GLP2-T

Tirzepatide (also known as LY3298176) is a first-in-class, synthetic 39-amino acid linear peptide engineered as a single-molecule dual agonist for both the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor. [1] Developed by Eli Lilly and Company, this “twincretin” approach harnesses the synergistic effects of targeting both incretin pathways simultaneously. [2]

The peptide is based on the native GIP sequence, modified with α-aminoisobutyric acid (Aib) residues at positions 2 and 13 for DPP-4 resistance, and a C20 fatty diacid moiety (eicosanedioic acid) attached via a hydrophilic linker to the lysine residue at position 20 to promote albumin binding (≥99%), yielding an approximately 5-day half-life (116.7 hours) enabling convenient once-weekly dosing. [3]

Tirzepatide functions as an imbalanced agonist — it exhibits binding affinity for the GIP receptor equivalent to native GIP, but approximately 5- to 13-fold weaker affinity for the GLP-1 receptor compared to native GLP-1. [6] Despite this imbalance, the dual mechanism produces superior outcomes across multiple clinical endpoints compared to selective GLP-1 receptor agonists. [7]

Tirzepatide has been approved by the FDA under the brand names Mounjaro® (type 2 diabetes, May 2022) and Zepbound® (chronic weight management, Nov 2023; obstructive sleep apnea, Dec 2024), and by the EMA for type 2 diabetes and weight management. [4] It is listed on the WADA Prohibited List under section S2 (Peptide Hormones, Growth Factors, Related Substances, and Mimetics). It is supplied as a sterile, preservative-free solution for subcutaneous injection — note that this product is not a lyophilized powder. [5]

1. Primary Receptor Targets — Dual GIP/GLP-1 Agonism

Tirzepatide is a first-in-class unimolecular dual agonist that simultaneously targets the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor. [1] It functions as an imbalanced agonist: binding affinity for the GIP receptor equals that of native GIP, while GLP-1 receptor affinity is approximately 5- to 13-fold weaker than native GLP-1. [6] Cryo-electron microscopy confirms the N-terminus of tirzepatide (Tyr1) forms hydrogen bonds with GLP-1R residues (e.g., Gln234), while Glu3 forms ionic bonds with Arg190, with analogous interactions at the GIPR. [8]

2. Biased Agonism — cAMP Over β-Arrestin

Unlike native GLP-1 which recruits both G-proteins and β-arrestin, tirzepatide exhibits biased agonism at the GLP-1 receptor: it preferentially activates cyclic adenosine monophosphate (cAMP) generation while inducing significantly lower β-arrestin recruitment. [9] This reduces receptor internalization and desensitization, maintaining GLP-1R availability at the cell surface for prolonged signaling. At the GIP receptor, tirzepatide mimics the signaling profile of native GIP. [10]

3. Downstream Signaling — cAMP/PKA, PI3K/AKT, AMPK, NF-κB

Binding to GIP/GLP-1 receptors initiates several key intracellular cascades: [11]

• cAMP/PKA Pathway: Upregulated intracellular cAMP activates Protein Kinase A, stimulating glucose-dependent insulin secretion from pancreatic β-cells.
• PI3K/AKT Pathway: Enhances mitochondrial function, reduces neuroinflammation, and promotes cell survival.
• AMPK Pathway: Activated in CNS and peripheral tissues, linked to metabolic regulation and energy homeostasis.
• NF-κB Inhibition: Suppresses the TLR4/NF-κB/NLRP3 inflammasome pathway, reducing pro-inflammatory cytokines (TNF-α, IL-6). [12]
• CREB/BDNF Pathway: In neuronal cells, activates pAkt/CREB/BDNF signaling to promote neuronal growth and survival. [13]

4. Tissue-Level Effects

Pancreas: Enhances both first- and second-phase insulin secretion in a glucose-dependent manner. Reduces fasting and postprandial glucagon secretion during hyperglycemia while preserving glucagonotropic function during hypoglycemia. [14]

Adipose Tissue: GIP receptor agonism improves insulin sensitivity in adipose tissue, increases adiponectin levels by 16–26%, and enhances lipid buffering via increased lipoprotein lipase (LPL) activity. [15]

