Research Profile — Weight Loss Research

Tirzepatide: Complete Dual Incretin Agonist Research Profile

LY3298176Dual incretin agonistGLP-1/GIP RA

Tirzepatide is a 39-amino-acid peptide that established the dual-incretin agonist class in metabolic research. Unlike single-pathway GLP-1 agonists, tirzepatide engages both GIP and GLP-1 receptor systems in parallel, producing coordinated effects on insulin secretion, appetite signaling, gastric emptying, and adipose tissue metabolism. Its clinical development programs (SURPASS for type 2 diabetes and SURMOUNT for obesity) generated some of the strongest weight and glycemic outcomes reported for non-surgical interventions. In research contexts, tirzepatide is frequently used as the reference standard for dual-agonist biology and as a comparator against next-generation triple agonists such as retatrutide.

Technical Specifications

CAS Number	2023788-19-2
Molecular Formula	C225H348N48O68
Molecular Weight	4813.45 g/mol
Amino Acids	39
Sequence	39-amino-acid synthetic peptide with C20 fatty diacid modification for albumin binding
Purity	>=99% (HPLC)
Appearance	White lyophilized powder
Salt Form	Acetate
Solubility	Soluble in water
Storage	-20C lyophilized, 2-8C reconstituted

Origin & Discovery

Tirzepatide was developed by Eli Lilly as a first-in-class dual agonist designed to activate both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. It combines a peptide backbone optimized for GIP receptor potency with engineered GLP-1 receptor activity and a C20 fatty diacid side chain that prolongs circulation through albumin binding, enabling once-weekly dosing in research and clinical settings.

Mechanism of Action

Tirzepatide produces metabolic effects through dual receptor agonism with biased signaling characteristics. GIP Receptor Agonism: Tirzepatide has high potency at the GIP receptor, where it enhances glucose-dependent insulin secretion and modulates adipose tissue handling of lipids. GIP signaling is also studied for central effects on appetite and food-reward circuitry. GLP-1 Receptor Agonism: Tirzepatide activates GLP-1 receptors to reduce appetite, delay gastric emptying, and support postprandial glycemic control. The GLP-1 component contributes to satiety and reduced caloric intake in long-duration studies. Glucose-Dependent Insulin Support: In pancreatic beta cells, dual incretin signaling amplifies insulin release when glucose is elevated, helping limit hypoglycemia risk relative to non-glucose-dependent secretagogues. Albumin Binding and Half-Life: The C20 fatty diacid moiety enables reversible albumin association, reducing renal clearance and enzymatic degradation, which supports once-weekly exposure in trial protocols. System-Level Effect: By combining intake reduction (satiety and gastric emptying) with improved insulin dynamics and broader adipometabolic signaling, tirzepatide creates a multi-axis energy balance shift that exceeds expected effects from isolated single-pathway incretin stimulation.

SURMOUNT Obesity Program

Jastreboff et al. (2022) reported SURMOUNT-1 outcomes in the New England Journal of Medicine for adults with obesity or overweight and weight-related complications. Across dose groups, tirzepatide produced substantial weight reduction over 72 weeks, with the highest-dose arm showing mean reductions above 20% from baseline. A large proportion of participants reached clinically meaningful weight-loss thresholds (>=5%, >=10%, >=15%). These data established dual incretin agonism as a major step-change in pharmacologic weight-management research.

Citations

Jastreboff AM, et al. (2022) "Tirzepatide once weekly for treatment of obesity." N Engl J Med, 387(3), 205-216.

SURPASS Type 2 Diabetes Program

The SURPASS program compared tirzepatide against placebo and active comparators in type 2 diabetes populations. Frías et al. (2021) demonstrated robust HbA1c and body-weight reductions in SURPASS-2 versus semaglutide 1.0 mg, with many participants achieving stringent glycemic targets. Across SURPASS studies, efficacy patterns were dose-dependent and generally accompanied by predictable gastrointestinal adverse effects during dose escalation.

Citations

Frias JP, et al. (2021) "Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes." N Engl J Med, 385(6), 503-515.
Dahl D, et al. (2022) "Tirzepatide in type 2 diabetes and increased cardiovascular risk (SURPASS-4)." Lancet, 398(10313), 1811-1824.

Cardiometabolic and Safety Signals

Beyond glycemic and weight endpoints, tirzepatide studies have shown favorable directional changes in triglycerides, blood pressure, and waist circumference. The most common adverse events are gastrointestinal, including nausea, vomiting, and diarrhea, typically concentrated during up-titration periods. Ongoing outcomes studies continue to refine long-term cardiovascular and renal interpretation for dual-agonist exposure.

Citations

Sattar N, et al. (2022) "Tirzepatide cardiovascular, metabolic and weight effects across SURPASS trials." Diabetes Obes Metab, 24(8), 1481-1490.

Frequently Asked Questions

What is tirzepatide?▼

Tirzepatide is a synthetic 39-amino-acid dual incretin receptor agonist that activates both GIP and GLP-1 receptors. It is a central reference compound in metabolic research for obesity and type 2 diabetes models.

How is tirzepatide different from semaglutide?▼

Semaglutide is a selective GLP-1 receptor agonist, while tirzepatide activates both GLP-1 and GIP receptors. The additional GIP pathway is associated with broader incretin signaling and has shown larger average weight reductions in several trial comparisons.

How is tirzepatide different from retatrutide?▼

Tirzepatide is a dual agonist (GLP-1/GIP). Retatrutide is a triple agonist (GLP-1/GIP/glucagon) that adds glucagon receptor activity to target energy expenditure pathways in addition to appetite and incretin biology.

What is the CAS number of tirzepatide?▼

The CAS registry number for tirzepatide is 2023788-19-2.