Metabolic/Weight

Macupatide

Research Reagent · Laboratory Use Only

Quick Answer

What does research show about macupatide for insulin sensitivity and type 2 diabetes?

Macupatide (LY3532226) is Eli Lilly's selective, once-weekly GIP receptor agonist peptide, distinct from dual GIP/GLP-1 agonists like tirzepatide. A Phase 1b randomised controlled trial published in Diabetes, Obesity and Metabolism (2026) found that macupatide, alone or combined with dulaglutide, significantly improved insulin sensitivity and beta cell function in adults with type 2 diabetes over 12 weeks, with a clean tolerability profile. It is now advancing through Phase 1/2 trials in obesity, including combination studies with the amylin agonist eloralintide.

PMID42229460↗DOI10.1111/dom.70863↗⟳ Reconstitution Calculator
Scientific AbstractPMID 42229460 · 2026

Macupatide (LY3532226) is a long-acting, once-weekly glucose-dependent insulinotropic polypeptide (GIP) receptor agonist developed by Eli Lilly, acylated for extended half-life and lacking activity at GLP-1 or glucagon receptors. In a Phase 1b, two-part, investigator- and participant-blind, randomised controlled trial conducted in adults with type 2 diabetes on metformin monotherapy (Diabetes, Obesity and Metabolism, 2026; PMID 42229460; NCT05407961), participants received macupatide alone, dulaglutide alone, or macupatide plus dulaglutide in combination. Insulin sensitivity (M value), insulin secretion rate (ISR), and clamp disposition index were assessed via hyperinsulinemic-euglycemic clamp at baseline and after 12 weeks of treatment.

3% with the combination; macupatide alone also significantly increased ISR. Combination therapy produced numerically greater improvements than either monotherapy across all measured indices. The most frequent adverse events were injection-site reactions and diarrhoea, with no new safety signals.

The authors concluded macupatide preserves and improves insulin sensitivity and beta cell function alone and alongside dulaglutide, supporting its advancement into Phase 2 development, where it is now being studied both as monotherapy for obesity (NCT06557356, completed December 2025) and in combination with the amylin agonist eloralintide (NCT07215559, NCT07589608) for obesity and type 2 diabetes.

Source:10.1111/dom.70863
Mechanistic Research SummaryCurated from PubMed

This data is for laboratory research purposes only. Not for human or animal consumption.

What is Macupatide?

Macupatide (development code LY3532226) is a long-acting, once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor agonist peptide developed by Eli Lilly for type 2 diabetes and obesity. Unlike Lilly's tirzepatide (a dual GIP/GLP-1 agonist), macupatide is selective for the GIP receptor alone, with no activity at GLP-1 or glucagon receptors — positioning it as both a standalone candidate and a combination partner for Lilly's amylin agonist eloralintide.

Mechanism of Action

Macupatide selectively activates the GIP receptor, a mechanism distinct from the GLP-1 pathway used by semaglutide and liraglutide. GIP receptor agonism has been associated with improved insulin sensitivity and beta cell function in early human studies, complementing rather than duplicating GLP-1-driven appetite suppression — a rationale for combining it with GLP-1 agonists (dulaglutide) or amylin agonists (eloralintide) in ongoing trials.

Observed Clinical Results

  • Phase 1b trial (Diabetes, Obesity and Metabolism, 2026; PMID 42229460; NCT05407961): In adults with type 2 diabetes on metformin, 12-week hyperinsulinemic-euglycemic clamp data showed M-value (insulin sensitivity) increases of 33.1% with macupatide alone, 10.4% with dulaglutide alone, and 38.3% with the combination; macupatide alone also significantly increased insulin secretion rate. Most common adverse events were injection-site reactions and diarrhoea.
  • Phase 1 dose-escalation trial in obesity (NCT06557356): Completed December 2025; evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple macupatide doses in participants with obesity.
  • Phase 2 combination trials (NCT07215559, NCT07589608): Macupatide and eloralintide, alone or in combination, in adults with obesity/overweight with and without type 2 diabetes.

Regulatory Status

Investigational — no regulatory approval as of August 2026. Early-stage (Phase 1b/Phase 2) clinical program; efficacy and safety data are preliminary. Not eligible for 503A compounding as an investigational biologic peptide.

Clinical Research Parameters
4 trials1 human study

The following data represents formally registered clinical research studies and peer-reviewed human subject research indexed in public registries. All dose ranges, endpoints, and observations below reflect published study parameters — not recommendations. For research reference only.

Registered Clinical Trials
ClinicalTrials.gov ↗
NCT05407961 ↗
COMPLETEDPhase I

A Study of LY3532226 in Participants With Type 2 Diabetes Mellitus

Phase 1b, two-part, investigator- and participant-blind, multiple-ascending-dose study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of macupatide (LY3532226) alone and in combination with dulaglutide in adults with type 2 diabetes on metformin monotherapy. Single-center study conducted in Germany. Results (12-week hyperinsulinemic-euglycemic clamp): M-value increases of 33.1% (macupatide alone), 10.4% (dulaglutide alone), and 38.3% (combination); macupatide alone also significantly increased insulin secretion rate. Published in Diabetes, Obesity and Metabolism, 2026.

Study Interventions
Macupatide (LY3532226), Dulaglutide, Macupatide + Dulaglutide
Primary Endpoints
Insulin sensitivity (M value) from hyperinsulinemic-euglycemic clamp; Insulin secretion rate (ISR)
Study Period
2022 → 2024-01
NCT06557356 ↗
COMPLETEDPhase I

A Study of LY3532226 in Participants With Obesity

Dose-escalation Phase 1, investigator- and participant-blind, placebo-controlled study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of macupatide (LY3532226) in participants with obesity. Results not yet published as of this update.

Study Interventions
Macupatide (LY3532226), Placebo
Primary Endpoints
Safety and tolerability; Pharmacokinetics; Pharmacodynamics
Study Period
2024-08-16 → 2025-12-12
NCT07215559 ↗
RECRUITINGPhase II

A Study of Macupatide (LY3532226) and Eloralintide (LY3841136), Alone or in Combination, in Adults With Obesity or Overweight and With Type 2 Diabetes

Study evaluating the GIP-agonist macupatide and the amylin agonist eloralintide, alone and in combination, for weight reduction in adults with obesity/overweight and type 2 diabetes.

Study Interventions
Macupatide (LY3532226), Eloralintide (LY3841136), Placebo
Primary Endpoints
Percent change in bodyweight from baseline
Study Period
2026
NCT07589608 ↗
RECRUITINGPhase IIn=400

A Study to Investigate Weight Management With Macupatide and Eloralintide, Alone or in Combination, in Adult Participants With Obesity or Overweight

Phase 2b study (master protocol W8M-MC-CWMM) examining the bodyweight-lowering efficacy and safety of macupatide plus eloralintide compared with placebo in approximately 400 adults with obesity or overweight without type 2 diabetes, ages 18-75. Planned participation approximately 64 weeks.

Study Interventions
Macupatide (LY3532226), Eloralintide (LY3841136), Placebo
Primary Endpoints
Percent change in bodyweight from baseline
Study Period
2026
Research Compliance Notice

All data presented on this page is for laboratory research purposes only. Macupatide is referenced here as a research reagent. This page does not constitute medical advice, clinical guidance, or endorsement of any compound for human or animal use. All referenced studies are available via PubMed (PMID: 42229460) and the DOI-linked journal publication. Researchers must consult applicable institutional and regulatory frameworks before conducting any protocols.

Related Compounds

Other Metabolic/Weight Research Compounds

Semaglutide
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Tirzepatide
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Retatrutide
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Liraglutide
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