Brenipatide(LY3537031): Eli Lilly's monthly dual GIP/GLP-1 agonist

What is Brenipatis?

Le Brenipatide(International Nonproprietary Name; Development Codes LY3537031 / LY-3537031) is a research peptide developed byEli LillyIt belongs to the class ofdual incretin agonists, like tirzepatide, but differs in its pharmacokinetics and development strategy. It simultaneously activates two receptors:

• GLP-1 Receiver(Glucagon-Like Peptide-1) — regulation of appetite, slowing of gastric emptying, stimulation of glucose-dependent insulin secretion
• GIP Receiver(Glucose-Dependent Insulinotropic Polypeptide) — potentiation of the insulinotropic effect, modulation of lipid metabolism in adipose tissue

Where tirzepatide, semaglutide and retatrutide require administrationweeklyBrenipatide was engineered to last much longer in the body — hence the objective of an injectiononce a month.

Mechanism of action: the dual incretin GIP/GLP-1

Co-activation of GLP-1 and GIP receptors produces synergistic effects on satiety, insulin sensitivity and energy expenditure — greater than what a mono-agonist GLP-1 can achieve.

Action on the GLP-1 receptor — appetite and blood sugar

Activation of GLP-1R in the hypothalamus and brainstem induces:

• A reduction in food intake and an increase in satiety signals
• A slowing of gastric emptying
• Glucose-dependent insulin stimulation and postprandial glucagon reduction

Action on the GIP receptor — metabolic potentiation

Activation of GIPR complements the GLP-1 pathway by potentiating the glucose-dependent insulinotropic effect and modulating lipid storage and mobilization in adipocytes. This dual stimulation aims for better glycemic control and greater metabolic efficiency than monoagonists.

A central action on the reward circuits

This is the most original axis of the Brenipatide. The GIP/GLP-1 signaling modulates thedopaminergic reward pathwaysin the central nervous system. It is precisely this central action — on the mechanisms of desire and compulsion — that Eli Lilly is exploring for neuropsychiatric and addiction indications, beyond metabolism.

The Brenipatide signature: monthly administration

The extended half-life is not a minor detail: it changes the very nature of the potential use. A monthly rather than weekly injection greatly reduces the burden of adherence — a crucial issue in populations where regular medication intake is difficult (addictions, psychiatric disorders).

A novel clinical approach: addiction and psychiatry

Unlike retatrutide or tirzepatide, whose development is primarily focused on obesity and diabetes, Eli Lilly is directing Brenipatide primarily towards thecentral nervous systemThe clinical program includes, in particular:

• Alcohol use disorder— phase 3 trialsRENEW-ALC-1 et RENEW-ALC-2(moderate to severe and risky use)
• Opioid use disorder— dedicated clinical study
• Psychiatric disorders— bipolar disorder, smoking cessation and relapse prevention
• Other avenues explored— asthma (stage 2), cardiovascular, hepatic, metabolic disorders and obesity

The RENEW-ALC-1 trial (NCT07219966) is a phase 3, randomized, double-blind, placebo-controlled study planning to enroll approximately 1,100 participants with moderate to severe alcohol use disorder, with a follow-up of approximately 56 weeks. Recruitment began in late 2025.

Brenipatide vs Tirzepatide vs Retatrutide

Positioning Brenipatide among the multi-receptor agonists of incretins clarifies its uniqueness:

Applications in research

In the laboratory, Brenipatide is of interest to several areas of preclinical and basic research:

• Study of GIP/GLP-1 co-signaling and its synergistic metabolic effects
• Models of the modulation of dopaminergic reward circuits (addiction, compulsion)
• Research on long-acting peptides and half-life engineering
• Comparison of double versus triple incretin profiles (vs tirzepatide and retatrutide)

Key points to remember

• Brenipatide (LY3537031) is adual agonist GIP/GLP-1developed by Eli Lilly
• His signature is amonthly administrationmade possible by a significantly extended half-life
• Its development is primarily aimed ataddiction and psychiatry(alcohol, opioids, bipolar disorder, tobacco), via the action of incretins on reward circuits
• Phase 3 trialsRENEW-ALC-1 / RENEW-ALC-2on alcohol use disorder, recruitment to begin at the end of 2025
• The exact sequence and molecular mass have not yet been published.
• No phase 3 efficacy results are available to date.

Scientific sources: Brenipatis — Wikipedia · NCT07219966 — RENEW-ALC-1 (Phase 3) · AdisInsight — Brenipatide (Eli Lilly)