SGLT2 inhibitors: actions in heart failure Flashcards
(10 cards)
What is the haemodynamic effect of SGLT2 inhibitors
○ SGLT2 inhibitors have a different diuretic mechanism compared to loop diuretics.
○ They appear to remove more fluid from the interstitial space than from the circulation.
○ This results in greater electrolyte-free water clearance, natriuresis (sodium excretion), and a reduction in volume load.
○ Reduced volume load may explain some of the protective effects observed in HF.
○ Heart failure is characterized by increased volume and inadequate arterial perfusion due to impaired cardiac function.
How do SGLT2 inhibitors modestly reduce BP
○ SGLT2 inhibitors cause a modest reduction in blood pressure.
○ This is attributed to the decrease in plasma volume and sodium due to diuresis and natriuresis.
○ However, the sources note that this modest BP reduction alone cannot fully explain the improvement in clinical outcomes in HF, as standard anti-hypertensive drugs do not demonstrate the same effects.
What effect do SGLT2 inhibitors have on Cardiac energy metabolism and ketone bodies
○ The heart muscle, cardiomyocytes, can use various substrates like glucose and fatty acids for energy.
○ While a healthy heart prefers free fatty acids, in HF, flexibility in energy substrate use is impaired, and glucose is preferentially utilized, which can lead to oxidative stress.
○ In advanced HF, insulin resistance can decrease glucose metabolism but paradoxically stimulates fatty acid uptake, leading to triglyceride accumulation, lipid toxicity, and left ventricular systolic dysfunction as the myocytes cannot effectively use the fatty acids.
What are the ketogenic actions of SGLT2 inhibitors
- SGLT2 inhibitors are thought to beneficially influence cardiac energy metabolism.
- They have ketogenic actions, causing the body to use fatty acids instead of carbohydrates, although this can also potentially lead to ketoacidosis in certain circumstances.
- SGLT2 inhibition increases plasma ketone concentration in patients with type 2 diabetes mellitus (T2DM), which is linked to increased liver ketone body synthesis.
- Ketone oxidation increases cardiac ATP production rates, and the consumption of ketones is accentuated in HF, which is thought to be protective.
- Therefore, an increase in ketone bodies may be a beneficial action of SGLT2i in HF
what effect do SGLT2 inhibitors have on Ketosis and HDACs
○ Ketosis, potentially induced by SGLT2 inhibitors, is associated with a decrease in histone deacetylases (HDACs).
○ HDACs are enzymes that regulate epigenetic gene modification and are linked to various cardiac disorders.
What effect do SGLT2 inhibitors have on adverse cardiac remodelling via NHE inhibition
○ Adverse cardiac remodeling is a significant issue in HF. Sodium-hydrogen exchangers (NHEs) are responsible for transferring sodium into cells in exchange for protons, maintaining sodium homeostasis and pH.
○ In diabetes, increased myocardial NHEs are observed, which leads to increased cytoplasmic sodium and calcium levels, potentially contributing to HF pathology.
○ Specifically, NHE3 in the proximal tubule is involved in sodium reuptake and shows increased expression in HF.
○ SGLT2 inhibitors can inhibit NHE1 and NHE3, thereby reducing intracellular sodium and calcium overload and potentially protecting cardiomyocytes.
What effect do SGLTSis have on inflammation
○ Activation of the immune system and inflammatory processes contribute to cardiac remodeling and progressive deterioration in HF.
○ SGLT2 inhibitors have been shown to decrease inflammatory factors, such as CRP and TNF-alpha.
What effects do SGLT2 inhibits have on epicardial fat mass
○ Epicardial adipose tissue (EFAT) is an organ that stores free fatty acids.
○ Excessive free fatty acids can lead to excessive reactive oxygen species (ROS) production.
○ EFAT is crucial in secreting adipokines that can cause myocardial inflammation, contributing to cardiac remodeling.
○ SGLT2 inhibitors have been shown to reduce EFM in patients with T2DM.
What effect do SGLT2is have on improvement in insulin resistance
What effect does SGLT2is have on nephroprotection
○ While primarily focused on HF, the sources also describe nephroprotective effects of SGLT2i.
○ In diabetes, dilation of the afferent arteriole leads to high intraglomerular pressure, hyperfiltration, and proteinuria.
○ SGLT2 inhibitors promote afferent vasoconstriction, which reduces intraglomerular hypertension
