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Study · Observational study · n = 113,404 · 2025

9 results

Target Trial Emulations of GLP-1 and Dual GLP-1/GIP Agonists to Reduce Major Adverse Liver Outcomes in Type 2 Diabetes.

Henney AE, Riley DR, Anson M, Azmi S, Alam U, Cuthbertson DJ

Liver international : official journal of the International Association for the Study of the Liver1 Oct 2025Cited by 5 (Europe PMC)

PMID40980971 (opens in a new tab)PMCIDPMC12452214 (opens in a new tab)DOI10.1111/liv.70367 (opens in a new tab)PepBankPUB-40980971
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Summary

BackgroundClinical trials suggest GLP-1 receptor agonists (RAs) and dual glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) RAs improve metabolic dysfunction associated with steatohepatitis (MASH) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to compare the estimate of the relative effect of tirzepatide, semaglutide, and liraglutide in reducing the risk of major adverse liver outcomes (MALOs) in patients with type 2 diabetes (T2D).Design, setting and participantsWe emulated target trials based on a real-world network of electronic health records (EHRs) from over 150 million patients. Three target trials were emulated, among eligible patients with T2D who had no prior MALO diagnosis, by comparing therapy involving tirzepatide, semaglutide, and liraglutide versus DPP4 inhibitor (DPP4i) therapy. We identified the first-ever diagnosis of MALO occurring within a 2-year follow-up period and compared across the treatment groups using Kaplan-Meier survival analyses. Cohorts underwent propensity score matching 1:1 for confounders. We performed sensitivity analyses relating to geographical location, combination with metformin, and by treatment adherence. We also performed head-to-head analyses of the incretin-based therapies.ResultsAfter matching, we identified three target trials comprised of 10 165, 56 702, and 8 301 patients treated with tirzepatide, semaglutide, and liraglutide, respectively (1:1 with reference patients) for a 2-year period. Tirzepatide (HR 0.53 [95% CI 0.40, 0.71]) and semaglutide (HR 0.81 [0.72, 0.90]) were associated with a significant reduction in the risk of incident MALO compared with DPP4i, whereas liraglutide was not (HR 1.04 [95% CI 0.79, 1.36]). In head-to-head comparisons, tirzepatide was associated with a significantly lower risk of incident MALO compared with liraglutide (HR 0.56 [95% CI 0.39, 0.79]), but not semaglutide (HR 0.83 [95% CI 0.63, 1.09]). Semaglutide was not associated with a reduced risk compared with liraglutide (HR 0.77 [95% CI 0.57, 1.05]).ConclusionTreatment with tirzepatide and, to a lesser extent, semaglutide, in patients with T2D, was associated with a lower incidence of MALO compared with DPP4i after 2 years; largely driven by a reduction in the rates of compensated and decompensated cirrhosis. A reduction in MALO was not demonstrated with the use of liraglutide. These findings highlight a comparative benefit of tirzepatide (and semaglutide) versus DPP4i and should prompt more robust, longer-term randomised controlled studies to evaluate their role in preventing MALO in this increasingly prevalent patient population with co-existing T2D and MASLD.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study9

9 results from studies that gave the peptide. 9 results from people.

  1. 01HumanObservational studyEfficacy outcome

    In T2D without prior MALO, semaglutide was associated with lower incident MALO versus DPP4 inhibitor therapy (HR 0.81, 95% CI 0.72 to 0.9).

    In plain wordsIn type 2 diabetes without previous major liver outcomes, semaglutide was linked to fewer major liver outcomes than DPP4 inhibitors.

