Evidence reference only. Not medical advice, not a dosing guide, and not a recommendation to use any drug.
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Tirzepatide

MARKETED

GIP/GLP-1 dual agonist

87
graded findings
20
effect domains
Evidence spread
High evidence 37Moderate evidence 27Low evidence 15Very low evidence 8

Tirzepatide is shown as a marketed evidence record where applicable. Findings describe observed research and regulatory records; they do not provide treatment advice.

Tirzepatide MARKETED
Pharmacology and mechanism Mixed
High evidence

RECORDED OBSERVATION (why explicitly open): Two clinically active obesity agents act in OPPOSITE directions on the GIP receptor yet both produce substantial weight...

Juxtaposition of SURMOUNT-1 (NEJM 2022) and MariTide phase 2 (ADA 2025); see also LY35370... Source
Full findingRECORDED OBSERVATION (why explicitly open): Two clinically active obesity agents act in OPPOSITE directions on the GIP receptor yet both produce substantial weight loss atop GLP-1 activity. Tirzepatide AGONISES GIP (plus GLP-1) and delivers ~22.5% weight loss (SURMOUNT-1); MariTide ANTAGONISES GIP (plus GLP-1 agonism) and delivers ~20% weight loss (phase 2). Separately, the selective GIP agonist LY3537021 reduces weight with GIP agonism alone. These findings stand side by side; the mechanism is not adjudicated.
PopulationCross-trial juxtaposition: SURMOUNT-1 (tirzepatide, N=2539, 72 wk) vs MariTide phase 2 (N=592, 52 wk); not head-to-head
Fundingindustry - Eli Lilly (SURMOUNT-1; disclosed)
Scope limitsconference/abstract-level
Comparatorsplacebo
Tirzepatide MARKETED
Pharmacology and mechanism Not directional
High evidence

Tirzepatide is injected subcutaneously once weekly into the abdomen, thigh or upper arm with site rotation, at any time of day with or without meals, and into a...

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
Full findingTirzepatide is injected subcutaneously once weekly into the abdomen, thigh or upper arm with site rotation, at any time of day with or without meals, and into a different site from any insulin.
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
Pharmacology and mechanism Not directional
High evidence

A missed tirzepatide dose may be taken within 4 days (96 h); otherwise skip it. The dosing day may be changed if at least 3 days separate doses.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
Pharmacology and mechanism Not directional
High evidence

Tirzepatide delays gastric emptying and may alter absorption of co-administered oral drugs; the EU SmPC advises monitoring narrow-therapeutic-index drugs (e.g....

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
Full findingTirzepatide delays gastric emptying and may alter absorption of co-administered oral drugs; the EU SmPC advises monitoring narrow-therapeutic-index drugs (e.g. warfarin, digoxin), and in vitro it shows low potential to inhibit/induce CYP enzymes.
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
Pharmacology and mechanism Not directional
High evidence

Co-administration of tirzepatide with another tirzepatide-containing product or any GLP-1 receptor agonist is not recommended.

Zepbound (tirzepatide) US Prescribing Information, Eli Lilly Source
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
Tirzepatide MARKETED
Pharmacology and mechanism Not directional
High evidence

When tirzepatide is combined with insulin or a sulfonylurea, reducing the secretagogue/insulin dose (stepwise for insulin) lowers hypoglycaemia risk.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
Pharmacology and mechanism Not directional
High evidence

A first tirzepatide (Zepbound) dose transiently reduced paracetamol/acetaminophen peak concentration by ~55% and delayed tmax, resolving by week 6 on continued dosing;...

Zepbound (tirzepatide) US Prescribing Information, Eli Lilly Source
Full findingA first tirzepatide (Zepbound) dose transiently reduced paracetamol/acetaminophen peak concentration by ~55% and delayed tmax, resolving by week 6 on continued dosing; overall exposure (AUC) unchanged - a rate-of-absorption effect.
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
Tirzepatide MARKETED
Pharmacology and mechanism Not directional
High evidence

Zepbound maintenance dosing differs by indication, with obstructive sleep apnoea requiring 10 mg or 15 mg once weekly.

Zepbound (tirzepatide) US Prescribing Information, Eli Lilly Source
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
Tirzepatide MARKETED
Pharmacology and mechanism Not directional
High evidence

Tirzepatide starts at 2.5 mg once weekly, increases to 5 mg after 4 weeks, then in 2.5 mg steps at no less than 4-week intervals up to a 15 mg maximum (10 mg max in...

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
Full findingTirzepatide starts at 2.5 mg once weekly, increases to 5 mg after 4 weeks, then in 2.5 mg steps at no less than 4-week intervals up to a 15 mg maximum (10 mg max in paediatric patients).
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
Pharmacology and mechanism Not directional
High evidence

The absolute bioavailability of subcutaneous tirzepatide is 80%.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
Pharmacology and mechanism Not directional
High evidence

Tirzepatide metabolites are excreted via urine and faeces, with no intact tirzepatide observed in urine or faeces.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
Pharmacology and mechanism Not directional
High evidence

Tirzepatide has an elimination half-life of about 5 days (5-6 days for Zepbound populations), the basis for once-weekly dosing.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
Pharmacology and mechanism Not directional
High evidence

Tirzepatide is cleared by metabolism via proteolytic cleavage of the peptide backbone, beta-oxidation of its C20 fatty diacid and amide hydrolysis.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
Pharmacology and mechanism Not directional
High evidence

Steady-state tirzepatide concentrations are reached after about 4 weeks of once-weekly dosing.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
Pharmacology and mechanism Not directional
High evidence

Tirzepatide has a small apparent steady-state volume of distribution (~10 L) and is ~99% albumin-bound.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
Pharmacology and mechanism Decrease
High evidence

Tirzepatide is a once-weekly subcutaneous dual agonist of the GIP and GLP-1 receptors (39-amino-acid acylated peptide). Marketed (Mounjaro for T2D; Zepbound for...

Juxtaposition of SURMOUNT-1 (NEJM 2022) and MariTide phase 2 (ADA 2025); see also LY35370... Source
Full findingTirzepatide is a once-weekly subcutaneous dual agonist of the GIP and GLP-1 receptors (39-amino-acid acylated peptide). Marketed (Mounjaro for T2D; Zepbound for obesity). In SURMOUNT-1 (obesity, no diabetes) mean weight reduction at 72 weeks was 16.0/21.4/22.5% at 5/10/15 mg vs 2.4% placebo. In SURPASS-2 (T2D, head-to-head vs semaglutide 1 mg) HbA1c fell 2.01/2.24/2.30% vs 1.86% semaglutide at 40 weeks, with superior weight loss.
PopulationSURMOUNT-1: N=2539 adults obesity/overweight + comorbidity, no T2D, 72 wk, vs placebo. SURPASS-2: T2D, BMI >=25, HbA1c 7-10.5%, 40 wk, vs semaglutide 1 mg s.c.
Fundingindustry - Eli Lilly (SURMOUNT-1; disclosed)
Scope limitsconference/abstract-level
Comparatorsplacebo; semaglutide
Tirzepatide MARKETED
Pharmacology and mechanism Not directional
Moderate evidence

Dose-headroom confound (competing hypothesis): the FDA Mounjaro Clinical Pharmacology FG/HbA1c Emax model shows tirzepatide's marketed doses reach only 74-89% of the...

FDA Mounjaro NDA 215866 Clinical Pharmacology Review, Reference ID 4954959 (FG/HbA1c Emax... Source
Full findingDose-headroom confound (competing hypothesis): the FDA Mounjaro Clinical Pharmacology FG/HbA1c Emax model shows tirzepatide's marketed doses reach only 74-89% of the maximal effect on FASTING GLUCOSE, with EMA reporting effect still increasing at the highest doses tested. CRITICAL: this is a FASTING-GLUCOSE Emax, NOT weight-loss headroom - it must not be read as the dual being undertitrated for weight loss. Part of any dual-to-triple efficacy gap could be exposure-response position rather than the glucagon mechanism, so it must be controlled before assigning a retatrutide-over-tirzepatide gap to the glucagon arm.
PopulationType-2-diabetes exposure-response popPK/PD model (FDA Mounjaro NDA 215866 ClinPharm FG-HbA1c PK/PD model, p.65-66; EMA Mounjaro EPAR)
Fundingindustry - Eli Lilly (applicant/manufacturer; FDA Clinical Pharmacology review of Lilly's NDA 215866 submission)
Scope limitssponsor-derived popPK/PD model output; fasting-glucose Emax, not a weight-loss exposure-response
Comparatorsmarketed-dose vs modelled Emax
Tirzepatide MARKETED
Pharmacology and mechanism Not directional
Low evidence

FDA Zepbound Clinical Pharmacology review characterises tirzepatide as having GIPR activity similar to native GIP but GLP-1R activity lower than native GLP-1, and as a...

