-1 and amylin receptors ^[19]. Its AMAZE phase 3 program in obesity is under way, and a phase 3 program in type 2 diabetes is planned ^[18][19].

Survodutide, from Boehringer Ingelheim, pairs the glucagon and GLP-1 receptors. In SYNCHRONIZE-1 it produced up to 16.6 percent average weight loss at 76 weeks against 3.2 percent on placebo ^[21]. Mazdutide, an oxyntomodulin analogue developed by Innovent Biologics under a license from Lilly, was approved in China in June 2025 for chronic weight management ^[22]. A Chinese approval carries no weight in the United States.

None of the five investigational drugs has an application listed in Drugs@FDA ^[23]. Each remains a trial drug in the United States, whatever a seller's listing says.

Elsewhere in this index