Rattibha

💥SGLT2 Inhibitors as Diuretics:
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⚡️SGLT2i: how is it’s diuretic effect potentially different from the Loop Diuretics?
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@RenalFellowNtwk
@NephJC
#NephJC
#SGLT2i

💥Let’s start with a Poll:
⚡️Loop Diuretics inhibit ❌ the Tubuloglomerular Feedback & ⬆️ Renin secretion
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💥Diuretics are used for Heart Failure therapy
⚡️The goal of diuretic therapy in Heart Failure is to achieve:
☄️Negative Na, Cl & Water balance
☄️⬇️ ECF volume
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💥In Heart Failure, there is Neurohumoral Adaptation in order to perfuse vital organs & this is achieved by:
⚡️⬆️ Systemic Pressure
⚡️⬆️ Myocardial Contractility
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💥What does Neurohumoral Adaptation involve?
💥Activation of the:
⚡️Sympathetic Nervous System
⚡️Renin-Angiotensin-Aldosterone System
⚡️Antidiuretic Hormone
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💥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
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💥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
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💥Loop diuretics ❌ the NKCC2 transporter in the Macula Densa ->
⬆️ Renin &
⬇️Tubuloglomerular Feedback (TGF)
‼️TGF ⬇️ the glomerular filtration when salt delivery to the Macula Densa ⬆️es
‼️Loop Diuretics ⬇️ TGF & ⬆️Neurohumoral Activation
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💥Loop diuretics also inhibit ❌ the NKCC1 transporter:
⚡️In the ear: causing ototoxicity
⚡️In the vascular smooth muscle: causing vasodilation
⚡️In afferent arteriole & in the mesangial cells near the Macula Densa: causing further ⬆️ in Renin
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💥Let’s take the Poll again:
⚡️Loop Diuretics inhibit ❌ the Tubuloglomerular Feedback & ⬆️ Renin secretion
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💥Loop Diuretics -> ⬇️ ECF volume
(if the Na intake remains low)
⚡️BUT as the ECF volume ⬇️es -> the natriuretuc response to Loop Diuretics ⬇️es
💥This is called the ‘Braking Phenomenon’👇🏽
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💥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)
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💥Braking Phenomenon involves:
⚡️Sympathetic Nervous System Activation
⚡️Renin-Angiotensin-Aldosterone Activation
⚡️Hypertrophy of the Distal Nephron (Nephron Remodeling): Diuretic Resistance👇🏽
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💥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 nephron
⚡️Let’s review the effect of SGLT2i as diuretics
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💥SGLT2i block the the Na/Glucose co-transporter in the proximal tubule
⚡️Increase Na delivery to the Macula Densa ‘activates’ the Tubuloglomerular Feedback (TGF)
‼️This is different from Loop Diuretics which ‘Inhibit’ the TGF
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💥SGLT2i have been shown to improve CV outcomes & ⬇️ Heart Failure hospitalizations among Diabetic patients in these clinical trials👇🏽
⚡️EMPA-REG
⚡️CANVAS
⚡️DECLARE-TIMI
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‼️The beneficial effect of SGLT2i in heart failure patients has been seen in both Diabetic & Non-Diabetic patients
‼️The DAPA-HF trial proves that the cardiac benefits of SGLT2i are independent of it’s glucose-lowering effect👇🏽
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💥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 ❤️
👇🏽👇🏽👇🏽
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💥How is the diuretic effect of SGLT2i different from Loop Diuretics?
⚡️Hypothesis👇🏽
SGLT2i ❌ Na & Glucose reabsorption in the prox. tubule, & unlike other diuretics, it results in both natriuresis & electrolyte-free water clearance (osmotic diuresis)
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💥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 diuretics
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💥What happens when healthy subjects are given SGLT2i & Loop Diuretics?
⚡️Randomized to Dapa or Bumex for 7 days
⚡️7 days later everybody got both diuretics
⚡️Bumex = 3-fold ⬆️ natriuresis
⚡️Natriuretic response was synergistic when both used together
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💥What happens when Empagliflozin vs. Placebo is used in pts. w/ Heart Failure?
Empagliflozin caused:
⚡️Modest Natriuresis
⚡️ ⬇️ in Blood & Plasma Volume BUT NO Neurohumoral Activation‼️
⚡️Synergistic Natriuresis w/ Loop Diuretics 👇🏽
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💥Contrasting effects of SGLT2i compared to Loop Diuretics:
⚡️Tubuloglomerular Feedback
⬆️ w/ SGLT2i
⚡️Neurohumoral Activation
⬇️ w/ SGLT2i
⚡️Electrolyte Imbalance
⬇️ w/ SGLT2i
💥Make SGLT2i an attractive diuretic choice in Heart Failure
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