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Study · Systematic review · 2026

10 results

Dose-Escalation Regimens for Incretin Mimetics in Type 2 Diabetes Are Associated With Tolerance for Nausea and Vomiting.

Nauck MA, Punov V, Kang YM, Lim S

Diabetes, obesity & metabolism27 Feb 2026Cited by 1 (Europe PMC)

PMID41757397 (opens in a new tab)PMCIDPMC13071187 (opens in a new tab)DOI10.1111/dom.70613 (opens in a new tab)PepBankPUB-41757397
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Summary

Aims/hypothesisInitial dose-escalation has been shown to mitigate gastrointestinal adverse events in people treated with incretin-based medications. We aimed to analyse dose-response relationships for the proportion of study participants reporting nausea and vomiting among those exposed to incretin mimetics approved for Type 2 diabetes (GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide) in Phase 1 (no or short dose escalation) and Phase 3 (with dose escalation) trials.MethodsNon-linear regression analysis (curve fitting) was used to estimate the dose that would elicit nausea or vomiting in 50% of exposed subjects (ED50). We used the ratio of ED50ies determined for Phase 1 and Phase 3 trials as an indicator of developing tolerance.ResultsThe development of tolerance for nausea and vomiting (indicated by a ratio of ED50ies Phase 3/Phase 1) for semaglutide (both s.c. and oral) and for tirzepatide was significantly higher than 1. Comparing all approved incretin-based medications, a higher ratio, indicating the development of more tolerance, was associated with (a) a longer drug escalation period and (b) a greater number of dose-escalation steps. This ED50 ratio (Phase 3/Phase 1) was also significantly associated with effect sizes for intended therapeutic actions of incretin mimetics (reductions in HbA1c and body weight).Conclusions/interpretationTaken together, optimised dose-escalation regimens may lead to greater tolerance for nausea and vomiting, which allows to use of higher doses, which are associated with greater therapeutic effectiveness.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study10

2 results from studies that gave the peptide. 2 results from people.

  1. 01HumanSystematic reviewSafety outcome

    In trials in type 2 diabetes, the ED50 ratio of Phase 3 to Phase 1 for nausea and vomiting with semaglutide (subcutaneous and oral) was significantly higher than 1, indicating development of tolerance.

    In plain wordsIn diabetes trials, people tolerated nausea and vomiting from semaglutide better when the dose was raised stepwise.

    Peptide
    Semaglutide
    Outcome
    IncreaseTolerance to nausea and vomiting (ED50 ratio Phase 3/Phase 1)
    Study

    n: not reported in source

    Outcome group
    Gastrointestinal adverse events · Gastrointestinal
    Studied dose
    Dose not stated · subcutaneous and oralAs given in this study (human).

    Source sentences

    Summary
    The development of tolerance for nausea and vomiting (indicated by a ratio of ED50ies Phase 3/Phase 1) for semaglutide (both s.c. and oral) and for tirzepatide was significantly higher than 1.
    1 context sentence
    Summary · context
    We aimed to analyse dose-response relationships for the proportion of study participants reporting nausea and vomiting among those exposed to incretin mimetics approved for Type 2 diabetes (GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide) in Phase 1 (no or short dose escalation) and Phase 3 (with dose escalation) trials.
  2. 02HumanSystematic reviewSafety outcome

    In trials in type 2 diabetes, the ED50 ratio of Phase 3 to Phase 1 for nausea and vomiting with tirzepatide was significantly higher than 1, indicating development of tolerance.

    In plain wordsIn diabetes trials, people tolerated nausea and vomiting from tirzepatide better when the dose was raised stepwise.

    Peptide
    Tirzepatide
    Outcome
    IncreaseTolerance to nausea and vomiting (ED50 ratio Phase 3/Phase 1)
    Study

    n: not reported in source

    Outcome group
    Gastrointestinal adverse events · Gastrointestinal
    Studied dose
    Dose not stated

    Source sentences

    Summary
    The development of tolerance for nausea and vomiting (indicated by a ratio of ED50ies Phase 3/Phase 1) for semaglutide (both s.c. and oral) and for tirzepatide was significantly higher than 1.
    1 context sentence
    Summary · context
    We aimed to analyse dose-response relationships for the proportion of study participants reporting nausea and vomiting among those exposed to incretin mimetics approved for Type 2 diabetes (GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide) in Phase 1 (no or short dose escalation) and Phase 3 (with dose escalation) trials.