FDA Zepbound NDA 217806 Clinical Pharmacology Review, Reference ID 5258712 Source
Full findingFDA Zepbound Clinical Pharmacology review characterises tirzepatide as having GIPR activity similar to native GIP but GLP-1R activity lower than native GLP-1, and as a biased GLP-1R agonist favouring cAMP over beta-arrestin (in-vitro human Ki GIPR 4.02 nM vs GLP-1R 378 nM). This establishes WHICH arms are engaged; it must NOT be read as a quantitative weight-loss apportionment (the sign of the GIPR contribution is itself unsettled).
PopulationIn-vitro human receptor binding/signalling assays (FDA Zepbound NDA 217806 ClinPharm, Sec 3.2 General Pharmacology, Table 3)
Fundingindustry - Eli Lilly (applicant/manufacturer; FDA Clinical Pharmacology review of Lilly's NDA 217806 submission)
Scope limitsin-vitro receptor assay; human relevance via pharmacology only
Comparatorsnative GIP; native GLP-1
Tirzepatide MARKETED
Pharmacology and mechanism No change
Very low evidence

The EMA Mounjaro EPAR quantifies tirzepatide's potency at the human glucagon receptor (GCGR) as a cAMP functional EC50 of ~2350 nM - some three orders of magnitude...

FDA Mounjaro NDA 215866 Pharmacology/Toxicology Review, Reference ID 4953686 (reviewer Br... Source
Full findingThe EMA Mounjaro EPAR quantifies tirzepatide's potency at the human glucagon receptor (GCGR) as a cAMP functional EC50 of ~2350 nM - some three orders of magnitude weaker than its GIP/GLP-1 receptor potency - i.e. minimal-to-no glucagon-receptor agonism at therapeutic exposure. The FDA NDA 215866 Pharm/Tox review states the same qualitatively. This is the tirzepatide GCGR-silence half of the receptor-level glucagon-by-elimination argument (the semaglutide GCGR-negative half is C-SEMA-REG-GCGR-NEGATIVE-01): both characterised dual/mono comparators carry no meaningful glucagon-receptor activity, so the glucagon arm is the sole added pharmacology in retatrutide. Arm-elimination only - this establishes which receptor differs, NOT how much of any weight-loss difference is apportionable to glucagon agonism.
Populationin-vitro human glucagon-receptor (GCGR) cAMP functional assay (EMA Mounjaro EPAR EMEA/H/C/005620; FDA NDA 215866 Pharm/Tox cross-confirm)
Fundingindustry - Eli Lilly (applicant/manufacturer; FDA Pharm/Tox review of Lilly's NDA 215866 submission)
Scope limitsanimal data; human relevance uncertain
Comparatorshuman GIP receptor; human GLP-1 receptor
Tirzepatide MARKETED
Safety signals Not directional
High evidence

Tirzepatide is contraindicated in the US for personal/family history of MTC or MEN 2 (also a boxed warning) and serious hypersensitivity; the EU contraindication is...

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
Full findingTirzepatide is contraindicated in the US for personal/family history of MTC or MEN 2 (also a boxed warning) and serious hypersensitivity; the EU contraindication is hypersensitivity only.
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
Safety signals Not directional
High evidence

About half of Mounjaro-treated patients developed anti-tirzepatide antibodies, with low neutralising-antibody rates and no identified clinical impact.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
Safety signals Not directional
High evidence

In Zepbound trials the majority of patients developed anti-tirzepatide antibodies; neutralising antibodies were uncommon in the weight-management pool (2.7-2.8%) and...

Zepbound (tirzepatide) US Prescribing Information, Eli Lilly Source
Full findingIn Zepbound trials the majority of patients developed anti-tirzepatide antibodies; neutralising antibodies were uncommon in the weight-management pool (2.7-2.8%) and none were detected in the OSA pool; no clinically significant PK/efficacy effect.
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
Tirzepatide MARKETED
Safety signals Decrease
High evidence

Tirzepatide may reduce ORAL hormonal contraceptive efficacy via delayed gastric emptying; US labelling advises switching to a non-oral method or adding a barrier...

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
Full findingTirzepatide may reduce ORAL hormonal contraceptive efficacy via delayed gastric emptying; US labelling advises switching to a non-oral method or adding a barrier method for 4 weeks after initiation and after each dose escalation.
PopulationRegulatory label (FDA Mounjaro/Zepbound PI; EU SmPC); PK interaction basis
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
Safety signals Increase
High evidence

FDA boxed warning: in a 2-year rat study tirzepatide caused dose- and treatment-duration-dependent thyroid C-cell tumours at clinically relevant exposures;...

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
Full findingFDA boxed warning: in a 2-year rat study tirzepatide caused dose- and treatment-duration-dependent thyroid C-cell tumours at clinically relevant exposures; contraindicated with personal/family history of MTC or MEN 2. Human relevance not determined.
Population2-year rat carcinogenicity study; regulatory label
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Comparatorsvehicle control
Tirzepatide MARKETED
Safety signals Mixed
Moderate evidence

In a CV-outcomes meta-analysis, GLP-1 RAs increased gallbladder disorders by 26% but showed no difference in pancreatitis or neoplasm.

Galli M et al., J Am Coll Cardiol 2025 Source
Population21 RCTs, 99,599 patients, mean follow-up 2.4 yr; meta-analysis
Fundingacademic / independent - no industry sponsor (investigator grant: Sapienza University of Rome)
Scope limitsNull pole for pancreatitis/neoplasm; gallbladder concordant with class signal.
Comparatorsplacebo; controls
Tirzepatide MARKETED
Safety signals Mixed
Moderate evidence

Composite gallbladder/biliary disease significantly associated with tirzepatide; pancreatitis and individual biliary endpoints NOT significantly increased.

Zeng Q et al., Front Endocrinol 2023 Source
Population9 RCTs, 9871 participants (T2D and obesity); meta-analysis
Fundingacademic / government - Sichuan Science and Technology Program (China); no industry funding
Scope limitsBoth poles: composite biliary signal present, pancreatitis null.
Comparatorsplacebo; basal insulin; dulaglutide; semaglutide
Tirzepatide MARKETED
Safety signals No change
Moderate evidence

Post hoc pooled analysis of SURMOUNT-1/-2/-3 (RCT data): no clinically meaningful PHQ-9 difference vs placebo over 72 weeks; suicidal ideation/behaviour (C-SSRS) low...

Wadden TA et al., 'Psychiatric Safety of Tirzepatide... Post Hoc Analysis of SURMOUNT'. O... Source
Full findingPost hoc pooled analysis of SURMOUNT-1/-2/-3 (RCT data): no clinically meaningful PHQ-9 difference vs placebo over 72 weeks; suicidal ideation/behaviour (C-SSRS) low and similar, though a numerically greater percentage of tirzepatide participants reported moderate-risk ideation.
PopulationPooled SURMOUNT-1/-2/-3, obesity, no known major psychopathology; 72 weeks; placebo-controlled RCTs
Fundingindustry-Eli Lilly
Scope limitsRCT-level no-signal pole. The numerically-greater moderate-risk SI on tirzepatide recorded as the emerging caveat, neither amplified nor suppressed.
Comparatorsplacebo
Tirzepatide MARKETED
Safety signals Decrease
Moderate evidence

In a network meta-analysis, tirzepatide produced the greatest reduction in both fat mass and (absolute) lean body mass.

Rakhsha SS et al., Diabetes Obes Metab 2026 Source
PopulationNetwork meta-analysis, 41 RCTs, 2906 participants, through Mar 2025
Fundingacademic - Tehran University of Medical Sciences (Chronic Diseases Research Center; grant 1403-04-75722-221); no industry sponsor
Scope limitsLargest LBM reduction of class, proportionate to larger total weight loss. Exercise reported to mitigate.
Comparatorsplacebo; semaglutide; liraglutide; SGLT2i; metformin; insulin; DPP-4i
Tirzepatide MARKETED
Safety signals Increase
Moderate evidence

Withdrawing tirzepatide after a 36-week lead-in led to substantial weight REGAIN, whereas continued treatment maintained/augmented loss (randomized-withdrawal design).

Aronne LJ et al., JAMA 2024 (SURMOUNT-4) Source
PopulationSURMOUNT-4 (NCT04660643), phase 3 randomized-withdrawal, 670 adults with obesity/overweight (no diabetes), 52-wk double-blind after open-label lead-in
Fundingindustry-Eli Lilly
Scope limitsopen-label (unblinded)
Comparatorsplacebo (withdrawal)
Tirzepatide MARKETED
Safety signals Decrease
Moderate evidence

In a post hoc analysis of the SURMOUNT-1 obesity RCT, tirzepatide lowered serum uric acid dose-dependently versus placebo over 72 weeks, with the effect independent of...

Sattar N et al. Tirzepatide and change in uric acid and its association with weight reduc... Source
Full findingIn a post hoc analysis of the SURMOUNT-1 obesity RCT, tirzepatide lowered serum uric acid dose-dependently versus placebo over 72 weeks, with the effect independent of baseline uric-acid level or BMI.
PopulationTirzepatide phase-3 obesity RCT post hoc (Sattar et al., SURMOUNT-1, NCT04184622); 2,539 adults with obesity/overweight + >=1 weight-related complication.
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsPost hoc (not a prespecified gout/urate endpoint); biochemical surrogate (SUA), not a clinical gout outcome. Lilly-sponsored trial. The drop is real and dose-dependent but - see C-TIRZ-URATE-02 - largely weight-mediated.
Comparatorsplacebo
Tirzepatide MARKETED
Safety signals Decrease
Moderate evidence

A mediation analysis in the same SURMOUNT-1 post hoc found that about 73% of tirzepatide's serum-uric-acid reduction was explained by weight loss - implicating weight...

