Stay up-to-date with advances in chronic kidney disease (CKD)! Join our esteemed Chief of Nephrology at Kashlak Memorial Hospital, Dr. Joel Topf, as he leads us through the latest on SGLT2 inhibitors, finerenone, potassium binders, and treatment of CKD-associated metabolic acidosis.
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SGLT2 inhibitors (SGLT2i)
Initiation of SGLT2i
SGLT2i are powerful renal-protective agents, with study after study showing benefit for patients with chronic kidney disease (CKD) (Heerspink et al 2020, Herrington et al 2023, Perkovic et al 2019, KDIGO 2022 guidelines). When considering initiation of renal-protective agents, Dr. Topf recommends referring to the Kidney Failure Risk Equation. This reference equation predicts the risk of dialysis in the next 2 or 5 years and provides a tangible number that patients can conceptualize. In a patient with CKD and albuminuria, in addition to maximizing RAAS inhibition, initiating an SGLT2i is an effective step in reducing major adverse kidney events.
What is the eGFR lower limit when initiating an SGLT2i?
Most studies of SGLT2i excluded patients with an eGFR less than 30 mL/min/1.73m2 (CANVAS, EMPA-REG, CREDENCE) (Neal et al 2017, Zinman et al 2015, Perkovic et al 2019.) Several studies have enrolled patients with lower eGFRs, including down to 25 mL/min/1.73m2 (DAPA-CKD) and 20 mL/min/1.73m2 (EMPA-KIDNEY) (Heerspink et al 2020, Herrington et al 2023.) None of these studies have shown decreased effectiveness of SGLT2i at lower eGFRs. Dr. Topf is comfortable initiating an SGLT2i in patients down to an eGFR of 20 mL/min/1.73m2, which is supported by the recommendations in the latest KDIGO guidelines (KDIGO 2022 guidelines).
If a patient’s eGFR drops further, Dr. Topf doesn’t pull off the SGLT2i, but rather leaves it on indefinitely, based on what was done in the major trials (expert opinion).
A key upcoming study addressing the question of SGLT2i use in patients with limited kidney function is the LIFECYCLE trial, which is enrolling patients with GFR < 20, kidney transplant patients, and patients on dialysis who are still making urine, all populations for which SGLT2i have not yet been studied in placebo-controlled trials.
What about initiation of SGLT2i in patients with poor glycemic control?
Dr. Topf recommends delaying initiation of an SGLT2i in a patient with very poor glycemic control (e.g. HbA1c > 10.5), as SGLT2i initiation in this population can increase the likelihood of osmotic diuresis, lightheadedness, and acute kidney injury.
SGLT2i – Adverse effects and monitoring
Dr. Topf emphasizes that SGLT2i are “set it and forget it” medications that do not require routine monitoring; thus, they are much simpler to manage than medications for hypercholesterolemia or hypertension.
Risk of AKI
The risk of acute kidney injury (AKI) with SGLT2i has been carefully studied in DAPA-CKD and EMPA-KIDNEY, which actually found a lower risk of AKI in patients on an SGLT2i, underscoring the renal-protective effects of these mediations (Heerspink et al 2020, Herrington et al 2023.)
Patients do often experience an acute drop in eGFR upon initiation of SGLT2i, but their outcomes are just as good as those who do not experience this drop. Thus, there is no need for routine monitoring of kidney function following SGLT2i initiation; indeed, in the EMPA-KIDNEY trial, patients were not seen for follow-up until 2 months after starting the medication (Herrington et al 2023.)
With regards to concurrent use of thiazide or loop diuretics: Dr. Topf’s practice is to generally continue a patient’s diuretics at the same dose when initiating an SGLT2i. In the studies of SGLT2i in patients with heart failure, diuretics were not stopped upon SGTL2 inhibitor initiation. Caution should be taken in patients with high HgbA1cs, as this group is at higher risk of osmotic diuresis. Dr. Topf also notes that he usually does not start a new diuretic at the same time as an SGLT2i, but rather waits until a patient is on a stable dose of a diuretic and their heart failure / edema is under control before initiating the SGLT2i (expert opinion).