    Peptide
    Semaglutide
    Outcome
    DecreaseIncident major adverse liver outcome
    Study

    n = 113,404

    Comparator
    DPP4 inhibitor therapy
    Outcome group
    Liver fat and liver function · Liver
    Studied dose
    Dose not stated

    Measurements

    Hazard ratio
    0.81
    semaglutide versus DPP4 inhibitor therapy
    95% CI
    0.72 to 0.9
    reported native contrast

    Source sentences

    Summary
    Tirzepatide (HR 0.53 [95% CI 0.40, 0.71]) and semaglutide (HR 0.81 [0.72, 0.90]) were associated with a significant reduction in the risk of incident MALO compared with DPP4i, whereas liraglutide was not (HR 1.04 [95% CI 0.79, 1.36]).
    5 context sentences
    Summary · context
    We emulated target trials based on a real-world network of electronic health records (EHRs) from over 150 million patients.
    Summary · context
    Three target trials were emulated, among eligible patients with T2D who had no prior MALO diagnosis, by comparing therapy involving tirzepatide, semaglutide, and liraglutide versus DPP4 inhibitor (DPP4i) therapy.
    Summary · context
    We identified the first-ever diagnosis of MALO occurring within a 2-year follow-up period and compared across the treatment groups using Kaplan-Meier survival analyses.
    Summary · context
    Cohorts underwent propensity score matching 1:1 for confounders.
    Summary · context
    After matching, we identified three target trials comprised of 10 165, 56 702, and 8 301 patients treated with tirzepatide, semaglutide, and liraglutide, respectively (1:1 with reference patients) for a 2-year period.
  2. 02HumanObservational studyEfficacy outcome

    In T2D without prior MALO, tirzepatide was associated with lower incident MALO versus DPP4 inhibitor therapy (HR 0.53, 95% CI 0.4 to 0.71).

    In plain wordsIn type 2 diabetes without previous major liver outcomes, tirzepatide was linked to fewer major liver outcomes than DPP4 inhibitors.

    Peptide
    Tirzepatide
    Outcome
    DecreaseIncident major adverse liver outcome
    Study

    n = 20,330

    Comparator
    DPP4 inhibitor therapy
    Outcome group
    Liver fat and liver function · Liver
    Studied dose
    Dose not stated

    Measurements

    Hazard ratio
    0.53
    tirzepatide versus DPP4 inhibitor therapy
    95% CI
    0.4 to 0.71
    reported native contrast

    Source sentences

    Summary
    Tirzepatide (HR 0.53 [95% CI 0.40, 0.71]) and semaglutide (HR 0.81 [0.72, 0.90]) were associated with a significant reduction in the risk of incident MALO compared with DPP4i, whereas liraglutide was not (HR 1.04 [95% CI 0.79, 1.36]).
    5 context sentences
    Summary · context
    We emulated target trials based on a real-world network of electronic health records (EHRs) from over 150 million patients.
    Summary · context
    Three target trials were emulated, among eligible patients with T2D who had no prior MALO diagnosis, by comparing therapy involving tirzepatide, semaglutide, and liraglutide versus DPP4 inhibitor (DPP4i) therapy.
    Summary · context
    We identified the first-ever diagnosis of MALO occurring within a 2-year follow-up period and compared across the treatment groups using Kaplan-Meier survival analyses.
    Summary · context
    Cohorts underwent propensity score matching 1:1 for confounders.
    Summary · context
    After matching, we identified three target trials comprised of 10 165, 56 702, and 8 301 patients treated with tirzepatide, semaglutide, and liraglutide, respectively (1:1 with reference patients) for a 2-year period.
  3. 03HumanObservational studyEfficacy outcome

    In T2D without prior MALO, liraglutide was not reported to reduce incident MALO versus DPP4 inhibitor therapy (HR 1.04, 95% CI 0.79 to 1.36).

    In plain wordsIn type 2 diabetes without previous major liver outcomes, liraglutide was not linked to fewer major liver outcomes than DPP4 inhibitors.