Studies that did not test the peptide alone8

In this study, the peptide was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking the peptide.

  1. 03HumanNot a test of Semaglutide aloneSystematic reviewOther

    Across all approved incretin-based medications pooled, a higher ED50 ratio was associated with a longer drug escalation period.

    In plain wordsAcross all approved incretin-based drugs together, more tolerance to nausea and vomiting went with a longer dose escalation period.

    Peptide
    Semaglutide
    Outcome
    IncreaseAssociation of ED50 ratio with length of dose escalation, all incretin-based medications
    Study

    n: not reported in source

    Outcome group
    Gastrointestinal adverse events · Gastrointestinal

    Source sentences

    Summary
    Comparing all approved incretin-based medications, a higher ratio, indicating the development of more tolerance, was associated with (a) a longer drug escalation period
    1 context sentence
    Summary · context
    We aimed to analyse dose-response relationships for the proportion of study participants reporting nausea and vomiting among those exposed to incretin mimetics approved for Type 2 diabetes (GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide) in Phase 1 (no or short dose escalation) and Phase 3 (with dose escalation) trials.

    In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.

  2. 04HumanNot a test of Tirzepatide aloneSystematic reviewOther

    Across all approved incretin-based medications pooled, a higher ED50 ratio was associated with a longer drug escalation period.

    In plain wordsAcross all approved incretin-based drugs together, more tolerance to nausea and vomiting went with a longer dose escalation period.

    Peptide
    Tirzepatide
    Outcome
    IncreaseAssociation of ED50 ratio with length of dose escalation, all incretin-based medications
    Study

    n: not reported in source

    Outcome group
    Gastrointestinal adverse events · Gastrointestinal

    Source sentences

    Summary
    Comparing all approved incretin-based medications, a higher ratio, indicating the development of more tolerance, was associated with (a) a longer drug escalation period
    1 context sentence
    Summary · context
    We aimed to analyse dose-response relationships for the proportion of study participants reporting nausea and vomiting among those exposed to incretin mimetics approved for Type 2 diabetes (GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide) in Phase 1 (no or short dose escalation) and Phase 3 (with dose escalation) trials.

    In this study, Tirzepatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Tirzepatide.

  3. 05HumanNot a test of Semaglutide aloneSystematic reviewOther

    Across all approved incretin-based medications pooled, a higher ED50 ratio was associated with a greater number of dose-escalation steps.

    In plain wordsAcross all approved incretin-based drugs together, more tolerance to nausea and vomiting went with more dose-escalation steps.

    Peptide
    Semaglutide
    Outcome
    IncreaseAssociation of ED50 ratio with number of dose-escalation steps, all incretin-based medications
    Study

    n: not reported in source

    Outcome group
    Gastrointestinal adverse events · Gastrointestinal

    Source sentences

    Summary
    (b) a greater number of dose-escalation steps.
    1 context sentence
    Summary · context
    We aimed to analyse dose-response relationships for the proportion of study participants reporting nausea and vomiting among those exposed to incretin mimetics approved for Type 2 diabetes (GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide) in Phase 1 (no or short dose escalation) and Phase 3 (with dose escalation) trials.

    In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.

  4. 06HumanNot a test of Tirzepatide aloneSystematic reviewOther

    Across all approved incretin-based medications pooled, a higher ED50 ratio was associated with a greater number of dose-escalation steps.

    In plain wordsAcross all approved incretin-based drugs together, more tolerance to nausea and vomiting went with more dose-escalation steps.

    Peptide
    Tirzepatide
    Outcome
    IncreaseAssociation of ED50 ratio with number of dose-escalation steps, all incretin-based medications
    Study

    n: not reported in source

    Outcome group
    Gastrointestinal adverse events · Gastrointestinal

    Source sentences

    Summary
    (b) a greater number of dose-escalation steps.
    1 context sentence
    Summary · context
    We aimed to analyse dose-response relationships for the proportion of study participants reporting nausea and vomiting among those exposed to incretin mimetics approved for Type 2 diabetes (GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide) in Phase 1 (no or short dose escalation) and Phase 3 (with dose escalation) trials.

    In this study, Tirzepatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Tirzepatide.

  5. 07HumanNot a test of Semaglutide aloneSystematic reviewOther

    Across incretin mimetics pooled, the ED50 ratio was significantly associated with the effect size for HbA1c reduction.

