Clinical Outcomes Following GLP-1 Receptor Agonist Initiation With Versus Without Background SGLT2 Inhibitor Therapy in Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes: A Propensity-Matched Real-World Analysis

Q: What are the key findings of this study?

Background SGLT2i therapy at GLP-1 RA initiation was associated with lower 1-year all-cause mortality (HR 0.66, P<0.001) and MACE (HR 0.78, P<0.001) in patients with HFpEF and type 2 diabetes.

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes mellitus (T2DM) (n=55976). Intervention: GLP-1 receptor agonist initiation with background SGLT2 inhibitor therapy vs. GLP-1 receptor agonist initiation without background SGLT2 inhibitor therapy. Primary outcome: One-year all-cause mortality (HR 0.66, 95% CI 0.61–0.71, p=<0.001).

Q: What does this research mean for the field?

In patients with HFpEF and type 2 diabetes initiating GLP-1 receptor agonists, background SGLT2 inhibitor therapy is associated with significantly lower one-year all-cause mortality and major adverse cardiovascular events compared to initiation without SGLT2 inhibitors. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To evaluate clinical outcomes following GLP-1 receptor agonist initiation with versus without background SGLT2 inhibitor therapy in patients with heart failure with preserved ejection fraction and type 2 diabetes.

Vikash Jaiswal; Maciej Banach; Asmita Gera; Muhammad Hanif; Mrithika Sankar; Agata Magdalena Bielecka-Dabrowa

doi:10.5114/aoms/242373

November 6, 2026Archives of Medical ScienceOpen Access

Clinical Outcomes Following GLP-1 Receptor Agonist Initiation With Versus Without Background SGLT2 Inhibitor Therapy in Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes: A Propensity-Matched Real-World Analysis

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Key result

Background SGLT2i with GLP-1 RA linked to ~34% lower 1-year mortality in HFpEF and diabetes.

HR 0.66
95% CI 0.61–0.71
P<0.001
n=55,976

Why the study?

While SGLT2i improve heart failure outcomes and GLP-1 RA confer cardiometabolic benefit, clinical outcomes after GLP-1 RA initiation in HFpEF and type 2 diabetes according to background SGLT2i use remained uncertain.

Does GLP-1 receptor agonist initiation on a background of SGLT2 inhibitor therapy reduce 1-year all-cause mortality and major adverse cardiovascular events compared with GLP-1 receptor agonist initiation without background SGLT2 inhibitor therapy in adults with HFpEF and type 2 diabetes?

Key Points

To evaluate clinical outcomes following GLP-1 receptor agonist initiation with versus without background SGLT2 inhibitor therapy in patients with heart failure with preserved ejection fraction and type 2 diabetes.
Retrospective propensity score-matched cohort analysis using electronic health records from 82 healthcare organizations within the TriNetX network.
Identified patients with heart failure with preserved ejection fraction (LVEF ≥50%) and type 2 diabetes initiating GLP-1 receptor agonists with versus without background SGLT2 inhibitor treatment.
Analyzed 27,988 matched pairs followed for one year, incorporating 60-day landmark analyses and a negative-control falsification outcome.
Background SGLT2 inhibitor therapy was associated with lower one-year all-cause mortality (HR 0.66, 95% CI 0.61–0.71; P < 0.001) and major adverse cardiovascular events (HR 0.78, 95% CI 0.73–0.84; P < 0.001).
In 60-day landmark analyses, associations persisted for mortality (HR 0.68, 95% CI 0.63–0.75; P < 0.001) and MACE (HR 0.83, 95% CI 0.77–0.91; P < 0.001).
Background SGLT2 inhibitor use was associated with fewer heart failure exacerbations (HR 0.85, 95% CI 0.77–0.93; P = 0.001) and hospitalizations or emergency department visits (HR 0.84, 95% CI 0.74–0.94; P = 0.004).

Study Design

Type

Cohort (n=55,976)

Multicenter

Yes

Structured PICO

Does GLP-1 receptor agonist initiation on a background of SGLT2 inhibitor therapy reduce 1-year all-cause mortality and major adverse cardiovascular events compared with GLP-1 receptor agonist initiation without background SGLT2 inhibitor therapy in adults with HFpEF and type 2 diabetes?

P

Population

55,976 propensity-matched adults (mean age 66.7 years, ~51% female) with HFpEF (LVEF ≥50%) and type 2 diabetes initiating GLP-1 RA therapy, followed for 1 year.

