Key result
SGLT2 inhibitors benefit heart failure across the LVEF spectrum via mechanisms beyond glycosuria and natriuresis.
Why the study?
Despite proven cardioprotective benefits across the spectrum of left ventricular dysfunction, the mechanisms by which sodium-glucose cotransport 2 inhibitors exert these effects remain poorly understood.
This review summarizes the cardioprotective benefits of SGLT2 inhibitors in heart failure and explores potential mechanisms of action beyond their diuretic and glycemic effects.
Answers are grounded in this paper and cite their sources.
Supports SGLT2 inhibitor use across the heart failure spectrum; leaves open the dominant nonglycosuric mechanisms.
Following the publication of several landmark clinical trials such as dapagliflozin in patients with heart failure and reduced ejection fraction, dapagliflozin evaluation to improve the lives of patients with preserved ejection fraction heart failure, and empagliflozin outcome trial in patients with chronic heart failure with preserved ejection fraction, sodium-glucose cotransport 2 inhibitors have been rapidly incorporated as a guideline-directed therapy in the treatment of heart failure. Moreover, their benefits appear to extend across the spectrum of left ventricular dysfunction which in some respects, can be seen as the holy grail of heart failure pharmacotherapy. Despite its plethora of proven cardioprotective benefits, the mechanisms by which it exerts these effects remain poorly understood, however, it is clear that these extend beyond that of promotion of glycosuria and natriuresis. Several hypotheses have emerged over the years including modification of cardiovascular risk profile via weight reduction, improved glucose homeostasis, blood pressure control, and natriuretic effect; however, these mechanisms do not fully explain the potent effects of the drug demonstrated in large-scale randomized trials. Other mechanisms may be at play, specifically the down-regulation of inflammatory pathways, improved myocardial sodium homeostasis, modulation of profibrotic pathways, and activation of nutrient deprivation signaling pathways promoting autophagic flux. This review seeks to summarize the cardioprotective benefits demonstrated in major clinical trials and provide a succinct review of the current theories of mechanisms of action, based on the most recent evidence derived from both clinical and laboratory data.
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Savage et al. (2024) conducted a review in Heart failure. SGLT2 inhibitors was evaluated. SGLT2 inhibitors provide cardioprotective benefits in heart failure across the spectrum of left ventricular dysfunction through mechanisms extending beyond glycosuria and natriuresis.
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