PP-RT1: Triple Receptor Agonist Research

PP-RT1 (LY3437943) is a triple receptor agonist that acts at the GIP, GLP-1 and glucagon receptors. It is an active subject of published metabolic research, and the summary below describes findings reported in the literature. PP-RT1 is supplied for laboratory research use only and is not approved for human or veterinary use. No conclusions can be drawn regarding safety or effects in humans.

The three receptor targets correspond to hormones involved in appetite and glucose regulation:

• GIP (gastric inhibitory peptide, or glucose-dependent insulinotropic polypeptide), an incretin hormone released from the gut after eating, which stimulates pancreatic beta-cells to secrete insulin.

• GLP-1 (glucagon-like peptide-1), a second incretin hormone that also acts on pancreatic beta-cells.

• Glucagon, produced by pancreatic alpha-cells, which signals hepatic glucose production.

Mechanism of Action of PP-RT1 Peptide

PP-RT1 is studied as a triagonist acting at three hormone pathways associated with appetite and energy metabolism: glucagon, gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1).

GIP is produced and secreted by the gut following food intake. Its release prompts pancreatic beta-cells to increase insulin production, raising circulating insulin. GLP-1 acts analogously and also increases circulating insulin levels, with downstream effects on blood glucose.

Glucagon, produced by pancreatic alpha-cells, plays two roles in glucose handling. It signals the liver to produce glucose by mobilising stored sugar, and in doing so contributes to the regulation of circulating glucose levels.

GLP-1 and glucagon have an additional documented influence on hunger and appetite through delayed gastric emptying. When gastric emptying is slowed, the transit of food from stomach to intestine is correspondingly slower, which affects post-prandial glucose levels. Studies have associated delayed gastric emptying with reduced food intake. GIP does not appear to affect gastric emptying.

Research Evidence

Work on the gut-brain axis and the role of gastrointestinal hormones in regulating metabolism, appetite and glucose homeostasis has opened routes for pharmacological investigation in recent decades, and has informed the development of new research compounds.

Compounds studied in this area include orlistat, phentermine-topiramate, naltrexone-bupropion, liraglutide, PP-SM1 and GIP/GLP-1. Each has received U.S. Food and Drug Administration authorisation for long-term use as a prescription medicine. PP-RT1 has not; it remains investigational.

Published reviews note that unmet needs remain in this research area, particularly around clinical endpoints and adverse effects. Available agents have not consistently achieved adequate glycemic control across all trial participants, and some participants experience adverse effects including weight gain, hypoglycemia and cardiovascular events.

PP-RT1 (LY3437943) was synthesised as a triagonist that simultaneously activates GLP-1, GIP and glucagon receptors (GCGRs). Initial preclinical and clinical findings have reported effects on glycemic control and body weight endpoints, and the compound is being evaluated for broader metabolic and cardiovascular endpoints.

PP-RT1 has reached Phase III investigation in obesity, type 2 diabetes and non-alcoholic fatty liver disease research. Phase II studies reported body weight endpoints at 24 and 48 weeks. The authors noted that further Phase III trials are required to assess effects and safety across broader populations.

The mechanisms of PP-RT1 and the full range of its research applications have not been fully characterised. Published reviews highlight the need for larger and longer clinical trials, and for further work on study protocols.

Research Application

• Mechanism of interest: PP-RT1 is a triple agonist targeting glucagon receptors, gastric inhibitory polypeptide receptors and glucagon-like peptide-1 receptors. Studies have examined its combined effect on insulin production, glucose homeostasis and appetite regulation.

• Reported trial findings: Clinical studies in phases 1 to 3 have measured body weight endpoints and glycemic control markers in participants with obesity or type 2 diabetes mellitus.

PP-RT1 is also being studied in relation to cardiovascular risk markers and non-alcoholic fatty liver disease, alongside glucose and body weight endpoints.

Ongoing research is needed to characterise the long-term safety profile of PP-RT1, to examine its effects in specific populations, and to elucidate its mechanisms in paediatric cohorts.

Future Perspective

Phase 2 data have prompted continued investigation of PP-RT1's effects on components of the metabolic syndrome, including triglycerides, high-density lipoprotein cholesterol, blood pressure and fasting glucose. Further research is required to establish the breadth of its effects across different settings and populations.

Research use statement. PP-RT1 is an investigational compound. The material supplied by Power Peptides is intended for laboratory research use only and is not approved by the U.S. Food and Drug Administration for human or veterinary use. It is not a drug, food or cosmetic, and must not be used in humans or animals.

References

1. L.L. Baggio et al. Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease (2021)

2. C.J. Bailey et al.Recent advances in peptide-based therapies for obesity and type 2 diabetes; Peptides (2024)

3. M. Chakhtoura et al. Pharmacotherapy of obesity: an update on the available medications and drugs under investigation; EClinicalMedicine (2023)

4. T. Coskun et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept