Introduction

Heart failure with preserved ejection fraction (HFpEF) represents a significant and growing challenge in cardiovascular medicine, accounting for more than half of all heart failure cases globally [1]. Unlike heart failure with reduced ejection fraction (HFrEF), where therapies have progressively improved patient outcomes, HFpEF remains a condition with limited treatment options and poor prognosis [2]. This disparity highlights the urgent need for targeted therapeutic strategies and a deeper understanding of HFpEF pathophysiology [3].

Diabetes mellitus, particularly type 2 diabetes mellitus (T2D), is a major risk factor for HFpEF [4]. Patients with T2D are at a significantly higher risk of developing HFpEF, and the coexistence of these conditions leads to worse clinical outcomes [5]. The interplay between diabetes and HFpEF is complex, involving mechanisms such as insulin resistance, chronic inflammation, endothelial dysfunction, and myocardial fibrosis [6]. This complexity necessitates innovative therapeutic approaches that can address both metabolic and cardiovascular aspects of the disease.

Recent advances in the management of T2D have brought sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) to the forefront as novel therapeutic classes with cardiovascular benefits extending beyond glycemic control [7]. SGLT2 inhibitors, such as empagliflozin and dapagliflozin, have demonstrated significant reductions in hospitalization for heart failure and improvements in cardiovascular outcomes in patients with T2D [8,9,10,11]. Similarly, GLP1-RA, including liraglutide and semaglutide, have shown promising cardiovascular benefits in clinical trials (12, 13).

Despite these advancements, the specific impact of GLP1-RA and SGLT2 inhibitors on HFpEF remains to be fully elucidated [14]. The potential synergistic effects of these two drug classes in managing HFpEF in diabetic patients present a novel area of investigation. Understanding how these medications can modulate myocardial fibrosis, improve diastolic function, and enhance overall cardiovascular health could pave the way for more effective treatment strategies for HFpEF [15].

This study aims to explore the comparative and synergistic effects of GLP1-RA and SGLT2 inhibitors on HFpEF in patients with T2D. By conducting a comprehensive analysis of existing clinical trial data and evaluating the impact of these drugs on key cardiac parameters, we aim to provide insights into their therapeutic potential and inform future clinical practices. The findings of this study could significantly advance the management of HFpEF in diabetic patients, offering new hope for improved outcomes in this challenging population.

Methods

Study design and participants

This meta-analysis followed the PRISMA guidelines [16] and included randomized controlled trials (RCTs) and observational studies evaluating the effects of GLP1-RA and SGLT2 inhibitors on heart failure with preserved ejection fraction (HFpEF) in patients with type 2 diabetes mellitus (T2D).

Inclusion criteria:

  • Adult patients (≥ 18 years) diagnosed with HFpEF (LVEF ≥ 50%) and type 2 diabetes mellitus.

  • Studies comparing GLP1-RA and/or SGLT2 inhibitors with placebo or other standard treatments. Combination therapies with both GLP1-RA and SGLT2 inhibitors were excluded to maintain a clear comparative analysis.

  • Studies reporting outcomes including LVEF, myocardial fibrosis (ECV), 6-minute walk test (6MWT), HbA1c, body weight, systolic blood pressure (SBP), as well as hard clinical endpoints (all-cause mortality, major adverse cardiovascular events [MACE], and rehospitalization rates)

Exclusion criteria:

# Studies involving patients with type 1 diabetes mellitus or other forms of heart failure (e.g., HFrEF).

# Non-randomized studies, case reports, reviews, and studies lacking sufficient data for analysis.

Data sources and search strategy

A systematic literature search was conducted in PubMed, MEDLINE, Cochrane Library, and EMBASE databases up to July 2024. Search terms included “HFpEF,” “type 2 diabetes mellitus,” “GLP1 receptor agonists,” “SGLT2 inhibitors,” and “cardiovascular outcomes.” Additional studies were identified by manually searching reference lists of relevant articles. 

Data extraction and quality assessment

Two independent reviewers screened the titles and abstracts for eligibility. Discrepancies were resolved by consensus or consultation with a third reviewer. Data extraction included study characteristics (author, year, design, sample size, follow-up duration), patient characteristics (age, gender, baseline LVEF, HbA1c, body weight, SBP), intervention details, and outcomes.

Quality assessment was conducted using the Cochrane Risk of Bias tool for RCTs and the Newcastle-Ottawa Scale for observational studies.

Statistical analysis

Primary outcomes

Changes in LVEF, myocardial fibrosis (ECV), and functional capacity (6MWT).

Secondary outcomes

HbA1c, body weight, SBP, all-cause mortality, MACE, and rehospitalization rates.

Meta-analyses were performed using a random-effects model to account for study heterogeneity. Effect sizes for dichotomous outcomes were expressed as odds ratios (OR) with 95% confidence intervals (CI), and as mean differences (MD) for continuous outcomes. Heterogeneity was assessed using the I² statistic. Funnel plots and Egger’s test evaluated publication bias.

Network meta-analysis

An exploratory network meta-analysis (NMA) was conducted to compare GLP1-RA, SGLT2 inhibitors, and other relevant antidiabetic agents (e.g., DPP-4 inhibitors, metformin, insulin) using a Bayesian framework. The NMA allowed comparisons across multiple treatments even without direct head-to-head trials.

Multivariate meta-analysis and meta-regression

A multivariate meta-analysis was performed to simultaneously assess multiple outcomes (LVEF, ECV, 6MWT, mortality, MACE, rehospitalization), accounting for correlations between these outcomes.

Meta-regression analyses explored the impact of potential confounders, including patient age, gender, baseline health status, study design, and follow-up duration. Subgroup analyses compared studies reporting hard endpoints with those that did not to evaluate the predictive value of surrogate outcomes.

Sensitivity analyses

Sensitivity analyses were conducted to assess the robustness of the findings by excluding studies with high risk of bias and by performing subgroup analyses based on study design, duration of follow-up, and baseline characteristics.

Ethical considerations

As this study involved meta-analysis of previously published data, ethical approval and informed consent were not required. This study was conducted in accordance with the Declaration of Helsinki.

Results

Study selection and characteristics From a total of 3,428 records identified, 2,764 remained after duplicate removal Fig. 1. Following title and abstract screening, 102 full-text articles were assessed, with 10 studies meeting the inclusion criteria, covering 3,428 patients (GLP1-RA: 1,654; SGLT2 inhibitors: 1,774). These studies, published between 2010 and 2023, had sample sizes ranging from 100 to 800 patients and follow-up durations from 6 months to 2 years (Table 1).

Fig. 1
figure 1

PRISMA flow diagram of the comparative effects of GLP1-RA and SGLT2i on heart failure with preserved ejection fraction in diabetic patients

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Table 1 Baseline characteristics of included studies
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Primary outcomes

Left ventricular ejection fraction (LVEF): Both GLP1-RA and SGLT2 inhibitors significantly improved LVEF compared to placebo Fig. 2:

Fig. 2
figure 2

Forest plot of LVEF changes

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  • GLP1-RA: MD 2.8% (95% CI 1.5 to 4.1, p < 0.001; I² = 48%).

  • SGLT2 inhibitors: MD 3.2% (95% CI 2.0 to 4.4, p < 0.001; I² = 25%).

Myocardial fibrosis (ECV):

SGLT2 inhibitors showed a greater reduction in myocardial fibrosis compared to GLP1-RA and placebo Fig. 3:

Fig. 3
figure 3

Forest plot of ECV changes

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  • SGLT2 inhibitors: MD -3.5% (95% CI -4.2 to -2.8, p < 0.001; I² = 75%).

  • GLP1-RA: MD -2.3% (95% CI -3.0 to -1.6, p < 0.001; I² = 50%).

Functional capacity (6MWT) Figure 4: Both treatments significantly improved functional capacity:

Fig. 4
figure 4

Forest plot of 6MWT changes

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# GLP1-RA: MD 45 m (95% CI 30 to 60, p < 0.001; I² = 20%).

# SGLT2 inhibitors: MD 50 m (95% CI 35 to 65, p < 0.001; I² = 30%).

Network meta-analysis results

The NMA, encompassing 15 studies with 5,200 patients, yielded the following key findings.

  • LVEF: SGLT2 inhibitors had the greatest effect (MD 3.5%, 95% CrI 2.1–4.9%), followed by GLP1-RA (MD 2.8%, 95% CrI 1.5–4.1%).

  • Myocardial fibrosis (ECV): SGLT2 inhibitors showed the greatest reduction (MD -3.8%, 95% CrI − 4.5% to -3.0%), followed by GLP1-RA (MD -2.5%, 95% CrI − 3.3% to -1.7%).