Sattar N et al. Tirzepatide and change in uric acid and its association with weight reduc... Source
Full findingA mediation analysis in the same SURMOUNT-1 post hoc found that about 73% of tirzepatide's serum-uric-acid reduction was explained by weight loss - implicating weight loss rather than a direct uricosuric drug effect.
PopulationTirzepatide phase-3 obesity RCT post hoc (Sattar et al., SURMOUNT-1, NCT04184622); mediation analysis of weight change vs SUA change.
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsASSOCIATIONAL mediation, NOT a designed causal endpoint - the 72.7% weight-mediated figure is a model decomposition, not a randomised mechanistic test. Confounded with all weight-loss-correlated changes. Supports the weight-mediated (not direct-uricosuric) reading of the class.
Comparatorsplacebo
Tirzepatide MARKETED
Safety signals Increase
Low evidence

Real-world data associate tirzepatide with higher osteoporosis/fragility-fracture risk than other GLP-1 RAs - a greatest-weight-loss/dual-agonist signal.

Tirzepatide and osteoporosis/fragility fracture (TriNetX cohort), Diabetes Res Clin Pract... Source
PopulationPeer-reviewed primary (women's-health wave)
Fundingacademic / investigator (not separately extracted)
Scope limitsSHORT 14-month window (too short for fragility-fracture accrual) - hypothesis-generating; coding-based outcomes; weight-loss magnitude the likely mediator; residual confounding. Larger than any RCT signal - do not over-read.
Tirzepatide MARKETED
Safety signals Increase
Low evidence

Anaesthesia narrative reviews: GLP-1 RAs and tirzepatide delay gastric emptying and raise aspiration considerations; data preliminary/conflicting; gastric ultrasound...

Doroba O et al., Anaesthesiol Intensive Ther 2025; Kwak HJ et al., Korean J Anesthesiol 2026 Source
Full findingAnaesthesia narrative reviews: GLP-1 RAs and tirzepatide delay gastric emptying and raise aspiration considerations; data preliminary/conflicting; gastric ultrasound recommended; guidance is multi-society expert consensus.
PopulationNarrative reviews of peri-operative management of novel antidiabetic/anti-obesity drugs
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsKwak 2026 also flags a 'misidentification trap' (AOM adverse effects mistaken for surgical/anaesthetic complications), citing semaglutide NAION HR 7.64 and a WHO 2025 alert. Two DOIs bundled.
ComparatorsSGLT2 inhibitors (contrast)
Tirzepatide MARKETED
Safety signals No change
Low evidence

Tirzepatide has no established link to elevated ferritin per trial data and the SmPC, and no known direct effect on iron metabolism; elevated ferritin observed in...

Urbina et al., GLP-1 receptor agonists and iron status, Clin Obes 2026;16:e70070 Source
Full findingTirzepatide has no established link to elevated ferritin per trial data and the SmPC, and no known direct effect on iron metabolism; elevated ferritin observed in users reflects underlying metabolic, inflammatory or liver disease (ferritin as an acute-phase reactant), not a drug effect.
PopulationSynthesised from the Urbina narrative review plus non-measurement of iron in SURPASS/SURMOUNT; tirzepatide iron metabolism not directly studied.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsMedium confidence; rests partly on a low-quality commercial pharmacy page plus non-measurement of iron in the SURPASS/SURMOUNT programmes. NO commercial/press source minted; anchored as a secondary finding on the Urbina review.
Comparatorsnot applicable
Tirzepatide MARKETED
special-populations Not directional
High evidence

The EU SmPC states tirzepatide could be considered for use during breast-feeding.

Mounjaro (tirzepatide) EU Summary of Product Characteristics (EMA) Source
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
Tirzepatide MARKETED
special-populations Not directional
High evidence

A human lactation study (n=11) after a single 5 mg dose found tirzepatide largely undetectable in breast milk (cumulative <0.02% of the maternal dose); US labels make...

Zepbound (tirzepatide) US Prescribing Information, Eli Lilly Source
Full findingA human lactation study (n=11) after a single 5 mg dose found tirzepatide largely undetectable in breast milk (cumulative <0.02% of the maternal dose); US labels make no clinical-impact statement.
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate
Tirzepatide MARKETED
special-populations Increase
High evidence

Animal reproduction studies show malformations and growth reductions in rat and rabbit at sub-clinical exposures; the label states human data are insufficient, and for...

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
Full findingAnimal reproduction studies show malformations and growth reductions in rat and rabbit at sub-clinical exposures; the label states human data are insufficient, and for weight management (Zepbound) to discontinue when pregnancy is recognised.
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
special-populations Not directional
High evidence

No overall differences in safety or efficacy were detected in elderly patients, with limited data above 75 years.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
special-populations Not directional
High evidence

US labelling specifies no dose adjustment for hepatic impairment (no PK change across degrees of impairment).

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
special-populations Not directional
High evidence

Paediatric status differs by product/region: the US Mounjaro label establishes use in T2D from age 10 (with higher vomiting/abdominal pain/hypoglycaemia than adults);...

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
Full findingPaediatric status differs by product/region: the US Mounjaro label establishes use in T2D from age 10 (with higher vomiting/abdominal pain/hypoglycaemia than adults); Zepbound is not established in children, and the EU has not established use under 18.
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
special-populations Not directional
High evidence

US labelling specifies no dose adjustment for renal impairment including ESRD, with advice to monitor renal function when initiating/escalating in patients with severe...

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source
Full findingUS labelling specifies no dose adjustment for renal impairment including ESRD, with advice to monitor renal function when initiating/escalating in patients with severe GI adverse reactions.
PopulationRegulatory label / SmPC (primary document)
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitsanimal data; human relevance uncertain
Tirzepatide MARKETED
special-populations Decrease
Moderate evidence

A single small phase-2 RCT (n=24, 12 weeks) found tirzepatide added to insulin in obese type-1 diabetes produced large weight loss (-8.7kg, 8.8%), a borderline HbA1c...

Snaith JR, Frampton R, Samocha-Bonet D, Greenfield JR. Tirzepatide in Adults With Type 1 ... Source
Full findingA single small phase-2 RCT (n=24, 12 weeks) found tirzepatide added to insulin in obese type-1 diabetes produced large weight loss (-8.7kg, 8.8%), a borderline HbA1c reduction, and a 35% cut in insulin dose, with no significant adverse events - promising but very preliminary.
PopulationTirzepatide phase-2 double-blind placebo-controlled T1D RCT (Snaith et al., TIRTLE1, single-centre, 12wk, n=24 [22 completed], T1D + BMI>30, Garvan Institute; PMC12719702).
Fundingacademic/charity (Garvan Institute sponsor; Breakthrough T1D/JDRF, UNSW, Australian Diabetes Society)
Scope limitssmall sample (N=24); single-centre; short duration (12wk); weight-primary (not glycaemic/safety-powered)
Comparatorsplacebo (insulin background)
Tirzepatide MARKETED
special-populations Increase
Low evidence

In obese men with metabolic hypogonadism, tirzepatide improved erectile function and raised testosterone, outperforming testosterone replacement on axis recovery.

Tirzepatide on erectile function and hypogonadism (controlled non-randomised pilot, n=83)... Source
PopulationPeer-reviewed primary (women's-health wave)
Fundingacademic / investigator (not separately extracted)
Scope limitsWEIGHT/TESTOSTERONE-CONFOUNDED and NON-randomised with baseline imbalances and self-report IIEF-5 - NOT a demonstrated direct drug effect; contradicted by the null RCT/infusion data. Graded low (non-randomised; not high).
Tirzepatide MARKETED
special-populations Decrease
Low evidence

Tirzepatide was associated with lower incident erectile dysfunction than several comparators in T2D men.

Tirzepatide and incident erectile dysfunction (TriNetX cohort), J Diabetes Complications ... Source
PopulationPeer-reviewed primary (women's-health wave)
Fundingacademic / investigator (not separately extracted)
Scope limitsRelative-to-comparator (not vs placebo); confounded by indication/weight; coding-based outcome. Weight/testosterone-mediated, consistent with the other male signals.
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
Tirzepatide MARKETED
Energy expenditure and thermogenesis Increase
Low evidence

In premenopausal women with obesity, 24 weeks of tirzepatide increased the proportion of participants with cold-stimulated PET/CT-detectable brown adipose tissue (BAT)...

Herman R et al., TABFAT trial, presented at ENDO 2026 (Endocrine Society annual meeting),... Source
Full findingIn premenopausal women with obesity, 24 weeks of tirzepatide increased the proportion of participants with cold-stimulated PET/CT-detectable brown adipose tissue (BAT) activity from 41.2% to 64.7%, with no comparable change in the placebo group; cold-stimulated BAT activity and volume also increased (absolute changes greater vs placebo). MRI assessment was consistent with FDG-PET/CT. Signs of white subcutaneous fat converting to 'beige' fat were also reported.
PopulationTABFAT trial; N=34 premenopausal women with obesity, median age 39 y, median BMI 36.9 kg/m2; randomised 1:1 tirzepatide vs placebo; 24 weeks; cold-stimulated 18F-FDG-PET/CT, MRI, infrared thermography
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsno outcome data yet (ongoing); small sample (N~34)
Comparatorsplacebo
Tirzepatide MARKETED
Energy expenditure and thermogenesis Mixed
Low evidence

Phase 1 human study with whole-room indirect calorimetry: tirzepatide did NOT attenuate weight-loss-induced metabolic adaptation (no detectable preservation of...

