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Study · Systematic review · 2026

8 results

Comparative Efficacy and Safety of Glucagon Receptor Agonists on Metabolic Outcomes: A Network Meta-Analysis of Randomised Controlled Trials.

Abulehia A, Ayesh H, Ayesh O, Jaber D, Asad T, Itbaisha A, Abugharbieh H, Gharbia R, Abu-Hilal LH, Leon BGC

Endocrinology, diabetes & metabolism1 Mar 2026Cited by 1 (Europe PMC)

PMID41787737 (opens in a new tab)PMCIDPMC12963462 (opens in a new tab)DOI10.1002/edm2.70187 (opens in a new tab)PepBankPUB-41787737
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Summary

IntroductionGlucagon receptor agonists (GRAs) are an emerging class of therapies for obesity and type 2 diabetes, demonstrating encouraging metabolic and weight-reducing effects. Several investigational GRA-based agents, including retatrutide, cotadutide, mazdutide, and survodutide, have reported promising results across early and mid-phase clinical trials. This comprehensive meta-analysis evaluates the efficacy and safety of these agents in individuals with type 2 diabetes, overweight, or obesity.MethodsPubMed, Cochrane, Embase, and Scopus databases were systematically searched. Fourteen randomised controlled trials meeting the inclusion criteria were analysed using frequentist network meta-analysis. Random-effects models were applied to assess mean differences (MD) in weight change, both absolute and percent changes, HbA1c, adverse events, and discontinuation due to adverse events. Heterogeneity was quantified using the I2 statistic.ResultsRetatrutide demonstrated the greatest weight reduction versus placebo (MD -13.44 kg; 95% CI [-18.38, -8.51]), followed by survodutide (MD -10.74 kg; 95% CI [-15.68, -5.80]) and mazdutide (MD -6.47 kg; 95% CI [-10.71, -2.24]). Cotadutide showed the smallest and nonsignificant effect (MD -3.41 kg; 95% CI [-11.63, 4.81]). Regarding HbA1c reduction, retatrutide showed the largest effect, followed by survodutide, mazdutide, and cotadutide; however, only the effect of retatrutide reached statistical significance. In terms of safety, mazdutide demonstrated the most favourable tolerability profile, whereas retatrutide and cotadutide were associated with comparatively lower tolerability.ConclusionsRetatrutide and survodutide exhibit the most favourable efficacy profiles for obesity and T2DM, with acceptable safety. These findings support their potential clinical use and highlight the need for future head-to-head trials.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study8

8 results from studies that gave the peptide. 8 results from people.

  1. 01HumanSystematic reviewEfficacy outcome

    In a network meta-analysis of adults with type 2 diabetes, overweight or obesity, retatrutide showed the greatest weight reduction versus placebo (mean difference -13.44 kg).

    In plain wordsIn a pooled analysis of trials, retatrutide lowered body weight more than placebo, and more than the other agents compared.

    Peptide
    Retatrutide
    Outcome
    DecreaseWeight change versus placebo
    Study

    n: not reported in source

    Comparator
    Placebo
    Outcome group
    Body weight · Metabolic and weight
    Studied dose
    Dose not stated

    Measurements

    Mean difference in weight
    −13.44 kg
    retatrutide vs placebo

    Source sentences

    Summary
    Retatrutide demonstrated the greatest weight reduction versus placebo (MD -13.44 kg; 95% CI [-18.38, -8.51]
    1 context sentence
    Summary · context
    Fourteen randomised controlled trials meeting the inclusion criteria were analysed using frequentist network meta-analysis.
  2. 02HumanSystematic reviewEfficacy outcome

    In a network meta-analysis of adults with type 2 diabetes, overweight or obesity, survodutide reduced weight versus placebo (mean difference -10.74 kg).

    In plain wordsIn a pooled analysis of trials, survodutide lowered body weight more than placebo.

    Peptide
    Survodutide
    Outcome
    DecreaseWeight change versus placebo
    Study

    n: not reported in source

    Comparator
    Placebo
    Outcome group
    Body weight · Metabolic and weight
    Studied dose
    Dose not stated

    Measurements

    Mean difference in weight
    −10.74 kg
    survodutide vs placebo

    Source sentences

    Summary
    survodutide (MD -10.74 kg; 95% CI [-15.68, -5.80]
    1 context sentence
    Summary · context
    Fourteen randomised controlled trials meeting the inclusion criteria were analysed using frequentist network meta-analysis.
  3. 03HumanSystematic reviewEfficacy outcome

    In a network meta-analysis of adults with type 2 diabetes, overweight or obesity, mazdutide reduced weight versus placebo (mean difference -6.47 kg).

    In plain wordsIn a pooled analysis of trials, mazdutide lowered body weight more than placebo.

