SGLT-2 Inhibition: From Basic to Clinical
Speakers: Ralph DeFronzo, David Cherney, Ele Ferrannini and Rajiv Agarwal

Few important take home points from the 2 hour amazing session on use of the SLGT inhibitors (glucoretics) and kidney diseases in diabetics.

1. Kidney has a significant role in glucose production along with liver as well and that is increased in diabetic patients.
2. There is increase reabsorption of proximal glucose in the kidney in DM patients.  The Tm of glucose re absorption is increased in DMII patients.
3. As your A1c increases, you start spilling glucose in the urine at a much earlier serum glucose level (in the low 30s).
4. SGLT2  blocks Na glucose reabsoprtion in the proximal tubule and leads to a salt and glucose diuresis.  But still SGLT-2 inhibitors only inhibit 40-50% of filtered glucose load.  This is because there is up regulation of SGLT-1 likely as a result (in the distal nephron). That is a low capacity but high affinity transporter. Since there is increased glucose delivery to it, it get’s active.  At full capacity, SGLT-1 takes back 30-35% of filtered glucose levels.  Ideally, a good blocker would block SGLT-1 and 2 better.  I had an older post on this while back on nephronpower.com
5. Tubular Feedback hypothesis and SGLT-2 inhibitors: In DMII, there is inappropriate TG feedback. There is up regulation of SGLT-2 to absorb more Na, this leads to increased afferent vasodilatation and eventually hyperfiltration and increased GFR in DMII. One of audience members challenged this notion and mentioned that ANP might be more important player here than TG feedback and we need ANP inhibitors as well along with SGLT-2 inhibitors.
6. Since SGLT-2 have a glucoretic effect – they lead to weight loss and good A1C control. And in addition, they are a natriuretic leading to better bp control and decrease in hyperfiltration.
7. Mice data show that there is REVERSAL of hyperfiltration with this agent.
8. A recent study in Circulation 2014 showed that  short-term treatment with the sodium glucose cotransporter 2 inhibitor empagliflozin attenuated renal hyperfiltration in subjects with T1D, likely by affecting tubular-glomerular feedback mechanisms.
9. If one thinks about this agent, it leads to suppression of TG feedback by decreasing natriuresis:- leading to constriction of the afferent arteriole and hence decreasing GFR.  That would lead to some increase in serum crt. Are we going to take the same 20-25% increase allowed as we do with ACEI/ARB? Are these increases in Crt renoprotective? We don’t  know…
10. A sub study in CKD patients has shown that it decreases GFR and albuminuria and significant effect on weight loss and blood pressure.
11. A Phase 3 study called CREDENCE is a randomized, double-blind, placebo-controlled, parallel group trial designed to enroll more than 3,700 patients with type 2 diabetes and diabetic nephropathy. The objective of the study is to examine whether canagliflozin can slow the progression of diabetic nephropathy, a form of renal impairment that is the most common cause of end-stage renal disease worldwide. So this will take a look at patients with CKD and their effect with this agent.
12. One of the inclusion criteria of this trial is that patients be on maximum tolerated dose of ACEI or ARB.  One concern I have with that is (ACEI and SGLT-2 inhibition): won’t that lead to hyperkalemia and significant increase in serum crt as we are now blocking both the afferent and efferent arteriole? We shall find out as physiology sometimes doesn’t always match up with evidence based studies.
13. Safety issues: Genital, mycotic infections, UTIs, hyperkalemia, volume depletion, increased LDL and elevation of crt.
14. Risk factors for causing volume depletion are low na diet, use of a loop diuretics concurrently, low baseline bp, age >75 and being on RAAS blockade, eGFR <60
15. Why hyperkalemia? Most were on K sparing diuretics as well or RAAS blockade and low Na diet as well
16. Increased LDL but also increased HDL – ratio evens out.
17. One of the speakers called this agent  “ Diuretic effect with brakes”

Post by Dr. Kenar Jhaveri, eAJKD Editor. 

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