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People with type 2 diabetes (T2D) on sodium-glucose cotransporter (SGLT)-2 inhibitors saw far less progression to kidney failure than T2D patients who didn't receive the agents, according to a meta-analysis.

Treatment with either empagliflozin (Jardiance), canagliflozin (Invokana), or dapagliflozin (Farxiga) was tied to a 33% reduction in relative risk for a composite endpoint requiring dialysis, kidney transplantation, or death from kidney disease (RR 0.67, 95% CI 0.52-0.86, P=0.0019), reported Brendon Neuen, MBBS, of the George Institute for Global Health in Australia, and colleagues.

In addition, treatment with an SGLT-2 inhibitor reduced the risk for end-stage kidney disease by 35% (RR 0.65, 95% CI 0.53-0.81) and acute kidney injury by 25% (RR 0.75, 95% CI 0.66-0.85).

The study, online in , included four clinical trials that looked at three different SGLT-2 inhibitors compared with placebo:

• EMPA-REG OUTCOME, which assessed the use of empagliflozin (10 mg, 25 mg)

• CANVAS Program, which looked at canagliflozin (100 mg, 300 mg)

• CREDENCE, canagliflozin (100 mg)

• DECLARE-TIMI 58, dapagliflozin (10 mg)

All four trials included in the analysis found this same renoprotective effect with an SGLT-2 inhibitor, with no heterogeneity seen across the studies (I²=0%, P-heterogeneity=0.53).

"These findings confirm those of the recently reported CREDENCE trial, where canagliflozin was shown to prevent loss of kidney function and kidney failure in people with type 2 diabetes," noted Neuen in a statement, adding that the findings show how this class of antidiabetics "clearly and powerfully reduce the risk of kidney failure."

"Clinical practice guidelines currently recommend treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers to slow the progression of kidney disease in people with diabetes," added co-study author Meg Jardine, PhD, also of the George Institute for Global Health.

She noted that the risk for kidney failure remains high, and that diabetes is currently the most common precipitating cause for dialysis.

"The results of this meta-analysis are very encouraging for people with diabetic kidney disease," Jardine said in the statement. "As more treatment options become available to halt the progression of the disease, it is hoped that fewer will go on to require more invasive and costly interventions such as dialysis and transplantation."

Study Details

For the study, a total of 38,723 participants with T2D were included in the analysis, of whom only 252 experienced one of the composite endpoint events (dialysis, transplantation, or death due to kidney disease). Additionally, only 335 patients developed end-stage kidney disease while on an SGLT-2 inhibitor, and 943 had acute kidney injury.

Even when the patients were divided according to baseline estimated glomerular filtration rate (eGFR), a significant benefit for renal protective was still noted across all subgroups:

• <90 mL/min per 1.73 m²: RR 0.37 (95% CI 0.21-0.63)

• 60 to <90 mL/min per 1.73 m²: RR 0.60 (95% CI 0.48-0.74)

• 45 to <60 mL/min per 1.73 m²: RR 0.55 (95% CI 0.39-0.76)

• <45 mL/min per 1.73 m²: RR 0.70 (95% CI 0.54-0.91)

Similarly, a significant reduction in progression to dialysis, kidney transplantation, or death from kidney disease was reported regardless of use of renin-angiotensin system (RAS) blockade -- RR 0.58, 95% CI 0.50-0.66 vs RR 0.71, 95% CI 0.49-1.02 (no RAS blockade) -- and across all levels of baseline albuminuria, as follows:

• Urine albumin-to-creatinine ratio (UACR) <30 mg/g: RR 0.46 (95% CI 0.33-0.63)

• UACR 30 to 300 mg/g: RR 0.69 (95% CI 0.47-1.00)

• UACR >300 mg/g: RR 0.52 (95% CI 0.38-0.69)

Writing in an , Richard Gilbert, MD, PhD, of the University of Toronto in Canada, praised the meta-analysis for providing more evidence that this class of antidiabetics can offer substantial kidney protection. He noted that prior to the major trials included in the meta-analysis, SGLT-2 inhibitors were actually expected to increase the risk for acute kidney injury due to "their effects on intravascular volume, arterial blood pressure, and glomerular afferent arteriolar tone."

However, the new findings reinforced the fact that SGLT-2 inhibitors can not only offer kidney protection in T2D, but also reduce risk in a "broad range of patients," such as those with a low eGFR.

"Ongoing trials of other SGLT-2 inhibitors will definitively demonstrate whether all agents in the class have similar kidney benefits," Neuen said.

On Aug. 27, 2019, the fast track designation to AstraZeneca's Farxiga for progression of renal failure and to prevent cardiovascular and renal death in patients with chronic kidney disease and T2D. Janssen also recently submitted a for Invokana to be indicated for chronic kidney disease in T2D, based on findings from the CREDENCE trial.

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