https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">SGLT2 Inhibitors as Diuretics:
Tweetorial

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">SGLT2i: how is it’s diuretic effect potentially different from the Loop Diuretics?
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@RenalFellowNtwk
@NephJC
#NephJC
#SGLT2i

https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">Let’s start with a Poll:

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Loop Diuretics inhibit https://abs.twimg.com/emoji/v2/... draggable="false" alt="❌" title="Cross mark" aria-label="Emoji: Cross mark"> the Tubuloglomerular Feedback & https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Upwards arrow" aria-label="Emoji: Upwards arrow"> Renin secretion
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">Diuretics are used for Heart Failure therapy

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">The goal of diuretic therapy in Heart Failure is to achieve:

https://abs.twimg.com/emoji/v2/... draggable="false" alt="☄️" title="Comet" aria-label="Emoji: Comet">Negative Na, Cl & Water balance
https://abs.twimg.com/emoji/v2/... draggable="false" alt="☄️" title="Comet" aria-label="Emoji: Comet">https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Downwards arrow" aria-label="Emoji: Downwards arrow"> ECF volume
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">In Heart Failure, there is Neurohumoral Adaptation in order to perfuse vital organs & this is achieved by:

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Upwards arrow" aria-label="Emoji: Upwards arrow"> Systemic Pressure
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Upwards arrow" aria-label="Emoji: Upwards arrow"> Myocardial Contractility
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">What does Neurohumoral Adaptation involve?

https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">Activation of the:

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Sympathetic Nervous System
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Renin-Angiotensin-Aldosterone System
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Antidiuretic Hormone
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">BUT there can be ‘Maladaptive’ consequences of persistent Neurohumoral Activation:

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Upwards arrow" aria-label="Emoji: Upwards arrow"> Preload (Congestion)
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Upwards arrow" aria-label="Emoji: Upwards arrow"> LV Afterload
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Upwards arrow" aria-label="Emoji: Upwards arrow"> Cardiac Hypertrophy/Fibrosis
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Upwards arrow" aria-label="Emoji: Upwards arrow"> Hyponatremia

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👆🏽" title="Up pointing backhand index (medium skin tone)" aria-label="Emoji: Up pointing backhand index (medium skin tone)">This is why Beta blockers & RAAS blockers work in https://abs.twimg.com/emoji/v2/... draggable="false" alt="❤️" title="Red heart" aria-label="Emoji: Red heart"> Failure
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">Loop Diuretics (LDs) are the most commonly used diuretics

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Loop diuretics -> https://abs.twimg.com/emoji/v2/... draggable="false" alt="❌" title="Cross mark" aria-label="Emoji: Cross mark"> NKCC2 transporter in the TAL of the LOHhttps://abs.twimg.com/emoji/v2/... draggable="false" alt="👇🏽" title="Down pointing backhand index (medium skin tone)" aria-label="Emoji: Down pointing backhand index (medium skin tone)">
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">NKCC2 transporter is responsible for reabsorption of ~25% of the filtered Na & Cl
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">Loop diuretics https://abs.twimg.com/emoji/v2/... draggable="false" alt="❌" title="Cross mark" aria-label="Emoji: Cross mark"> the NKCC2 transporter in the Macula Densa ->

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Upwards arrow" aria-label="Emoji: Upwards arrow"> Renin &
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Downwards arrow" aria-label="Emoji: Downwards arrow">Tubuloglomerular Feedback (TGF)

https://abs.twimg.com/emoji/v2/... draggable="false" alt="‼️" title="Double exclamation mark" aria-label="Emoji: Double exclamation mark">TGF https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Downwards arrow" aria-label="Emoji: Downwards arrow"> the glomerular filtration when salt delivery to the Macula Densa https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Upwards arrow" aria-label="Emoji: Upwards arrow">es

https://abs.twimg.com/emoji/v2/... draggable="false" alt="‼️" title="Double exclamation mark" aria-label="Emoji: Double exclamation mark">Loop Diuretics https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Downwards arrow" aria-label="Emoji: Downwards arrow"> TGF & https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Upwards arrow" aria-label="Emoji: Upwards arrow">Neurohumoral Activation
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">Loop diuretics also inhibit https://abs.twimg.com/emoji/v2/... draggable="false" alt="❌" title="Cross mark" aria-label="Emoji: Cross mark"> the NKCC1 transporter:

