Key result
Adding GLP-1RA to SGLT-2i linked to ~20% lower 2-year risk of death, MI, or stroke vs DPP-4i.
Why the study?
SGLT-2 inhibitors and GLP-1 receptor agonists both reduce major cardiovascular events in type 2 diabetes and are increasingly used together, but whether adding GLP-1RA to background SGLT-2i therapy provides incremental cardiovascular benefit beyond SGLT-2i alone remained uncertain.
Does initiation of GLP-1RA as add-on therapy to SGLT-2i reduce major adverse cardiovascular events compared with DPP-4i in adults with type 2 diabetes?
Observational (n=79,792)
Yes
Does initiation of GLP-1RA as add-on therapy to SGLT-2i reduce major adverse cardiovascular events compared with DPP-4i in adults with type 2 diabetes?
In adults with type 2 diabetes already receiving SGLT-2 inhibitors, adding a GLP-1 receptor agonist significantly reduces major adverse cardiovascular events compared with adding a DPP-4 inhibitor, supporting combination therapy to reduce residual cardiovascular risk.
Answers are grounded in this paper and cite their sources.
May support GLP-1RA over DPP-4i but should not change practice; leaves open RCT confirmation.
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.
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Montealegre et al. (2026) conducted an observational in Type 2 diabetes (n=79,792). GLP-1RA add-on therapy (87% semaglutide) to background SGLT-2i vs. DPP-4i add-on therapy (94% alogliptin) to background SGLT-2i was evaluated on Composite of all-cause death, myocardial infarction, or stroke over up to 2 years (HR 0.80, 95% CI 0.63-0.99). Add-on GLP-1RA to background SGLT-2i reduced the 2-year risk of all-cause death, MI, or stroke vs DPP-4i (HR 0.80; 95% CI 0.63-0.99; ARR 1.57%).
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