Incremental cardiovascular benefit of GLP-1RA added to SGLT2i in type 2 diabetes: a target trial emulation in the US veterans health administration

Background/Introduction

SGLT-2 inhibitors (SGLT-2i) and GLP-1 receptor agonists (GLP-1RA) reduce major cardiovascular events in type 2 diabetes and are increasingly used together in clinical practice. Whether initiation of GLP-1RA as add-on therapy to SGLT-2i provides incremental cardiovascular benefit beyond SGLT-2i alone remains uncertain.

Purpose

To determine whether initiation of GLP-1RA as add-on therapy to SGLT-2i, compared with DPP-4i (a comparator with neutral cardiovascular effects), reduces major adverse cardiovascular events in adults with type 2 diabetes.

Methods

We emulated a target trial using national US Veterans Health Administration data (2013–2024). Adults with type 2 diabetes receiving background SGLT-2i who newly initiated GLP-1RA were compared with active-comparator new users of DPP-4i. Inverse probability of treatment and censoring weights were used to adjust for baseline and time-varying confounding in a marginal structural modeling framework. The primary analysis estimated the per-protocol effect. The primary outcome comprised the composite of all-cause death, myocardial infarction, or stroke over a follow-up of up to 2 years. Hospitalization for heart failure was a pre-specified secondary endpoint.

Results

Among 79,792 adults (53,339 GLP-1RA; 26,453 DPP-4i), the mean age was 65 years, and 39% had prevalent atherosclerotic cardiovascular disease. Background SGLT-2i use was predominantly empagliflozin (>99%). Eighty-seven percent of GLP-1RA initiators received semaglutide; 94% of DPP-4i initiators received alogliptin. After weighting, baseline characteristics were well balanced (all standardized mean differences <0.1).

GLP-1RA initiation was associated with a lower risk of the composite cardiovascular outcome compared with DPP-4i (HR 0.80; 95% CI 0.63, 0.99), corresponding to an absolute 2-year risk reduction of 1.57% (95% CI -3.06%, -0.04%). GLP-1RA was also associated with a lower risk of myocardial infarction (HR 0.68; 95% CI 0.50, 0.95). Associations for all-cause death (HR 0.81; 95% CI 0.62, 1.07), stroke (HR 0.73; 95% CI 0.49, 1.10), and hospitalization for heart failure (HR 0.75; 95% CI 0.58, 1.06) were directionally consistent but did not reach statistical significance. Findings were consistent across pre-specified high-risk subgroups, including body mass index, prevalent cardiovascular disease, and baseline AHA PREVENT 10-year cardiovascular-kidney-metabolic risk equation.

Conclusions

In this large target trial emulation of adults with type 2 diabetes receiving SGLT-2i therapy, add-on GLP-1RA was associated with significant reductions in major adverse cardiovascular events compared with DPP-4i, with consistent directional reductions across individual cardiovascular outcomes. These findings support combination GLP-1RA and SGLT-2i therapy as a strategy to further reduce residual cardiovascular risk in clinical practice.Figure