Research Dossier on 

Dual Agonist of GLP-1, GIP

(Incretin Mimetics)

(Dual GIP/GLP-1 receptor agonist; once-weekly acylated peptide)

Classification & Molecular Identity

Amino acid sequence, molecular weight, structural motifs

Tirzepatide is a synthetic, acylated 39-amino-acid peptide that acts as a single-molecule agonist at the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R). It contains non-canonical residues (e.g., Aib) for protease resistance and an ε-amino–linked C20 diacid fatty moiety (via a spacer at Lys^20) to prolong exposure through albumin association, enabling once-weekly dosing. Although different sources present the exact residue list in various notations, the design retains the class-B GPCR N-terminal pharmacophore that docks into the transmembrane core of GIPR/GLP-1R, while the acyl side chain confers ~5-day pharmacokinetics in humans [review: Diabetes Obes Metab 2021; PMID: 34558484].

Molecular mass. The theoretical mass of the peptide (including acylation) is ≈ 4.8–5.1 kDa (salt form dependent). Public chemistry documents tabulate related characteristics for the clinical drug substance (tirzepatide sodium); the clinical literature consistently emphasizes weekly exposure derived from fatty-acid acylation rather than the exact mass per se (PMID: 34558484).

Discovery history (lab, year, species)

Tirzepatide (LY3298176) was discovered at Eli Lilly & Co. during efforts to combine GIP and GLP-1 biology in a unimolecular scaffold. Proof-of-concept in animals showed robust glycaemic control and body-weight effects vs selective GLP-1R agonists, leading to first-in-human studies (Phase 1) and a pivotal SURPASS program in type 2 diabetes (T2D) during 2018–2021, followed by SURMOUNT trials in obesity (2022–2024) [PMID: 34558484].

Endogenous vs synthetic origin

• Endogenous ligands. GIP and GLP-1 are gut incretins released post-prandially from K- and L-cells, respectively; both act via class-B GPCRs to augment glucose-dependent insulin secretion.

• Synthetic analog. Tirzepatide is not endogenous; it is a medicinally optimized peptide with dual agonism and albumin-binding acylation to extend t½ and enable weekly administration (PMID: 34558484).

Homologs, analogs, derivatives

• GLP-1R mono-agonists: semaglutide, dulaglutide, liraglutide.

• Triple agonists: investigational GLP-1/GIP/glucagon receptor agonists (e.g., retatrutide).

• Other duals: exendin-based or oxyntomodulin-based molecules with mixed receptor activities are at earlier stages; none share the full clinical evidence base of tirzepatide to date (PMID: 34558484).

Historical Development & Research Trajectory

Key milestones (selected)

• SURPASS-1 (T2D, monotherapy)—Ludvik et al. Lancet 2021: tirzepatide 5/10/15 mg once weekly for 40 weeks improved HbA1c by −1.87 to −2.07 percentage points and reduced body weight by −7.0 to −9.5 kg vs placebo (all investigational doses used in study) (PMID: 34186022).

• SURPASS-2 (T2D, vs semaglutide 1 mg)—Frías et al. NEJM 2021: 40 weeks, tirzepatide 5/10/15 mg once weekly reduced HbA1c by −2.01/−2.24/−2.30 pp and weight by −7.6/−9.3/−11.2 kg, each superior to semaglutide 1 mg (investigational comparator dose; all investigational doses used in study) (PMID: 34170647).

• SURPASS-3 (T2D, vs insulin degludec)—Del Prato et al. Lancet 2021: tirzepatide achieved larger HbA1c and weight reductions than basal insulin over 52 weeks; MRI substudy showed liver fat reduction (PMID: 34370970; MRI substudy PMCID/PMID: 35238644).

• SURPASS-4 (T2D, high CV risk, vs insulin glargine)—Del Prato et al. Lancet 2021: 52 weeks, tirzepatide improved glycaemia and weight with less hypoglycaemia vs glargine; exploratory CV events collected for meta-analyses (PMID: 34706258).

• SURPASS-5 (T2D, add-on to insulin glargine)—Dahl et al. JAMA 2022: 40 weeks, tirzepatide added to basal insulin reduced HbA1c by up to −2.4 pp and weight by −10 kg vs insulin titration plus placebo (PMID: 35015057).

