What does this research mean for the field?

In real-world clinical practice, GLP-1 receptor agonists reduce major adverse cardiovascular events in type 2 diabetes patients at high cardiovascular risk, but do not provide cardiovascular event reduction in lower-risk patients who do not meet LEADER trial inclusion criteria. Novelty: ClaimNovelty.CONFIRMATORY. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

What question did this study set out to answer?

The aim is to evaluate whether the cardioprotective effects of GLP-1RA observed in the LEADER trial apply to a real-world population, including those at lower cardiovascular risk.

June 7, 2026

2202-P: The Cardioprotective Effect of Glucagon-Like Peptide 1 Receptor Agonist in a Trial Inspired, and Wider, Population Individuals Living with Type 2 Diabetes: A Target Trial Emulation Study in CPRD

Key Points

The aim is to evaluate whether the cardioprotective effects of GLP-1RA observed in the LEADER trial apply to a real-world population, including those at lower cardiovascular risk.
Emulated the LEADER RCT using individuals with type 2 diabetes from CPRD, comparing GLP-1RA and DPP4i users.
Applied LEADER inclusion criteria to identify a trial-matched sample and a non-trial population.
Utilized longitudinal targeted maximum likelihood estimation to model 3-point MACE risk.
Cumulative risk of MACE was 5.7% for GLP-1RA versus 7.1% for DPP4i within the trial-matched group (risk ratio 0.8, 95% CI 0.79 to 0.83).
In the non-trial population, MACE risk was 3.4% for both groups (risk ratio 1.0, 95% CI 1.0 to 1.01).
No cardiovascular event reduction was observed in individuals not meeting LEADER criteria.

Abstract

Introduction and Objective: The LEADER randomised controlled trial (RCT) demonstrated a reduction in 3-point MACE with GLP-1RA in people with type 2 diabetes at high cardiovascular risk compared to placebo. Whether these benefits translate in the real-world, or in those at lower cardiovascular risk, is uncertain. We emulated the LEADER RCT in individuals with type 2 diabetes from the UK Clinical Practice Research Datalink (CPRD) using DPP4i as a control drug. Methods: Individuals prescribed GLP-1RA or DPP4i within CPRD were identified and LEADER inclusion criteria were applied to identify a trial-based sample, and individuals who did not meet these criteria were entered into a non-trial group. In both groups, we used longitudinal targeted maximum likelihood estimation (LTMLE) to model the risk of 3-point MACE, adjusting for baseline and time-varying covariates. Results: In total, 306,930 individuals-initiated treatment with either GLP-1RA or DPP4i with 23,401 in the trial-matched sample and 141,286 in the non-trial sample. The trial-matched population were younger than the non-trial population (60±13 vs 73±18), more likely to be female (49 vs 42%), and more likely to be white (81 vs 66%), with a lower HbA1c (71±17 vs 74±18). At 3 years, the cumulative risk of MACE in the trial-based population was 5.7% (95% CI, 6.4 to 7.7%) for GLP-1RA and 7.1% (4.6 to 6.9%) for DPP4i users representing a risk difference of -1.4% (-1.33 to -1.35%) and risk ratio of 0.8 (0.79 to 0.83). In the non-trial population, cumulative risk of MACE was 3.4% in both GLP-1RA and DPP4i users (0.28 to 0.40 and 0.32 to 0.36 respectively) with a risk difference of 0% (0 to 0%) and a risk ratio of 1.0 (1.0 to 1.01). Conclusion: In real-world use, GLP-1RA was associated with reduced MACE in individuals who met the LEADER trial inclusion criteria. There was no observed cardiovascular event reduction in individuals who do not meet these criteria. Disclosure J.J. Thomas: None. G. Martine-Edith: None. S. Gharibzadeh: None. A.I. Adler: None. J.K. Mader: Research Support; Current; A. Menarini Diagnostics. Advisory Panel; Current; Abbott Diabetes. Speaker's Bureau; Current; Abbott Diabetes. Advisory Panel; Current; Becton, Dickinson and Company. Speaker's Bureau; Current; Becton, Dickinson and Company. Advisory Panel; Current; Insulet Corporation, Eli Lilly and Company. Speaker's Bureau; Current; Eli Lilly and Company. Advisory Panel; Current; Sanofi. Speaker's Bureau; Current; Sanofi. Advisory Panel; Current; Novo Nordisk A/S. Speaker's Bureau; Current; Novo Nordisk A/S. Advisory Panel; Current; Roche Diagnostics. Speaker's Bureau; Current; Roche Diagnostics. Advisory Panel; Current; Medtronic, Tandem Diabetes Care, Inc., Omnipod. Stock/Shareholder; Current; decide Clinical Software GmbH. Advisory Panel; Current; Dexcom, Inc. Speaker's Bureau; Current; Dexcom, Inc., Sinocare, Buzud. Advisory Panel; Current; Biomea Fusion, Pharmasens. Stock/Shareholder; Current; elyte Diagnostics. Other - CMO (unpaid); Current; elyte Diagnostics. Speaker's Bureau; Current; A. Menarini Diagnostics. Board Member; Current; OMNIA by AI APS. Advisory Panel; Current; Triple Jump. K. Khunti: None. S. Misra: Other - Speaker honorarium for a single presentation at a conferences; Ended; A. Menarini Diagnostics, Lilly Diabetes. Advisory Panel; Ended; Insulet Corporation. Other - Speaker honoararium for a single presentation at a conferences; Ended; Sanofi. P. Choudhary: Advisory Panel; Current; Medtronic. Speaker's Bureau; Current; Medtronic. Research Support; Current; Medtronic. Consultant; Current; Medtronic. Speaker's Bureau; Current; Abbott. Advisory Panel; Current; Abbott. Research Support; Current; Abbott. Speaker's Bureau; Current; Dexcom, Inc. Advisory Panel; Current; Dexcom, Inc. Research Support; Current; Dexcom, Inc. Consultant; Current; Dexcom, Inc. Speaker's Bureau; Current; Insulet Corporation. Advisory Panel; Current; Insulet Corporation. Research Support; Current; Insulet Corporation. Consultant; Current; Insulet Corporation. Speaker's Bureau; Current; Sanofi. Consultant; Current; Sanofi. Speaker's Bureau; Current; Lilly. Advisory Panel; Current; Lilly. Consultant; Current; Lilly. Advisory Panel; Current; Ypsomed AG. Advisory Panel; Ended; Embecta. Speaker's Bureau; Current; Roche Diabetes Care. Research Support; Current; Roche Diabetes Care. Consultant; Current; Roche Diabetes Care. Advisory Panel; Current; Vertex Pharmaceuticals Incorporated. Consultant; Current; Glooko, Inc., Cambridge Mechatronics Ltd, vTv Therapeutics. Funding Funded by the European Union under contract number 101095556. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or European Health and Digital Executive Agency (HADEA). Neither the European Union nor the granting authority can be held responsible for them. This work has received funding from the UK Research and Innovation.

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