Thread by @HanCardiomd

This fantastic review on SGLT2-inhibitors; discusses some of the cutting-edge hypotheses & concepts currently being explored around this drug class in an attempt better understand the molecular mechanics of this novel agent link.springer.com/article/10.100… @ShelleyZieroth @AndrewJSauer

SGLT2-inhibitors; more than just glycosuria and diuresis

Early mechanistic work around conventional Tx targets seem to be inconclusive. There are some emerging theories around its effect on myocardial energetics and calcium balance as well as on renal physiology @mvaduganathan

Unlike conventional sodium-driven diuretics, SGLT2i-mediated free water excretion is expected to be more efficient in relieving signs & symptoms of interstitial congestion without adversely compromising intravascular fluid status or causing reflex sympathetic activation @noshreza

By inhibiting sodium resorption in the proximal nephron thereby increasing distal delivery, SGLT2-inhibitors can restore tubuloglomerular feedback and normalise renal blood flow @DrRyanPDaly @FH_Verbrugge @AndrewJSauer @lamcardio @HFpEF @NadeenFaza @hvanspall @Nephro_Sparks

SGLT2 is not expressed on the heart, yet there is strong pre-clinical evidence that SGLT2i influence Ca2+ handling by modulating intracytoplasmic Na+ in the cardiomyocyte. This is supported by evidence that empagliflozin ⬆️ SERCA2a efficiency and reduces RyR2-dependent Ca2+ leak

SGLT2i may also preserve mitochondrial function and reduce oxidative damage. SGLT2i achieve this by inhibiting NHE1 (SGLT2-inhibitors inactivate NHE1 by binding to its Na+ binding site) and possibly SGLT1 as well (all SGLT2i have intrinsic SGLT1 blocking ability @Nephro_Sparks

In the early stages,with adequate cellular functional reserve,optimizing the molecular milieu within the cardiomyocyte with SGLT2i(i.e.⬆️ Ca2+ handling,efficient myocardial energetics,optimized oxygen delivery etc.)along with modest ⤴️in ventricular loading(i.e. diuresis &
⬇️BP)

In such advanced circumstances, improving haemodynamic loading becomes key, with the heavy lifting being done by neurohormonal modulators and SGLT2-inhibitors playing an important, but secondary role. @HFpEF @lamcardio @MihaiTrofenciuc @ShelleyZieroth @hvanspall @FH_Verbrugge

If this hypothesis is true, then SGLT2i will very likely be the first therapeutic agent to be beneficial in HFpEF where cardiomyocyte dysfunction predominates – we will have to wait and see if this is borne out in the large clinical trials currently underway . #cardiotwitter