Adding GLP-1 Drugs to SGLT2 Inhibitors Cuts Death Risk by 57% in Heart Failure Patients With Diabetes | Research

The takeaway

In a propensity-matched study of over 46,000 heart failure patients with type 2 diabetes, adding a GLP-1 receptor agonist to an SGLT2 inhibitor reduced all-cause death by 57% and hospitalization by 13% compared to SGLT2 inhibitor alone.

57% lower death risk
All-cause mortality was 2.8% vs 6.3% at 1 year when GLP-1 receptor agonists were added to SGLT2 inhibitors in heart failure patients with type 2 diabetes

What the researchers found

After propensity score matching (23,240 patients per group), combining SGLT2 inhibitors with GLP-1 receptor agonists versus SGLT2 inhibitor monotherapy produced:

- All-cause death: 2.8% vs 6.3% (HR 0.43, 95% CI 0.39-0.48, p<0.001) — a 57% relative risk reduction

- Hospitalization: 32.9% vs 36.4% (HR 0.87, 95% CI 0.84-0.90, p<0.001) — a 13% relative risk reduction

These results were observed over a 1-year follow-up period in patients with both heart failure and type 2 diabetes.

Why it matters

Heart failure with diabetes is a devastating combination with very high mortality. While each drug class individually reduces cardiovascular risk, this study provides some of the first large-scale evidence that combining them yields dramatically better survival. A 57% reduction in death risk is a remarkable finding that could change how clinicians approach this common patient population.

How the study worked

Multicenter retrospective observational study using the TriNetX database (January 2018 – December 2021). From 928,981 patients with heart failure and type 2 diabetes, 168,422 received an SGLT2 inhibitor. The combination group initiated a GLP-1 RA within 6 months of starting an SGLT2i. Propensity score matching yielded 23,240 patients per group. Outcomes (all-cause death, hospitalization) were assessed over 1 year.

What this study cannot tell us

This is a retrospective observational study, so it cannot establish causation. Despite propensity score matching, residual confounding is possible — patients receiving combination therapy may have been healthier or had better healthcare access. The 57% mortality reduction is larger than typically seen in randomized trials, suggesting possible selection bias. The TriNetX database may not capture all relevant clinical variables. No differentiation was made between specific GLP-1 RAs or SGLT2is.

How to read the evidence

This is a large retrospective observational study using propensity score matching from a multicenter database. While the sample size is very large and the matching methodology is robust, the observational design cannot fully account for unmeasured confounders, and the magnitude of benefit may be influenced by selection bias.

When this study was published

Published in 2025, this study addresses one of the most pressing current questions in cardio-diabetology and provides timely evidence for combination therapy strategies.

The bigger picture

This study addresses a critical question in modern cardio-diabetology: whether the combination of SGLT2 inhibitors and GLP-1 receptor agonists provides additive benefit. The striking mortality reduction supports the concept that these drug classes work through complementary mechanisms — SGLT2i primarily through fluid and hemodynamic effects, GLP-1 RA through metabolic, anti-inflammatory, and cardiovascular pathways. This could accelerate adoption of dual therapy in guidelines.

Questions still open

Will a randomized controlled trial confirm the magnitude of mortality benefit from SGLT2i + GLP-1 RA combination in heart failure?
Which specific combinations of SGLT2i and GLP-1 RA are most effective for heart failure patients with diabetes?
Does the combination benefit extend to heart failure patients without diabetes?

Common questions

Why combine SGLT2 inhibitors and GLP-1 drugs instead of using just one?

These two drug classes work through different mechanisms. SGLT2 inhibitors primarily reduce fluid overload and improve heart hemodynamics, while GLP-1 receptor agonists address metabolic dysfunction, reduce inflammation, and provide cardiovascular protection through separate pathways. This study suggests the complementary mechanisms produce substantially better outcomes together — patients on both drugs had less than half the death rate of those on an SGLT2 inhibitor alone.

Is a 57% reduction in death risk reliable from this type of study?

While the magnitude of benefit is striking, it's important to note this is an observational study, not a randomized trial. Patients who received both drugs may have been healthier overall or had better access to care, which could inflate the apparent benefit. Randomized trials are needed to confirm the exact magnitude. However, the very large sample size and consistent statistical significance strongly suggest a real benefit from combination therapy.

Read the original research

Combination therapy with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in heart failure patients with type 2 diabetes.

BMJ open diabetes research & care, 13(6)

View on PubMed ↗Publisher’s paper ↗

Citation

Kishimori, Takefumi; Kato, Takao; Wada, Atsuyuki; Tani, Akira; Yamaji, Ryosuke; Koike, Jumpei; Iwasaki, Yoshihiro; Matsumoto, Takahiro; Yagi, Takafumi; Okada, Masaharu. (2025). Combination therapy with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in heart failure patients with type 2 diabetes.. BMJ open diabetes research & care, 13(6). https://doi.org/10.1136/bmjdrc-2025-005364