Emulating the LEADER trial in China: a regulatory science case study on non-interventional research

Area of Science:

• Cardiovascular Safety Research
• Real-World Evidence (RWE) in Clinical Trials
• Pharmacovigilance and Drug Safety

Background:

• Real-world evidence (RWE) requires validation against randomized controlled trials (RCTs) for regulatory use.
• Emulating RCTs with claims data presents methodological and operational challenges.
• Understanding liraglutide's cardiovascular safety is crucial for diabetes management.

Purpose of the Study:

• To emulate the LEADER trial using Chinese claims data to assess liraglutide's cardiovascular safety.
• To evaluate the concordance between RWE and RCT findings for liraglutide.
• To examine challenges in emulating RCTs with real-world claims data.

Main Methods:

• Emulated the LEADER trial protocol using the Beijing Municipal Medical Insurance Database (2020-2024).
• Identified new users of liraglutide and dipeptidyl peptidase-4 inhibitors (DPP4i) as active comparators.
• Utilized propensity score matching, Cox proportional hazards models, and negative control outcomes to assess cardiovascular safety and confounding.

Main Results:

• The study included 17,772 patients, with a median follow-up of 35 months.
• Liraglutide showed a trend toward reduced 3-point Major Adverse Cardiovascular Events (MACE) risk (HR 0.90; P=0.063) compared to DPP4i.
• Sensitivity analyses indicated potential benefits and confirmed the absence of unmeasured confounding, aligning with LEADER trial findings.

Conclusions:

• This target trial emulation study validated liraglutide's cardiovascular safety profile, demonstrating non-inferiority to DPP-4 inhibitors for MACE risk.
• While the primary analysis showed a trend towards benefit, sensitivity analyses supported the robustness of liraglutide's safety findings.
• The study highlights the feasibility and challenges of using claims data for emulating RCTs to inform regulatory decision-making.