    Peptide
    Liraglutide
    Outcome
    Direction not reportedIncident major adverse liver outcome
    Study

    n = 16,602

    Comparator
    DPP4 inhibitor therapy
    Outcome group
    Liver fat and liver function · Liver
    Studied dose
    Dose not stated

    Measurements

    Hazard ratio
    1.04
    liraglutide versus DPP4 inhibitor therapy
    95% CI
    0.79 to 1.36
    reported native contrast

    Source sentences

    Summary
    Tirzepatide (HR 0.53 [95% CI 0.40, 0.71]) and semaglutide (HR 0.81 [0.72, 0.90]) were associated with a significant reduction in the risk of incident MALO compared with DPP4i, whereas liraglutide was not (HR 1.04 [95% CI 0.79, 1.36]).
    5 context sentences
    Summary · context
    We emulated target trials based on a real-world network of electronic health records (EHRs) from over 150 million patients.
    Summary · context
    Three target trials were emulated, among eligible patients with T2D who had no prior MALO diagnosis, by comparing therapy involving tirzepatide, semaglutide, and liraglutide versus DPP4 inhibitor (DPP4i) therapy.
    Summary · context
    We identified the first-ever diagnosis of MALO occurring within a 2-year follow-up period and compared across the treatment groups using Kaplan-Meier survival analyses.
    Summary · context
    Cohorts underwent propensity score matching 1:1 for confounders.
    Summary · context
    After matching, we identified three target trials comprised of 10 165, 56 702, and 8 301 patients treated with tirzepatide, semaglutide, and liraglutide, respectively (1:1 with reference patients) for a 2-year period.
  4. 04HumanObservational studyEfficacy outcome

    In T2D without prior MALO, tirzepatide was associated with lower incident MALO versus Liraglutide (HR 0.56, 95% CI 0.39 to 0.79).

    In plain wordsIn type 2 diabetes without previous major liver outcomes, tirzepatide was linked to fewer major liver outcomes than liraglutide.

    Peptide
    Tirzepatide
    Outcome
    DecreaseIncident major adverse liver outcome
    Study

    n: not reported in source

    Comparator
    Liraglutide
    Outcome group
    Liver fat and liver function · Liver
    Studied dose
    Dose not stated

    Measurements

    Hazard ratio
    0.56
    tirzepatide versus Liraglutide
    95% CI
    0.39 to 0.79
    reported native contrast

    Source sentences

    Summary
    In head-to-head comparisons, tirzepatide was associated with a significantly lower risk of incident MALO compared with liraglutide (HR 0.56 [95% CI 0.39, 0.79]), but not semaglutide (HR 0.83 [95% CI 0.63, 1.09]).
    5 context sentences
    Summary · context
    We emulated target trials based on a real-world network of electronic health records (EHRs) from over 150 million patients.
    Summary · context
    Three target trials were emulated, among eligible patients with T2D who had no prior MALO diagnosis, by comparing therapy involving tirzepatide, semaglutide, and liraglutide versus DPP4 inhibitor (DPP4i) therapy.
    Summary · context
    We identified the first-ever diagnosis of MALO occurring within a 2-year follow-up period and compared across the treatment groups using Kaplan-Meier survival analyses.
    Summary · context
    Cohorts underwent propensity score matching 1:1 for confounders.
    Summary · context
    We also performed head-to-head analyses of the incretin-based therapies.
  5. 05HumanObservational studyEfficacy outcome

    In T2D without prior MALO, tirzepatide was not reported to reduce incident MALO versus Semaglutide (HR 0.83, 95% CI 0.63 to 1.09).

    In plain wordsIn type 2 diabetes without previous major liver outcomes, tirzepatide was not linked to fewer major liver outcomes than semaglutide.

    Peptide
    Tirzepatide
    Outcome
    Direction not reportedIncident major adverse liver outcome
    Study

    n: not reported in source

    Comparator
    Semaglutide
    Outcome group
    Liver fat and liver function · Liver
    Studied dose
    Dose not stated

    Measurements

    Hazard ratio
    0.83
    tirzepatide versus Semaglutide
    95% CI
    0.63 to 1.09
    reported native contrast

