1) Welcome to a new #accredited #tweetorial on the MoA & Renal Impact of Therapies Commonly Used in Pts with or At Risk for #DKD Progression: Improved Glycemic Control & #RAASi. Our expert author is Hans-Joachim Anders, MD, @hjanders_hans from @LMU_Uniklinikum of @LMU_Muenchen
2) This #accredited #tweetorial series on the foundations of #diabetickidneydisease #DKD through the lens of #T2D is supported by an independent educational grant from the Boehringer Ingelheim/Lilly Alliance and is intended for healthcare providers.
3) This activity is accredited for #physicians #physicianassociates #nurses #NPs #pharmacists. Past programs still eligible for credit can be found at http://www.ckd-ce.com. Faculty disclosures are at https://ckd-ce.com/disclosures/. FOLLOW US for regular programs by expert faculty!
4a) Let’s start with a case. 48♂️ with #T2D diagnosed 10Y ago referred for hypertension and suspected #DKD. Normal birth weight, no edema, meds include #metformin, #acarbose, amlodipine. BP 155/95. BMI 33.
5) What would be your assessment & approach?
— @CKD_ce (@ckd_ce) May 10, 2022
A. Likely advanced #DKD causing HTN, retinopathy; no biopsy
B. Hypertensive crisis; admit to the hospital
C. Poorly controlled #T2D with complications; initiate #insulin
D. Hypertensive nephropathy; increase amlodipine dose
6a) What did you respond?
👉A. History & exam favor this approach
👉B. Problems are chronic; there's no emergency
👉C. #T2D is surely poorly controlled but insulin not best option
👉D. Vasodilators e.g. amlodipine are less potent to ⬇️ #UACR because . . .
6b) . . . they ⬆️ single nephron GFR by dilating the afferent arteriole. See 🔓
7) What are the key mechanisms of injury to #kidney in #diabetes?
👉Activation of the #RAAS
👉Hemodynamic & metabolic overload of #nephrons (involving SGLT2 receptor)
👉Stress response signaling via #mineralocorticoid receptor
👉Endothelial dysfunction & podocyte shear stress
8a) Ok, let`s go through key pathomechanisms driving #CKD in #T2D
👉Hemodynamic overload ➡️SNGFR ⬆️➡️ #podocyte shear stress ➡️ #podocyte loss ➡️ ⬆️#UACR, #FSGS
👉#Obesity or pregnancy ➡️more fluid to filter
👉#Hyperglycemia = inactivates tubuloglomerular feedback
(cont)
8b)
👉#RAAS activation ➡️constriction of vas efferens
👉⬇️Filtration surface ➡️low birth weight, post-#AKI or #CKD ➡️ #nephron loss
👉Salt and/or protein-rich diet ➡️SNGFR⬆️ = podocyte shear stress⬆️
(cont)
8c)
👉Metabolic overload ➡️ prox. tubule oxidative stress ➡️TEC loss & cytokine release/inflammation ➡️ interst. #fibrosis ➡️#nephron loss
👉#Obesity more fluid ➡️more Na+ to reabsorb
👉#Hyperglycemia, Na+ or protein-rich diet ➡️more solutes to reabsorb
(cont)
8d)
👉Same for other solutes (P, HCO3, amino acids)
👉Reabsorption surface⬇️➡️low birth wgt, post-#AKI or #CKD➡️#nephron loss
#Mineralocorticoid receptor signaling➡️persist. stress response➡️interst. #inflammation #fibrosis➡️#nephron loss
👉Persist. neurohumoral/#RAS activation
9) Now let`s focus on what glycemic control can do for #DKD
Let`s compare the effects of #insulin, #metformin, #DPP4i, #SGLT2, #GLP-1
Check also:
10a) What does glycemic control with #insulin/#metformin do for #DKD ?
👍Improves A1c as expected, BUT
👎More episodes severe #hypoglycemia as #riskfactor for cognitive defects
👎No consistent effect on #DKD in first 8 years
(cont)
10b)
👎No consistent effect on major #CVevents in the first 10 years
See 🔓
11) What does glycemic control with #DPP4i do for #DKD ?
👎A meta-analysis of 8 RCTs (n=39.040) ➡️ no effect of #DPP4i on slope of #eGFR, #UACR, and all-cause #mortality.
See 🔓
12a) What does glycemic control with #SGLT2i do for #DKD ?
👍Meta-analysis of 4 RCTs (n=38.723) showed
👍RR 0.67, 95% CI 0.52-0.86 for #ESKD or death for #kidneydisease
👍RR 0.65, 95% CI 0.53-0.81 for #ESKD
(cont)
12b)
👍RR 0.75, 95% CI 0.66-0.85 for #AKI
↔️Irrespective of #UACR
See https://pubmed.ncbi.nlm.nih.gov/31495651/ by @ckd_ce faculty @brendonneuen et al
13) What does glycemic control with #GLP-1 agonists for #DKD ?
Meta-analysis of 8 RCTs (n=60,080) ➡️
👍RR 0.88, 95% CI 0.82-0.94 for all-cause #mortality
👍RR 0.79, 95% CI 0.73-0.87 for composite macro-#UACR, 2xSCr, -40%eGFR, #ESKD or renal death
See
14) Given this evidence from numerous large RCTs, the recent @goKDIGO guidelines recommend #metformin + #SGLT2i as a first line dual drug therapy for glucose control in pts with #T2D+#CKD.
🔓
15a) The🥇learning point here is:
It`s no longer good enough to reduce #A1c, as this is actually a poor surrogate for clinical outcomes.
15b) Now it`s all about drugs with efficacy on reducing such outcomes:
#metformin, #SGLT2i, #GLP-1 agonists, #MRA, and #RAASi. Unlike #insulin these reduce the hemodynamic and metabolic workload of the remaining #nephrons = longer dialysis-free lifespan!
