'Strongest Evidence Yet' That Diabetes Drugs Are Renoprotective

Miriam E. Tucker

September 12, 2019

Results from a new meta-analysis provide "the strongest evidence yet" that sodium-glucose cotransporter-2 (SGLT2) inhibitors should be offered to patients with type 2 diabetes who are at risk for progressive kidney disease.

Findings from pooled data from the EMPA-REG OUTCOME trial of empagliflozin (Jardiance, Boehringer Ingelheim), the CANVAS and CREDENCE trials of canagliflozin (Invokana, Janssen), and the DECLARE-TIMI 58 trial of dapagliflozin (Farxiga, AstraZeneca) were published online September 5 in Lancet Diabetes & Endocrinology by Brendon L. Neuen, a PhD candidate at the The George Institute for Global Health, University of New South Wales, Sydney, Australia, and colleagues. 

The analysis, comprised of 38,723 participants from six continents, demonstrated "clear evidence that SGLT2 inhibitors reduce the risk of dialysis, transplantation, or death due to kidney disease, as well as a range of other major kidney outcomes, and that these drugs also provide protection against acute kidney injury," Neuen and colleagues write.

In an accompanying editorial, Richard Gilbert, MD, PhD, professor of medicine at the University of Toronto, Ontario, Canada, comments on the importance of the lack of signal for an increase in acute kidney injury with SGLT2 inhibitors.

That concern had arisen from reports to the US Food and Drug Administration, which subsequently added warnings to the labels of some, but not all, SGLT2 inhibitors 

Now, Gilbert points out, not only was there no increase in acute kidney injury in the randomized controlled trials, but Neuen and colleagues found a reduction in risk (relative risk, 0.75; P < .0001).

And "because patients with low estimated glomerular filtration rate [eGFR] are at particularly high risk of acute kidney injury, the inclusion of data from CREDENCE in this updated meta-analysis improves confidence in this finding," he adds.

Findings Call Into Question Current Restrictions on SGLT2 Use

In many countries SGLT2 inhibitors are not currently approved for patients with lower eGFR levels, largely because of insufficient glucose-lowering efficacy.

But it appears that nephroprotection with SGLT2 inhibitors, especially at a low eGFR, is glucose independent. 

In this new analysis, benefit was found for all levels of kidney function, including a risk reduction of about 30% in the composite primary outcome of dialysis, transplantation, or death due to kidney disease even in patients with baseline eGFR below 45 mL/min/1.73m2.

"Because these individuals are at much greater risk of kidney failure than those with higher eGFRs, the absolute benefits of SGLT2 inhibition are likely to be at least as large as those for people with higher eGFRs," write the study authors.

"The clear evidence of renoprotection across the spectrum of kidney function studied to date calls into question the existing restrictions on the use of SGLT2 inhibitors in people with reduced kidney function and suggests that many more individuals with type 2 diabetes at high risk of kidney failure are likely to benefit from treatment with these drugs," they add.  

Overall, they say, "To the best of our knowledge, these results provide the strongest evidence yet that SGLT2 inhibitors should be routinely offered to individuals with type 2 diabetes at risk of progressive kidney disease."

Gilbert agrees: "After years of stagnation, we are now on the brink of a new paradigm in the prevention and treatment of kidney disease in people with type 2 diabetes."

"Evidence of Renoprotection Across Spectrum of Kidney Function"

All four studies compared an SGLT2 inhibitor with matching placebo. CREDENCE was a dedicated kidney outcome study, and the other three were cardiovascular outcome trials that also included renal endpoints as secondary outcomes.

The proportion of study participants with an eGFR less than 60 mL/min/1.73m² ranged from 7.4% in DECLARE-TIMI to 58% to 58.9% in CREDENCE. Most participants in the three cardiovascular outcomes trials had a urine albumin-to-creatinine ratio (UACR) of less than 30 mg/g at baseline, whereas UACR higher than 300 mg/g was an entry criterion in CREDENCE.

Compared with placebo, SGLT2 inhibitors reduced the risk of dialysis, transplantation, or death due to kidney disease by 33%, the risk of end-stage renal disease by 35%, and the composite of substantial loss of kidney function, end-stage renal disease, or death due to kidney disease by 42%, with all effects consistent across studies.

Notably, the effect on the primary composite outcome was consistent irrespective of baseline albuminuria (P for trend = .66) and use of renin-angiotensin system (RAS) blockade (P for heterogeneity = .31).

There was some evidence that the magnitude of benefit may have attenuated across lower eGFR subgroups (P for trend = .073), but "clear, separately significant evidence of benefit was apparent for all eGFR subgroups," Neuen and colleagues say, including for participants with a baseline eGFR lower than 45 mL/min/1.73m² in whom there was the 30% relative risk reduction.  

"These data provide us with assurance in extrapolating the findings of CREDENCE to the majority of patients with an eGFR lower than 60 mL/min/1.73m² without macroalbuminuria," writes Gilbert in his editorial.

And indeed, new guidance to this effect was issued by the American Diabetes Association (ADA) in June.

"For patients with type 2 diabetes and diabetic kidney disease, consider use of an SGLT2 inhibitor in patients with an eGFR ≥ 30 mL/min/1.73m2 and particularly in those with > 300 mg/g albuminuria to reduce risk of chronic kidney disease [CKD] progression, cardiovascular events, or both," the ADA recommends.

Other Renal Outcomes Trials of SGLT2 Inhibitors Are Ongoing

Other renal outcomes trials of SGLT2 inhibitors in patients with type 2 diabetes and CKD are ongoing and will yield further information.

They include Dapa-CKD with dapagliflozin in 4000 patients with a baseline eGFR of 25-75 mL/min/1.73m2. Results are due in November 2020.

And Boehringer Ingelheim and Lilly's ongoing study of empagliflozin (EMPA-KIDNEY) has a similar patient population and will enroll 5000 patients with moderate to severe CKD (down to eGFR 20 mL/min/1.73m2). Results are expected in June 2022.

There was no funding source for this study. Neuen has reported receiving travel support from Janssen. Grant has reported receiving research grants to his institution from, serving on advisory boards for, and receiving honoraria for continuing medical education talks from Boehringer Ingelheim and AstraZeneca. He has also reported serving on advisory boards for and receiving honoraria for continuing medical education talks from Janssen.

Lancet Diabetes Endocrinol. Published online September 5, 2019. Abstract, Editorial

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