Thread by @RosenelliEM

Ready for a short @thecurbsiders recap #tweetorial on #SGLT2Inhibitors Ep 204 #NephMadness Hat tip to the Shownotes @BrighamSK @PaulNWilliamz @DoctorWatto @kidney_boy @HannahRAbrams

SGLT2i Pearls:

1. SGLT2 inhibitors have significant long-term protection of GFR. However, because they cause afferent arteriolar vasoconstriction, expect to see an acute drop in GFR after initiating.

2. SGLT2 inhibitors work w/ ACEi/ARBs & can still provide improvement in renal outcomes for pts w/ diabetic kidney disease on max dose ACEi/ARB.

3. Patients already on thiazide can experience significant volume loss with SGLT2i initiation. Consider reducing or stopping thiazides

SGLT2i Mechanisms of Action:

Traditionally, tubuloglomerular feedback has been considered a major mechanism of sodium-glucose cotransporter 2 inhibitor (SGLT2i) effect in diabetic kidney disease.

The effectiveness of SGLT2is in other indications and beyond what is seen in other afferent arteriolar vasoconstrictors point to the potential importance of other mechanisms, such as decreasing inflammation and altering oxygen metabolism.

The first step of diabetic kidney disease is that hyperglycemia causes hyperfiltration and subsequent increased reabsorption of glucose.

Sodium is reabsorbed at an increased rate along with that glucose, meaning that the macula densa ‘sees’ less sodium

The macul then acts as though there is not enough blood flow to the glomerulus.

The afferent arteriole vasodilates, increasing intraglomerular pressure, and over time this contributes to fibrosis and nephron loss. ajkdblog.org/2020/03/13/nep…

SGLT2 inhibition stops that increased reabsorption of glucose and sodium and therefore prevents the afferent arteriole from vasodilating.

This reduces intraglomerular pressure and protects the nephron

ajkdblog.org/2020/03/13/nep…

This works w/ the effect of ACEi/ARB which inhibit vasoconstriction of the efferent arteriole;

SGLT2i can still provide improvement in renal outcomes for diabetic kidney disease in pts on maximum doses of ACE inhibitor (which increases efferent flow). pubmed.ncbi.nlm.nih.gov/30990260/

Several proposed mechanisms may explain some of the effects of SGLT2is. SGLT2is have been shown in vitro to reduce inflammatory markers. pubmed.ncbi.nlm.nih.gov/23390498/

May also limit podocyte dysfunction and act on upregulated SGLT2 expression in proteinuria.pubmed.ncbi.nlm.nih.gov/30089717/

In animal models it has been shown to upregulate VEGF expression

pubmed.ncbi.nlm.nih.gov/30045814/

These two effects may decrease nephron fibrosis and cardiac inflammation.

SGLT2 inhibitors also change the oxygen consumption of the nephron by suppressing Na-K-ATPase activity in the proximal tubule pubmed.ncbi.nlm.nih.gov/26041448/

Cardiac protection from SGLT2 inhibitors also points to a mechanism other than TG feedback: the heart doesn’t have SGLT2 cotransporters.

SGLT2i may block Na-H exchange in the heart to decrease oxidative damage & thrombosis as well as promote natriuresis ajkdblog.org/2020/03/13/nep…

Increased risk of amputation with SGLT2i was noted in the CANVAS trial, but this finding was not reproduced in the CREDENCE trial.

Genital fungal infections are common, and these are usually responsive to antifungal treatment and do not require stopping the medication

Fournier’s gangrene is also rare though a potential risk of these medications ncbi.nlm.nih.gov/pubmed/31060053

Euglycemic diabetic ketoacidosis is another rare though possible side effect as patients may have DKA with normal blood glucose levels given the induced glycosuria.

The CANVAS and CREDENCE trial both showed that patients with diabetes treated with canagliflozin experienced less cardiovascular events, and those in the CREDENCE trial had less kidney failure.

ncbi.nlm.nih.gov/pubmed/28605608
pubmed.ncbi.nlm.nih.gov/30990260/

In the DAPA-HF trial of heart failure patients with reduced ejection fraction, even though 60% of patients did not have diabetes, SGLT2i were associated with significant decrease in risk of worsening heart failure or cardiovascular death. pubmed.ncbi.nlm.nih.gov/31535829/

Limited evidence currently exists for the effect of SGLT2i on outcomes in kidney transplant patients; however, they appear to be safe. ajkdblog.org/2020/03/13/nep…