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SGLT2 Inhibitors as Diuretics:Tweetorial
SGLT2i: how is it’s diuretic effect potentially different from the Loop Diuretics?1/
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Let’s start with a Poll:Loop Diuretics inhibit 
the Tubuloglomerular Feedback & 
Renin secretion 2/
Diuretics are used for Heart Failure therapyThe goal of diuretic therapy in Heart Failure is to achieve:
Negative Na, Cl & Water balance
ECF volume 3/
In Heart Failure, there is Neurohumoral Adaptation in order to perfuse vital organs & this is achieved by: Systemic Pressure Myocardial Contractility4/
What does Neurohumoral Adaptation involve?Activation of the:Sympathetic Nervous SystemRenin-Angiotensin-Aldosterone SystemAntidiuretic Hormone 5/
BUT there can be ‘Maladaptive’ consequences of persistent Neurohumoral Activation: Preload (Congestion) LV Afterload Cardiac Hypertrophy/Fibrosis Hyponatremia
This is why Beta blockers & RAAS blockers work in 
Failure 6/
Loop Diuretics (LDs) are the most commonly used diuretics Loop diuretics -> NKCC2 transporter in the TAL of the LOH
NKCC2 transporter is responsible for reabsorption of ~25% of the filtered Na & Cl 7/
Loop diuretics the NKCC2 transporter in the Macula Densa -> Renin & Tubuloglomerular Feedback (TGF)
TGF the glomerular filtration when salt delivery to the Macula Densa esLoop Diuretics TGF & Neurohumoral Activation8/
Loop diuretics also inhibit the NKCC1 transporter:In the ear: causing ototoxicityIn the vascular smooth muscle: causing vasodilation In afferent arteriole & in the mesangial cells near the Macula Densa: causing further in Renin 9/
Let’s take the Poll again:Loop Diuretics inhibit the Tubuloglomerular Feedback & Renin secretion 10/
Loop Diuretics -> ECF volume(if the Na intake remains low)
BUT as the ECF volume es -> the natriuretuc response to Loop Diuretics esThis is called the ‘Braking Phenomenon’11/
Braking Phenomenon can be protective & detrimental. How?Long term diuretic use can cause extreme contraction of the ECF volume (
protective)But it can also cause ‘diuretic resistance’ in congested heart failure patients ( detrimental)12/
Braking Phenomenon involves:Sympathetic Nervous System Activation Renin-Angiotensin-Aldosterone Activation Hypertrophy of the Distal Nephron (Nephron Remodeling): Diuretic Resistance13/
To overcome diuretic resistance a commonly used strategy is ‘sequential nephron blockade’ by adding a different class of diuretics targeting a different area of the nephronLet’s review the effect of SGLT2i as diuretics 14/
SGLT2i block the the Na/Glucose co-transporter in the proximal tubuleIncrease Na delivery to the Macula Densa ‘activates’ the Tubuloglomerular Feedback (TGF)This is different from Loop Diuretics which ‘Inhibit’ the TGF 15/
SGLT2i have been shown to improve CV outcomes & Heart Failure hospitalizations among Diabetic patients in these clinical trialsEMPA-REGCANVASDECLARE-TIMI16/
The beneficial effect of SGLT2i in heart failure patients has been seen in both Diabetic & Non-Diabetic patientsThe DAPA-HF trial proves that the cardiac benefits of SGLT2i are independent of it’s glucose-lowering effect17/
How do SGLT2i improve CV outcomes? Possibly due to:
in Preload (diuretic effect) in Afterload ( BP) Improvement in Cardiac Bioenergetics by switching from glucose to ketone bodies as source of energy Na/H Exchange in the 18/
How is the diuretic effect of SGLT2i different from Loop Diuretics?HypothesisSGLT2i
Na & Glucose reabsorption in the prox. tubule, & unlike other diuretics, it results in both natriuresis & electrolyte-free water clearance (osmotic diuresis) 19/
Hypothesis: Osmotic diuresis & electrolyte free water clearance w/ SGLT2i results in:Greater in interstitial volume relative to the in intravascular volume Limiting the aberrant reflex Neurohumoral Activation seen w/ other diuretics20/
What happens when healthy subjects are given SGLT2i & Loop Diuretics?Randomized to Dapa or Bumex for 7 days7 days later everybody got both diuretics Bumex = 3-fold natriuresisNatriuretic response was synergistic when both used together21/
What happens when Empagliflozin vs. Placebo is used in pts. w/ Heart Failure?Empagliflozin caused:
Modest Natriuresis in Blood & Plasma Volume BUT NO Neurohumoral ActivationSynergistic Natriuresis w/ Loop Diuretics 22/
Contrasting effects of SGLT2i compared to Loop Diuretics:Tubuloglomerular Feedback w/ SGLT2iNeurohumoral Activation w/ SGLT2iElectrolyte Imbalance w/ SGLT2iMake SGLT2i an attractive diuretic choice in Heart Failure End/
