Kardiologia polskaJan 7, 2026

Four-drug treatment combining SGLT2 inhibitors, GLP-1 receptor agonists, ARNI, and MRA in heart failure patients with preserved pumping and type 2 diabetes

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 8, 2026

Abstract

During a median follow-up of 54 months, quadruple combination therapy significantly reduced major adverse cardiovascular events in patients with HFpEF and type 2 diabetes mellitus.

Participants receiving quadruple therapy (SGLT2i, GLP-1RA, ARNI, and MRA) had lower rates of major adverse cardiovascular events (79 out of 174) compared to other combinations.
Quadruple therapy was associated with a reduction in cardiovascular mortality (46 out of 174) and improved left ventricular ejection fraction or heart failure category transitions.
Higher levels of N-terminal pro-B-type natriuretic peptide were identified as an independent risk factor for adverse outcomes.
In patients with an ejection fraction of less than 60%, quadruple therapy led to a lower incidence of composite endpoint events compared to those with an ejection fraction over 60%.

Simplified

BACKGROUND: Treatments for heart failure with preserved ejection fraction (HFpEF) remain inconclusive.

AIMS: We aim to explore in this prospective and observational cohort study that how combined therapy with sodium-dependent glucose transporters 2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), angiotensin receptor-neprilysin inhibitor (ARNI) or mineralocorticoid receptor antagonists (MRA) impact clinical outcomes in HFpEF patients with type 2 diabetes mellitus (T2DM).

MATERIAL AND METHODS: We enrolled 1445 HFpEF patients with T2DM from a prospective cohort between October 2018 and October 2022. The patients were divided into five groups based on their medications at 3 months after discharge: defined as a combination of SGLT2i, GLP-1RA, ARNI and MRA. The primary outcome is the major adverse cardiovascular (CV) events (MACEs), corresponding to the CV mortality and/or HF rehospitalization. The secondary outcome is the CV mortality as well as the left ventricular ejection fraction (LVEF) change or HF category transitions.

RESULTS: During a median follow-up period of 54 (27-75) months, participants with quadruple combination shows the most benefits, corresponding to MACEs (79/174; P <0.001), CV mortality (46/174; P = 0.03), LVEF change or HF transitions. Quadruple combination was a protective factor for MACEs, while higher N-terminal pro-B-type natriuretic peptide level was an independent risk factor. For participants with LVEF less than 60%, quadruple combination reduced incidence of composite endpoints events than those with LVEF over 60%.

CONCLUSIONS: The quadruple combination therapy with SGLT2i, GLP-1RA, ARNI and MRA in HFpEF patients with T2DM was associated with favorable clinical outcomes, especially in participants with LVEF less than 60%.

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Four-drug treatment combining SGLT2 inhibitors, GLP-1 receptor agonists, ARNI, and MRA in heart failure patients with preserved pumping and type 2 diabetes

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