Cardiovascular benefits from SGLT2 inhibition in type 2 diabetes mellitus patients is not impaired with phosphate flux related to pharmacotherapy

Abstract

The beneficial cardiorenal outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) have been substantiated by multiple clinical trials, resulting in increased interest in the multifarious pathways by which their mechanisms act. The principal effect of SGLT2i (-flozin drugs) can be appreciated in their ability to block the SGLT2 protein within the kidneys, inhibiting glucose reabsorption, and causing an associated osmotic diuresis. This ameliorates plasma glucose elevations and the negative cardiorenal sequelae associated with the latter. These include aberrant mitochondrial metabolism and oxidative stress burden, endothelial cell dysfunction, pernicious neurohormonal activation, and the development of inimical hemodynamics. Positive outcomes within these domains have been validated with SGLT2i administration. However, by modulating the sodium-glucose cotransporter in the proximal tubule (PT), SGLT2i consequently promotes sodium-phosphate cotransporter activity with phosphate retention. Phosphatemia, even at physiologic levels, poses a risk in cardiovascular disease burden, more so in patients with type 2 diabetes mellitus (T2DM). There also exists an association between phosphatemia and renal impairment, the latter hampering cardiovascular function through an array of physiologic roles, such as fluid regulation, hormonal tone, and neuromodulation. Moreover, increased phosphate flux is associated with an associated increase in fibroblast growth factor 23 levels, also detrimental to homeostatic cardiometabolic function. A contemporary commentary concerning this notion unifying cardiovascular outcome trial data with the translational biology of phosphate is scant within the literature. Given the apparent beneficial outcomes associated with SGLT2i administration notwithstanding negative effects of phosphatemia, we discuss in this review the effects of phosphate on the cardiometabolic status in patients with T2DM and cardiorenal disease, as well as the mechanisms by which SGLT2i counteract or overcome them to achieve their net effects. Content drawn to develop this conversation begins with proceedings in the basic sciences and works towards clinical trial data.

Keywords: Sodium-glucose cotransporter 2, Phosphate, Hyperphosphatemia, Cardiovascular, Canagliflozin, Dapagliflozin, Empagliflozin, Endothelial

Core Tip: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have received increased attention regarding their pleiotropic effects given their markedly impressive performance in cardiovascular outcome trials (CVOT). Preliminary evidence shows that their role as antidiabetic agents is not their sole mechanism in achieving these cardiorenal protective properties. Therefore, investigation in the auxiliary properties that they hold concomitant with glucose control, vindicated by not only CVOTs, but meta-analyses, retrospective studies, and case reports has led to increased interest in delineating their global pharmacodynamic effects across the spectrum of gene expression and molecular modulation to end-organ translational biology. Such a full profile of their effects is not yet understood given the refractory period between clinical evidence supporting their utilization and a proclivity for their implementation in practical clinical environments. In this review, we answer inquiries regarding how via a multifarious avenues, SGLT2 inhibitors, while carrying a negative effect of induced phosphatemia (which is deleterious to the heart), compensate for this phenomenon, retaining their propensity for net cardiac benefit upon pharmacotherapeutic administration under appropriate clinical circumstances.