Risk of mycotic genital infections, UTI, and Fournier’s gangrene
SGLT2 inhibitor use does increase the risk of UTIs and, more notably, mycotic genital infections (jock itch, yeast infections), though Dr. Topf emphasizes that these risks are minor compared to the enormous benefits that SGLT2i offer in terms of preventing dialysis and death from cardiac/renal complications. The risk of Fournier’s gangrene from SGLT2i is very low (Wang et al 2020).
Pearls when talking to patients about SGLT2i
Dr. Topf offers two pearls for talking to patients about SGLT2i:
1. Don’t say these are “new medications,” as they have been around since 2013; instead, Dr. Topf explains to patients that the medications have existed for a while but that we now have a new understanding of how they are among the most powerful kidney-protective and heart-protective drugs ever discovered.
2. Patients love to hear that the SGLT2i compound comes from apple bark!
What is finerenone, and what is the evidence supporting its benefit in patients with CKD?
Finerenone is a novel mineralocorticoid receptor antagonist (MRA) (Bakris et al 2020). MRAs block the receptor for aldosterone, a hormone that promotes sodium retention and has pro-fibrotic activity in the heart and kidney. Unlike traditional MRAs (spironolactone and eplerenone), finerenone is a non-steroidal medication and has a shorter half-life than the other agents. Finerenone has less of an effect on blood pressure than the other MRAs.
Notably, while spironolactone and eplerenone have evidence for improving heart failure outcomes when combined with ACE-i/ARBs, their effectiveness for improving renal outcomes has not been studied in a dedicated trial, and post-hoc analyses of renal outcomes in the heart failure trials of these MRAs did not a yield a signal (Vaduganathan et al 2022). However, finerenone is noteworthy as it has not only been shown to improve cardiac outcomes in the FIGERO trial (Filippatos et al 2022), but was also shown to improve renal outcomes (reducing major adverse kidney events) in the FIDELO trial (with a hazard ratio of 0.82) (Bakris et al 2020.) These trials were conducted in patients with diabetes; trials of finerenone in patients without diabetes are ongoing.
When should finerenone be considered?
Dr. Topf recommends that a patient with CKD should first be started on an ACE-i/ARB, then an SGLT2i, and then have their ACE-i/ARB adjusted to make sure they are on maximum therapy. If at that point their blood pressure is not controlled, Dr. Topf would recommend turning to eplerenone or spironolactone rather than finerenone, as these agents are more effective than finerenone at improving blood pressure. If, however, the patient’s blood pressure is under good control but they are still experiencing residual proteinuria, finerenone may be a good option.
Hyperkalemia with finerenone use
Hyperkalemia is a major issue with use of MRAs, including finerenone. Notably, the entry criteria for the FIDELIO trial specified that patients needed to have a potassium less than 4.8 (even after maximizing ACE-i/ARB therapy), which is very stringent (Bakris et al 2020). Despite this precaution, a significant degree of hyperkalemia was observed in the trial, with 22% exhibiting a potassium >5.5 and 5% exhibiting a potassium >6, with 11% of patients on potassium binders and 70% on diuretics (Bakris et al 2020). Thus, hyperkalemia is an important consideration with use of this medication.
Potassium binders include the older, traditional binder SPS (which causes significant GI upset / diarrhea and has a very unpleasant taste), as well as the newer binders SZC and patiromer, which are tolerated much better.
Dr. Topf considers potassium binders in the following populations: 1) patients with advanced heart failure, who really benefit from RAAS inhibition and thus potassium binders are justified to keep administering RAAS inhibition, 2) patients with difficult to control hypertension, who also derive significant benefit from RAAS inhibition, 3) patients who cannot be initiated on first-line therapy (e.g. ACE-i/ARB) without significant hyperkalemia, and 4) patients with GFR <10 who do not want to start dialysis and are opting for conservative care.
