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Effect of Empagliflozin on Circulating Proteomics in Heart Failure: Mechanistic Insights from the EMPEROR Program

Faiez Zannad ¹, João Pedro Ferreira ^1 2, Javed Butler ^3 4, Gerasimos Filippatos ⁵, James L Januzzi ⁶, Mikhail Sumin ⁷, Matthias Zwick ⁸, Maral Saadati ⁹, Stuart J Pocock ¹⁰, Naveed Sattar ¹¹, Stefan D Anker ^12 13, Milton Packer

Naveed Sattar gave 3 talks at ESC and was also a co-author on the Emperor heart failure trials biomarker paper published in EHJ on Friday and along with several other Glasgow colleagues (Ian Ford, Chris Packard, Robin Young, Michele Robertson, Peter Macfarlane), contributed to the CTT meta-analysis of Statin-related muscle side effects, published in the Lancet on Monday to wide media interest.  

Background

Sodium glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study.

Aims

To explore the effect of empagliflozin on circulating levels of intracellular proteins in patients with heart failure, using large-scale proteomics.

Methods

Over 1250 circulating proteins were measured at baseline, week 12 and week 52 in 1134 patients from EMPEROR-Reduced and EMPEROR-Preserved, using the Olink® Explore 1536 platform. Statistical and bioinformatical analyses identified differentially expressed proteins (empagliflozin vs placebo), which were then linked to demonstrated biological actions in the heart and kidneys.

Results

At week 12, 32 of 1283 proteins fulfilled our threshold for being differentially expressed, i.e., their levels were changed by ≥10% with a false discovery rate < 1% (empagliflozin vs placebo). Among these, nine proteins demonstrated the largest treatment effect of empagliflozin: insulin-like growth factor-binding protein 1, transferrin receptor protein 1, carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyltransferase 2, thymosin beta-10, U-type mitochondrial creatine kinase, insulin-like growth factor-binding protein 4, and adipocyte fatty acid-binding protein 4. The changes of the proteins from baseline to week 52 were generally concordant with the changes from baseline to week 12, except empagliflozin reduced levels of kidney injury molecule-1 by ≥10% at week 52, but not at week 12.

The most common biological action of differentially-expressed proteins appeared to be the promotion of autophagic flux in the heart, kidney or endothelium, a feature of 6 proteins. Other effects of differentially-expressed proteins on the heart included the reduction of oxidative stress, inhibition of inflammation and fibrosis, and the enhancement of mitochondrial health and energy, repair and regenerative capacity. The actions of differentially expressed proteins in the kidney involved promotion of autophagy, integrity and regeneration, suppression of renal inflammation and fibrosis, and modulation of renal tubular sodium reabsorption.

Conclusions

Changes in circulating protein levels in patients with heart failure are consistent with the findings of experimental studies that have shown that the effects of SGLT2 inhibitors are likely related to actions on the heart and kidney to promote autophagic flux, nutrient deprivation signaling and transmembrane sodium transport.

Link to Paper

Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials.Introduction

Atherosclerotic cardiovascular diseases, chiefly myocardial infarction and ischaemic stroke, accounted for approximately 18 million deaths worldwide in 2019,1 and low-density lipoprotein (LDL) cholesterol is a major causal risk factor.2 Randomised controlled trials have shown that the long-term reduction of LDL cholesterol concentrations with an 3-hydroxy 3-methylglutaryl-coenzyme A reductase inhibitor (ie, a statin) reduces the incidence of myocardial infarction and of ischaemic stroke by approximately a quarter for every 1 mmol/L LDL cholesterol reduction achieved, which corresponds to the avoidance of approximately 50 major vascular events in those with pre-existing vascular disease (secondary prevention), and 25 major vascular events when used for primary prevention, in every 1000 people administered this therapy for 5 years.

2 Moreover, a more intensive statin regimen (ie, 40–80 mg atorvastatin once per day, or 20–40 mg rosuvastatin once per day), which could reduce LDL cholesterol by 2 mmol/L, would prevent twice as many major vascular events, and longer treatment yields greater benefits. For a given reduction in LDL cholesterol, similar proportional reductions in risk are seen across a wide range of patients (including men and women, older and younger patients, and those with and without a previous history of cardiovascular disease).3,  4,  5,  6 Consequently, statins are now used by millions of people worldwide.

Statistical analysis

All variables for which the data were extracted were specified previously.15 Data were converted into a common format on the basis of the Clinical Data Interchange Standards Consortium Study Data Tabulation Model.17 Adverse events were mapped to a common dictionary (the Medical Dictionary for Regulatory Activities version 20.0).

Results

Individual participant data were available from 19 randomised double-blind trials of any statin regimen versus placebo (123 940 patients) and four randomised double-blind trials of more intensive versus less intensive statin therapy (30 724 patients; table 1). Of the 19 double-blind trials of any statin regimen versus placebo, one study23 compared a less intensive statin regimen versus placebo (6605 patients).

Paper Published in the Lancet

 

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First published: 1 September 2022