  • Functional capacity (6MWT): GLP1-RA had the highest improvement (MD 50 m, 95% CrI 35 to 65 m), followed closely by SGLT2 inhibitors (MD 48 m, 95% CrI 33 to 63 m).

Multivariate meta-analysis results

The multivariate meta-analysis confirmed significant effects of both GLP1-RA and SGLT2 inhibitors on combined outcomes (LVEF, ECV, 6MWT, mortality, MACE, rehospitalization), with SGLT2 inhibitors showing a slightly stronger impact on myocardial fibrosis and rehospitalization rates.

The meta-regression analysis identified significant covariates.

  • Patient age: Older age was associated with smaller LVEF improvement (p = 0.03) and higher rehospitalization risk (p = 0.02).

  • Gender: A higher proportion of male patients was linked to greater functional capacity improvement (p = 0.04).

  • Baseline LVEF: Higher baseline LVEF correlated with smaller reductions in myocardial fibrosis (p = 0.01) and greater functional capacity improvement (p = 0.03).

  • Baseline HbA1c: Lower baseline HbA1c levels were associated with greater mortality (p = 0.02) and MACE reductions (p = 0.03).

  • Study design: RCTs showed a more consistent effect on MACE and rehospitalization reduction (p < 0.05).

  • Follow-up duration: Longer follow-up was linked to greater LVEF improvements and rehospitalization reduction (p = 0.01).

Association between surrogate and hard endpoints

Significant associations were found between surrogate endpoints and hard outcomes:

  • 6MWT: Improvements in 6MWT were linked to reduced mortality (p = 0.02) and rehospitalization (p = 0.01). Each 10-meter increase in 6MWT reduced mortality odds by 5% (OR = 0.95, 95% CI 0.90 to 0.99).

  • LVEF: Increases in LVEF were associated with reduced MACE (p = 0.03) and mortality (p = 0.04). Each 1% increase in LVEF reduced MACE risk by 3% (OR = 0.97, 95% CI 0.94 to 1.00).

  • Myocardial fibrosis (ECV): Reductions in ECV were linked to lower rehospitalization rates (p = 0.03). Each 1% decrease in ECV reduced rehospitalization odds by 4% (OR = 0.96, 95% CI 0.92 to 0.99).

Secondary outcomes

Glycemic control (HbA1c) Fig.5

Fig. 5
figure 5

Forest plot of HbA1c changes

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  • GLP1-RA: MD -1.1% (95% CI -1.4 to -0.8, p < 0.001; I² = 45%).

  • SGLT2 inhibitors: MD -1.0% (95% CI -1.3 to -0.7, p < 0.001; I² = 20%).

Body weight Fig.6

Fig. 6
figure 6

Forest plot of body weight changes

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  • GLP1-RA: MD -2.5 kg (95% CI -3.1 to -1.9, p < 0.001; I² = 40%).

  • SGLT2 inhibitors: MD -2.0 kg (95% CI -2.6 to -1.4, p < 0.001; I² = 35%).

Systolic blood pressure (SBP) Fig. 7

Fig. 7
figure 7

Forest plot of SBP changes

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  • GLP1-RA: MD -5.2 mmHg (95% CI -6.5 to -3.9, p < 0.001; I² = 25%).

  • SGLT2 inhibitors: MD -4.8 mmHg (95% CI -6.0 to -3.6, p < 0.001; I² = 30%).

Quality of life (KCCQ)

# GLP1-RA: MD 7.5 points (95% CI 4.2 to 10.8, p < 0.001) # SGLT2 inhibitors: MD 8.2 points (95% CI 5.1 to 11.3, p < 0.001).

Sensitivity analyses and publication bias

Sensitivity analyses confirmed the robustness of the primary and secondary outcomes. Excluding studies with high risk of bias did not alter the results. Subgroup analyses by study design, follow-up duration, and baseline characteristics yielded consistent findings. Funnel plots and Egger’s test indicated no significant publication bias (p > 0.05 for all primary outcomes) Figs. 8, 9, 10, 11, 12 and 13.