• SURMOUNT-1 (obesity without diabetes)—Jastreboff et al. NEJM 2022: 72 weeks, tirzepatide 5/10/15 mg led to mean weight changes of −15.0/−19.5/−20.9 % vs −3.1 % placebo (all investigational doses used in study) (PMID: 35658024).

• SURMOUNT-3 (JAMA 2023): after a 12-week intensive lifestyle lead-in (≥5 % weight loss), 72 weeks of tirzepatide produced additional −18.4 % vs −2.5 % placebo; 85 % reached ≥10 % total loss (PMID: 37773904).

• SURMOUNT-4 (JAMA 2023): 36-week open-label tirzepatide lead-in yielded −21 % loss; randomized continuation vs withdrawal for 52 weeks showed maintenance/continued loss on drug vs regain off drug (PMID: 37909105).

• Cardiovascular outcomes—SURPASS-CVOT (NCT04255433) completed enrollment to compare tirzepatide vs dulaglutide for MACE-3; a positive top-line result was reported late-2024, with peer-reviewed publication pending at the time of writing (registry entry).

Paradigm shifts & controversies

1. GIP is (likely) beneficial in obesity. Prior dogma emphasized GLP-1R and downplayed GIPR efficacy in T2D. Tirzepatide’s outcomes argue that co-agonism at GIPR meaningfully amplifies weight loss and glycaemic controlbeyond GLP-1R alone (PMID: 34558484).

2. Energy balance vs glycaemia. SURMOUNT results (−15% to −21% mean losses) approach metabolic-surgery-adjacent magnitudes for many participants (PMID: 35658024, 37909105), motivating re-evaluation of mechanisms (e.g., energy expenditure, adipose GIPR effects) and long-term weight-maintenance strategies.

3. Safety class effects. Like potent GLP-1R agonists, tirzepatide presents GI adverse events, gallbladder disease risk, and HR increases; questions remain about diabetic retinopathy risk with rapid glycaemic lowering (class signal for semaglutide) though tirzepatide data so far are inconclusive (PMID: 34170647, 34706258).

Evolution of scientific interest

After landmark T2D trials (2021), the field pivoted to obesity, NASH/NAFLD-adjacent endpoints, sleep apnoea, heart failure with preserved EF (HFpEF) phenotypes, and cardiovascular outcomes, with multiple ongoing registrational or label-expansion programs (ClinicalTrials.gov).

Mechanisms of Action

Primary and secondary receptor interactions

Tirzepatide is a balanced but GIP-biased co-agonist—high potency at GIPR, robust GLP-1R activation, and no glucagon receptor activity. Binding triggers cAMP signaling in pancreatic β-cells (potentiating glucose-dependent insulin secretion), reduces α-cell glucagon (via GLP-1R), slows gastric emptying, reduces appetite, and improves adipose and hepatic insulin sensitivity (PMID: 34558484).

GIP-specific hypotheses (preclinical/clinical inferences):

• Adipose: GIPR activation may augment insulin-mediated lipid handling, increasing fat oxidation during energy restriction; chronic GIPR stimulation combined with GLP-1R reduces adiposity more than GLP-1R alone (PMID: 34558484).

• CNS: Additive or synergistic satiety with GLP-1R signaling; lower nausea at equivalent weight loss has been discussed but remains context-specific (PMID: 34170647).

Intracellular signaling pathways

• β-cell: GIPR/GLP-1R → Gs → cAMP/PKA/Epac2, facilitating insulin granule exocytosis; enhanced with elevated glucose.

• Hepatocyte/adipocyte: Secondary improvements in insulin signaling (AKT), lipid flux, and inflammation(adipokine milieu) post weight loss; MRI-substudies show liver fat reductions concordant with improved HOMA-IR (PMID: 35238644).

• GI/CNS: Vagal and hypothalamic circuits modulated via GLP-1R; gastric emptying slows acutely, with partial tachyphylaxis over time—contributing to glucose and satiety effects (PMID: 34558484).

CNS vs peripheral effects

• CNS: Appetite suppression, reward-circuit modulation, nausea.

• Peripheral: Pancreas (insulin/glucagon), GI tract (emptying), adipose (lipid mobilization & storage), liver (de-novo lipogenesis down, fat oxidation up), and cardiorespiratory markers (HR increase ~2–5 bpm; class effect) (PMID: 34706258, 35658024).

