In a post-hoc analysis of the CREDENCE study, there were no safety signals when the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (Invokana, Janssen) was continued in patients with an estimated glomerular filtration rate (eGFR) that fell below 30 mL/min/1.73m2.
Overall, 4% of patients (n = 174) had an eGFR level that dropped below 30 mL/min/1.73m2 between screening and randomization in CREDENCE, which showed that canagliflozin significantly reduced the risk of kidney failure and cardiovascular events in 4000 participants with type 2 diabetes and chronic kidney disease.
“The consistent benefit of canagliflozin in the overall CREDENCE population and in patients with eGFR < 30 mL/min/1.73m2 at randomization suggests that there is no reason to discontinue treatment until the commencement of maintenance dialysis or receipt of a kidney transplant,” George L. Bakris, MD, University of Chicago, Illinois, and colleagues summarize.
However, “We would not recommend initiating treatment 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 monitor patients closely and to continue treatment based on individual tolerability, even when eGFR drops below 30 or until the commencement of chronic dialysis or receipt of a kidney transplant,” they note.
“Evidence Base Is Growing, Which Is Great”
The researchers and editorialists say they are waiting for further analysis of results from the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial, which recruited participants with an eGFR down to 25 mL/min/1.73m2.
And data from the Study of Heart and Kidney Protection With Empagliflozin (EMPA-Kidney), which enrolled patients with an eGFR as low as 20 mL/min/1.73m2, with or without proteinuria, will also provide more information.
“Once available, data from these two trials will provide additional insight into the safety and efficacy of SGLT2 inhibitors in people with very low eGFR and no proteinuria,” according to Zoungas and Polkinghorne.
Bakris and colleagues are also anticipating findings from the Effects of Dapagliflozin in Nondiabetic Patients With Proteinuria (DIAMOND) trial, which recruited participants with an eGFR as low as 25 mL/min/1.73m2.
Results of the DAPA-CKD study were first reported at the virtual European Society of Cardiology (ESC) 2020 meeting and published the following month in the New England Journal of Medicine. The findings showed that dapagliflozin cut the incidence of substantially worsened CKD by an average of 39% compared with placebo when added to standard treatment, both in CKD patients with and without diabetes.
Those data only “provide a subgroup analysis by eGFR < 45 or ≥ 45,” Zoungas noted in an email to Medscape Medical News.
“The further data analyses we are waiting on from DAPA-CKD are in the very low eGFR group (< 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 current study analyzed data from 84 patients in the canagliflozin group and 90 patients in the placebo group whose eGFR dropped below 30 mL/min/1.73m2 about 29 days before randomization.
Patients in both groups had a similar diabetes duration (17 years), A1c (8.1%), blood pressure (139/76 mmHg), and albumin to creatinine ratio. They were a mean age of 65 years, 61% were men, and 66% were White.
Researchers regularly assessed adverse events and eGFR during a median follow up of 2.6 years.
Patients with eGFR < 30 or ≥ 30 mL/min/1.73m2 had similar rates of kidney failure (hazard ratio, 0.67 and 0.70, respectively) and major cardiovascular events, although due to the small sample size and low number of events the confidence intervals were wide and overlapping, indicating uncertainty.
The mean rate of decline in eGFR was 66% lower (–1.30 vs –3.83 mL/min/1.73m2/year) in the canagliflozin group and the urinary albumin-to-creatinine ratio was 33% lower in the canagliflozin group, “in keeping with the effects for the overall trial population over the study period,” Zoungas and Polkinghorne note.
“Importantly,” they add, “the incidence of acute kidney injury was not different in the canagliflozin versus placebo group and an acute reversible decline in eGFR (3 weeks after drug commencement) was not observed.”
“As one might expect,” they continue, overall severe adverse events, drug discontinuations, and discontinuations due to adverse events were more common in the < 30 vs ≥ 30 mL/min/1.73m2 eGFR group.
Euglycemic Ketoacidosis Not Reported in Post-Hoc Analysis
However, the number of euglycemic ketoacidosis events was not reported in this post-hoc analysis, which is “an important omission” according to the editorialists, as there was a 10 fold greater risk of euglycemic ketoacidosis with canagliflozin in the overall trial population in CREDENCE.
“Understanding the risk of this serious complication for this vulnerable patient population (already at risk of uremic acidosis), will be critical for safe prescribing,” they write.
“Further trials and real-world observational studies will hopefully address this concern. In the interim, detailed patient education on appropriate use of SGLT2 inhibitor with fasting, procedures, and sick day management will assist in minimizing any risk of harm.”
Bakris and colleagues have reported receiving research support and consulting fees from Janssen in relation to their roles on the CREDENCE steering committee. Zoungas has reported payment to Monash University from Eli Lilly, Boehringer-Ingelheim, MSD, AstraZeneca, Novo Nordisk, Sanofi, and Servier, for participation in advisory boards, expert committees, or educational meetings outside the submitted work. Cherney has reported being a consultant to and has received research funding from AstraZeneca and several other companies.