LY3437943 TRIPLE-1: triple-agonist research signals

LY3437943 is the first compound to make it through Phase 2 trials as a triple agonist of three incretin/glucagon-family receptors: GIP, GLP-1, and glucagon. The Phase 2 trial published in NEJM 2023 (often called TRIPLE-1 in research shorthand) is the first solid clinical data the field has on what adding the third receptor — glucagon — actually does. The findings are striking and the design choices are worth understanding for any research model using LY3437943.

Trial design

338 adults with obesity, randomized to: placebo, LY3437943 1 mg weekly, 4 mg (with two different titration schedules), 8 mg (two schedules), or 12 mg, all subcutaneous. Duration 48 weeks. Primary outcomes: weight change at 24 weeks and at 48 weeks.

The two titration schedules at 4 mg and 8 mg are worth noting — researchers wanted to characterize whether faster vs. slower titration affected tolerability or efficacy. (Spoiler: slower is better tolerated; efficacy is similar.)

Headline weight findings

For comparison: tirzepatide 15 mg at 72 weeks (SURMOUNT-1) achieved −20.9%. LY3437943 12 mg at 48 weeks reached −24.2%. This is the largest published weight reduction at this timepoint among approved-or-pipeline incretin compounds.

Why the glucagon receptor matters

GIP and GLP-1 are incretins — they amplify glucose-dependent insulin secretion and reduce appetite. Glucagon does the opposite of insulin metabolically: it mobilizes hepatic glucose, increases energy expenditure, and promotes lipolysis. Activating glucagon receptors alongside the incretins produces a combination effect that the dual agonists (tirzepatide) don't access: weight loss driven not just by reduced energy intake but also by elevated energy expenditure.

The clinical signal of glucagon activation is visible in LY3437943's resting-energy-expenditure measurements — small but consistent increases above placebo. This is mechanistically novel and is probably why the percentage weight reductions exceed what's seen in dual-agonist trials at equivalent durations.

The interesting open question: glycemia

Adding glucagon to an incretin compound creates a potential downside — glucagon raises blood glucose. The trial reported small increases in fasting glucose in the lower-dose LY3437943 arms (early in titration), but the larger GLP-1/GIP signal at therapeutic doses overcame this. HbA1c reductions at 48 weeks were comparable to other incretin compounds, suggesting the net effect on glycemia is neutral-to-favorable at maintenance doses.

For research models studying glucose-dependent vs. independent mechanisms, LY3437943's mixed signal during titration is methodologically interesting — it lets you observe receptor-specific contributions in a way single-receptor compounds can't.

Adverse events

GI events were the dominant tolerability signal, similar magnitude to tirzepatide and semaglutide trials: nausea 27–55% (dose-dependent), diarrhea 16–37%, vomiting 5–32%. Higher doses produced more events; slower titration moderated them.

Limitations

This is Phase 2 — single trial, n=338, 48 weeks. Phase 3 (TRIUMPH series) is ongoing as of 2026 and will refine the picture. For research models using LY3437943 today, the TRIPLE-1 data is the most rigorous reference available.

Notes

This is a research summary of published clinical data. It is not a recommendation for any specific research protocol or design. For research use only.

Reference

1. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist LY3437943 for Obesity — a Phase 2 Trial. NEJM 2023;389:514–526. PMID: 37366315