Hormonal, metabolic, immune interactions

• Hormonal: Insulin ↑ (glucose-dependent), glucagon ↓, ghrelin ↓, possible changes in adiponectin/leptin via fat-mass loss.

• Metabolic: HbA1c reductions typically −1.9 to −2.4 pp in T2D at 10–15 mg; weight −7 to −12 kg in T2D and −15% to −21% in obesity over 72 weeks (PMID: 34170647, 35658024).

• Inflammatory/hepatic: Liver fat and ALT commonly improve; formal NASH histology trials are ongoing (PMID: 35238644).

Evidence grading (A–C)

• A (replicated RCT evidence): Dual GIPR/GLP-1R agonism → superior HbA1c and weight reductions vs GLP-1RA or basal insulin; liver-fat lowering (MRI) (PMIDs: 34186022, 34170647, 34370970, 35658024).

• B (plausible translational mechanisms): Adipose-centric GIP benefits, CNS satiety synergy, and improved hepatic fat; direct measurements of energy expenditure increments remain inconclusive (PMID: 34558484).

• C (uncertain/controversial): Whether GIPR contributes materially to adverse-event mitigation (e.g., nausea reduction) at equal efficacy is not established; long-term retinopathy risk remains unclear (class signal from semaglutide vs neutral tirzepatide analyses so far).

Pharmacokinetics & Stability

ADME profile (human)

• Absorption: After subcutaneous injection, Tmax occurs within 8–72 h (typically 12–48 h).

• Distribution: Strong albumin binding from C20 diacid side-chain; apparent Vd approximates extracellular space.

• Metabolism: Proteolytic degradation and β-oxidation/phase-II of the acyl side chain; no major CYP liabilities (peptide-class expectation).

• Elimination half-life: ~5 days, supporting once-weekly dosing (PMID: 34558484).

• Steady state: Achieved after ~4–5 half-lives; accumulation factor ~1.2–1.6 depending on dose and sampling schedule (PMID: 34558484).

Plasma half-life & degradation pathways

The long t½ derives from albumin association (depot + slowed renal filtration) and protease resistance from Aibresidues. Population-PK analyses suggest dose-proportional exposure across 5–15 mg and limited covariate impact beyond body weight (PMID: 34132401).

Stability in vitro & in vivo

As with other acylated incretins, tirzepatide is supplied as a solution/pen designed for refrigerated storage with room-temperature windows; degradation kinetics are manufacturer-documented (outside scope here). Biophysical stability in plasma is consistent with weekly pharmacology.

Preclinical Evidence

Animal pharmacology (summary)

• Glycaemia & weight: In diet-induced obese rodents and non-human primates, tirzepatide produced greater weight loss and improved glucose vs GLP-1R agonists alone; β-cell function improved (HOMA-B surrogates, insulin secretion) (PMID: 34558484).

• Mechanism: Co-activation of GIPR increased adipose lipid clearance and may have blunted counter-regulatory nausea signaling seen with GLP-1R-only agents (hypothesis) (PMID: 34558484).

• Cardiovascular/renal biomarkers: Early studies show favorable changes in BP, lipids, and albuminuriasecondary to weight/glycaemia; outcome-level animal data are not definitive.

Dose ranges tested (illustrative; all investigational)

Rodent doses (µg·kg⁻¹ to mg·kg⁻¹ SC weekly) were titrated to mirror human exposure; translational PK-PD bridging underpins the 5–15 mg human range (PMID: 34558484).

MRI-liver fat substudy (human, SURPASS-3)

An MRI-PDFF substudy demonstrated absolute liver-fat reductions of ~−8 to −10 % from baseline (dose-dependent) at 52 weeks compared with insulin degludec, aligning with improved ALT and metabolic surrogates (PMID: 35238644).

Human Clinical Evidence

Type 2 diabetes (SURPASS program; selected trials)

SURPASS-1 (monotherapy, 40 weeks)

• Design: Double-blind RCT vs placebo.

• Investigational doses used in study: 5, 10, 15 mg once-weekly SC.

• Results: HbA1c −1.87/−1.89/−2.07 pp; weight −7.0/−8.5/−9.5 kg; AEs mostly GI (nausea, diarrhea, vomiting) and mild-to-moderate (PMID: 34186022).