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">In the ear: causing ototoxicity

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">In the vascular smooth muscle: causing vasodilation

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">In afferent arteriole & in the mesangial cells near the Macula Densa: causing further https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Upwards arrow" aria-label="Emoji: Upwards arrow"> in Renin
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">Let’s take the Poll again:

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Loop Diuretics inhibit https://abs.twimg.com/emoji/v2/... draggable="false" alt="❌" title="Cross mark" aria-label="Emoji: Cross mark"> the Tubuloglomerular Feedback & https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Upwards arrow" aria-label="Emoji: Upwards arrow"> Renin secretion

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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">Loop Diuretics -> https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Downwards arrow" aria-label="Emoji: Downwards arrow"> ECF volume
(if the Na intake remains low)

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">BUT as the ECF volume https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Downwards arrow" aria-label="Emoji: Downwards arrow">es -> the natriuretuc response to Loop Diuretics https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Downwards arrow" aria-label="Emoji: Downwards arrow">es

https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">This is called the ‘Braking Phenomenon’https://abs.twimg.com/emoji/v2/... draggable="false" alt="👇🏽" title="Down pointing backhand index (medium skin tone)" aria-label="Emoji: Down pointing backhand index (medium skin tone)">
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">Braking Phenomenon can be protective & detrimental. How?https://abs.twimg.com/emoji/v2/... draggable="false" alt="👇🏽" title="Down pointing backhand index (medium skin tone)" aria-label="Emoji: Down pointing backhand index (medium skin tone)">

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Long term diuretic use can cause extreme contraction of the ECF volume (https://abs.twimg.com/emoji/v2/... draggable="false" alt="✅" title="White heavy check mark" aria-label="Emoji: White heavy check mark"> protective)

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">But it can also cause ‘diuretic resistance’ in congested heart failure patients (https://abs.twimg.com/emoji/v2/... draggable="false" alt="❌" title="Cross mark" aria-label="Emoji: Cross mark"> detrimental)
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">Braking Phenomenon involves:

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Sympathetic Nervous System Activation

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Renin-Angiotensin-Aldosterone Activation

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Hypertrophy of the Distal Nephron (Nephron Remodeling): Diuretic Resistancehttps://abs.twimg.com/emoji/v2/... draggable="false" alt="👇🏽" title="Down pointing backhand index (medium skin tone)" aria-label="Emoji: Down pointing backhand index (medium skin tone)">
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">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

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Let’s review the effect of SGLT2i as diuretics
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">SGLT2i block the the Na/Glucose co-transporter in the proximal tubule

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Increase Na delivery to the Macula Densa ‘activates’ the Tubuloglomerular Feedback (TGF)

https://abs.twimg.com/emoji/v2/... draggable="false" alt="‼️" title="Double exclamation mark" aria-label="Emoji: Double exclamation mark">This is different from Loop Diuretics which ‘Inhibit’ the TGF
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">SGLT2i have been shown to improve CV outcomes & https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Downwards arrow" aria-label="Emoji: Downwards arrow"> Heart Failure hospitalizations among Diabetic patients in these clinical trialshttps://abs.twimg.com/emoji/v2/... draggable="false" alt="👇🏽" title="Down pointing backhand index (medium skin tone)" aria-label="Emoji: Down pointing backhand index (medium skin tone)">

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">EMPA-REG
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">CANVAS
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">DECLARE-TIMI
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="‼️" title="Double exclamation mark" aria-label="Emoji: Double exclamation mark">The beneficial effect of SGLT2i in heart failure patients has been seen in both Diabetic & Non-Diabetic patients

https://abs.twimg.com/emoji/v2/... draggable="false" alt="‼️" title="Double exclamation mark" aria-label="Emoji: Double exclamation mark">The DAPA-HF trial proves that the cardiac benefits of SGLT2i are independent of it’s glucose-lowering effecthttps://abs.twimg.com/emoji/v2/... draggable="false" alt="👇🏽" title="Down pointing backhand index (medium skin tone)" aria-label="Emoji: Down pointing backhand index (medium skin tone)">
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">How do SGLT2i improve CV outcomes?
Possibly due to:

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Downwards arrow" aria-label="Emoji: Downwards arrow"> in Preload (diuretic effect)

