Sizing SGLT2 Inhibitors Up: From a Molecular to a Morpho-Functional Point of View

Abstract

Sodium–glucose cotransporter 2 inhibitors (SGLT2i), or gliflozins, have recently been shown to reduce cardiovascular death and hospitalization in patients with heart failure, representing a revolutionary therapeutic tool. The purpose of this review is to explore their multifaceted mechanisms of actions, beyond their known glucose reduction power. The cardioprotective effects of gliflozins seem to be linked to the maintenance of cellular homeostasis and to an action on the main metabolic pathways. They improve the oxygen supply for cardiomyocytes with a considerable impact on both functional and morphological myocardial aspects. Moreover, multiple molecular actions of SGLT2i are being discovered, such as the reduction of both inflammation, oxidative stress and cellular apoptosis, all responsible for myocardial damage. Various studies showed controversial results concerning the role of SGLT2i in reverse cardiac remodeling and the lowering of natriuretic peptides, suggesting that their overall effect has yet to be fully understood. In addition to this, advanced imaging studies evaluating the effect on all four cardiac chambers are lacking. Further studies will be needed to better understand the real impact of their administration, their use in daily practice and how they can contribute to benefits in terms of reverse cardiac remodeling.

Current Approaches to Worsening Heart Failure: Pathophysiological and Molecular Insights

“…Sotagliflozin is a combined SGLT1i and SGLT2i, with predominantly SGLT2 inhibitory capacity [37,38]. SGLT1 mediates the reabsorption of glucose in the gastrointestinal tract, resulting in a reduction in glycaemia, insulin and glucose-dependent insulinotropic polypeptide (GIP), and an increase in plasma glucagon-like peptide 1 (GLP-1) [37][38][39][40]. The last two effects have been recently associated with an improvement in type 2 diabetes mellitus (T2DM) and cardiovascular outcomes.…”

“…SGLT2 is expressed in the first proximal convoluted tubule segment, reabsorbing about 90% of the glucose in the peritubular capillaries [39]. The dual inhibition of SGLT1 and SGLT2 may provide a combined effect, causing the decrease in serum glucose levels through reduced intestinal absorption and increased urinary output [37][38][39][40]. Moreover, SGLTi possesses a myocardial anti-remodelling effect, reduces inflammation and oxidative stress and induces a cardiomyocytes metabolic shift [39,40].…”

“…The dual inhibition of SGLT1 and SGLT2 may provide a combined effect, causing the decrease in serum glucose levels through reduced intestinal absorption and increased urinary output [37][38][39][40]. Moreover, SGLTi possesses a myocardial anti-remodelling effect, reduces inflammation and oxidative stress and induces a cardiomyocytes metabolic shift [39,40]. Given the great impact of SGLT2i on HF treatment, the effects of Sotagliflozin were studied in the SOLOIST-WHF trial [38].…”

The Ketogenic Effect of SGLT-2 Inhibitors—Beneficial or Harmful?

“…These coordinated cellular responses result from the widespread activation of SIRT-1 across all bodily cells as a consequence of SGLT2 inhibitor administration. This, in turn, leads to a systemic state of metabolic insufficiency, thereby strengthening the renoprotective benefits provided by these inhibitors [188,189].…”