SURPASS-2 (vs semaglutide 1 mg, 40 weeks)

• Design: Head-to-head active comparator.

• Investigational doses used in study: 5, 10, 15 mg weekly vs semaglutide 1 mg.

• Results: HbA1c −2.01/−2.24/−2.30 pp vs −1.86 pp; weight −7.6/−9.3/−11.2 kg vs −5.7 kg; more GI AEs at higher doses; hypoglycaemia low and mainly with concomitant insulin/SU (PMID: 34170647).

SURPASS-3 (vs insulin degludec, 52 weeks)

• Investigational doses: 5/10/15 mg weekly.

• Results: Greater HbA1c and weight reductions vs basal insulin; MRI-PDFF liver-fat improved substantially (PMID: 34370970; 35238644).

SURPASS-4 (high CV risk, vs insulin glargine, 52 weeks)

• Investigational doses: 5/10/15 mg.

• Results: Superior glycaemia/weight; hypoglycaemia fewer events than insulin; HR ↑ ~2–5 bpm; gallbladder events infrequent but present (class observation) (PMID: 34706258).

SURPASS-5 (add-on to insulin glargine, 40 weeks)

• Investigational doses: 5/10/15 mg.

• Results: HbA1c up to −2.4 pp; weight −10 kg; GI AEs common, generally mild–moderate; severe hypoglycaemiauncommon (PMID: 35015057).

Obesity without diabetes (SURMOUNT program)

SURMOUNT-1 (72 weeks)

• Investigational doses: 5/10/15 mg weekly.

• Results: Mean weight change −15.0/−19.5/−20.9 % vs −3.1 % placebo; ≥5/10/15/20 % loss achieved by 85/70/56/36 % at 15 mg; GI AEs dose-related; gallbladder events low but higher than placebo (PMID: 35658024).

SURMOUNT-3 (lifestyle lead-in)

• Design: After 12-week lifestyle program yielding ≥5 % loss, 72 weeks of tirzepatide produced additional −18.4 %vs −2.5 % with placebo; ≥10 % total loss in 85 % (PMID: 37773904).

SURMOUNT-4 (withdrawal/maintenance)

• Design: 36-week open-label lead-in to −21 % loss; randomized continuation vs withdrawal for 52 weeks.

• Results: Continued therapy maintained or augmented loss; withdrawal led to regain (PMID: 37909105).

Cardiovascular outcomes

• SURPASS-CVOT (NCT04255433) compares tirzepatide to dulaglutide on MACE-3 in T2D with established CVD/high risk. A positive top-line result was communicated in late-2024; peer-reviewed results pending.

Safety & Toxicology

Class & trial-level signals

• Gastrointestinal (very common): Nausea, diarrhea, vomiting, constipation; usually dose-dependent and transientduring escalation (PMIDs: 34170647, 35658024).

• Hypoglycaemia: Low with monotherapy; risk increases with insulin or sulfonylureas (PMIDs: 35015057, 34186022).

• Heart rate: Modest HR increase (~2–5 bpm, dose-related); clinical significance Unknown; observed across incretin class (PMID: 34706258).

• Gallbladder/biliary: Events are uncommon but increased vs placebo in obesity trials—consistent with rapid weight loss and class observations; absolute risks remain low (PMID: 35658024).

• Pancreatitis: Rare; meta-analyses across incretins show no major excess risk, but case reports exist—ongoing surveillance recommended (PMID: 34558484).

• Diabetic retinopathy: Rapid HbA1c fall is a known risk factor (signal with semaglutide in SUSTAIN-6); tirzepatide-specific signal is not established; caution advised in high-risk retinopathy until more data (PMID: 34170647).

• Thyroid C-cell tumors (rodents): A class warning for long-acting incretins in rodents; human relevance unknown.

Body composition & lean mass

Analyses suggest fat-mass–predominant loss with expected proportional lean-mass decrease; ongoing trials incorporate DXA/MRI to refine phenotypes (PMIDs: 35658024, 34370970, 35238644).

Hepatic/renal

ALT and liver fat often improve; eGFR/albuminuria effects are favorable in T2D subgroups (hypothesis-generating) (PMID: 35238644).