16) Whew! That's a game changer. Think on how these impact on clinical practice–and return tomorrow for more education & your link to 🆓CE/#CME! 👏to @kidneydoc101 @RenalFellowNtwk @swissnephro @RealDr_Pepper @SethiRenalPath @drjosflynn @KidneyPath
17) Thank you for coming back! You are learning from @hjanders_hans all about glycemic control & #RAASi in #CKD+#T2D while you earn🆓CE/#CME! 👍to @kdjhaveri @KuppeChristoph @LinusButt @Renalpathsoc @JeanHouMD @ChristophWanne4 @mvaduganathan
18) So, certain anti-diabetic drugs prevent #CKD progression by reducing
👉hemodynamic overload of remaining #nephrons
👉metabolic overload of remaining #nephrons
#metformin, #SGLT2i, #GLP-1 agonists
How do inhibitors of the #RAASi integrate into this concept?
19) The #RAAS is another stress response system during salt/fluid depletion.
Its components help to recover salt and fluid (= volume). #Aldosterone links to MR signaling.
20) The #RAAS is balanced by #ACE2-mediated AT peptides Ang1-9 and Ang1-7 activating the MAS receptor. 👉@PepaSolerR, @MotrapuManga @ConxitaJacobs @edgarvlermamd
See
21a) However, chronic “stress” makes sickness ➡️ persistent molecular stress responses including #RAAS ➡️ pathophysiology and tissue pathology.
In #T2D triggers for persistent renin-release from the macula densa/MD include:
(cont)
21b)
👉Stenosis of afferent arteries or arterioles
👉Sympathetic tone ⬆️
👉Renal cell activation due to #inflammation & #fibrosis
👉#SGLT2-driven proximal Na+ reabsorption ⬆️➡️ Na+ delivery to MD ⬇️
See🔓
22a) In turn, persistent activation of the #RAAS leads to:
👉#HTN
👉Constricted eff. arteriole and MC contraction ➡️ SNGFR/hyperfiltration ⬆️➡️ #podocyte shear stress ➡️ hemodynamic overload
👉ATII & adrenal aldo ➡️ #HTN, MR signaling ➡️#inflammation & #fibrosis
(cont)
22b)
👉Hypervolemia ➡️⬆️ SNGFR ➡️⬆️ tubular reabsorption ➡️ metabolic overload
See
23) In 2010 there were these options to block the #RAAS and now there is also the #MRA #finerenone
24) Which RAASi you would prefer in our patient with #T2D & #CKD?
— @CKD_ce (@ckd_ce) May 11, 2022
Short recap:
48♂️, 10Y #T2D, #DKD, BP 155/95. BMI 33, K 4.9, Creat 1.5, #UACR 1,9g/g, kidneys 12cm, ocular exam: Cotton wool spots, focal hemorrhages, fundus hypertonicus III
25) Interesting choice. Let`s look at the evidence for #Aliskiren as add-on to SoC with #ACEi/ARB for pts with #T2D & #CKD
The AVOID phase 2 trial suggested efficacy and safety:
RR 0.80, 95% CI 9-30 for #UACR
See 🔓
26a) However, subsequent ALTITUDE Ph 3 trial was 🛑 for⬆️risk of #hyperkalemia & episodes of low #BP. Conclusion of @NEJM: “#aliskiren plus #ACEi/ARB in #T2D & high risk for CV & renal events is not supported and may even be harmful.”
26b) Of further note: Also no effect on renal composite endpoint!
See 🔓
27) Now, let`s look at the evidence for #ACEi/ARB in #T2D & #CKD
A large number of #RCTs support efficacy and safety for various endpoints such as
👍Preventing #ESKD and death
👍Preventing #macroalbuminuria
👍Preventing #microalbuminuria
See
28) Therefore, @goKDIGO 2012 recommendations are still valid in 2022:
🔓
29a) Now, let`s look at the evidence for #MRA.
#Spironolactone, #Eplerenone as traditional #MRA hold the risk for #hyperkalemia and #gynecomastia, & thus are not approved for #CKD
In contrast, the non-steroidal #MRA #Finerenone was approved for tx of #T2D & #CKD
(cont)
29b) A pooled #FIDELITY analysis of the #RCTs #FIDELIO & #FIGARO summarizes the CV and #kidney outcomes: 🔓https://pubmed.ncbi.nlm.nih.gov/35023547/ . Learn more about this & earn even more 🆓CE/#CME at
30) With #Finereone➡️still small risk for #hyperkalemia. Tempting to speculate that triple therapy #RAASi & #MRA & #SGLT2i could solve this problem, but not yet demonstrated. A recent meta-analysis of dual #RAASi & #SGLT2i trials supports this concept: 🔓
31a) Thus, our patient (short recap):
48♂️, 10Y #T2D, #DKD, BP 155/95. BMI 33, K 4.9, Creat 1.5, #UACR 1,9g/g, kidneys 12cm, ocular exam: Cotton wool spots, focal hemorrhages, fundus hypertonicus III …
31b) … should benefit from:
#Metformin & #SGLT2i & maybe #GLP-1 for glucose control & CV risk
#ACEi or #ARB & #SGLT2i & maybe #Finerenone to control #BP & prevent #ESKD + CV events
Adding a #diuretic may help #BP control
32) And that's it! YOU MADE IT! 0.5h CE/#CME credit. Go claim your certificate at https://ckd-ce.com/dkd10/. We invite you to FOLLOW @ckd_ce (and @cardiomet_CE) for more outstanding education and credit for 🇪🇺🇬🇧🇨🇦🇺🇸 clinicians! Always expert authors like @hjanders_hans !
Originally tweeted by @CKD_ce (@ckd_ce) on May 10, 2022.