Impact of diabetes on spironolactone benefits in HFpEF and frailty: a TOPCAT secondary analysis

Q: What are the key findings of this study?

Spironolactone was associated with a 30% lower risk of the primary composite outcome of CV death, aborted cardiac arrest, or HF hospitalization in frail HFpEF patients (adjusted HR 0.70, P=0.003).

Q: What is the clinical evidence from this study?

Study design: RCT. Population: Heart failure with preserved ejection fraction (HFpEF) and frailty (n=1519). Intervention: Spironolactone vs. Placebo. Primary outcome: Composite of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization (HR 0.70, 95% CI 0.55–0.89, p=0.003).

Q: What does this research mean for the field?

Spironolactone is associated with a 30% lower risk of the primary composite outcome of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization in frail patients with HFpEF, without consistent interaction by diabetes status. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Ying Lu; Keyang Zheng; Hong Tao

doi:10.1186/s12872-026-06810-9

November 3, 2026BMC Cardiovascular DisordersOpen Access

Impact of diabetes on spironolactone benefits in HFpEF and frailty: a TOPCAT secondary analysis

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Key result

Spironolactone is linked to ~30% lower risk of composite CV events in frail HFpEF patients.

HR 0.70
95% CI 0.55–0.89
P=0.003
n=1,519

Why the study?

Does diabetes mellitus status modify the association between spironolactone and the composite of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization in patients with HFpEF and frailty?

Key Points

To determine whether diabetes alters the association between spironolactone treatment and clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF) and frailty.
Post hoc analysis of 1,519 patients with HFpEF and frailty enrolled in the Americas cohort of the TOPCAT trial.
Assessed outcomes using multivariable Cox proportional hazards models stratified by diabetes status with formal treatment-by-diabetes interaction testing over a mean follow-up of 2.57 years.
In the overall cohort, spironolactone was associated with reduced risks of the primary composite outcome (adjusted HR 0.70, 95% CI 0.55–0.89), cardiovascular mortality (HR 0.54, 95% CI 0.36–0.80), and heart failure hospitalization (HR 0.73, 95% CI 0.56–0.97).
A nominally significant treatment-by-diabetes interaction was detected only for cardiovascular mortality (P for interaction = 0.049; HR 0.55, 95% CI 0.37–0.82 in non-diabetes vs HR 0.91, 95% CI 0.61–1.36 in diabetes), but not for the primary composite endpoint (P for interaction = 0.699) or heart failure hospitalization (P for interaction = 0.885).
In sensitivity analyses utilizing a stricter frailty index cutoff (FI > 0.25, n=1374), the treatment-by-diabetes interaction for cardiovascular mortality attenuated and was no longer statistically significant (P for interaction = 0.069).

Study Design

Type

RCT (n=1,519)

Blinding

Double-blind

Randomization

Randomized

Multicenter

Yes

Structured PICO

Does diabetes mellitus status modify the association between spironolactone and the composite of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization in patients with HFpEF and frailty?

P

Population

1,519 older adults (mean age 71.4 years, 49.2% female) from the Americas cohort of TOPCAT with HFpEF (LVEF ≥45%) and frailty (frailty index >0.21), followed for a mean of 2.57 years.

I

Intervention

Spironolactone (mineralocorticoid receptor antagonist) over a mean follow-up of 2.57 years, stratified by baseline diabetes mellitus status

C

Comparator

Placebo, stratified by baseline diabetes mellitus status

O

Outcome

Composite of cardiovascular death, hospitalization for heart failure, or aborted cardiac arrest over a mean follow-up of 2.57 yearscomposite

Main Result

Hazard Ratio: 0.7 (95% CI 0.55–0.89)

p-value: p=0.003

In patients with HFpEF and frailty from the TOPCAT Americas cohort, spironolactone was associated with lower risks of the primary composite outcome and HF hospitalization regardless of diabetes status, while a potential diabetes interaction for cardiovascular mortality was inconsistent across sensitivity analyses.

Limitations

Post hoc analysis restricted to participants enrolled in the Americas, limiting generalizability to other geographic regions.
Potential for unmeasured or residual confounding, including inability to adjust for BNP or NT-proBNP due to >50% missing data.
Lack of a universally accepted frailty cut-off for HFpEF, with the >0.21 threshold classifying over 90% of the cohort as frail.
Modest sample sizes in diabetes-stratified subgroups and potentially insufficient follow-up duration to detect smaller or longer-term effects.
Lack of direct biomarker or mechanistic evidence to confirm differential pathophysiology between diabetic and non-diabetic subgroups.
Competing non-cardiovascular death events were censored in cause-specific Cox models, meaning hazard ratios do not reflect absolute cumulative incidence.
Post hoc analysis restricted to participants enrolled in the Americas, limiting generalizability to other regions
Potential for unmeasured or residual confounding, including inability to adjust for BNP or NT-proBNP due to >50% missing data
Lack of a universally accepted frailty cut-off for HFpEF, with the FI threshold of >0.21 classifying over 90% of the cohort as frail
Treatment-by-diabetes interaction for cardiovascular mortality was attenuated and not consistently significant in sensitivity analyses

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

May support spironolactone consideration in frail HFpEF; hypothesis-generating post hoc analysis needing prospective confirmation.

Abstract

Background This study aimed to investigate whether diabetes modifies the association between spironolactone and clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF) and frailty. Methods This post hoc analysis of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT) included participants with HFpEF and frailty enrolled from the Americas. The primary outcome was the composite of cardiovascular death, aborted cardiac arrest or HF hospitalization. Cox proportional hazard models were utilized to evaluate the association of spironolactone with clinical outcomes, with prespecified stratification by diabetes status and formal testing of treatment-by-diabetes interactions. Results Among 1,519 patients with HFpEF and frailty, spironolactone was associated with lower risks of the primary composite endpoint (adjusted HR 0.70, 95% CI 0.55–0.89), cardiovascular mortality (HR 0.54, 95% CI 0.36–0.80), and HF hospitalization (HR 0.73, 95% CI 0.56–0.97) in fully adjusted models. A nominally significant treatment-by-diabetes interaction was observed for cardiovascular mortality (P for interaction < 0.05) but not for the primary composite endpoint or other secondary outcomes. This interaction was attenuated and no longer statistically significant in sensitivity analyses. Conclusion In this post hoc analysis of patients with HFpEF and frailty from the TOPCAT Americas cohort, spironolactone was associated with favorable clinical outcomes. A treatment-by-diabetes interaction was evident only for cardiovascular mortality and was not consistent across the primary or other secondary endpoints. These hypothesis-generating findings require confirmation in dedicated prospective randomized trials. Clinical trial number not applicable.

Discussion

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Cite This Study

Lu et al. (2026) conducted an RCT in Heart failure with preserved ejection fraction (HFpEF) and frailty (n=1,519). Spironolactone vs. Placebo was evaluated on Composite of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization (HR 0.70, 95% CI 0.55–0.89, p=0.003). Spironolactone was associated with a 30% lower risk of the primary composite outcome of CV death, aborted cardiac arrest, or HF hospitalization in frail HFpEF patients (adjusted HR 0.70, P=0.003).

synapsesocial.com/papers/6aeb26127efe0c3bfbad2885 https://doi.org/10.1186/s12872-026-06810-9

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Impact of diabetes on spironolactone benefits in HFpEF and frailty: a TOPCAT secondary analysis

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Impact of diabetes on spironolactone benefits in HFpEF and frailty: a TOPCAT secondary analysis

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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