CNS: Acts on the hypothalamus to regulate appetite and satiety. Animal research (Bossi et al., 2025) indicates tirzepatide temporarily increases energy expenditure shortly after dosing, unlike semaglutide which initially reduces it. [16]

Liver: Reduces liver fat content and stiffness; in the SYNERGY-NASH trial, resolved MASH without worsening fibrosis in up to 62% of participants. [17]

5. Pharmacokinetics — Once-Weekly Dosing

The C20 fatty diacid enables 99% albumin binding, yielding a half-life of ~5 days (116.7 hours), bioavailability of ~80% SC, T_max of 8–72 hours, and V_d of ~10.3 L. [3] Metabolism occurs via proteolytic cleavage, β-oxidation of the fatty diacid moiety, and amide hydrolysis. Metabolites are excreted via urine and feces. [18]

6. Dose-Response Relationships

Clinical trials demonstrate clear dose-dependent efficacy across all indications: [19]

• HbA1c (SURPASS-1): −1.87% (5 mg), −1.89% (10 mg), −2.07% (15 mg)
• Weight loss (SURMOUNT-1): −15.0% (5 mg), −19.5% (10 mg), −20.9% (15 mg)
• MASH resolution (SYNERGY-NASH): 44% (5 mg), 56% (10 mg), 62% (15 mg)

🧠 Type 2 Diabetes (SURPASS Program)

Tirzepatide has been studied across the SURPASS clinical trial program (SURPASS-1 through SURPASS-6, plus SURPASS-CVOT) in over 17,000 study subjects with type 2 diabetes mellitus (T2DM). In SURPASS-2 (n=1,879), tirzepatide demonstrated superiority over semaglutide 1 mg, with HbA1c reductions of −2.01% to −2.30% vs. −1.86%, and weight loss of −7.6 to −11.2 kg vs. −5.7 kg. [7] The landmark SURPASS-CVOT (n=13,299) confirmed cardiovascular tolerability with a MACE HR of 0.92 vs. dulaglutide. [20]

⚖️ Obesity & Weight Management (SURMOUNT Program)

In the pivotal SURMOUNT-1 trial (n=2,539 adults with obesity, without T2DM), tirzepatide produced weight reductions of −15.0% (5 mg), −19.5% (10 mg), and −20.9% (15 mg) at 72 weeks vs. −3.1% with placebo. [21] The 3-year SURMOUNT-1 extension showed sustained weight reduction (−12.3% to −19.7%) and a 94% reduction in risk of progression to T2D (HR 0.07). [22]

In the head-to-head SURMOUNT-5 trial (n=751), tirzepatide achieved −20.2% weight loss vs. −13.7% for semaglutide 2.4 mg, establishing superiority. [23]

See also: AOD-9604 for related weight management research.

❤️ Heart Failure (SUMMIT Trial)

The SUMMIT trial (n=731) investigated tirzepatide in study subjects with heart failure with preserved ejection fraction (HFpEF) and obesity, showing a 38% reduction in risk of CV death/worsening heart failure (HR 0.62) and 6.9-point greater improvement in KCCQ-CSS (Kansas City Cardiomyopathy Questionnaire). [24]

💤 Obstructive Sleep Apnea (SURMOUNT-OSA)

The SURMOUNT-OSA trials (n=469) demonstrated that tirzepatide reduced the apnea-hypopnea index (AHI) by up to 62.8% (−25.3 to −29.3 events/hr vs. −5.3 to −5.5 placebo) in study subjects with moderate-to-severe OSA and obesity. The FDA-registered Zepbound for OSA in December 2024. [25]

🫁 Liver Disease (SYNERGY-NASH)

In the Phase 2 SYNERGY-NASH trial (n=190), tirzepatide achieved MASH resolution without worsening fibrosis in 44% (5 mg), 56% (10 mg), and 62% (15 mg) vs. 10% placebo. Fibrosis improvement (≥1 stage) occurred in ~51–55% of tirzepatide groups vs. 30% placebo. [17]

🧠 Neuroprotection (Preclinical)

