SGLT2 inhibitors Flashcards
SGLT2i
SGLT2i
SGLT2 inhibitors.
Hyperglycemia is well known to promote glomerular hyperfiltration in DKD. Lowering caloric intake or weight loss after bariatric surgery has been shown to reverse this aberrance in kidney hemodynamics. While the pathogenesis of hyperfiltration is incompletely understood, it is hypothesized that activation of the RAAS leading to afferent arteriolar vasodilation and efferent arteriolar vasoconstriction increases intraglomerular pressure and this sends the kidney down the road of irreversible damage
SGLT2 inhibitors were not merely glucose-lowering drugs. Yes, there were small decreases in HbA1C (~0.5%), blood pressure (~2-5 mm Hg), and weight (~2-3 kg), but these modest effects could not fully explain the reduction in CV events and mortality.
SGLT2 inhibitors work in patients with DKD on RAAS blockade, which produces efferent vasoconstriction, but the crucial question remains: Why?
The most commonly postulated mechanism involves tubuloglomerular feedback (TGF). The macula densa with the juxtaglomerular apparatus (JGA) maintains a stable glomerular filtration rate by sensing distal sodium and chloride delivery and modulating changes in the afferent arteriolar tone. In DKD, a multistep process results in the kidney misunderstanding an individual’s volume status and consequently, in hyperfiltration:
Persistent hyperglycemia upregulates glucose reabsorption (and secondarily, sodium and chloride reabsorption) in the proximal tubule
This decreases sodium and chloride delivery to the macula densa which is mistaken for decreased kidney perfusion
This results in decreased adenosine production
A decrease in afferent arteriolar tone increasing blood flow to the glomerulus is signaled
When patients start an SGLT2 inhibitor, the process is reversed:
Glucose (as well as sodium and chloride) reabsorption is blocked in the proximal tubule
This increases sodium delivery to the thick ascending limb of the loop of Henle
This increases the activity of the Na-K-2Cl co-transporter, an energy-requiring process where adenosine triphosphate (ATP) is broken down to adenosine
Increased adenosine acts in a paracrine manner on the afferent arteriolar smooth muscle cells and leads to afferent arteriolar vasoconstriction, decreasing blood flow to the glomerulus
This afferent vasoconstriction combines synergistically with the efferent vasodilation produced by RAAS blockade to reduce intraglomerular pressure and glomerular filtration
This phenomenon can be recognized in the first few weeks of SGLT2 inhibitor treatment where there is an acute reduction in GFR followed by stabilization. This acute drop in GFR can be seen after a single dose of SGLT2i showcasing the acute nature of tubuloglomerular feedback. Trial data shows that this effect is completely reversible after a 30-day washout period.
Non-Tubuloglomerular Feedback
The average weight loss with these drugs is around 2-3% of the body weight. SGLT2 inhibitors also lead to chronic osmotic diuresis due to loss of glucose and water, which lead to fluid losses (this glucosuria puts patients at a higher risk for genital mycotic infections). This is demonstrated by the increase in urine output from baseline after SGLT2i initiation. This diuresis may also help blood pressure control, with all SGLT2i trials showing a consistent 2-5 mm Hg lowering of blood pressure compared to controls. Besides these obviously beneficial non-TGF pathways, there are other hypothesized mechanisms for the benefits of SGLT2i
Reduction of inflammation and fibrosis:
Increased intracellular glucose concentrations in the proximal tubules of patients with diabetes mellitus (DM) induces inflammatory cytokines, fibrotic mediators, and reactive oxygen specie
Alteration of oxygen consumption and lowering cortical hypoxia:
The kidneys are second only to the heart when it comes to oxygen consumption. This is almost entirely due to the high oxygen requirement of the Na-K-ATPase. In diabetes, this energy consumption is enhanced by SGLT2 overactivation, proximal tubular hypertrophy, and hyperfiltration
Alteration of energy metabolism:
Cardioprotective effect (secondary renoprotection): In addition to decreased ventricular loading due to a decrease in preload, SGLT2 inhibitors also have direct effects on myocardial tissue through the following mechanisms, mostly studied in heart failure.
SGLT2 inhibitors also inhibit sodium hydrogen exchangers. Heart failure models show that SGLT2i block NHE1 in the myocardium (despite no SGLT2 receptors in myocytes) and NHE3 in the proximal tubule. NHE1 inhibition reduces intracellular sodium and calcium which decreases pro-oxidant and pro-thrombotic states. NHE3 inhibition promotes natriuresis.
Conversion from fatty acids to beta-hydroxybutyrate improves cardiac energy efficiency as mentioned above.
Anti-fibrotic effects by suppressing collagen synthesis, inhibiting myofibroblast differentiation and reducing pro-inflammatory cytokines (IL6). This directly translates to reduced LV mass and improved ejection fraction.
SGLT2i-induced inhibition of the sympathetic nervous system has also been purported as a potential mechanism by which they improve CV outcomes. With a continual output of new literature about possible mechanisms coming our way, we will learn more in the future.
SGLT2
two main functions of SGLT2 on the kidney tubules: natriuresis and glucosuria. The SGLT2 receptor is responsible for resorption of one sodium ion for every glucose molecule in the early proximal tubule. In diabetes, kidney hypertrophy leads to increased SGLT2 expression and activity. Tubuloglomerular feedback from decreased sodium concentration at the macula densa leads to vasoconstriction of arterioles. This results in a mismatch between kidney tubular oxygen requirements and delivery. SGLT2i can help prevent hypoxia related kidney injury by blocking SGLT2 at the proximal tubules
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pacientes com tfg>20
prioridade ACR>200mg/g
falencia cardiaca
contraindicacoes relativas=
infeccoes genitais
cetoacidose diabetica
ulceras de mmii
imunossupressao
isglt2
follow up
- efeitos adversos
- queda da tfg
intervencao
cangliflozina 100mg
dapagliflozina 10mg
empagliflozina 10mg
educar o pac= sick day protocol
perioperative care
foot care
hipoglicemia
risco de uso com insulina ou sulfonilureia
historia de hipoglicemia severa
hba1c menor q o alvo
deplecao de volume
uso de diureticos concomitantes
historia de ira