Notably, while we know that potassium binders are successful in reducing potassium, and theoretically these agents should improve cardiac and renal outcomes by enabling longer use of RAAS inhibition, there have not actually been randomized trials that have investigated whether potassium binders improve hard outcomes. The DIAMOND trial of patiromer vs. placebo was initially designed to evaluate whether use of potassium binders affects cardiovascular mortality, but unfortunately the primary outcome was altered to simply look at change in potassium. This change was made due to enrollment difficulties during the COVID pandemic (Butler et al 2022).
Chronic metabolic acidosis is frequently seen in CKD. It is theorized to be harmful to long-term kidney function since an elevated acid load requires to the kidney to work harder to get rid of the excess protons, which increases endothelin, angiotensin II, and aldosterone, all of which leads to fibrosis and nephron loss. Nephron loss in turn leaves the kidneys with fewer nephrons to deal with the same acid load, resulting in each nephron shouldering a greater proton burden, thus leading to a vicious cycle.
(Of note, when a patient with CKD has a low bicarbonate, Dr. Topf emphasizes that we should not diagnose metabolic acidosis without seeing a pH. This is because there could be a respiratory alkalosis that is responsible for the low bicarbonate. In fact, in a 1980 study looking at ABGs in a single hospital, respiratory alkalosis was twice as common as metabolic acidosis (Hodgkin et al, 1980). Dr. Topf urges us to make sure we know what we are treating!)
Several studies (including a London study and a multi-institutional Italian study (both open-label)) have shown that oral bicarbonate treatment in patients with CKD IV and chronic metabolic acidosis is beneficial for slowing progression of CKD, reducing dialysis initiation, and improving mortality (Brito-Ashurst et al, 2009, Di Iorio et al, 2019.)
However, a follow-up multi-center double-blinded study of oral bicarbonate for metabolic acidosis in elderly patients with CKD in Britain did not show any impact on initiation of dialysis (BiCARB study group, 2020). While initially, there was good separation in the metabolic acidosis curves in patients on placebo or oral bicarbonate, these curves eventually converged. According to Dr. Topf, it may be that most people had temporary metabolic acidosis that would have resolved on its own without treatment, and that many people in the placebo group may not have even needed treatment. Additionally, the H+ binder veviromer, while promising in phase II trials, did not demonstrate any difference from placebo in the double-blinded phase III study (trial stopped early in 2022; unpublished). Thus, Dr. Topf notes that while treatment of metabolic acidosis with oral bicarbonate is recommended in the current KDIGO CKD guidelines, there are some well-done negative trials, and mileage may vary.
An added consideration is accumulating evidence that a diet rich in fruits and vegetables may be as effective as oral bicarbonate. Work by Nimrit Goraya investigating the renal acid load of different foods has demonstrated that fruits and vegetables are alkali in nature and thus have a negative acid potential. Interestingly, compared to oral bicarbonate, consumption of a diet rich in fruits and vegetables (delivered to the patient) was as effective in maintaining GFR (and also had beneficial impacts on blood pressure, weight, and cholesterol) (Goraya et al, 2013.)
Listeners will develop strategies for the optimal prescribing of SGLT2i, finerenone, and potassium binders as well as managing metabolic acidosis in patients with CKD.
After listening to this episode listeners will…
Dr. Topf reports that he has served as an advisor for Beyer (maker of finerenone; relationship has not ended), Cara Therapeutics (relationship has not ended), Astra Zeneca (relationship has ended), and Tricida (relationship has ended.) The Curbsiders report no relevant financial disclosures. A balanced range of therapeutic options were discussed on this podcast episode.
Gandhi MM, Topf J, Williams PN, Watto MF. “#384: Updates in Chronic Kidney Disease with Dr. Joel Topf.” The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list. March 6, 2023.
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