First Triple-Receptor Peptide Drug Showed Powerful Blood Sugar and Weight Loss in Phase 1b Diabetes Trial
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.
Quick Facts
What This Study 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.
Key Numbers
How They Did This
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.
Why This Research 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.
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%.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- -8.96 kg weight loss in 12 weeks The 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
- Evidence Grade:
- 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.
- Study Age:
- 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.
- Original Title:
- 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.
- Published In:
- Lancet (London, England), 400(10366), 1869-1881 (2022)
- Authors:
- Urva, Shweta(4), Coskun, Tamer(12), Loh, Mei Teng, Du, Yu, Thomas, Melissa K, Gurbuz, Sirel, Haupt, Axel, Benson, Charles T, Hernandez-Illas, Martha, D'Alessio, David A, Milicevic, Zvonko
- Database ID:
- RPEP-06556
Evidence Hierarchy
Frequently Asked Questions
Why add a glucagon receptor to a diabetes drug when glucagon raises blood sugar?
It seems counterintuitive, but glucagon does more than raise blood sugar — it also increases energy expenditure (calorie burning), promotes fat breakdown, reduces appetite, and may reduce liver fat. When combined with GLP-1 and GIP receptor activity that powerfully lower blood sugar, the net effect is better blood sugar control plus enhanced weight loss and metabolic improvement. The key is balancing all three receptor activities so the blood sugar-raising effect of glucagon is outweighed by the blood sugar-lowering effects of GLP-1 and GIP.
How does this compare to Ozempic and Mounjaro?
Ozempic (semaglutide) activates one receptor (GLP-1). Mounjaro (tirzepatide) activates two (GIP + GLP-1). LY3437943 (retatrutide) activates all three (GIP + GLP-1 + glucagon). Each generation has shown progressively greater weight loss and metabolic improvements. While direct comparisons require head-to-head trials, the 8.96 kg weight loss in just 12 weeks in this phase 1b study, and the subsequent phase 2 results showing up to 24% body weight loss, suggest the triple agonist approach may be the most effective peptide therapy yet developed.
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Cite This Study
https://rethinkpeptides.com/research/RPEP-06556APA
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
MLA
Urva, Shweta, et al. "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, 2022. https://doi.org/10.1016/S0140-6736(22)02033-5
RethinkPeptides
RethinkPeptides Research Database. "LY3437943, a novel triple GIP, GLP-1, and glucagon receptor ..." RPEP-06556. Retrieved from https://rethinkpeptides.com/research/urva-2022-ly3437943-a-novel-triple
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Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.