In a publish-hoc prognosis of the CREDENCE survey, there were no security signals when the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (Invokana, Janssen) became once continued in sufferers with an estimated glomerular filtration fee (eGFR) that fell below 30 mL/min/1.73m2.
Total, 4% of sufferers (n = 174) had an eGFR stage that dropped below 30 mL/min/1.73m2 between screening and randomization in CREDENCE, which showed that canagliflozin deal reduced the threat of kidney failure and cardiovascular occasions in 4000 people with kind 2 diabetes and chronic kidney illness.
“The consistent supreme thing about canagliflozin within the final CREDENCE inhabitants and in sufferers with eGFR < 30 mL/min/1.73m2 at randomization suggests that there’s never such a thing as a cause to end remedy till the graduation of repairs dialysis or receipt of a kidney transplant,” George L. Bakris, MD, University of Chicago, Illinois, and colleagues summarize.
On the opposite hand, “We would no longer imply initiating remedy with SGLT2 inhibitor in eGFR < 30 mL/min/1.73m2 until results of the other pending trials are available,” they caution in their new article published online November 19 in the Clinical Journal of the American Society of Nephrology.
In an accompanying editorial, Sophia Zoungas, MBBS, PhD, and Kevan R. Polkinghorne, PhD, from Monash University in Melbourne, Australia, come to similar conclusions.
This new analysis of CREDENCE is “compelling,” they write.
However, “until [results from ongoing trials become available], it would seem reasonable for clinicians to commence SGLT2 inhibitors based on current indication (patients with type 2 diabetes and proteinuric kidney disease with eGFR > 30), to watch sufferers carefully and to continue remedy in response to particular particular person tolerability, even when eGFR drops below 30 or till the graduation of chronic dialysis or receipt of a kidney transplant,” they present.
“Proof Deplorable Is Rising, Which Is Big”
The researchers and editorialists scream they’re looking ahead to further prognosis of outcomes from the DAPA-CKD (Dapagliflozin and Prevention of Detrimental Outcomes in Power Kidney Illness) trial, which recruited people with an eGFR all the vogue down to 25 mL/min/1.73m2.
And recordsdata from the Gape of Heart and Kidney Protection With Empagliflozin (EMPA-Kidney), which enrolled sufferers with an eGFR as low as 20 mL/min/1.73m2, with or with out proteinuria, can even provide more data.
“Once readily obtainable, knowledge from these two trials will provide extra perception into the safety and efficacy of SGLT2 inhibitors in of us with very low eGFR and no proteinuria,” in response to Zoungas and Polkinghorne.
Bakris and colleagues are also waiting for findings from the Results of Dapagliflozin in Nondiabetic Sufferers With Proteinuria (DIAMOND) trial, which recruited people with an eGFR as low as 25 mL/min/1.73m2.
Results of the DAPA-CKD survey were first reported at the virtual European Society of Cardiology (ESC) 2020 meeting and published the following month within the New England Journal of Medicine. The findings showed that dapagliflozin cleave again the incidence of substantially worsened CKD by a median of 39% when put next with placebo when added to normal remedy, both in CKD sufferers with and with out diabetes.
Those knowledge handiest “provide a subgroup prognosis by eGFR < 45 or ? 45," Zoungas eminent in an email to Medscape Medical Records.
“The further knowledge analyses we are waiting on from DAPA-CKD are within the very low eGFR neighborhood (< 30 mL/min/1.73m2),” she continued, “and will add to the CREDENCE findings and give us greater confidence in use [of SGLT2 inhibitors] with more advanced kidney disease.”
“The total numbers studied at this level are still relatively small but all consistent,” Zoungas noted. “The evidence base is growing, which is great.”
As previously reported by Medscape Medical News, a number of experts have said they believe the threshold for use of SGLT2 inhibitors will be able to drop below an eGFR of 30 mL/min/1.73m2 once the further analysis from DAPA-CKD becomes available.