    Source sentences

    Summary
    In head-to-head comparisons, tirzepatide was associated with a significantly lower risk of incident MALO compared with liraglutide (HR 0.56 [95% CI 0.39, 0.79]), but not semaglutide (HR 0.83 [95% CI 0.63, 1.09]).
    5 context sentences
    Summary · context
    We emulated target trials based on a real-world network of electronic health records (EHRs) from over 150 million patients.
    Summary · context
    Three target trials were emulated, among eligible patients with T2D who had no prior MALO diagnosis, by comparing therapy involving tirzepatide, semaglutide, and liraglutide versus DPP4 inhibitor (DPP4i) therapy.
    Summary · context
    We identified the first-ever diagnosis of MALO occurring within a 2-year follow-up period and compared across the treatment groups using Kaplan-Meier survival analyses.
    Summary · context
    Cohorts underwent propensity score matching 1:1 for confounders.
    Summary · context
    We also performed head-to-head analyses of the incretin-based therapies.
  6. 06HumanObservational studyEfficacy outcome

    In T2D without prior MALO, semaglutide was not reported to reduce incident MALO versus Liraglutide (HR 0.77, 95% CI 0.57 to 1.05).

    In plain wordsIn type 2 diabetes without previous major liver outcomes, semaglutide was not linked to fewer major liver outcomes than liraglutide.

    Peptide
    Semaglutide
    Outcome
    Direction not reportedIncident major adverse liver outcome
    Study

    n: not reported in source

    Comparator
    Liraglutide
    Outcome group
    Liver fat and liver function · Liver
    Studied dose
    Dose not stated

    Measurements

    Hazard ratio
    0.77
    semaglutide versus Liraglutide
    95% CI
    0.57 to 1.05
    reported native contrast

    Source sentences

    Summary
    Semaglutide was not associated with a reduced risk compared with liraglutide (HR 0.77 [95% CI 0.57, 1.05]).
    5 context sentences
    Summary · context
    We emulated target trials based on a real-world network of electronic health records (EHRs) from over 150 million patients.
    Summary · context
    Three target trials were emulated, among eligible patients with T2D who had no prior MALO diagnosis, by comparing therapy involving tirzepatide, semaglutide, and liraglutide versus DPP4 inhibitor (DPP4i) therapy.
    Summary · context
    We identified the first-ever diagnosis of MALO occurring within a 2-year follow-up period and compared across the treatment groups using Kaplan-Meier survival analyses.
    Summary · context
    Cohorts underwent propensity score matching 1:1 for confounders.
    Summary · context
    We also performed head-to-head analyses of the incretin-based therapies.
  7. 07HumanObservational studyEfficacy outcome

    In T2D without prior MALO, liraglutide was linked to higher incident MALO risk than tirzepatide; the published tirzepatide-versus-liraglutide HR 0.56 (95% CI 0.39-0.79) retains its original orientation.

    In plain wordsIn T2D without prior major liver outcomes, liraglutide was linked to higher major liver-outcome risk than tirzepatide.

    Peptide
    Liraglutide
    Outcome
    IncreaseIncident major adverse liver outcomes versus tirzepatide
    Study

    n: not reported in source

    Comparator
    tirzepatide
    Outcome group
    Liver fat and liver function · Liver
    Studied dose
    Dose not stated

    Measurements

    Published tirzepatide-versus-liraglutide HR
    0.56
    original orientation; not inverted
    95% CI
    0.39 to 0.79
    original tirzepatide-relative contrast

    Source sentences

    Summary
    In head-to-head comparisons, tirzepatide was associated with a significantly lower risk of incident MALO compared with liraglutide (HR 0.56 [95% CI 0.39, 0.79]), but not semaglutide (HR 0.83 [95% CI 0.63, 1.09]).
    5 context sentences
    Summary · context
    We emulated target trials based on a real-world network of electronic health records (EHRs) from over 150 million patients.
    Summary · context
    Three target trials were emulated, among eligible patients with T2D who had no prior MALO diagnosis, by comparing therapy involving tirzepatide, semaglutide, and liraglutide versus DPP4 inhibitor (DPP4i) therapy.
    Summary · context
    We identified the first-ever diagnosis of MALO occurring within a 2-year follow-up period and compared across the treatment groups using Kaplan-Meier survival analyses.
    Summary · context
    Cohorts underwent propensity score matching 1:1 for confounders.
    Summary · context
    We also performed head-to-head analyses of the incretin-based therapies.
  8. 08HumanObservational studyEfficacy outcome

    In T2D without prior MALO, semaglutide was the reference in a comparison without reported tirzepatide benefit; the published tirzepatide-versus-semaglutide HR 0.83 (95% CI 0.63-1.09) remains in original orientation, without a reverse-effect test.

