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NEW ORLEANS -- Patients with diabetes taking empagliflozin (Jardiance) had slower progression of kidney disease than did patients taking placebo, researchers said here.
A sub-analysis of the landmark EMPA-REG trial of more than 7,000 patients revealed that empagliflozin -- the first type 2 diabetes drug to show cardiovascular benefit in a post-marketing trial -- was associated with lower incident or worsening nephropathy versus placebo (12.7% of patients versus 18.8%, hazard ratio 0.61, 95% CI 0.53-0.70, P<0.001) after about 2.5 years.
In addition, 1.5% of patients in the treatment group and 2.6% of patients in the placebo group had a doubling of serum creatinine levels for a relative risk reduction of 44%. Renal-replacement therapy was started in 0.3% of patients on empagliflozin group and 0.6% in the placebo group for a relative risk reduction of 55%, according to , from Würzburg University Clinic in Germany, and colleagues.
The study results were presented at the American Diabetes Association annual meeting and simultaneously published in the .
"This looks like a major breakthrough," said , a nephrologist at St. John Providence Hospital in Detroit, Michigan. But he added that the results would need replicating in a cohort that has worse diabetic nephropathy, since only those who had mild kidney impairment and met other criteria were included in EMPA-REG.
"We are talking about a minority of a minority of patients at risk" that were included in this trial, said Topf, who was not associated with the study.
Still, the findings could have significant clinical application. "We have so little to offer patients with diabetic kidney disease, and an option that doesn't lower blood pressure or cause hyperkalemia is a game changer," he wrote in an email to 鶹ý.
There were no significant differences between the group on empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) receptor agonist, and the group on placebo in the rates of incident albuminuria. And the percentage of patients who had an adverse serious events were similar between the two groups.
The cardiovascular results from EMPA-REG were announced last September. Renal outcomes were a pre-specified secondary outcome from that trial, which was an FDA-mandated post-marketing trial to determine that empagliflozin did not excessively raise the risk of cardiovascular complications, a mandate that must meet.
All patients in the trial had type 2 diabetes, established cardiovascular disease, and an estimated glomerular filtration rate (eGFR) of at least 30 ml per minute per 1.73 m2 of body surface area. At baseline, the eGFR was 45-59 ml per minute per 1.73 m2 in 17.8% of the patients and 30-44 ml per minute per 1.73 m2 in 7.7%. More than one-quarter (28%) of patients had microalbuminuria and 11% had macroalbuminuria. The median duration of treatment was 2.6 years, with a median observation time of 3.1 years.
The entirety of the improved microvascular outcomes were driven by the renal aspect, which is why the entire paper was dedicated to renal outcomes, the authors explained. A composite outcome made up of incident or worsening nephropathy or cardiovascular death was also significantly lower in the treatment group. In the empagliflozin group, 11.2% progressed towards macroalbuminuria versus 16.2% in the placebo group, a relative risk reduction of 38%.
"What normally would reduce the risk of regression of diabetic nephropathy would be a very robust difference in glycemic control, but in the EMPA-REG study, the difference in glycemic control was rather small, which could suggest that this is a more direct effect of SGLT-2 inhibitors," said , at the University of Copenhagen, in an interview with 鶹ý.
The authors suggested that the mechanism by which the drug affected renal outcomes is multi-factorial. Knop, who was not associated with the study, suggested that given empagliflozin's renal and cardiovascular benefits, it might be prescribed more often, instead of dipeptidyl peptidase-4 (DPP-4) inhibitors and sulfonylureas.
The eGFR decreased in the first 4 weeks of the trial for the empagliflozin group, while the placebo group saw a small increase. But over the long term, eGFR remained stable in the treatment group and declined steadily in the control group.
"What this trial does is it gives reassurance that we can use this medication among patients with kidney disease, that it is efficacious, and that it in fact that it appears to improve renal function," said , of the Walter Reed National Military Medical Center in Bethesda, Md., adding that though the results were limited to those with mild kidney impairment, there are a lot of patients who fall under that category.
It is not yet clear if the beneficial effects of empagliflozin are a class effect and thus apply to two other SGLT-2 inhibitors -- canagliflozin (Invokana) and dapagliflozin (Forxiga) -- which are undergoing post-marketing surveillance trials. Topf said that the empagliflozin results need to be replicated with these other drugs.
"That would add a lot of validity to the outcomes," he wrote.
Disclosures
The study was funded by Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Some co-authors are employees of Boehringer Ingelheim.
Wanner and co-authors disclosed multiple relevant relationships with industry including Boehringer Ingelheim, Eli Lilly, AstraZeneca, Novo Nordisk, Merck, Intarcia, Sanofi, Takeda, Novartis, and Janssen.
Primary Source
New England Journal of Medicine
Wanner, C et al "Empagliflozin and progression of kidney disease in type 2 diabetes" N Engl J Med 2016; DOI: 10.1056/NEJMoa1515920.