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Downwards arrow" aria-label="Emoji: Downwards arrow"> in Afterload (https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Downwards arrow" aria-label="Emoji: Downwards arrow"> BP)

https://abs.twimg.com/emoji/v2/... draggable="false" alt="✅" title="White heavy check mark" aria-label="Emoji: White heavy check mark"> Improvement in Cardiac Bioenergetics by switching from glucose to ketone bodies as source of energy

https://abs.twimg.com/emoji/v2/... draggable="false" alt="❌" title="Cross mark" aria-label="Emoji: Cross mark"> Na/H Exchange in the https://abs.twimg.com/emoji/v2/... draggable="false" alt="❤️" title="Red heart" aria-label="Emoji: Red heart">
https://abs.twimg.com/emoji/v2/... draggable="false" alt="👇🏽" title="Down pointing backhand index (medium skin tone)" aria-label="Emoji: Down pointing backhand index (medium skin tone)">https://abs.twimg.com/emoji/v2/... draggable="false" alt="👇🏽" title="Down pointing backhand index (medium skin tone)" aria-label="Emoji: Down pointing backhand index (medium skin tone)">https://abs.twimg.com/emoji/v2/... draggable="false" alt="👇🏽" title="Down pointing backhand index (medium skin tone)" aria-label="Emoji: Down pointing backhand index (medium skin tone)">
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">How is the diuretic effect of SGLT2i different from Loop Diuretics?

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Hypothesishttps://abs.twimg.com/emoji/v2/... draggable="false" alt="👇🏽" title="Down pointing backhand index (medium skin tone)" aria-label="Emoji: Down pointing backhand index (medium skin tone)">

SGLT2i https://abs.twimg.com/emoji/v2/... draggable="false" alt="❌" title="Cross mark" aria-label="Emoji: Cross mark"> 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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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">Hypothesis: https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Upwards arrow" aria-label="Emoji: Upwards arrow">Osmotic diuresis & https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Upwards arrow" aria-label="Emoji: Upwards arrow"> electrolyte free water clearance w/ SGLT2i results in:

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Greater https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Downwards arrow" aria-label="Emoji: Downwards arrow"> in interstitial volume relative to the https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Downwards arrow" aria-label="Emoji: Downwards arrow"> in intravascular volume

https://abs.twimg.com/emoji/v2/... draggable="false" alt="‼️" title="Double exclamation mark" aria-label="Emoji: Double exclamation mark">Limiting the aberrant reflex Neurohumoral Activation seen w/ other diuretics
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">What happens when healthy subjects are given SGLT2i & Loop Diuretics?

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Randomized to Dapa or Bumex for 7 days
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">7 days later everybody got both diuretics

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Bumex = 3-fold https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Upwards arrow" aria-label="Emoji: Upwards arrow"> natriuresis
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Natriuretic response was synergistic when both used together
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">What happens when Empagliflozin vs. Placebo is used in pts. w/ Heart Failure?

Empagliflozin caused:

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Modest Natriuresis

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign"> https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Downwards arrow" aria-label="Emoji: Downwards arrow"> in Blood & Plasma Volume BUT NO Neurohumoral Activationhttps://abs.twimg.com/emoji/v2/... draggable="false" alt="‼️" title="Double exclamation mark" aria-label="Emoji: Double exclamation mark">

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Synergistic Natriuresis w/ Loop Diuretics https://abs.twimg.com/emoji/v2/... draggable="false" alt="👇🏽" title="Down pointing backhand index (medium skin tone)" aria-label="Emoji: Down pointing backhand index (medium skin tone)">
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">Contrasting effects of SGLT2i compared to Loop Diuretics:

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Tubuloglomerular Feedback
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Upwards arrow" aria-label="Emoji: Upwards arrow"> w/ SGLT2i

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Neurohumoral Activation
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Downwards arrow" aria-label="Emoji: Downwards arrow"> w/ SGLT2i

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⚡️" title="High voltage sign" aria-label="Emoji: High voltage sign">Electrolyte Imbalance
https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Downwards arrow" aria-label="Emoji: Downwards arrow"> w/ SGLT2i

https://abs.twimg.com/emoji/v2/... draggable="false" alt="💥" title="Collision symbol" aria-label="Emoji: Collision symbol">Make SGLT2i an attractive diuretic choice in Heart Failure

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