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Reaffirmation of Mechanistic Proteomic Signatures Accompanying SGLT2 Inhibition in Patients With Heart Failure: A
Milton Packer1, João Pedro Ferreira2, Javed Butler3
1Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas, USA; Imperial College London, London, United Kingdom.
Background:
Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a distinctive pattern of direct biological effects on the heart and kidney under experimental conditions, but the meaningfulness of these signatures for patients with heart failure has not been fully defined.
Objectives:
We performed the first mechanistic validation study of large-scale proteomics in a double-blind randomized trial of any treatment in patients with heart failure.
Methods:
In a discovery cohort from the EMPEROR (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and Reduced Ejection Fraction) program, we studied the effect of randomized treatment with placebo or empagliflozin on 1,283 circulating proteins in 1,134 patients with heart failure with a reduced or preserved ejection fraction. In a validation cohort, we expanded the number to 2,155 assessed proteins, which were measured in 1,120 EMPEROR participants who had not been studied previously.
Results:
In the validation cohort, 25 proteins were the most differentially enriched by empagliflozin (ie, ≥15% between-group difference and false discovery rate <1% at 12 weeks with known effects on the heart or kidney): 1) 13 proteins promote autophagy and other cellular quality-control functions (IGFBP1, OTUB1, DNAJB1, DNAJC9, RBP2, IST1, HSPA8, H-FABP, FABP6, ATPIFI, TfR1, EPO, IGBP1); 2) 12 proteins enhance mitochondrial health and ATP production (UMtCK, TBCA, L-FABP, H-FABP, FABP5, FABP6, RBP2, IST1, HSPA8, ATPIFI, TfR1, EPO); 3) 7 proteins augment cellular iron mobilization or erythropoiesis (TfR1, EPO, IGBP1, ERMAP, UROD, ATPIF1, SNCA); 4) 3 proteins influence renal tubular sodium handling; and 5) 9 proteins have restorative effects in the heart or kidneys, with many proteins exerting effects in >1 domain. These biological signatures replicated those observed in our discovery cohort. When the threshold for a meaningful between-group difference was lowered to ≥10%, there were 58 additional differentially enriched proteins with actions on the heart and kidney, but the biological signatures remained the same.
Conclusions:
The replication of mechanistic signatures across discovery and validation cohorts closely aligns with the experimental effects of SGLT2 inhibitors. Thus, the actions of SGLT2 inhibitors-to promote autophagy, restore mitochondrial health and production of ATP, promote iron mobilization and erythropoiesis, influence renal tubular ion reabsorption, and normalize cardiac and renal structure and function-are likely to be relevant to patients with heart failure. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction [EMPEROR-Preserved], NCT03057951; EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced], NCT03057977).
Insights
Sodium-glucose cotransporter 2 (SGLT2) inhibitors show distinct biological effects in heart failure patients. This study validated these mechanisms using large-scale proteomics, confirming their relevance for treating heart failure.
Area of Science:
- Cardiology
- Nephrology
- Pharmacology
Background:
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors have known experimental effects on the heart and kidney.
- The clinical significance of these effects in heart failure patients remains to be fully elucidated.
Purpose of the Study:
- To conduct the first mechanistic validation study using large-scale proteomics in a randomized trial for heart failure patients.
- To investigate the impact of empagliflozin on circulating proteins in patients with heart failure.
Main Methods:
- A discovery cohort from the EMPEROR program analyzed 1,283 proteins in 1,134 heart failure patients treated with placebo or empagliflozin.
- A validation cohort expanded this analysis to 2,155 proteins in 1,120 new EMPEROR participants.
Main Results:
- Empagliflozin significantly altered 25 proteins involved in autophagy, mitochondrial health, ATP production, iron mobilization, erythropoiesis, and renal sodium handling.
- These protein signatures were consistent between discovery and validation cohorts.
- Lowering the significance threshold revealed additional proteins, but the core biological signatures remained unchanged.
Conclusions:
- The validated mechanistic signatures align with the known experimental effects of SGLT2 inhibitors.
- The findings suggest that SGLT2 inhibitors promote autophagy, restore mitochondrial function, enhance iron mobilization, influence renal tubular function, and normalize cardiac/renal structures, all relevant to heart failure treatment.