E

Exposure

Initiation of GLP-1 receptor agonist (GLP-1 RA) therapy on a background of baseline SGLT2 inhibitor (SGLT2i) therapy, followed for 1 year

C

Comparator

Initiation of GLP-1 receptor agonist (GLP-1 RA) therapy without background SGLT2 inhibitor (SGLT2i) therapy, propensity-score matched 1:1 on 38 demographic, clinical, medication, and laboratory variables

O

Outcome

All-cause mortality and major adverse cardiovascular events (MACE, composite of myocardial infarction, ischemic stroke, and death) at 1 year after the index event (defined as 1 day after GLP-1 RA initiation), with 60-day landmark analyseshard clinical

Main Result

Hazard Ratio: 0.66 (95% CI 0.61–0.71)

p-value: p=<0.001

In a large propensity-matched real-world cohort of patients with HFpEF and type 2 diabetes initiating GLP-1 receptor agonist therapy, concomitant background SGLT2 inhibitor use was associated with a 34% lower hazard of 1-year all-cause mortality and a 22% lower hazard of MACE compared with initiating a GLP-1 receptor agonist without background SGLT2i.

Limitations

Retrospective EHR analysis subject to coding errors and residual confounding despite propensity matching
HFpEF identified via diagnosis codes and LVEF ≥50% without independent clinical adjudication
Drug dose, adherence, discontinuation, and specific GLP-1 RA agents were not fully characterized
Deaths occurring outside participating healthcare organizations may have been missed
Follow-up was limited to one year
Retrospective EHR analysis subject to coding errors, residual confounding, and treatment-selection bias despite propensity score matching and sensitivity analyses
HFpEF was identified using a diagnosis code and documented LVEF ≥50% without independent clinical adjudication
Drug dose, adherence, discontinuation, and specific GLP-1 RA agent were not fully characterized
Deaths occurring outside participating healthcare systems may be missed
Follow-up was limited to one year and available data do not permit mediation analyses

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Implication

May support combined SGLT2i and GLP-1 RA use in HFpEF with diabetes; hypothesis-generating, requiring randomized confirmation.

Abstract

Introduction SGLT2 inhibitors (SGLT2i) improve heart failure outcomes, and GLP-1 receptor agonists (GLP-1 RA) confer cardiometabolic benefit. However, outcomes after GLP-1 RA initiation according to background SGLT2i use remain uncertain. Material and Methods Using TriNetX, we compared GLP-1 RA initiation in patients with HFpEF and type 2 diabetes with versus without background SGLT2i. Cohorts were propensity-matched 1:1 and followed for one year, with 60-day landmark analyses. Results Among 27,988 matched pairs, background SGLT2i was associated with lower one-year all-cause mortality (HR 0.66, 95% CI 0.61–0.71) and major adverse cardiovascular events (MACE; HR 0.78, 95% CI 0.73–0.84; both P < 0.001). Landmark analyses were consistent for ACM (HR 0.68, 95% CI 0.63–0.75) and MACE (HR 0.83, 95% CI 0.77–0.91). Conclusions In HFpEF with type 2 diabetes, GLP-1 RA initiation on a background of SGLT2i therapy was associated with lower mortality and MACE than initiation without SGLT2i.

Discussion

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Cite This Study

Jaiswal et al. (2026) conducted a cohort in Heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes mellitus (T2DM) (n=55,976). GLP-1 receptor agonist initiation with background SGLT2 inhibitor therapy vs. GLP-1 receptor agonist initiation without background SGLT2 inhibitor therapy was evaluated on One-year all-cause mortality (HR 0.66, 95% CI 0.61–0.71, p=<0.001). Background SGLT2i therapy at GLP-1 RA initiation was associated with lower 1-year all-cause mortality (HR 0.66, P<0.001) and MACE (HR 0.78, P<0.001) in patients with HFpEF and type 2 diabetes.

synapsesocial.com/papers/6af1d893f9a8addd138b1ca4 https://doi.org/10.5114/aoms/242373

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Clinical Outcomes Following GLP-1 Receptor Agonist Initiation With Versus Without Background SGLT2 Inhibitor Therapy in Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes: A Propensity-Matched Real-World Analysis

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Clinical Outcomes Following GLP-1 Receptor Agonist Initiation With Versus Without Background SGLT2 Inhibitor Therapy in Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes: A Propensity-Matched Real-World Analysis

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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