Comparative Context

Related peptides

• Semaglutide (GLP-1RA): robust weight-loss and CV benefit (SELECT); head-to-head (SURPASS-2) showed tirzepatide superior for HbA1c and weight at 10–15 mg vs semaglutide 1 mg (PMID: 34170647).

• Dulaglutide (GLP-1RA): positive CVOT; comparator in SURPASS-CVOT (results pending).

• Retatrutide (GLP-1/GIP/glucagon): investigational triple agonist with larger early weight-loss signals; comparative mechanism differs (adds glucagon-receptor agonism).

Advantages (research perspective)

• Dual-receptor pharmacology with weekly dosing;

• Consistent superiority vs GLP-1RA or basal insulin in T2D;

• Large mean weight-loss (−15% to −21%) in obesity without diabetes (PMID: 35658024).

Disadvantages/constraints

• GI tolerability requires titration;

• HR increase and gallbladder events necessitate monitoring;

• Long-term CV/renal outcomes peer-review pending;

• Retinopathy risk with rapid glycaemic improvement remains uncertain.

Research category placement

Tirzepatide is a reference dual incretin for studying GIP/GLP-1 synergy, energy balance, hepatic fat, HFpEF/OSAphenotypes, and for comparative pharmacology vs mono- and tri-agonists.

Research Highlights

• Weekly dual incretin with ~5-day t½ and albumin-binding acylation (PMID: 34558484).

• T2D efficacy: HbA1c reductions ~−2.0 to −2.4 pp; weight −7 to −12 kg across 40–52 weeks (PMIDs: 34186022, 34170647, 34370970, 34706258, 35015057).

• Obesity efficacy (no diabetes): −15% to −21% mean loss at 72 weeks; maintenance depends on continued therapy (PMIDs: 35658024, 37909105).

• Liver fat: MRI-PDFF reductions aligned with metabolic improvements (PMID: 35238644).

• Safety: GI AEs, HR ↑, gallbladder events low but present; pancreatitis rare; retinopathy signal uncertain (PMIDs: 34170647, 35658024).

Conflicting/uncertain evidence.

• Energy expenditure change vs intake reduction—not fully resolved;

• Retinopathy and long-term CV/renal outcomes—await peer-reviewed CVOT;

• Comparative tolerability at equipotent weight loss vs high-dose GLP-1RA—mixed.

Potential Research Applications (no clinical claims; research-use framing)

1. Mechanistic dissection of GIPR/GLP-1R synergy

   • Use biased-agonism assays (β-arrestin vs cAMP) in β-cells, adipocytes, hypothalamic neurons; CRISPR knockout of GIPR or GLP-1R to parse relative contributions (PMID: 34558484).

2. Energy-balance physiology

   • Whole-room calorimetry and indirect calorimetry under tirzepatide vs GLP-1RA to quantify REE and RERchanges; pair with intragastric barostat and CNS fMRI food-cue paradigms.

3. Hepato-metabolic implications

   • Controlled MRI-PDFF/MRE studies to link liver-fat reduction with lipidomics/transcriptomics; randomized comparisons vs pioglitazone/GLP-1RA in NAFLD-T2D phenotypes (PMID: 35238644).

4. Cardio-renal axes

   • HFpEF and CKD mechanistic trials with echo, CPET, and albuminuria endpoints to clarify beyond-glycaemia/weight benefits; integrate inflammatory and fibrosis biomarkers.

5. Long-term weight-maintenance models

   • Evaluate dose-cycling, combination with lifestyle/adjuncts, and behavioral reinforcement to minimize regain post-loss (PMID: 37909105).

Safety & Toxicology (expanded)

• GI tolerability: Gradual dose escalation reduces nausea/vomiting; antiemetic needs are typically low, but discontinuation rises at 15 mg when titration is rapid (PMIDs: 34170647, 35658024).

• Gallbladder: Monitor in rapid weight-loss phases; absolute rates low but higher than placebo in SURMOUNT-1 (PMID: 35658024).

• Pancreas: Rare acute pancreatitis events across incretin class; causality not established—maintain pharmacovigilance (PMID: 34558484).

• Retina: Early DR worsening with rapid A1c fall is a known phenomenon; tirzepatide RCTs have not shown a clear signal, but high-risk individuals warrant surveillance (PMID: 34170647).

