LY3437943 (retatrutide), the first single peptide to activate GIP, GLP-1, and glucagon receptors simultaneously, reduced HbA1c by up to 1.6% and body weight by up to 8.96 kg over 12 weeks in people with type 2 diabetes.
-8.96 kg weight loss in 12 weeksThe highest dose of this first-in-class triple receptor peptide agonist produced nearly 9 kg placebo-adjusted weight loss in just 12 weeks, with even greater losses expected at longer durations
What the researchers found
At 12 weeks, the three highest dose groups of LY3437943 showed significant placebo-adjusted reductions in mean daily plasma glucose: -2.8, -3.1, and -2.9 mmol/L respectively. HbA1c decreased by -1.4%, -1.6%, and -1.2% (placebo-adjusted) at these doses. Bodyweight reduction was dose-dependent, reaching -8.96 kg (90% CI -11.16 to -6.75) in the highest dose group (3/6/9/12 mg escalation).
The peptide's pharmacokinetics were dose-proportional with a half-life of approximately 6 days, supporting once-weekly dosing. Treatment-emergent adverse events occurred in 63% of LY3437943 recipients (vs 54% placebo), primarily gastrointestinal. However, 29 of 72 participants discontinued prematurely across all groups.
Why it matters
This trial represents the next frontier in peptide-based metabolic medicine. While GLP-1 agonists (semaglutide) and dual GIP/GLP-1 agonists (tirzepatide) have transformed diabetes and obesity treatment, adding glucagon receptor activity could deliver even greater weight loss by increasing energy expenditure. This 'triple agonist' approach is the most ambitious attempt yet to harness multiple gut hormone pathways in a single peptide molecule.
How the study worked
Phase 1b, proof-of-concept, double-blind, placebo-controlled, randomized, multiple-ascending dose trial at four US sites. Adults aged 20–70 with type 2 diabetes (HbA1c 7.0–10.5%, BMI 23–50) received once-weekly subcutaneous LY3437943, placebo, or dulaglutide 1.5 mg for 12 weeks. Five ascending dose cohorts were studied, with the two highest using stepwise dose escalation. Each cohort randomized minimum 9 to LY3437943, 3 to placebo, and 1 to dulaglutide. Primary outcome was safety/tolerability; pharmacodynamics and pharmacokinetics were secondary.
What this study cannot tell us
This is a small phase 1b study (72 participants) designed primarily for safety rather than efficacy. The 12-week duration is short for assessing long-term metabolic outcomes. The high discontinuation rate (29/72 = 40%) across all groups raises concerns about tolerability and study retention. The dulaglutide comparator arm (only 5 participants) was too small for meaningful efficacy comparison. Gastrointestinal side effects were common, consistent with the GLP-1 class. The study was funded by Eli Lilly, the drug's developer.
How to read the evidence
This is a phase 1b randomized controlled trial published in The Lancet — the highest-tier journal. While small and primarily designed for safety, it provides rigorous proof-of-concept evidence with robust pharmacodynamic data. Larger phase 2 and 3 trials are needed to confirm efficacy and establish the optimal risk-benefit profile.
When this study was published
Published in 2022, this Lancet study launched the clinical development of retatrutide (LY3437943). Since then, phase 2 results have been published showing weight loss of up to 24%, confirming the promise seen in this early trial.
The bigger picture
LY3437943 (later named retatrutide) represents the evolutionary next step beyond semaglutide (single agonist) and tirzepatide (dual agonist). The inclusion of glucagon receptor activity is the key innovation: while counterintuitive (glucagon raises blood sugar), glucagon also increases energy expenditure, promotes fat burning, and reduces appetite. When balanced with GLP-1 and GIP effects that lower blood sugar, the net result may be superior metabolic outcomes. This Lancet publication launched the clinical development program that led to larger phase 2 trials showing remarkable weight loss of up to 24%.
Questions still open
- Will the glucagon component cause blood sugar elevations in some patients that counteract the GLP-1 benefit?
- Can the triple agonist approach achieve greater weight loss than tirzepatide while maintaining a tolerable side effect profile?
- What is the long-term cardiovascular safety of simultaneously stimulating three metabolic hormone receptors?
Common questions
Why add a glucagon receptor to a diabetes drug when glucagon raises blood sugar?
How does this compare to Ozempic and Mounjaro?
Read the original research
LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial.
Lancet (London, England), 400(10366), 1869-1881
Citation
Urva, Shweta; Coskun, Tamer; Loh, Mei Teng; Du, Yu; Thomas, Melissa K; Gurbuz, Sirel; Haupt, Axel; Benson, Charles T; Hernandez-Illas, Martha; D'Alessio, David A; Milicevic, Zvonko. (2022). LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial.. Lancet (London, England), 400(10366), 1869-1881. https://doi.org/10.1016/S0140-6736(22)02033-5