    In plain wordsIn T2D without prior liver outcomes, the semaglutide comparison showed no reported tirzepatide benefit; reverse effects were unreported.

    Peptide
    Semaglutide
    Outcome
    Direction not reportedIncident major adverse liver outcomes in semaglutide/tirzepatide comparison
    Study

    n: not reported in source

    Comparator
    tirzepatide
    Outcome group
    Liver fat and liver function · Liver
    Studied dose
    Dose not stated

    Measurements

    Published original-orientation HR
    0.83
    tirzepatide versus semaglutide; not inverted
    95% CI
    0.63 to 1.09
    original orientation; no reverse test

    Source sentences

    Summary
    In head-to-head comparisons, tirzepatide was associated with a significantly lower risk of incident MALO compared with liraglutide (HR 0.56 [95% CI 0.39, 0.79]), but not semaglutide (HR 0.83 [95% CI 0.63, 1.09]).
    5 context sentences
    Summary · context
    We emulated target trials based on a real-world network of electronic health records (EHRs) from over 150 million patients.
    Summary · context
    Three target trials were emulated, among eligible patients with T2D who had no prior MALO diagnosis, by comparing therapy involving tirzepatide, semaglutide, and liraglutide versus DPP4 inhibitor (DPP4i) therapy.
    Summary · context
    We identified the first-ever diagnosis of MALO occurring within a 2-year follow-up period and compared across the treatment groups using Kaplan-Meier survival analyses.
    Summary · context
    Cohorts underwent propensity score matching 1:1 for confounders.
    Summary · context
    We also performed head-to-head analyses of the incretin-based therapies.
  9. 09HumanObservational studyEfficacy outcome

    In T2D without prior MALO, liraglutide was the reference in a comparison without reported semaglutide benefit; the published semaglutide-versus-liraglutide HR 0.77 (95% CI 0.57-1.05) remains in original orientation, without a reverse-effect test.

    In plain wordsIn T2D without prior liver outcomes, the liraglutide comparison showed no reported semaglutide benefit; reverse effects were unreported.

    Peptide
    Liraglutide
    Outcome
    Direction not reportedIncident major adverse liver outcomes in liraglutide/semaglutide comparison
    Study

    n: not reported in source

    Comparator
    semaglutide
    Outcome group
    Liver fat and liver function · Liver
    Studied dose
    Dose not stated

    Measurements

    Published original-orientation HR
    0.77
    semaglutide versus liraglutide; not inverted
    95% CI
    0.57 to 1.05
    original orientation; no reverse test

    Source sentences

    Summary
    Semaglutide was not associated with a reduced risk compared with liraglutide (HR 0.77 [95% CI 0.57, 1.05]).
    5 context sentences
    Summary · context
    We emulated target trials based on a real-world network of electronic health records (EHRs) from over 150 million patients.
    Summary · context
    Three target trials were emulated, among eligible patients with T2D who had no prior MALO diagnosis, by comparing therapy involving tirzepatide, semaglutide, and liraglutide versus DPP4 inhibitor (DPP4i) therapy.
    Summary · context
    We identified the first-ever diagnosis of MALO occurring within a 2-year follow-up period and compared across the treatment groups using Kaplan-Meier survival analyses.
    Summary · context
    Cohorts underwent propensity score matching 1:1 for confounders.
    Summary · context
    We also performed head-to-head analyses of the incretin-based therapies.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 4Current

    12 Oct 2026, 11:11 UTC

    Study results updated

  2. Versions 2 to 3

    9 Oct 2026, 03:07 UTC

    The same notice was added 2 times, first on 9 Oct 2026, 03:06 UTC. The status did not change between them.

    Study data updated · source update from Europe PMC

  3. Version 1

    9 Oct 2026, 03:04 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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