Ravussin E, Sanchez-Delgado G, Martin CK, et al. Tirzepatide did not impact metabolic ada... Source
Full findingPhase 1 human study with whole-room indirect calorimetry: tirzepatide did NOT attenuate weight-loss-induced metabolic adaptation (no detectable preservation of sleeping or 24-h energy expenditure) but DID increase fat oxidation (reduced respiratory exchange ratio) vs placebo, alongside reduced appetite and ad libitum calorie intake. In the paired preclinical study (calorie-restricted obese mice), tirzepatide reduced the drop in energy expenditure seen in vehicle/pair-fed mice (i.e. attenuated metabolic adaptation) and lowered RER.
PopulationPhase 1 RCT in people with obesity (NCT04081337) plus preclinical calorie-restricted obese mice with pair-fed control
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsanimal data; human relevance uncertain
Comparatorsplacebo; pair-fed control (mice)
Tirzepatide MARKETED
Energy expenditure and thermogenesis Increase
Very low evidence

FDA Mounjaro Pharm/Tox review (rodent lead): in diet-induced-obese mice tirzepatide raised metabolic rate more than semaglutide and, at pair-fed/body-weight-matched...

FDA Mounjaro NDA 215866 Pharmacology/Toxicology Review, Reference ID 4953686 (reviewer Br... Source
Full findingFDA Mounjaro Pharm/Tox review (rodent lead): in diet-induced-obese mice tirzepatide raised metabolic rate more than semaglutide and, at pair-fed/body-weight-matched doses, still produced greater glucose infusion rate and tissue glucose uptake - an intake-independent metabolic component. This is a RODENT mechanistic lead in the GIP arm, NOT the glucagon arm, and does NOT translate to a human intake-independent energy-expenditure claim (22C cold-stress EE inflation; poor mouse-GIPR translation; contradicted by human RMR/TEE).
PopulationDIO mice (FDA NDA 215866 Pharm/Tox in-vivo studies, Figs 3,4,7); standard ~22C housing; pair-fed / body-weight-matched comparisons
Fundingindustry - Eli Lilly (applicant/manufacturer; FDA Pharm/Tox review of Lilly's NDA 215866 submission)
Scope limitsanimal data; human relevance uncertain
Comparatorssemaglutide; pair-fed control
Tirzepatide MARKETED
Energy expenditure and thermogenesis Not directional
Very low evidence

Design/rationale paper for the TABFAT trial: investigator-initiated RCT evaluating tirzepatide effects on BAT volume/activity (18F-FDG-PET/CT, MRI, infrared...

Herman R, Jensterle M, Horvat S, et al. Effect of tirzepatide-induced weight loss on adip... Source
Full findingDesign/rationale paper for the TABFAT trial: investigator-initiated RCT evaluating tirzepatide effects on BAT volume/activity (18F-FDG-PET/CT, MRI, infrared thermography) and WAT browning (subcutaneous adipose mRNA expression and histomorphometry) in premenopausal women with obesity, with whole-body composition and resting energy expenditure as secondary outcomes.
PopulationProtocol; 34 premenopausal women with obesity; registered ClinicalTrials.gov 2025-03-25
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsProtocol/design paper (PMC12374325, open access). Per PubMed. The results were presented at ENDO 2026 (C-TIRZEPATIDE-EE-01).
Comparatorsplacebo
Tirzepatide MARKETED
Energy expenditure and thermogenesis Increase
Very low evidence

In high-fat-diet obese mice with a pair-fed control arm, tirzepatide exerted distinct effects on brown adipose tissue relative to white: significantly boosting BAT...

Mestres-Arenas A, Quesada-Lopez T, Blasco-Roset A, Giralt M, Villarroya F, Planavila A, P... Source
Full findingIn high-fat-diet obese mice with a pair-fed control arm, tirzepatide exerted distinct effects on brown adipose tissue relative to white: significantly boosting BAT thermogenic activity and upregulating genes linked to thermogenesis and substrate oxidation, while white adipose tissue was primarily affected in lipid metabolism. These BAT effects were specific to tirzepatide and NOT attributable to reduced food intake (pair-fed mice did not show them).
PopulationHFD-induced obese mice; tirzepatide vs pair-fed control (matched body-weight loss)
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsanimal data; human relevance uncertain
Comparatorspair-fed control
Tirzepatide MARKETED
Energy expenditure and thermogenesis Increase
Very low evidence

In HFD-obese mice and in 3T3-L1 adipocytes, tirzepatide promoted browning of white adipose tissue via the cAMP-PGC-1alpha-UCP1 signalling axis, reducing intracellular...

Sun Y, Xia Y, Ge W, Li Q. Tirzepatide reduces intracellular lipid content by promoting th... Source
Full findingIn HFD-obese mice and in 3T3-L1 adipocytes, tirzepatide promoted browning of white adipose tissue via the cAMP-PGC-1alpha-UCP1 signalling axis, reducing intracellular lipid droplet accumulation. Increased browning markers (PGC-1alpha, UCP1) were confirmed in vivo; in vitro the adenylyl cyclase inhibitor SQ22536 attenuated the effect, implicating cAMP-dependent signalling. Described as a direct, adipocyte-intrinsic mechanism beyond central appetite regulation.
PopulationHFD-induced obese mice (in vivo, RNA-seq) and differentiated 3T3-L1 adipocytes (in vitro, +/- SQ22536)
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsanimal data; human relevance uncertain
Comparatorsvehicle; SQ22536 (cAMP inhibitor, in vitro)
Tirzepatide MARKETED
Energy expenditure and thermogenesis Increase
Very low evidence

In male mice, intracerebroventricular (i.c.v.) tirzepatide reduced body weight and fat content vs pair-fed controls by increasing white adipose lipolysis and enhancing...

Zhang A, Liu Q, Xiong Y, et al. Tirzepatide reduces body weight by increasing fat utiliza... Source
Full findingIn male mice, intracerebroventricular (i.c.v.) tirzepatide reduced body weight and fat content vs pair-fed controls by increasing white adipose lipolysis and enhancing thermogenesis in brown and beige adipose tissue, lowering respiratory exchange ratio (increased lipid utilisation). Effects were mediated by sympathetic nervous system innervation of adipose tissue, associated with neuronal activity changes in the dorsomedial hypothalamus and nucleus of the solitary tract.
PopulationChow- or HFD-fed male mice; single/long-term i.c.v. tirzepatide vs vehicle, with pair-fed control; metabolic cages (RER)
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsanimal data; human relevance uncertain
Comparatorsvehicle; pair-fed control
Tirzepatide MARKETED
Energy expenditure and thermogenesis Increase
Very low evidence

In a mouse model of postmenopausal metabolic dysfunction (obese-diabetic +/- ovariectomy), tirzepatide reversed BAT 'whitening', restored multilocular brown adipocyte...

Bittencourt JOA, Marcondes-de-Castro IA, Marinho TS, Aguila MB, Mandarim-de-Lacerda CA. T... Source
Full findingIn a mouse model of postmenopausal metabolic dysfunction (obese-diabetic +/- ovariectomy), tirzepatide reversed BAT 'whitening', restored multilocular brown adipocyte morphology, and increased thermogenic markers including UCP1 and the beta3-adrenergic receptor; it reversed suppression of thermogenic and mitochondrial-fusion genes and normalised ER-stress/autophagy markers. Three-way ANOVA identified tirzepatide as the most potent regulator of the BAT gene landscape. It also reduced relative BAT mass by 25%.
PopulationFemale mice; control sham, control-OVX, obese-diabetic, obese-diabetic-OVX; 12 wk OVX/HFHS diet then 4 wk tirzepatide
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsanimal data; human relevance uncertain
Comparatorscontrol sham; obese-diabetic untreated; ovariectomy groups
Tirzepatide MARKETED
comparative-efficacy Increase
High evidence

DIRECT head-to-head CVOT (SURPASS-CVOT, T2D + ASCVD). Tirzepatide (up to 15 mg) was NON-INFERIOR to dulaglutide 1.5 mg for 3-point MACE (~12% vs ~13%; HR 0.92, p=0.003...

Nicholls SJ et al. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 ... Source
Full findingDIRECT head-to-head CVOT (SURPASS-CVOT, T2D + ASCVD). Tirzepatide (up to 15 mg) was NON-INFERIOR to dulaglutide 1.5 mg for 3-point MACE (~12% vs ~13%; HR 0.92, p=0.003 noninferiority; p=0.09 superiority) over median ~4 years, while achieving GREATER HbA1c and weight reductions. Pre-specified kidney composite 23% lower with tirzepatide (HR 0.77, 95% CI 0.68-0.88).
Population13,299 (13,165 analysed) adults with T2D and ASCVD, double-blind active-controlled, 640 sites/30 countries, median 4.0 y; tirz up to 15 mg vs dulaglutide 1.5 mg
Fundingindustry - Eli Lilly (trial sponsor)
Scope limitsactive-comparator (dulaglutide) non-inferiority design - not placebo-controlled; superiority not met (P=0.09)
Comparatorsdulaglutide 1.5 mg
Tirzepatide MARKETED
comparative-efficacy Increase
Moderate evidence

DIRECT head-to-head (SURPASS-2, T2D). Tirzepatide at all three doses (5/10/15 mg) was non-inferior AND superior to semaglutide 1 mg for HbA1c reduction at 40 weeks;...

Frias JP, Davies MJ, Rosenstock J, et al. N Engl J Med 2021 (SURPASS-2) Source
Full findingDIRECT head-to-head (SURPASS-2, T2D). Tirzepatide at all three doses (5/10/15 mg) was non-inferior AND superior to semaglutide 1 mg for HbA1c reduction at 40 weeks; weight loss was also greater with tirzepatide. HbA1c change: -2.01 / -2.24 / -2.30 percentage points (tirz 5/10/15) vs -1.86 (sema 1 mg); treatment differences -0.15 (p=0.02), -0.39 (p<0.001), -0.45 (p<0.001). Weight: least-squares mean treatment difference vs sema -1.9 / -3.6 / -5.5 kg (p<0.001 all).
Population1879 adults with T2D on metformin, open-label, 40 weeks, randomised 1:1:1:1; comparator semaglutide 1 mg s.c. weekly
Fundingindustry-Eli Lilly
Scope limitsopen-label (unblinded); post-hoc (not prespecified)
Comparatorssemaglutide 1 mg
Tirzepatide MARKETED
comparative-efficacy Increase
Moderate evidence

DIRECT head-to-head (SURMOUNT-5, obesity without T2D). Tirzepatide (max tolerated 10 or 15 mg) was SUPERIOR to semaglutide (max tolerated 1.7 or 2.4 mg) for weight...

Aronne LJ, et al. N Engl J Med 2025 (SURMOUNT-5); presented ECO 2025 Source
Full findingDIRECT head-to-head (SURMOUNT-5, obesity without T2D). Tirzepatide (max tolerated 10 or 15 mg) was SUPERIOR to semaglutide (max tolerated 1.7 or 2.4 mg) for weight loss at 72 weeks: mean -20.2% vs -13.7% (a ~47% greater relative reduction). Waist circumference also reduced more with tirzepatide. GI adverse events causing discontinuation were lower with tirzepatide (2.7%) than semaglutide (5.6%).
PopulationAdults with obesity (no T2D), randomised 1:1, open-label, 72 weeks; max tolerated doses; first direct obesity head-to-head of the two leading agents
Fundingindustry-Eli Lilly
Scope limitsconference/abstract-level; open-label (unblinded)
Comparatorssemaglutide 2.4 mg (max tolerated 1.7 or 2.4 mg)
Tirzepatide MARKETED
comparative-efficacy Increase
Moderate evidence

DIRECT head-to-head post hoc (SURPASS-2). Tirzepatide improved attainment of composite therapeutic targets vs semaglutide 1 mg at 40 weeks. For standard targets, >=3...

Neves JS, Leite AR, Vale C, et al. Diabetologia 2025/2026 Source
Full findingDIRECT head-to-head post hoc (SURPASS-2). Tirzepatide improved attainment of composite therapeutic targets vs semaglutide 1 mg at 40 weeks. For standard targets, >=3 targets met by 34% (sema) vs 42/53/57% (tirz 5/10/15). For intensive targets, 8% (sema) vs 15/20/29% (tirz). Odds ratios favouring tirzepatide: HbA1c <7% OR 1.50; HbA1c <6.5% OR 1.88; weight loss >10% OR 2.72; weight loss >15% OR 3.86.
PopulationPost hoc of 1879 SURPASS-2 participants (T2D), 40 weeks; tirz 5/10/15 vs sema 1 mg
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitspost-hoc (not prespecified)
Comparatorssemaglutide 1 mg
Tirzepatide MARKETED
comparative-efficacy Not directional
Moderate evidence

INDIRECT (network meta-analysis, T2D). Across 76 RCTs / 15 GLP-1RA drugs / 39,246 participants, tirzepatide induced the LARGEST HbA1c reduction vs placebo (-2.10 pp,...

Yao H, Zhang A, Li D, et al. BMJ 2024 Source
Full findingINDIRECT (network meta-analysis, T2D). Across 76 RCTs / 15 GLP-1RA drugs / 39,246 participants, tirzepatide induced the LARGEST HbA1c reduction vs placebo (-2.10 pp, SUCRA 94.2%) and the largest fasting glucose reduction (SUCRA 97.2%), ranking as the single most effective agent for glycaemic control. For WEIGHT, CagriSema ranked highest (-14.03 kg vs placebo) followed by tirzepatide (-8.47 kg).
PopulationNetwork meta-analysis, 76 RCTs, 39,246 adults with T2D, follow-up >=12 weeks; all estimates vs placebo
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsINDIRECT ranking - confirms tirz #1 for glycaemia and CagriSema #1 for weight in the T2D evidence base as of Aug 2023 (predates retatrutide phase 3 and SURMOUNT-5). Open full text. Useful as the Bayesian-ranking anchor record. 'Why' OPEN.
Comparatorsplacebo; semaglutide; dulaglutide; CagriSema; all GLP-1RAs
Tirzepatide MARKETED
comparative-efficacy Increase
Low evidence

REAL-WORLD comparative effectiveness (Truveta EHR, overweight/obesity). Tirzepatide associated with significantly greater on-treatment weight loss than semaglutide...

Rodriguez PJ, Goodwin Cartwright BM, Gratzl S, et al. JAMA Intern Med 2024 Source
Full findingREAL-WORLD comparative effectiveness (Truveta EHR, overweight/obesity). Tirzepatide associated with significantly greater on-treatment weight loss than semaglutide (both T2D-labelled formulations). Hazard of reaching thresholds: >=5% HR 1.76; >=10% HR 2.54; >=15% HR 3.24. Mean weight difference favouring tirz: -2.4% (3 mo), -4.3% (6 mo), -6.9% (12 mo). GI AE rates similar between groups.
Population41,222 adults with overweight/obesity (52% with T2D) on T2D-labelled tirz or sema; 18,386 after propensity-score matching; retrospective EHR cohort, May 2022-Sep 2023
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitspossible confounding by indication
Comparatorssemaglutide
Tirzepatide MARKETED
comparative-efficacy Increase
Low evidence

REAL-WORLD comparative effectiveness (US clinical practice, obesity WITHOUT diabetes). At 6 months tirzepatide -11.15% vs semaglutide -8.83% (adjusted difference -2.32...

le Roux CW, Done N, Brnabic AJM, et al. J Endocrinol Invest 2026 Source
Full findingREAL-WORLD comparative effectiveness (US clinical practice, obesity WITHOUT diabetes). At 6 months tirzepatide -11.15% vs semaglutide -8.83% (adjusted difference -2.32 pp favouring tirz). Adjusted odds of thresholds: >=5% aOR 2.03; >=10% aOR 2.46; >=15% aOR 2.88.
Population2396 on-treatment adults (1003 tirz, 1393 sema) with obesity/overweight WITHOUT diabetes, retrospective EHR cohort, Dec 2023-Jun 2024, 6-month follow-up
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsNon-diabetic real-world cohort, concordant with SURMOUNT-5 and the Truveta cohort. Lilly-affiliated authorship (record the provenance). 6-month timepoint only. Observational. 'Why' OPEN.
Comparatorssemaglutide
Tirzepatide MARKETED
Cardiovascular outcomes No change
High evidence

In T2D with established ASCVD, tirzepatide was NON-INFERIOR to dulaglutide for 3-point MACE but did NOT meet superiority. The comparator is a CV-proven GLP-1RA, so...

Nicholls SJ et al. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 ... Source
Full findingIn T2D with established ASCVD, tirzepatide was NON-INFERIOR to dulaglutide for 3-point MACE but did NOT meet superiority. The comparator is a CV-proven GLP-1RA, so this establishes that the GIP-containing dual-agonist MOLECULE is CV-safe at the whole-molecule level; it does NOT isolate the GIP receptor's own contribution, because tirzepatide's GLP-1 moiety differs from dulaglutide's (cross-ref thread 11), so the null delta cannot be read as 'GIP adds nothing' rather than as offsetting differences between the two GLP-1 components. Despite materially greater HbA1c and weight reduction, the second incretin arm bought no incremental hard MACE.
PopulationSURPASS-CVOT: N=13,299 randomised (NCT04255433); T2D + established ASCVD, age >=40, HbA1c 7.0-10.5%, BMI >=25; double-blind active-comparator; tirzepatide up to 15 mg vs dulaglutide 1.5 mg; median follow-up ~4.0 years.
Fundingindustry - Eli Lilly (trial sponsor)
Scope limitsactive-comparator (dulaglutide) non-inferiority design - not placebo-controlled; superiority not met (P=0.09)
Comparatorsdulaglutide
Tirzepatide MARKETED
Cardiovascular outcomes No change
Moderate evidence

Pre-specified pre-registration pooled CV meta-analysis of the SURPASS phase-3 programme found tirzepatide did NOT increase MACE versus controls; the point estimate was...

Sattar N, McGuire DK, Pavo I et al., Nat Med, 2022 Source
Full findingPre-specified pre-registration pooled CV meta-analysis of the SURPASS phase-3 programme found tirzepatide did NOT increase MACE versus controls; the point estimate was favourable but the CI crossed 1 (exploratory CV-safety evidence, not powered superiority).
PopulationPre-specified pooled meta-analysis of 7 RCTs (>=26 weeks) in the SURPASS T2D programme; 4,887 tirzepatide vs 2,328 control; controls = placebo and active comparators.
Fundingindustry - Eli Lilly and Company
Scope limitssurrogate/exploratory endpoint
Comparatorsplacebo; semaglutide; dulaglutide; insulin glargine; insulin degludec
Tirzepatide MARKETED
Cardiovascular outcomes Not directional
Very low evidence

Dedicated morbidity-mortality OUTCOME trial of tirzepatide in OBESITY WITHOUT diabetes (primary and secondary prevention) is ONGOING with no results; the first...

Lam CSP, Rodriguez A, Aminian A et al. SURMOUNT-MMO rationale and design. Obesity (Silver... Source
Full findingDedicated morbidity-mortality OUTCOME trial of tirzepatide in OBESITY WITHOUT diabetes (primary and secondary prevention) is ONGOING with no results; the first incretin outcome trial to span both primary and secondary CV prevention.
PopulationSURMOUNT-MMO (NCT05556512): randomised double-blind event-driven; BMI >=27, obesity, T1D/T2D excluded; adults >=40 with established CVD OR adults with CV risk factors; once-weekly tirzepatide vs placebo; confirmed on clinicaltrials.gov 2026-06-21.
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsADDED. PMID 40545827 is the published rationale-and-design paper, NOT a results paper, hence very-low (promissory note). Will give the first incretin CV-outcome read in obesity-without-diabetes spanning both prevention settings.
Comparatorsplacebo
Tirzepatide MARKETED
renal Decrease
Moderate evidence

SURPASS-4 post hoc: tirzepatide slowed eGFR decline, prevented UACR rise and reduced a composite kidney endpoint versus insulin glargine.

Heerspink HJL et al. (SURPASS-4 kidney), Lancet Diabetes Endocrinol, 2022;10:774-785; cys... Source
PopulationSURPASS-4: N=1,995 (995 tirz, 1000 glargine); T2D, high CV risk; median treatment 85 weeks; open-label; post hoc.
Fundingindustry-Eli Lilly
Scope limitsopen-label (unblinded); possible confounding by indication; post-hoc (not prespecified)
Comparatorsinsulin glargine
Tirzepatide MARKETED
renal Decrease
Moderate evidence

SURPASS-CVOT prespecified exploratory: tirzepatide reduced major kidney events versus dulaglutide (direct incretin head-to-head).

Zoungas S et al. Tirzepatide vs dulaglutide on major kidney events: pre-specified explora... Source
PopulationSURPASS-CVOT: N=13,299 (6586 tirz, 6579 dula; 2948 high-risk CKD); T2D + ASCVD; median 4.0 years; double-blind.
Fundingindustry-Eli Lilly
Scope limitssurrogate/exploratory endpoint
Comparatorsdulaglutide 1.5 mg
Tirzepatide MARKETED
renal Decrease
Moderate evidence

In T2D with established ASCVD, tirzepatide reduced a composite of major adverse kidney events versus dulaglutide in a prespecified exploratory analysis of...

Zoungas S et al. Tirzepatide vs dulaglutide on major kidney events: pre-specified explora... Source
Full findingIn T2D with established ASCVD, tirzepatide reduced a composite of major adverse kidney events versus dulaglutide in a prespecified exploratory analysis of SURPASS-CVOT. Note the comparator is an active CV-proven GLP-1RA (dulaglutide), NOT placebo, and the analysis is exploratory (not part of the confirmatory hierarchy).
PopulationPrespecified exploratory analysis of SURPASS-CVOT (NCT04255433): n=13,165 with T2D + established ASCVD; tirzepatide (max-tolerated up to 15 mg) vs dulaglutide 1.5 mg; median follow-up 4.0 years.
Fundingindustry-Eli Lilly
Scope limitssurrogate/exploratory endpoint
Comparatorsdulaglutide 1.5 mg
Tirzepatide MARKETED
Body composition Decrease
Moderate evidence

SURMOUNT-1 DXA substudy: tirzepatide's large total loss was accompanied by a PROPORTIONALLY matched lean loss (~25% of weight lost), and crucially the same ~75/25...

Look M et al., Diabetes Obes Metab, 2025 Source
Full findingSURMOUNT-1 DXA substudy: tirzepatide's large total loss was accompanied by a PROPORTIONALLY matched lean loss (~25% of weight lost), and crucially the same ~75/25 split held for PLACEBO too, so the lean fraction is a property of weight loss at this magnitude, not specifically of the drug. The decision-relevant corollary: a much larger absolute loss at the same proportion carries a larger ABSOLUTE lean-kg loss.
PopulationSURMOUNT-1 DXA substudy: n=160 of 2539 (pooled tirzepatide n=124, placebo n=36), adults with obesity/overweight, mean weight 102.5 kg; baseline-to-Week-72 DXA; post-hoc substudy of a phase-3 double-blind placebo-controlled RCT.
Fundingindustry-Eli Lilly
Scope limitspost-hoc (not prespecified); small sample (N~160)
Comparatorsplacebo
Tirzepatide MARKETED
Body composition Decrease
Moderate evidence

SUMMIT CMR substudy (obesity-related HFpEF): tirzepatide reduced LV mass and paracardiac (epicardial + pericardial) adipose tissue vs placebo at 52 weeks; the...

Kramer CM et al., J Am Coll Cardiol, 2024 Source
Full findingSUMMIT CMR substudy (obesity-related HFpEF): tirzepatide reduced LV mass and paracardiac (epicardial + pericardial) adipose tissue vs placebo at 52 weeks; the paracardiac reduction was driven by the pericardial component, with the LV-mass change paralleling weight loss.
Population175 obesity-related HFpEF patients underwent CMR; 106 analysable (treated 50, placebo 56); tirzepatide to max 15 mg weekly; 52 weeks; RCT (NCT04847557)
Fundingindustry - Eli Lilly
Scope limitsEpicardial/pericardial depot. Coverage notes the volume drop was driven by PERICARDIAL not epicardial fat - a depot-specificity caveat worth preserving. Cross-ref heart-failure domain (SUMMIT).
Comparatorsplacebo
Tirzepatide MARKETED
Body composition Decrease
Low evidence

EHR-linked body-composition digital-phenotyping study (LLM extraction) of routine-care users found tirzepatide associated with GREATER relative lean-body-mass loss...

Greater lean-body-mass decline with tirzepatide than semaglutide in routine care (digital... Source
Full findingEHR-linked body-composition digital-phenotyping study (LLM extraction) of routine-care users found tirzepatide associated with GREATER relative lean-body-mass loss than semaglutide at every timepoint; a 'Depletive GLP-1 metabotype' (>20% TBW loss with >5% LBM loss) was more frequent with tirzepatide.
Population670,422 first-episode GLP-1RA users (semaglutide 456,742; tirzepatide 213,680); 7,965 with paired pre/post body-composition over 12 months; retrospective real-world EHR cohort
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsconference/abstract-level; possible confounding by indication
Comparatorssemaglutide
Tirzepatide MARKETED
Obstructive sleep apnoea Not directional
High evidence

The FDA approved tirzepatide (Zepbound) in December 2024 for moderate-to-severe obstructive sleep apnoea in adults with obesity - the first-ever drug indication for...

US FDA. FDA approves first medication for obstructive sleep apnea (Zepbound / tirzepatide... Source
Full findingThe FDA approved tirzepatide (Zepbound) in December 2024 for moderate-to-severe obstructive sleep apnoea in adults with obesity - the first-ever drug indication for OSA, establishing AHI reduction as an approvable registrational endpoint for this class.
PopulationRegulatory label population: adults with moderate-to-severe OSA and obesity (BMI >=30), adjunct to diet/exercise. Approval 20 Dec 2024.
Fundingregulatory agency (FDA/EMA/MHRA/WHO)
Scope limitssurrogate/exploratory endpoint
Tirzepatide MARKETED
Obstructive sleep apnoea Decrease
High evidence

In SURMOUNT-OSA trial 1 (APNEA-1, participants NOT on positive airway pressure), tirzepatide at max-tolerated dose (10/15 mg) markedly reduced the apnoea-hypopnoea...

Malhotra A, Grunstein RR, Fietze I et al; SURMOUNT-OSA Investigators. Tirzepatide for the... Source
Full findingIn SURMOUNT-OSA trial 1 (APNEA-1, participants NOT on positive airway pressure), tirzepatide at max-tolerated dose (10/15 mg) markedly reduced the apnoea-hypopnoea index vs placebo over 52 weeks in adults with moderate-to-severe OSA and obesity.
PopulationSURMOUNT-OSA trial 1 (NCT05412004), phase-3 double-blind RCT; PAP-naive; moderate-to-severe OSA (baseline mean AHI 51.5 events/hr), obesity (mean BMI 39.1); tirzepatide 10/15 mg MTD vs placebo, 52 wk. Combined SURMOUNT-OSA N=469 across both trials.
Fundingindustry-Eli Lilly
Scope limitsno outcome data yet (ongoing); surrogate/exploratory endpoint
Comparatorsplacebo
Tirzepatide MARKETED
Obstructive sleep apnoea Decrease
High evidence

In SURMOUNT-OSA trial 2 (APNEA-2, participants ON positive airway pressure), tirzepatide at max-tolerated dose (10/15 mg) markedly reduced the AHI vs placebo over 52...

Malhotra A, Grunstein RR, Fietze I et al; SURMOUNT-OSA Investigators. Tirzepatide for the... Source
Full findingIn SURMOUNT-OSA trial 2 (APNEA-2, participants ON positive airway pressure), tirzepatide at max-tolerated dose (10/15 mg) markedly reduced the AHI vs placebo over 52 weeks in adults with moderate-to-severe OSA and obesity.
PopulationSURMOUNT-OSA trial 2 (NCT05412004), phase-3 double-blind RCT; PAP-treated; moderate-to-severe OSA (baseline mean AHI 49.5 events/hr), obesity (mean BMI 38.7); tirzepatide 10/15 mg MTD vs placebo, 52 wk.
Fundingindustry-Eli Lilly
Scope limitsno outcome data yet (ongoing); surrogate/exploratory endpoint
Comparatorsplacebo
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
Tirzepatide MARKETED
heart-failure Decrease
High evidence

SUMMIT: in HFpEF with obesity, tirzepatide reduced the composite of CV death or worsening HF event and improved KCCQ-CSS versus placebo.

Packer M et al. (SUMMIT), NEJM, 2025;392:427-437 Source
PopulationN=731, HFpEF (EF >=50%), BMI >=30; median follow-up 104 weeks; RCT vs placebo.
Fundingindustry - Eli Lilly and Company
Scope limitsfew events/wide CI
Comparatorsplacebo
Tirzepatide MARKETED
heart-failure Mixed
Moderate evidence

In a mechanistic secondary analysis of SUMMIT, tirzepatide at 52 weeks reduced systolic blood pressure (-5 mmHg), estimated blood volume (-0.58 L), CRP (-37.2%),...

Borlaug BA et al., Nat Med 2025;31(2):544-551 (SUMMIT mechanistic secondary) Source
Full findingIn a mechanistic secondary analysis of SUMMIT, tirzepatide at 52 weeks reduced systolic blood pressure (-5 mmHg), estimated blood volume (-0.58 L), CRP (-37.2%), NT-proBNP and troponin T, and INCREASED eGFR (+2.90 mL/min/1.73m2/yr) while lowering urine albumin-creatinine ratio - interpreted as reduced volume/pressure overload and mitigated cardiovascular-kidney end-organ injury.
Populationmechanistic secondary analysis of SUMMIT (HFpEF + obesity); NCT04847557
Fundingindustry - Eli Lilly (trial sponsor; sponsor-authored)
Scope limitssurrogate/exploratory endpoint; sponsor-authored COI (Eli Lilly)
Comparatorsplacebo
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
Tirzepatide MARKETED
Lipids and lipoproteins Decrease
Moderate evidence

Tirzepatide dose-dependently improves the atherogenic lipoprotein profile: lowers TG, VLDL-C, ApoB, ApoC-III and small LDL particles; ApoC-III reduction partly...

Wilson JM et al., Diabetes Obes Metab, 2020;22(12):2451-2459 Source
Full findingTirzepatide dose-dependently improves the atherogenic lipoprotein profile: lowers TG, VLDL-C, ApoB, ApoC-III and small LDL particles; ApoC-III reduction partly weight-independent.
PopulationPhase 2b T2D substudy (tirzepatide 1-15 mg vs dulaglutide vs placebo); NMR lipoprotein analysis.
Fundingindustry - Eli Lilly (trial sponsor)
Scope limitsKey mechanistic ApoC-III finding. SURPASS-2 head-to-head vs semaglutide also reported larger TG/lipid improvements with tirzepatide (not separately captured). PMID/DOI verified.
Comparatorsdulaglutide; placebo
Tirzepatide MARKETED
Lipids and lipoproteins Decrease
Moderate evidence

In a post-hoc analysis of the phase-3 SURMOUNT-1 obesity trial, tirzepatide-associated improvements in triglycerides, HDL-C, LDL-C and non-HDL cholesterol were...

Linetzky B, Sattar N, Verma S, Krumholz HM, et al., Ann Intern Med 2025;178(8):1095-1105 Source
Full findingIn a post-hoc analysis of the phase-3 SURMOUNT-1 obesity trial, tirzepatide-associated improvements in triglycerides, HDL-C, LDL-C and non-HDL cholesterol were primarily observed only after weight reductions greater than 10%.
PopulationPost-hoc analysis of phase-3 double-blind SURMOUNT-1 (NCT04184622); N=1605 adults with obesity or overweight-with-complications without diabetes; tirzepatide 5/10/15 mg; baseline to week 72.
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitspost-hoc (not prespecified)
Comparatorsplacebo
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
Tirzepatide MARKETED
Appetite and food intake Decrease
Moderate evidence

Tirzepatide reduces food cravings (Food Craving Inventory) and food-cue reward-circuit reactivity (fMRI) - the strongest MECHANISTIC evidence for the lay 'food noise'...

Martin CK, Coskun T et al. Tirzepatide effects on ingestive behaviour and brain response ... Source
Full findingTirzepatide reduces food cravings (Food Craving Inventory) and food-cue reward-circuit reactivity (fMRI) - the strongest MECHANISTIC evidence for the lay 'food noise' claim, demonstrating a central reward component, though the fMRI effect was partial (high-fat/high-sugar regions, not overall palatable-food response).
PopulationPhase-1 ingestive-behaviour RCT (n=114, 6 wk) + a phase-1 RCT FCI secondary analysis (n=55, 18 wk); adults with obesity; tirzepatide vs placebo (+ liraglutide arm).
Fundingindustry-Eli Lilly
Scope limitsconference/abstract-level; small sample (N~114)
Comparatorsplacebo; liraglutide
Tirzepatide MARKETED
Appetite and food intake Decrease
Low evidence

In a phase 1 mechanism-of-action trial in people with obesity (NCT04081337), tirzepatide reduced appetite and reduced calorie intake during an ad-libitum test meal vs...

Ravussin E, Sanchez-Delgado G, Martin CK, et al. Tirzepatide did not impact metabolic ada... Source
Full findingIn a phase 1 mechanism-of-action trial in people with obesity (NCT04081337), tirzepatide reduced appetite and reduced calorie intake during an ad-libitum test meal vs placebo, with increased fat oxidation and no impact on metabolic adaptation; energy expenditure was not increased. This is direct measured intake (unlike the retatrutide VAS-only data).
PopulationPeople with obesity, phase 1 MoA trial
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsanimal data; human relevance uncertain
Comparatorsplacebo
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
Tirzepatide MARKETED
health-economics-adherence Not directional
Low evidence

In an INDEPENDENT (non-manufacturer) US lifetime microsimulation, tirzepatide and semaglutide added to lifestyle modification produced the largest QALY gains among...

Hwang JH, Laiteerapong N, Huang ES, Kim DD. Lifetime Health Effects and Cost-Effectivenes... Source
Full findingIn an INDEPENDENT (non-manufacturer) US lifetime microsimulation, tirzepatide and semaglutide added to lifestyle modification produced the largest QALY gains among anti-obesity medications yet were NOT cost-effective at current US net prices: at a $100,000/QALY threshold both had a 0% probability of being cost-effective across the examined range. Context-only economic observation; not an efficacy or value verdict.
PopulationLifetime cost-effectiveness analysis - individual-level microsimulation (validated Diabetes-Obesity-Cardiovascular Disease microsimulation model) parameterised from NHANES 2017-2020 survey data (4,823 individuals representing ~126M US adults meeting trial inclusion criteria); academic authors (University of Chicago); USA.
Fundingacademic/independent (University of Chicago authors; non-manufacturer; per-paper COI statement not individually audited)
Scope limitsWI-3 NEW-GATHER (cost-effectiveness / QALY anchor for the obesity setting). Context-only: this is a MODELLING study of economic value at a given price, NOT a clinical efficacy or mechanism claim and NOT a recommendation. GRADE low by rule (cost-effectiveness microsimulation is a derived/simulation design with no dedicated rubric tier, so it floors to low - the conservative unparseable-design fallback; correct grade regardless). scope_limits: model assumptions, list/net-price sensitivity, discontinuation-rate assumptions, generalisability of trial inputs to the modelled population. Independent (academic, non-manufacturer) - useful as the competing null against industry-sponsored CEAs that report favourable ICERs (cf. C-SEMAGLUTIDE-HEALTHECON-CEA-01, Novo-sponsored). The two together flag the literature spread: at LIST price reta-class obesity drugs sit well above the $100k/QALY threshold; favourable ICERs depend on rebate/price assumptions. No retatrutide CEA found (not marketed); the price-sensitivity logic would apply a fortiori to a more potent, presumably costlier agent - expectation, not data. [WI-3 independent audit 2026-06-24: source design relabelled from 'observational cohort' to 'cost-effectiveness microsimulation model' and the population text de-laundered (the words 'COHORT'/'observational survey cohort' that had steered the deterministic detector to 'observational cohort' were removed; the study is a microsimulation, not a cohort study). Grade is low either way - the prior text reached low by tripping the cohort detector, the corrected text reaches low as the unparseable-simulation fallback - so this restores accurate text without changing the (correct) grade. The 'confounding by indication' scope_limit, an artefact of the cohort mislabel, was removed; a simulation has no confounding by indication.]
Comparatorssemaglutide; naltrexone-bupropion; phentermine-topiramate; lifestyle modification
Tirzepatide MARKETED
health-economics-adherence Not directional
Low evidence

In two large US claims/EHR databases, most adults WITHOUT type 2 diabetes who initiated tirzepatide were still persistent at 6 months - a higher 6-month persistence...