Bakris told Medscape Medical News, “SGLT2 inhibitors are cardiorenal risk-reducing agents irrespective of diabetes status — they have benefits in nondiabetic disease and heart failure.”
“With DAPA-CKD and our subanalysis, it is clear benefits are still there if started at an eGFR 25 or higher,” he said. However, importantly, “the current label in the US reads that [an SGLT2 inhibitor] can be started down to an eGFR of 30 and continued if on one,” he added.
Late-Stage Diabetic Kidney Disease
“Until now the mainstay of managing patients with [diabetic kidney disease and] very low eGFR (late stage 4 and stage 5 CKD) has been close monitoring and/or preparation for kidney replacement therapy,” Zoungas and Polkinghorne note.
CREDENCE randomized 4401 patients with type 2 diabetes, eGFR 30 – > 90 mL/min/1.73m2, and a urinary albumin-to-creatinine ratio of > 300 to 5000 mg/g.
The sizzling survey analyzed knowledge from 84 sufferers within the canagliflozin neighborhood and 90 sufferers within the placebo neighborhood whose eGFR dropped below 30 mL/min/1.73m2 about 29 days sooner than randomization.
Sufferers in both groups had an identical diabetes period (17 years), A1c (8.1%), blood tension (139/76 mmHg), and albumin to creatinine ratio. They were a imply age of 65 years, 61% were males, and 66% were White.
Researchers on a standard basis assessed adverse occasions and eGFR all the design thru a median discover up of two.6 years.
Sufferers with eGFR < 30 or ? 30 mL/min/1.73m2 had related charges of kidney failure (hazard ratio, 0.67 and zero.70, respectively) and important cardiovascular occasions, though attributable to the tiny pattern dimension and low different of occasions the self belief intervals were wide and overlapping, indicating uncertainty.
The imply fee of decline in eGFR became once 66% lower (–1.30 vs –3.83 mL/min/1.73m2/year) within the canagliflozin neighborhood and the urinary albumin-to-creatinine ratio became once 33% lower within the canagliflozin neighborhood, “according to the effects for the final trial inhabitants over the survey period,” Zoungas and Polkinghorne present.
“Importantly,” they add, “the incidence of acute kidney wound became once no longer assorted within the canagliflozin versus placebo neighborhood and an acute reversible decline in eGFR (3 weeks after drug graduation) became once no longer noticed.”
“As one would possibly maybe maybe well interrogate,” they continue, overall severe adverse occasions, drug discontinuations, and discontinuations attributable to adverse occasions were more total within the < 30 vs ? 30 mL/min/1.73m2 eGFR neighborhood.
Euglycemic Ketoacidosis Now no longer Reported in Put up-Hoc Prognosis
On the opposite hand, the different of euglycemic ketoacidosis occasions became once no longer reported on this publish-hoc prognosis, which is “a crucial omission” in response to the editorialists, as there became once a 10 fold higher threat of euglycemic ketoacidosis with canagliflozin within the final trial inhabitants in CREDENCE.
“Idea the threat of this serious complication for this susceptible patient inhabitants (already at threat of uremic acidosis), will seemingly be crucial for stable prescribing,” they write.
“Further trials and trusty-world observational be taught will confidently take care of this pains. Within the interim, detailed patient training on appropriate enlighten of SGLT2 inhibitor with fasting, procedures, and sick day management will abet in minimizing any threat of wound.”
Bakris and colleagues have reported receiving be taught make stronger and consulting charges from Janssen in relation to their roles on the CREDENCE steerage committee. Zoungas has reported price to Monash University from Eli Lilly, Boehringer-Ingelheim, MSD, AstraZeneca, Novo Nordisk, Sanofi, and Servier, for participation in advisory boards, expert committees, or academic conferences outdoors the submitted work. Cherney has reported being a specialist to and has got be taught funding from AstraZeneca and several other corporations.
Clin J Am Soc Nephrol. Published on-line November 19, 2020. Article, Editorial
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