Preclinical studies suggest tirzepatide may have neuroprotective effects in Alzheimer’s and Parkinson’s disease models. In APP/PS1 mice (Alzheimer’s model), tirzepatide reduced amyloid-beta plaque density, decreased astrocytic activation, and reduced neuronal ROS production. [26] In neuroblastoma cells, it prevented high-glucose-induced neurodegeneration via CREB/BDNF pathway modulation. [13]

🫀 Kidney Protection (Exploratory)

Exploratory analyses from SURPASS-4 indicate tirzepatide may delay eGFR decline and reduce albuminuria compared to insulin glargine, prompting ongoing studies targeting chronic kidney disease outcomes. [27]

Animal Studies

• Metabolic/Energy (Mice, Bossi 2025): 10 nmol/kg SC daily × 4 weeks — 15.6 g weight loss (vs. 8.3 g semaglutide, +2.7 g vehicle). Temporarily increased energy expenditure and fat oxidation. [16]
• Food Preference (Mice/Rats, Geisler 2022): Selectively reduced palatable high-fat/sugar food intake while preserving chow intake. Effect abolished in GLP-1R knockout mice. [28]
• Carcinogenicity (Rats, 2-year): Dose-dependent increase in thyroid C-cell tumors at clinically relevant exposures (Boxed Warning). Not tumorigenic in 6-month transgenic mouse study. [29]
• Sepsis-Induced Cardiomyopathy (Mice, Liu 2023): Attenuated inflammatory response, inhibited TLR4/NF-κB/NLRP3 pathway, reduced cardiac injury markers (CK-MB, LDH, AST). [12]
• Alzheimer’s Disease (APP/PS1 Mice, Yang 2024): 10 nmol/kg IP weekly × 8 weeks — reduced amyloid-β plaques, astrocytic activation, and neuronal ROS production. [26]
• Neuroprotection In Vitro (Fontanella 2024): 0.2 µM in SHSY5Y cells prevented HG-induced GLUT3/GLUT4 downregulation and DNA methylation changes in CREB/BDNF promoters. [13]

Human Clinical Trials

• SURPASS-1 (T2DM, n=478): HbA1c −1.87% to −2.07% vs. +0.04% placebo; weight loss −7.0 to −9.5 kg. [19]
• SURPASS-2 (T2DM, n=1,879): Superior to semaglutide 1 mg in HbA1c (−2.01–−2.30% vs. −1.86%) and weight (−7.6–−11.2 kg vs. −5.7 kg). [7]
• SURPASS-CVOT (T2DM+CVD, n=13,299): MACE HR 0.92 vs. dulaglutide (non-inferiority confirmed). All-cause death HR 0.84. [20]
• SURMOUNT-1 (Obesity, n=2,539): Weight loss −15.0% to −20.9% at 72 weeks; 3-year follow-up: 94% T2D risk reduction. [21] [22]
• SURMOUNT-5 (Obesity, n=751): −20.2% tirzepatide vs. −13.7% semaglutide 2.4 mg — superiority confirmed. [23]
• SUMMIT (HFpEF+Obesity, n=731): 38% reduction in CV death/worsening HF (HR 0.62); KCCQ-CSS improved 6.9 pts. [24]
• SURMOUNT-OSA (OSA+Obesity, n=469): AHI reduced 55–63% (−25–29 events/hr vs. −5 placebo). [25]
• SYNERGY-NASH (MASH, n=190): Resolution in 44–62% vs. 10% placebo; fibrosis improved in ~51–55% vs. 30%. [17]

Regulatory Status

FDA: Approved — Mounjaro® (T2DM, May 2022), Zepbound® (obesity, Nov 2023; OSA, Dec 2024). [4]

EMA: Approved (Mounjaro) for T2DM and weight management.

WADA: Prohibited in competition and out-of-competition (S2 — Peptide Hormones).

reported tolerability profile: Most common AEs are GI (nausea 12–33%, diarrhea 12–23%, vomiting 2–13%, constipation). Boxed Warning for thyroid C-cell tumors based on rat data. Pancreatitis and gallbladder events reported at low rates. Hypoglycemia risk low as monotherapy. [29]