Surrogate endpoint evaluation using data from one large global randomized controlled trial.

Geybels M, Wolthers BO, Kreiner FF, Rasmussen S, Bauer R

BMC medical informatics and decision making20 May 2021Cited by 2 (Europe PMC)

PMID34016120PMCIDPMC8139150DOI10.1186/s12911-021-01516-8PepBankPUB-34016120

Summary

BackgroundRobust identification of surrogate endpoints can help accelerate the development of pharmacotherapies for diseases traditionally evaluated using true endpoints associated with prolonged follow-up. The meta-analysis-based surrogate endpoint evaluation (SEE) integrates data from multiple, usually smaller, trials to statistically confirm a surrogate endpoint as a robust proxy for the true endpoint. To test the applicability of SEE when only a single, larger trial is available, we analysed the cardiovascular (CV) survival endpoint from the large multinational trial LEADER (9340 subjects) that confirmed the CV safety of a diabetes drug (liraglutide). We evaluated if using country as a trial unit adequately facilitated the meta-analysis and calculation of R² by country group.MethodsData were grouped by country, ensuring at least 30 CV deaths (497 in total) in each of the nine resulting by-country groups. In a two-step SEE on the grouped dataset, we first fitted the group-specific Cox proportional hazard models; next, on the trial-level, we regressed the estimated hazard ratio (HR; liraglutide vs placebo) of the true endpoints (CV death: 497 events, or all-cause death: 828 events) on the HR of the surrogate endpoint (major CV adverse event [MACE]: 1302 events) and derived the group-specific R² and its 95% confidence interval (CI).ResultsGroup-level surrogacy of MACE was supported for CV death but not for all-cause death, with [Formula: see text] values of 0.85 [0.63;1.00]_{95% CI} and 0.23 [0.00;0.67]_{95% CI}, respectively. Sensitivity analyses using different grouping approaches (e.g. grouping by region) corroborated the robustness of the conclusions as well as the appropriateness of the data-grouping approaches.ConclusionsWe derived a specific grouping approach to successfully apply SEE on data from a single trial. This may allow for the statistically robust identification and validation of surrogate endpoints based on the abundance of large monolithic outcome trials conducted as part of drug development programmes in, for example, diabetes.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study2

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone2

In this study, Liraglutide 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 Liraglutide.

01HumanNot a test of Liraglutide aloneRandomized controlled trialOther
In a reanalysis of the LEADER trial of liraglutide versus placebo, MACE was supported as a group-level surrogate for cardiovascular death (R2 0.85, 95% CI 0.63 to 1.00).
In plain wordsIn a reanalysis of a liraglutide trial, major cardiovascular events worked well as a stand-in for cardiovascular death. This is not a drug effect.
Peptide
Liraglutide
Outcome
Not applicableGroup-level surrogacy of MACE for cardiovascular death (R2)
Study
n = 9,340
Comparator
Placebo
Outcome group
Overall treatment effect · Cardiovascular
Measurements
R2
0.85 ratio
MACE vs CV death
Source sentences
Summary
Group-level surrogacy of MACE was supported for CV death but not for all-cause death, with [Formula: see text] values of 0.85 [0.63;1.00]_{95% CI}
1 context sentence(design, population, supporting numbers)
Summary · context
To test the applicability of SEE when only a single, larger trial is available, we analysed the cardiovascular (CV) survival endpoint from the large multinational trial LEADER (9340 subjects) that confirmed the CV safety of a diabetes drug (liraglutide).
In this study, Liraglutide 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 Liraglutide.
Show in the study text Report a problemFND-3401612001
02HumanNot a test of Liraglutide aloneRandomized controlled trialOther
In a reanalysis of the LEADER trial of liraglutide versus placebo, MACE was not supported as a group-level surrogate for all-cause death (R2 0.23, 95% CI 0.00 to 0.67).
In plain wordsIn a liraglutide trial reanalysis, major cardiovascular events did not predict death from any cause well. This is not a drug effect.
Peptide
Liraglutide
Outcome
Not applicableGroup-level surrogacy of MACE for all-cause death (R2)
Study
n = 9,340
Comparator
Placebo
Outcome group
Overall treatment effect · Cardiovascular
Measurements
R2
0.23 ratio
MACE vs all-cause death
Source sentences
Summary
Group-level surrogacy of MACE was supported for CV death but not for all-cause death, with [Formula: see text] values of 0.85 [0.63;1.00]_{95% CI} and 0.23 [0.00;0.67]_{95% CI}, respectively.
1 context sentence(design, population, supporting numbers)
Summary · context
To test the applicability of SEE when only a single, larger trial is available, we analysed the cardiovascular (CV) survival endpoint from the large multinational trial LEADER (9340 subjects) that confirmed the CV safety of a diabetes drug (liraglutide).
In this study, Liraglutide 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 Liraglutide.
Show in the study text Report a problemFND-3401612002

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Version 2Current
12 Oct 2026, 11:11 UTC
Study results updated
Version 1
9 Oct 2026, 03:05 UTC
First added · source update from Europe PMC

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