    In plain wordsAcross incretin drugs together, more tolerance to nausea and vomiting was linked to a larger drop in HbA1c.

    Peptide
    Semaglutide
    Outcome
    Not applicableAssociation of ED50 ratio with HbA1c reduction effect size, incretin mimetics
    Study

    n: not reported in source

    Outcome group
    Glycemic control · Metabolic and weight

    Source sentences

    Summary
    This ED50 ratio (Phase 3/Phase 1) was also significantly associated with effect sizes for intended therapeutic actions of incretin mimetics (reductions in HbA1c and body weight).
    1 context sentence
    Summary · context
    We aimed to analyse dose-response relationships for the proportion of study participants reporting nausea and vomiting among those exposed to incretin mimetics approved for Type 2 diabetes (GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide) in Phase 1 (no or short dose escalation) and Phase 3 (with dose escalation) trials.

    In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.

  6. 08HumanNot a test of Tirzepatide aloneSystematic reviewOther

    Across incretin mimetics pooled, the ED50 ratio was significantly associated with the effect size for HbA1c reduction.

    In plain wordsAcross incretin drugs together, more tolerance to nausea and vomiting was linked to a larger drop in HbA1c.

    Peptide
    Tirzepatide
    Outcome
    Not applicableAssociation of ED50 ratio with HbA1c reduction effect size, incretin mimetics
    Study

    n: not reported in source

    Outcome group
    Glycemic control · Metabolic and weight

    Source sentences

    Summary
    This ED50 ratio (Phase 3/Phase 1) was also significantly associated with effect sizes for intended therapeutic actions of incretin mimetics (reductions in HbA1c and body weight).
    1 context sentence
    Summary · context
    We aimed to analyse dose-response relationships for the proportion of study participants reporting nausea and vomiting among those exposed to incretin mimetics approved for Type 2 diabetes (GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide) in Phase 1 (no or short dose escalation) and Phase 3 (with dose escalation) trials.

    In this study, Tirzepatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Tirzepatide.

  7. 09HumanNot a test of Semaglutide aloneSystematic reviewOther

    Across incretin mimetics pooled, the ED50 ratio was significantly associated with the effect size for body weight reduction.

    In plain wordsAcross incretin drugs together, more tolerance to nausea and vomiting was linked to a larger weight loss.

    Peptide
    Semaglutide
    Outcome
    Not applicableAssociation of ED50 ratio with body weight reduction effect size, incretin mimetics
    Study

    n: not reported in source

    Outcome group
    Body weight · Metabolic and weight

    Source sentences

    Summary
    This ED50 ratio (Phase 3/Phase 1) was also significantly associated with effect sizes for intended therapeutic actions of incretin mimetics (reductions in HbA1c and body weight).
    1 context sentence
    Summary · context
    We aimed to analyse dose-response relationships for the proportion of study participants reporting nausea and vomiting among those exposed to incretin mimetics approved for Type 2 diabetes (GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide) in Phase 1 (no or short dose escalation) and Phase 3 (with dose escalation) trials.

    In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.

  8. 10HumanNot a test of Tirzepatide aloneSystematic reviewOther

    Across incretin mimetics pooled, the ED50 ratio was significantly associated with the effect size for body weight reduction.

    In plain wordsAcross incretin drugs together, more tolerance to nausea and vomiting was linked to a larger weight loss.

    Peptide
    Tirzepatide
    Outcome
    Not applicableAssociation of ED50 ratio with body weight reduction effect size, incretin mimetics
    Study

    n: not reported in source

    Outcome group
    Body weight · Metabolic and weight

    Source sentences

    Summary
    This ED50 ratio (Phase 3/Phase 1) was also significantly associated with effect sizes for intended therapeutic actions of incretin mimetics (reductions in HbA1c and body weight).
    1 context sentence
    Summary · context
    We aimed to analyse dose-response relationships for the proportion of study participants reporting nausea and vomiting among those exposed to incretin mimetics approved for Type 2 diabetes (GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide) in Phase 1 (no or short dose escalation) and Phase 3 (with dose escalation) trials.

    In this study, Tirzepatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Tirzepatide.

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 3Current

    11 Oct 2026, 00:04 UTC

    Study results updated

  2. Version 2

    9 Oct 2026, 03:07 UTC

    Study data updated · source update from Europe PMC

  3. Version 1

    9 Oct 2026, 03:06 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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