Incretin Research Update: Retatrutide, CagriSema and Amylin Combinations Lead EASD 2026

Overview

The 62nd Annual Meeting of the European Association for the Study of Diabetes (EASD), held in Milan in late September 2026, produced a dense set of incretin and amylin data. Four datasets stand out for researchers tracking receptor pharmacology: a phase 3 retatrutide trial in type 2 diabetes, new CagriSema topline results, a phase 2b amylin plus tirzepatide combination, and an indirect comparison between tirzepatide and high-dose semaglutide.

The common thread is that the field is moving past single-receptor agonism toward combinations that add amylin or glucagon activity on top of GLP-1 and GIP signaling.

Retatrutide: TRIUMPH-2

Retatrutide, an investigational once-weekly agonist at the GIP, GLP-1, and glucagon receptors developed by Eli Lilly, reported phase 3 TRIUMPH-2 results in The Lancet alongside the EASD presentation. The trial enrolled 1,152 adults with obesity and type 2 diabetes at 92 sites in 8 countries, followed for 80 weeks.

Under the treatment-regimen estimand, mean body weight change in the highest dose arm was 18.8%, compared with 5.1% for placebo. HbA1c fell by up to 1.6 percentage points, versus 0.2 with placebo. The result is notable because populations with type 2 diabetes typically show an attenuated weight response to incretin agonists.

Gastrointestinal events were the most common adverse events. Hypotension and dysesthesia occurred more often than with placebo, consistent with signals seen across the retatrutide program. Eli Lilly plans to submit a biologics license application in the first quarter of 2027. The glucagon receptor component is the mechanistic differentiator; see Retatrutide vs Tirzepatide vs Semaglutide for a receptor-level comparison.

CagriSema: REIMAGINE 5 and REDEFINE 9

Novo Nordisk reported topline phase 3 results on September 21 for CagriSema, a fixed combination of cagrilintide, a long-acting amylin receptor agonist, and Semaglutide.

In REIMAGINE 5, adults with type 2 diabetes received CagriSema or tirzepatide at a lower maintenance dose. At week 60, weight loss was 12.4% with CagriSema versus 9.1% with tirzepatide, with comparable HbA1c reductions. The comparator dose is the key caveat: tirzepatide can be escalated well above the dose tested, so the result does not establish how the two compare at maximum doses.

In REDEFINE 9, adults with overweight or obesity lost 21.0% of body weight at week 68 with CagriSema, versus 2.0% with placebo. An FDA decision on the CagriSema weight management application is expected in the fourth quarter of 2026.

EloraTZP: Amylin Added to Tirzepatide

Eli Lilly presented phase 2b data on EloraTZP, a combination of eloralintide, an investigational selective amylin receptor agonist, with Tirzepatide. The 48-week trial randomized 367 adults with obesity or overweight and type 2 diabetes across placebo, each agent alone, and four combination arms.

The highest combination arm produced mean weight loss of 23.3%, compared with 14.8% for tirzepatide alone at its highest dose, with HbA1c reductions of up to 2.9 points. Gastrointestinal events were more frequent in the combination arms, and discontinuation due to adverse events ranged from 10.8% to 27.0%. Investigators reported that escalating tirzepatide first and adding eloralintide afterward produced gastrointestinal rates similar to tirzepatide alone.

Tirzepatide vs High-Dose Semaglutide: An Indirect Comparison

An indirect treatment comparison funded by Eli Lilly set tirzepatide data from SURMOUNT-1 against high-dose semaglutide data from STEP UP. Under the treatment-regimen estimand, the highest tirzepatide dose was associated with 4.5 percentage points more weight loss. Under the efficacy estimand, the gap narrowed to 1.8 points and was not statistically significant. No head-to-head trial exists at these doses, so the analysis is hypothesis-generating. For background, see Semaglutide vs Tirzepatide.

What the Data Pattern Shows

Two methodological lessons run through these results. First, estimand choice matters: the same trial data can support different conclusions depending on whether participants who stopped treatment are counted. Second, comparator dose matters: a head-to-head result describes only the doses tested.

For in vitro and non-clinical research on these mechanisms, receptor selectivity is the central variable. Amylin, glucagon, GIP, and GLP-1 receptor activity can only be attributed to a compound of confirmed identity and purity; otherwise assay results cannot be compared across studies. The line between legitimate research peptide commerce and gray-market distribution is analytical verification, not the molecules sold. Third-party HPLC Purity Testing, mass spectrometry identity confirmation, and batch-specific COAs are the standard, not a feature. GENEVIUM supplies RETA, TIRZ, and SEMA for research use only.

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