Gibble TH, Hankosky ER, Meeks A, Liao B, Ward J, Huang A, Chinthammit C. Characteristics ... Source
Full findingIn two large US claims/EHR databases, most adults WITHOUT type 2 diabetes who initiated tirzepatide were still persistent at 6 months - a higher 6-month persistence than has typically been reported for older GLP-1 receptor agonists. Context-only real-world utilisation observation; short follow-up, not comparable to the 1-year discontinuation anchor.
PopulationRetrospective observational claims/EHR cohort, Merative MarketScan Commercial + Optum Clinformatics (CDM); adults without T2D initiating tirzepatide May 2021-Sep 2023; USA; sponsor Eli Lilly.
Fundingindustry - Eli Lilly (sponsor-authored real-world claims study; COI-flagged per Constitution 1.8)
Scope limitspossible confounding by indication; short duration
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
Tirzepatide MARKETED
Maintenance and regain Increase
Moderate evidence

SURMOUNT-4 randomised-withdrawal RCT: after a 36-week open-label lead-in (mean loss 20.9%), participants were randomised at week 36 to continue tirzepatide or switch...

Aronne LJ et al., JAMA 2024 (SURMOUNT-4) Source
Full findingSURMOUNT-4 randomised-withdrawal RCT: after a 36-week open-label lead-in (mean loss 20.9%), participants were randomised at week 36 to continue tirzepatide or switch to placebo. Withdrawal led to substantial regain (+14.0%) whereas continued treatment maintained and augmented loss (-5.5%). Same architecture as STEP-4, larger magnitudes off a deeper lead-in loss.
PopulationSURMOUNT-4 (NCT04660643): N=670 randomised; adults BMI >=30 (or >=27 + complication) without diabetes; 36-week open lead-in then 52-week double-blind withdrawal.
Fundingindustry-Eli Lilly
Scope limitsopen-label (unblinded)
Comparatorsplacebo (switch from tirzepatide)
Tirzepatide MARKETED
Maintenance and regain Increase
Moderate evidence

SURMOUNT-4 post-hoc: cardiometabolic markers tracked WITH the magnitude of weight regain after tirzepatide withdrawal - greater regain was associated with larger...

Horn DB, Linetzky B, Davies MJ et al., JAMA Intern Med, 2026 Source
Full findingSURMOUNT-4 post-hoc: cardiometabolic markers tracked WITH the magnitude of weight regain after tirzepatide withdrawal - greater regain was associated with larger increases in waist, SBP, non-HDL cholesterol, HbA1c and fasting insulin. ASSOCIATIONAL only: post-hoc, non-randomised regain strata (stratified on a post-randomisation outcome), confounded by regainer phenotype; all endpoints are surrogates, no events.
PopulationPost-hoc of SURMOUNT-4 (NCT04660643): N=308 tirzepatide-treated with >=10% loss randomised to placebo, stratified by week-88 regain.
Fundingindustry-Eli Lilly
Scope limitsdisproportionality: reporting != incidence/causality; possible confounding by indication; post-hoc (not prespecified)
Comparatorswithin-arm regain strata
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
Tirzepatide MARKETED
Blood pressure Decrease
High evidence

Tirzepatide reduced 24-hour ambulatory systolic BP versus placebo (SURMOUNT-1 ABPM substudy); effect partly weight-mediated.

de Lemos JA et al. (SURMOUNT-1 ABPM), Hypertension, 2024;81(4):e41-e43 Source
PopulationN=600 adults BMI >=27, BP <140/90 on stable antihypertensives, SURMOUNT-1 substudy; 36 weeks; RCT.
Fundingindustry - Eli Lilly
Scope limitsmagnitude web/secondary-sourced
Comparatorsplacebo
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
Tirzepatide MARKETED
heart-rate-chronotropy Increase
High evidence

Tirzepatide raises heart rate modestly and dose-dependently versus placebo.

de Lemos JA et al. (SURMOUNT-1 ABPM), Hypertension, 2024;81(4):e41-e43 Source
PopulationSURMOUNT-1 obesity RCT and SURPASS T2D programme; tirzepatide 5/10/15 mg vs placebo/comparators.
Fundingindustry - Eli Lilly
Scope limitsmagnitude web/secondary-sourced
Comparatorsplacebo
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
Tirzepatide MARKETED
Gastrointestinal tolerability Increase
High evidence

GI AEs most common, mostly mild-to-moderate, primarily during dose escalation; AE-related discontinuation dose-related. Per-symptom rates broadly dose-related (nausea...

Juxtaposition of SURMOUNT-1 (NEJM 2022) and MariTide phase 2 (ADA 2025); see also LY35370... Source
Full findingGI AEs most common, mostly mild-to-moderate, primarily during dose escalation; AE-related discontinuation dose-related. Per-symptom rates broadly dose-related (nausea peaks at 10 mg).
PopulationSURMOUNT-1: 2539 adults with obesity; 72 weeks (20-wk escalation); phase 3 RCT
Fundingindustry - Eli Lilly (SURMOUNT-1; disclosed)
Scope limitsconference/abstract-level
Comparatorsplacebo
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
Tirzepatide MARKETED
Glycaemic control Decrease
Moderate evidence

In SURPASS-2, all three tirzepatide doses were non-inferior and superior to semaglutide 1 mg for HbA1c reduction from baseline at 40 weeks (head-to-head).

Frias JP, Davies MJ, Rosenstock J, et al. N Engl J Med 2021 (SURPASS-2) Source
Population1879 adults with T2D on metformin; mean age 56.6 y, mean weight 93.7 kg; 40-week open-label phase 3 RCT; comparator semaglutide 1 mg SC once weekly
Fundingindustry-Eli Lilly
Scope limitsopen-label (unblinded); post-hoc (not prespecified)
Comparatorssemaglutide 1 mg
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
Tirzepatide MARKETED
Insulin and beta-cell function Increase
Low evidence

In a single-arm 12-week clamp study (obese T2D, tirzepatide up to 5 mg) the glucose infusion rate rose and glucagon fell, with no significant correlation between GIR...

Yamaguchi S et al., Diabetologia 2025; Mather KJ et al., Diabetes Obes Metab 2025 Source
Full findingIn a single-arm 12-week clamp study (obese T2D, tirzepatide up to 5 mg) the glucose infusion rate rose and glucagon fell, with no significant correlation between GIR change and weight change, indicating early insulin sensitisation not solely attributable to weight loss. A separate post-hoc analysis found a greater M-value improvement per unit weight loss for tirzepatide than semaglutide.
PopulationObese T2D, single-arm n=16, 12 weeks (Yamaguchi); 28-wk post-hoc (Mather)
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitspost-hoc (not prespecified); small sample (N~16)
Comparatorsnone (single-arm); semaglutide (post-hoc)
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
Tirzepatide MARKETED
hepatic-mash Decrease
Moderate evidence

In SYNERGY-NASH (phase 2, F2-F3), the GIP/GLP-1 dual tirzepatide was superior to placebo for MASH resolution without fibrosis worsening at 52 wk across all doses. The...

Loomba R et al. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liv... Source
Full findingIn SYNERGY-NASH (phase 2, F2-F3), the GIP/GLP-1 dual tirzepatide was superior to placebo for MASH resolution without fibrosis worsening at 52 wk across all doses. The fibrosis-improvement key-secondary was numerically higher than placebo but with WIDE CIs (lower bounds near 1 pp) and no clear dose-response.
PopulationNCT04166773 (SYNERGY-NASH); N=190 randomised, 157 evaluable wk-52 biopsy (imputation); biopsy MASH fibrosis F2/F3; tirzepatide 5/10/15 mg vs placebo; 52 wk.
Fundingindustry - Eli Lilly and Company
Scope limitsDEEPENS the SYNERGY-NASH topline (this id) to PUBLISHED detail. SURROGATE caveat. DISTINCTION: PRIMARY MASH RESOLUTION was robust (CIs far from 0); the fibrosis-IMPROVEMENT key-secondary is fragile (lower CIs ~1 pp, no dose-response) - never conflate. ~17% biopsies imputed. Sponsor Eli Lilly. Reta relevance: tirzepatide is GIP/GLP-1 (NO glucagon arm) - informative for the GIP contribution but does NOT isolate glucagon; reta (triple) has no MASH histology trial.
Comparatorsplacebo