September 09, 2019
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SGLT2 inhibitors offer ‘clear and powerful reductions’ for major kidney outcomes in type 2 diabetes

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A meta-analysis of four recent cardiovascular and kidney outcomes trials assessing the use of SGLT2 inhibitors among patients with type 2 diabetes suggests that the drug class offers nephroprotective benefits across all levels of kidney function, regardless of albuminuria status, according to findings published in The Lancet Diabetes & Endocrinology.

Brendon L. Neuen

“Three recent large cardiovascular outcomes trials demonstrated that SGLT2 inhibitors have beneficial effects on a range of albuminuria and creatinine-based kidney outcomes, but it was only recently that the CREDENCE trial specifically evaluated the effect of an SGLT2 inhibitor, canagliflozin, on a primary kidney outcome and was specifically powered to do so,” Brendon L. Neuen, MBBS, a doctoral student at The George Institute for Global Health based at the University of Oxford, told Endocrine Today. “With CREDENCE recently published, we undertook a systematic review and meta-analysis of all the available evidence to assess the effect of these drugs on major kidney outcomes, including the most important patient-centered outcomes, which are the need for dialysis, transplantation or renal death.”

Neuen and colleagues analyzed data from four randomized controlled trials with 38,723 participants assigned to an SGLT2 inhibitor or placebo, assessing effects on major kidney outcomes among people with type 2 diabetes: EMPA-REG Outcome (empagliflozin; Jardiance, Boehringer Ingelheim), CANVAS and CREDENCE (canagliflozin; Invokana, Janssen) and DECLARE-TIMI 58 (dapagliflozin; Farxiga, AstraZeneca). Primary outcome was a composite of dialysis, transplantation or renal death. Researchers used random-effects models to calculate summary relative risks and random-effects meta-regression analysis to explore effect modification by subgroups of baseline estimated glomerular filtration rate, albuminuria, and use of renin-angiotensin system (RAS) blockers.

Across studies, 252 participants required dialysis or transplantation or died of kidney disease, 335 developed end-stage renal disease, and 943 had acute kidney injury.

 
A meta-analysis of four recent cardiovascular and kidney outcomes trials assessing the use of SGLT2 inhibitors among patients with type 2 diabetes suggests that the drug class offers nephroprotective benefits across all levels of kidney function, regardless of albuminuria status.
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Researchers found that SGLT2 inhibitors substantially reduced the composite risk for dialysis, transplantation or renal death by 33% (RR = 0.67; 95% CI, 0.52-0.86), with the observed effect consistent across the four trials (P for heterogeneity = .53). SGLT2 inhibitors also reduced ESRD by 35% (RR = 0.65; 95% CI, 0.53-0.81) and risk for acute kidney injury by 25% (RR = 0.75; 95% CI, 0.66-0.85).

“The two most important findings were that there was a substantial, clear and powerful reduction in the risk for dialysis, transplantation or renal death, and that is important from a patient perspective, as kidney failure has profound consequences,” Neuen said in an interview. “However, these drugs also reduce the risk for acute kidney injury by about one-quarter. That was somewhat surprising, given the early concerns that these drugs might increase the risk for acute kidney injury because of the way they work. That has not been the case in the randomized trials to date.”

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Neuen noted that the findings were largely powered by CREDENCE, which was designed to assess kidney outcomes; however, there was no evidence of differences across the trials. Additionally, although researchers observed that the proportional effect of SGLT2 inhibitors might attenuate with declining kidney function (P for trend = .073), there was evidence of benefit across all eGFR subgroups, even for participants with a baseline eGFR of 30 mL/min/1.73 m² to 45 mL/min/1.73 m².

Baseline albuminuria status and use of RAS blockade did not change the findings, Neuen said.

“This meta-analysis reinforces the findings reported in the CREDENCE trial, and it provides the strongest evidence yet that these drugs should be routinely offered to individuals with type 2 diabetes at risk for progressive kidney disease,” Neuen said. “There are clear and powerful reductions in the risk for several major kidney outcomes, and there are clear benefits across all levels of kidney function, irrespective of albuminuria and the use of RAS blockade.” – by Regina Schaffer

For more information:

Brendon L. Neuen, MBBS, can be reached at The George Institute for Global Health, University of New South Wales, P.O. Box M201, Missenden Road, NSW 2050, Australia; email: bneuen@georgeinstitute.org.au.

Disclosures: Neuen reports he has received travel support from Janssen. Please see the study for all other authors’ relevant financial disclosures.