Monthly Research Briefing

The next generation of incretin agonists.

The first GLP-1 receptor agonists redefined what was possible in metabolic research. The next wave goes further — combining GLP-1 activity with GIP, glucagon, or amylin signaling to test whether multi-receptor engagement can deliver larger, more durable effects on body weight, hepatic fat, and cardiometabolic endpoints. This briefing covers two of the most-watched candidates currently in Phase 3 trials.

Retatrutide

LY3437943 · Lilly

Triple Agonist GLP-1 · GIP · Glucagon Phase 3

Mechanism

Once-weekly subcutaneous peptide engineered as a triagonist at GLP-1, GIP, and glucagon receptors. GLP-1R and GIPR activation drive appetite suppression and insulinotropic effects; glucagon-receptor agonism is hypothesized to increase energy expenditure and hepatic lipid oxidation, distinguishing it mechanistically from dual GIP/GLP-1 agonists.

Trial Status

Eli Lilly's TRIUMPH program — >5,800 participants across TRIUMPH-1 (NCT05929066, obesity), TRIUMPH-3 (obesity + CVD), TRIUMPH-4 (obesity + CKD), and the cardiovascular outcomes trial TRIUMPH-Outcomes (NCT06383390). TRIUMPH-1 topline has been released; broader readouts ongoing through 2026.

Key Finding · Phase 2 Obesity

In a 48-week trial of 338 adults with obesity, retatrutide produced dose-dependent placebo-subtracted weight reduction of ~22 percentage points at the 12-mg dose. Adverse-event profile was gastrointestinal-dominant, consistent with prior incretin agonists. Established proof-of-concept for triple-receptor agonism.

Jastreboff AM, et al. N Engl J Med 2023;389(6):514–526. PMID: 37366315.
pubmed.ncbi.nlm.nih.gov/37366315

Key Finding · Hepatic Steatosis

48-week Phase 2a substudy in 98 participants with MASLD showed large relative reductions in MRI-PDFF liver fat at the 8-mg and 12-mg doses, with a high proportion achieving resolution of hepatic steatosis. No histological/biopsy endpoints assessed in this readout.

Sanyal AJ, et al. Nat Med 2024;30(7):2037–2048. PMID: 38858523.
pubmed.ncbi.nlm.nih.gov/38858523

Why it matters for researchers First triagonist to reach Phase 3 obesity and cardiovascular outcomes trials. The glucagon-receptor arm is the key mechanistic variable distinguishing retatrutide from tirzepatide — making it a natural research-context comparator for understanding incretin pharmacology.

Survodutide

BI 456906 · Boehringer Ingelheim / Zealand

Dual Agonist GLP-1 · Glucagon Phase 3 MASH Breakthrough

Mechanism

Once-weekly subcutaneous glucagon-derived peptide engineered as a dual agonist of GLP-1 and glucagon receptors, with a C18 fatty diacid for extended half-life. Pharmacology data indicate full GLP-1R and partial GCGR agonism — thought to combine appetite suppression with elevated energy expenditure and hepatic lipid oxidation.

Trial Status

Phase 3 SYNCHRONIZE obesity program: SYNCHRONIZE-1 (NCT06066515, completed), SYNCHRONIZE-2 (T2D, NCT06066528, completed), SYNCHRONIZE-CVOT (~5,500 participants, active). Separate Phase 3 MASH program launched following FDA Breakthrough Therapy designation.

Key Finding · Phase 2 Dose Finding

46-week dose-finding trial in adults with overweight/obesity without T2D showed dose-dependent placebo-adjusted weight reductions, with the 4.8 mg arm reaching the largest mean reduction. Gastrointestinal adverse events were dose-related and most common during dose escalation.

Le Roux CW, et al. Lancet Diabetes Endocrinol 2024;12(3):162–173. PMID: 38330987.
pubmed.ncbi.nlm.nih.gov/38330987

Key Finding · Phase 2 MASH

48-week trial in 293 adults with biopsy-confirmed MASH (F1–F3 fibrosis): 62% of participants on 4.8 mg achieved histologic MASH improvement without worsening fibrosis vs 14% on placebo. Fibrosis improvement signals were also observed.

Sanyal AJ, et al. N Engl J Med 2024;391(4):311–319. PMID: 38847460.
pubmed.ncbi.nlm.nih.gov/38847460

Why it matters for researchers Provides a parallel data point to retatrutide for understanding the contribution of glucagon-receptor agonism to weight loss and hepatic outcomes. The MASH Phase 2 readout is among the largest peptide-based fibrosis studies to date and a key reference for any GCGR-related research design.