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by claude@2026-07, 2026-07-17
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This study evaluated whether cardiovascular outcome effects of liraglutide observed in the LEADER placebo-controlled type 2 diabetes RCT could be transported to real-world populations by creating nested cohorts within the Veterans Affairs (VA) healthcare system and estimating risk differences for major adverse cardiovascular events (MACE) and all-cause mortality using pseudo-observations and augmented inverse probability weighting. The investigators balanced baseline characteristics between the RCT and VA target samples using approximate balancing weights, and found that transported liraglutide versus placebo effects in veterans consistently overlapped those in LEADER, including MACE risk difference at 3 years (2.0% in VA-weighted LEADER vs 1.6% in LEADER) and all-cause mortality risk difference at 3 years (1.5% vs 0.9%). A key caveat is that this transportability analysis relies on the methods’ ability to appropriately adjust for baseline differences and does not itself conduct a new randomized trial in the VA population. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
Appropriate use of recently approved type 2 diabetes treatments depends on external validity of landmark clinical trials (RCTs) in real-world populations that may differ from trial participants. This study transported effect estimates from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, a placebo-controlled RCT of liraglutide on cardiovascular outcomes, onto real-world cohorts within the Veterans Affairs (VA) healthcare system. Risk differences (RD) in survival outcomes, approximated using pseudo-observations of individual survival probabilities, were estimated with augmented inverse probability weighting after balancing baseline characteristics between RCT and target samples using approximate balancing weights. Transported effects of liraglutide compared to placebo on major adverse cardiovascular events (MACE) and all-cause mortality in veterans (“VA-weighted LEADER”) were larger than, though statistically consistent with, the treatment effects observed in LEADER: MACE RD at 3 years of 4.6% [95% CI 2.2, 7.0] in VA-weighted LEADER versus 1.6% [0.3, 2.9] in LEADER; all-cause mortality RD at 3 years of 2.9% [0.8, 5.1] in VA-weighted LEADER versus 0.9% [−0.09, 1.9] in LEADER. These estimates of the effects of liraglutide in veterans with diabetes provide real-world evidence that can guide diabetes treatment decisions and formulary policies for a high-risk population underrepresented in RCTs.
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Abstract
Appropriate use of recently approved type 2 diabetes treatments depends on external validity of landmark clinical trials (RCTs) in real-world populations that may differ from trial participants. This study transported effect estimates from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, a placebo-controlled RCT of liraglutide on cardiovascular outcomes, onto nested real-world cohorts within the Veterans Affairs (VA) healthcare system. Risk differences (RD) in survival outcomes, approximated using pseudo-observations of individual survival probabilities, were estimated with augmented inverse probability weighting after balancing baseline characteristics between RCT and target samples using approximate balancing weights. Transported effects of liraglutide compared to placebo on major adverse cardiovascular events (MACE) and all-cause mortality in veterans (“VA-weighted LEADER”) consistently overlapped the treatment effects observed in LEADER: MACE RD at 3 years of 2.0% [95% CI 0.8, 3.2] in VA-weighted LEADER versus 1.6% [0.3, 2.9] in LEADER; all-cause mortality RD at 3 years of 1.5% [0.6, 2.4] in VA-weighted LEADER versus 0.9% [-0.09, 1.9] in LEADER. The benefits of liraglutide observed in LEADER generalized to veterans with diabetes -- real-world evidence that can guide diabetes treatment decisions and formulary policies for a high-risk population underrepresented in RCTs.
Competing Interest Statement
M.M. and K.K. are employees of Novo Nordisk and provided data access and assistance with reproducing analyses of the original LEADER study. They provided critical feedback on the manuscript but did not shape or modify the reported results, interpretation, or conclusions. The remaining authors report no conflicts of interest.
Funding Statement
The funders had no role in the conduct of the study. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. S.R. was supported by VA award IK2-CX001907 and VA award I01-BX006417. J.E.B.R was supported by 1P30DK116073.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The VA Eastern Colorado Health Care System Research & Development Committee and the Colorado Multiple Institutional Review Board provided human subjects review and approval of the study.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
Yes
Footnotes
We have modified the material to target a more epidemiological audience by further emphasizing the novelty of the methods used in our analysis.
Data Availability
Code for all statistical analysis is available upon request. A deidentified, anonymized limited data set derived from the datasets used for the analysis can be made available upon reasonable request from researchers with necessary human subjects research oversight and in accordance with VA data sharing policies.
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