Fig. 8
figure 8

Funnel plot for assessing publication bias SBP (% change)

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Fig. 9
figure 9

Funnel plot for assessing publication bias LVEF (% change)

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Fig. 10
figure 10

Funnel plot for assessing publication bias ECV (% change)

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Fig. 11
figure 11

Funnel plot for assessing publication bias 6MWT (% change)

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Fig. 12
figure 12

Funnel plot for assessing publication bias HBA1c (% change)

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Fig. 13
figure 13

Funnel plot for assessing publication bias body weight (% change)

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Discussion

This meta-analysis highlights the significant cardiovascular benefits of GLP1-RA and SGLT2 inhibitors in managing heart failure with preserved ejection fraction (HFpEF) in patients with type 2 diabetes mellitus (T2D) Fig. 14. Both drug classes demonstrated improvements in left ventricular ejection fraction (LVEF), reductions in myocardial fibrosis, and enhanced functional capacity. These findings underscore the potential of these therapies to not only improve surrogate markers but also translate into meaningful clinical outcomes such as reduced mortality, major adverse cardiovascular events (MACE), and rehospitalization rates [17,18,19,20,21,22].

Fig. 14
figure 14

Graphical summary

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Myocardial fibrosis and cardiac function

SGLT2 inhibitors showed a greater reduction in myocardial fibrosis compared to GLP1-RA, which is consistent with their mechanisms of action, including osmotic diuresis, natriuresis, and attenuation of inflammation [23]. This is supported by Bernardi et al. [24], who emphasized the potential of SGLT2 inhibitors in reducing myocardial fibrosis and improving cardiac function in HFpEF​. The reduction in extracellular volume fraction (ECV) with SGLT2 inhibitors indicates a decrease in pathological fibrosis, which is crucial for improving myocardial stiffness and diastolic function in HFpEF [25].

Surrogate endpoints and clinical outcomes

Our analysis demonstrated significant associations between surrogate endpoints (LVEF, ECV, 6MWT) and hard clinical outcomes, validating the use of these measures as predictors of long-term benefits in HFpEF management. Improvements in these surrogates correlated with reductions in mortality, MACE, and rehospitalization, reinforcing their role in routine clinical practice [26, 27].

Comparative efficacy of GLP1-RA and SGLT2 inhibitors

The network meta-analysis (NMA) provided a comprehensive comparison, ranking SGLT2 inhibitors as the most effective for improving LVEF, reducing myocardial fibrosis, and lowering rehospitalization rates. GLP1-RA also showed substantial benefits, particularly in enhancing functional capacity. These findings suggest that while both drug classes are beneficial, SGLT2 inhibitors may offer superior outcomes in specific clinical contexts, particularly in reducing myocardial fibrosis.

Influence of patient characteristics and study design

Meta-regression analyses revealed that older patients and those with higher baseline LVEF derived less benefit, particularly in terms of LVEF improvement and rehospitalization reduction. This underscores the need for personalized treatment strategies, especially in older populations and those with better baseline cardiac function [28, 29]. The influence of study design on outcome consistency highlights the importance of robust randomized controlled trials (RCTs) in generating reliable evidence for clinical guidelines.

Clinical implications and future research

The comprehensive cardiovascular and metabolic benefits of GLP1-RA and SGLT2 inhibitors support their integration into standard HFpEF treatment protocols for diabetic patients. While our meta-analysis provides strong evidence, the inclusion of observational studies and the variability in study designs contribute to heterogeneity. Future research should focus on long-term outcomes, including more diverse patient populations and considering the effects of background therapies like ACEI/ARB, which were variably included in the studies analyzed. A network meta-analysis could further refine our understanding by accounting for these concomitant treatments.

Limitations

This meta-analysis combines data from RCTs and observational studies, which may affect the overall strength of the conclusions. The included studies varied in design, patient populations, and follow-up duration, contributing to heterogeneity. Moreover, most studies focused on short- to medium-term outcomes, leaving the long-term effects of GLP1-RA and SGLT2 inhibitors on HFpEF to be fully elucidated. Future research should address these gaps, providing more high-quality RCT data, particularly with longer follow-up periods.

Conclusion

This meta-analysis demonstrates that GLP1-RA and SGLT2 inhibitors significantly improve key cardiovascular outcomes in HFpEF patients with T2D. Both drug classes enhance LVEF, reduce myocardial fibrosis, and improve functional capacity, while also offering substantial benefits in glycemic control, weight management, and blood pressure reduction. These findings support the use of GLP1-RA and SGLT2 inhibitors as integral components of HFpEF management in diabetic patients, with the potential to improve clinical outcomes and quality of life. Further research is needed to explore the long-term benefits and mechanistic insights of these therapies.