• HR/BP: HR ↑ modestly; BP tends to fall with weight loss; clinical significance of HR change unknown (PMID: 34706258).

• Neoplasia: Rodent C-cell tumors are a class label; human relevance unknown.

Limitations & Controversies

• Durability: Weight-loss maintenance requires continued exposure (PMID: 37909105).

• Mechanistic ambiguity: The precise GIPR contribution—satiety vs adipose-metabolic effects—remains debated (PMID: 34558484).

• Outcome data: Definitive CV/renal benefits await peer-review from CVOT; cross-trial comparisons must be cautious.

• Equivalence vs high-dose GLP-1RA: Direct comparisons vs higher-dose semaglutide (e.g., 2.4 mg) in obesity are indirect; ongoing studies will clarify.

Future Directions

• Publish SURPASS-CVOT results and embed phenotyping (OSA, HFpEF, CKD) in post-hoc analyses.

• Head-to-head obesity efficacy and tolerability vs high-dose GLP-1RA; dose-response curves to define best-tolerated regimens.

• Combination pharmacology (e.g., tirzepatide + SGLT2 inhibitor or metformin) for cardio-renal endpoints.

• NASH trials with histology to translate MRI-PDFF signals to fibrosis outcomes.

• Mechanistic imaging (PET/fMRI) to parse satiety circuits and reward adaptation over long horizons.

References

Design, PK and reviews

• Brown E, Cuthbertson DJ, Wilding JPH. Newer GLP-1 receptor agonists and GIP/GLP-1 co-agonist tirzepatide in T2D and obesity. Diabetes Obes Metab. 2021;23(7):1682-1691. PMID: 34558484.

• Urva S, et al. Population PK of tirzepatide. Clin Pharmacokinet. 2021. PMID: 34132401.

T2D SURPASS trials

• Ludvik B, et al. SURPASS-1: tirzepatide monotherapy vs placebo. Lancet. 2021;398:143-155. PMID: 34186022.

• Frías JP, et al. SURPASS-2: tirzepatide vs semaglutide 1 mg. N Engl J Med. 2021;385:503-515. PMID: 34170647.

• Del Prato S, et al. SURPASS-3: vs insulin degludec; MRI-PDFF substudy. Lancet. 2021;398:583-598. PMID: 34370970; MRI liver-fat substudy: Lancet Diabetes Endocrinol. 2022;10: (PMID: 35238644).

• Del Prato S, et al. SURPASS-4: high CV risk, vs glargine. Lancet. 2021;398:1811-1824. PMID: 34706258.

• Dahl D, et al. SURPASS-5: add-on to insulin glargine. JAMA. 2022;327:534-545. PMID: 35015057.

Obesity SURMOUNT trials

• Jastreboff AM, et al. SURMOUNT-1: obesity without diabetes. N Engl J Med. 2022;387:205-216. PMID: 35658024.

• Garvey WT, et al. SURMOUNT-3. JAMA. 2023;330(17): (−18.4 % additional loss). PMID: 37773904.

• Rubino D, et al. SURMOUNT-4. JAMA. 2023;330(22): (maintenance vs withdrawal). PMID: 37909105.

Registry/outcomes

• SURPASS-CVOT: ClinicalTrials.gov NCT04255433.

• Ongoing obesity/CV/renal programs listed in ClinicalTrials.gov (accessed 2025).

Mechanism and ancillary topics

• Nauck MA, Meier JJ. Incretin therapies: GIP revisited. Lancet Diabetes Endocrinol. 2019. (background on GIP physiology).

• Safety synthesis across incretins (pancreas, gallbladder, HR): see review PMID: 34558484 and individual SURPASS/SURMOUNT RCTs above.

Illustrative investigational doses used in cited studies:
• T2D (SURPASS-1/2/3/4/5): 5, 10, 15 mg once weekly SC for 40–52 weeks.
• Obesity (SURMOUNT-1): 5, 10, 15 mg once weekly SC for 72 weeks.
• Lifestyle-lead-in/maintenance (SURMOUNT-3/4): 10–15 mg once weekly SC during double-blind phases.

⚠️ Disclaimer This peptide is intended strictly for laboratory research use. It is not FDA-approved or authorized for human use, consumption, or therapeutic application.