    Peptide
    Mazdutide
    Outcome
    DecreaseWeight change versus placebo
    Study

    n: not reported in source

    Comparator
    Placebo
    Outcome group
    Body weight · Metabolic and weight
    Studied dose
    Dose not stated

    Measurements

    Mean difference in weight
    −6.47 kg
    mazdutide vs placebo

    Source sentences

    Summary
    mazdutide (MD -6.47 kg; 95% CI [-10.71, -2.24]
    1 context sentence
    Summary · context
    Fourteen randomised controlled trials meeting the inclusion criteria were analysed using frequentist network meta-analysis.
  4. 04HumanSystematic reviewEfficacy outcome

    In a network meta-analysis, retatrutide showed the largest HbA1c reduction, and its effect reached statistical significance.

    In plain wordsIn a pooled analysis of trials, retatrutide lowered HbA1c the most among the agents compared, and this was statistically significant.

    Peptide
    Retatrutide
    Outcome
    DecreaseHbA1c reduction
    Study

    n: not reported in source

    Comparator
    Placebo
    Outcome group
    Glycemic control · Metabolic and weight
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Regarding HbA1c reduction, retatrutide showed the largest effect, followed by survodutide, mazdutide, and cotadutide; however, only the effect of retatrutide reached statistical significance.
    1 context sentence
    Summary · context
    Fourteen randomised controlled trials meeting the inclusion criteria were analysed using frequentist network meta-analysis.
  5. 05HumanSystematic reviewEfficacy outcome

    In a network meta-analysis, the HbA1c effect of survodutide did not reach statistical significance.

    In plain wordsIn a pooled analysis of trials, survodutide did not lower HbA1c by a statistically significant amount.

    Peptide
    Survodutide
    Outcome
    No significant changeHbA1c reduction
    Study

    n: not reported in source

    Comparator
    Placebo
    Outcome group
    Glycemic control · Metabolic and weight
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Regarding HbA1c reduction, retatrutide showed the largest effect, followed by survodutide, mazdutide, and cotadutide; however, only the effect of retatrutide reached statistical significance.
    1 context sentence
    Summary · context
    Fourteen randomised controlled trials meeting the inclusion criteria were analysed using frequentist network meta-analysis.
  6. 06HumanSystematic reviewEfficacy outcome

    In a network meta-analysis, the HbA1c effect of mazdutide did not reach statistical significance.

    In plain wordsIn a pooled analysis of trials, mazdutide did not lower HbA1c by a statistically significant amount.

    Peptide
    Mazdutide
    Outcome
    No significant changeHbA1c reduction
    Study

    n: not reported in source

    Comparator
    Placebo
    Outcome group
    Glycemic control · Metabolic and weight
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Regarding HbA1c reduction, retatrutide showed the largest effect, followed by survodutide, mazdutide, and cotadutide; however, only the effect of retatrutide reached statistical significance.
    1 context sentence
    Summary · context
    Fourteen randomised controlled trials meeting the inclusion criteria were analysed using frequentist network meta-analysis.
  7. 07HumanSystematic reviewSafety outcome

    In a network meta-analysis, mazdutide had the most favourable tolerability profile among the agents compared.

    In plain wordsIn a pooled analysis of trials, mazdutide was the best tolerated of the agents compared.

    Peptide
    Mazdutide
    Outcome
    Direction not reportedTolerability profile
    Study

    n: not reported in source

    Outcome group
    Adverse events · Whole body
    Studied dose
    Dose not stated

    Source sentences

    Summary
    mazdutide demonstrated the most favourable tolerability profile
    1 context sentence
    Summary · context
    Fourteen randomised controlled trials meeting the inclusion criteria were analysed using frequentist network meta-analysis.
  8. 08HumanSystematic reviewSafety outcome

    In a network meta-analysis, retatrutide was associated with comparatively lower tolerability.

    In plain wordsIn a pooled analysis of trials, retatrutide was less well tolerated than mazdutide.

    Peptide
    Retatrutide
    Outcome
    Direction not reportedTolerability profile
    Study

    n: not reported in source

    Outcome group
    Adverse events · Whole body
    Studied dose
    Dose not stated

    Source sentences

    Summary
    whereas retatrutide and cotadutide were associated with comparatively lower tolerability
    1 context sentence
    Summary · context
    Fourteen randomised controlled trials meeting the inclusion criteria were analysed using frequentist network meta-analysis.

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

    9 Oct 2026, 18:17 UTC

    Study results updated

  2. Versions 2 to 3

    9 Oct 2026, 03:06 UTC

    The same notice was added 2 times, first on 9 Oct 2026, 03:04 UTC. The status did not change between them.

    Study data updated · source update from Europe PMC

  3. Version 1

    9 Oct 2026, 02:47 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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