Thread by @aishaikh

💥SGLT2 Inhibitors as Diuretics:
Tweetorial

⚡️SGLT2i: how is it’s diuretic effect potentially different from the Loop Diuretics?
1/

@RenalFellowNtwk
@NephJC
#NephJC
#SGLT2i

💥Let’s start with a Poll:

⚡️Loop Diuretics inhibit ❌ the Tubuloglomerular Feedback & ⬆️ Renin secretion
2/

💥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
3/

💥In Heart Failure, there is Neurohumoral Adaptation in order to perfuse vital organs & this is achieved by:

⚡️⬆️ Systemic Pressure
⚡️⬆️ Myocardial Contractility
4/

💥What does Neurohumoral Adaptation involve?

💥Activation of the:

⚡️Sympathetic Nervous System
⚡️Renin-Angiotensin-Aldosterone System
⚡️Antidiuretic 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 ⬆️es

‼️Loop Diuretics ⬇️ TGF & ⬆️Neurohumoral Activation
8/

💥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
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 ⬇️es

💥This 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 Resistance👇🏽
13/

💥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
14/

💥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
15/

💥SGLT2i have been shown to improve CV outcomes & ⬇️ Heart Failure hospitalizations among Diabetic patients in these clinical trials👇🏽

⚡️EMPA-REG
⚡️CANVAS
⚡️DECLARE-TIMI
16/

‼️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👇🏽
17/

💥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?

⚡️Hypothesis👇🏽

SGLT2i ❌ 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 diuretics
20/

💥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
21/

💥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 👇🏽
22/

💥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

End/