August 9, 2021Cardiovascular DiabetologyOpen Access

Proteomic mechanistic profile of patients with diabetes at risk of developing heart failure: insights from the HOMAGE trial

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Why the study?

Patients with diabetes mellitus are at increased risk of developing heart failure, but differences in proteomic profiles and responses to spironolactone compared to non-diabetics remained to be clarified.

Does spironolactone alter the proteomic profile or have differential effects on cardiac remodeling and fibrosis biomarkers in patients at risk for heart failure with versus without diabetes?

Structured PICO

Does spironolactone alter the proteomic profile or have differential effects on cardiac remodeling and fibrosis biomarkers in patients at risk for heart failure with versus without diabetes?

Population

527 patients at increased risk of developing heart failure (age ≥60 years, cardiovascular risk defined by coronary artery disease OR ≥2 risk factors including diabetes, treated hypertension, microalbuminuria, abnormal ECG, and elevated NT-proBNP/BNP; LVEF ≥45%), including 217 with diabetes and 310 without diabetes.

Intervention

Spironolactone for 9 months

Comparator

Standard care (for the spironolactone intervention comparison) and non-diabetic patients (for the baseline proteomic comparison)

Outcome

Plasma concentrations of 276 protein biomarkers (Olink Proseek Multiplex cardiovascular and inflammation panels) at baseline and 9 monthssurrogate

In patients at risk for heart failure, diabetes is associated with a distinct pro-inflammatory and proteolytic biomarker profile, but this does not attenuate the beneficial anti-remodeling and anti-fibrotic effects of spironolactone.

Limitations

Absolute numbers of expression levels were not available (only relative quantifications)
Cannot state causal relationship between proteins/pathways and diabetes based on the data

Implication

Spironolactone effects on remodeling biomarkers appear similar regardless of diabetes; hypothesis-generating for uniform use pending outcome trials.

Abstract

BACKGROUND: Patients with diabetes mellitus (DM) are at increased risk of developing heart failure (HF). The "Heart OMics in AGEing" (HOMAGE) trial suggested that spironolactone had beneficial effect on fibrosis and cardiac remodelling in an at risk population, potentially slowing the progression towards HF. We compared the proteomic profile of patients with and without diabetes among patients at risk for HF in the HOMAGE trial. METHODS: Protein biomarkers (n = 276) from the Olink®Proseek-Multiplex cardiovascular and inflammation panels were measured in plasma collected at baseline and 9 months (or last visit) from HOMAGE trial participants including 217 patients with, and 310 without, diabetes. RESULTS: Twenty-one biomarkers were increased and five decreased in patients with diabetes compared to non-diabetics at baseline. The markers clustered mainly within inflammatory and proteolytic pathways, with granulin as the key-hub, as revealed by knowledge-induced network and subsequent gene enrichment analysis. Treatment with spironolactone in diabetic patients did not lead to large changes in biomarkers. The effects of spironolactone on NTproBNP, fibrosis biomarkers and echocardiographic measures of diastolic function were similar in patients with and without diabetes (all interaction analyses p > 0.05). CONCLUSIONS: Amongst patients at risk for HF, those with diabetes have higher plasma concentrations of proteins involved in inflammation and proteolysis. Diabetes does not influence the effects of spironolactone on the proteomic profile, and spironolactone produced anti-fibrotic, anti-remodelling, blood pressure and natriuretic peptide lowering effects regardless of diabetes status. Trial registration NCT02556450.