New data from the EMPA-REG OUTCOME trial with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) show that the drug significantly reduced the incidence of worsening nephropathy by 39% in the population of type 2 diabetes patients studied (ie, those who were at high cardiovascular risk).
The results were received to spontaneous applause here today at the American Diabetes Association (ADA) 2016 Scientific Sessions when presented by nephrologist Christoph Wanner, MD, of the Würzberg University Clinic, Germany; they were also simultaneously published in New England Journal of Medicine with Dr Wanner as lead author.
The assessment of renal outcomes in EMPA-REG was a prespecified outcome of the trial, Dr Wanner noted, and he added that the beneficial effects on the kidney observed in the trial “were there early and continued for the whole of the study.” Moreover, these effects were observed with both doses of empagliflozin employed (10 mg and 25 mg once daily).
“Empagliflozin reduced clinically relevant renal events when added to standard of care in patients with type 2 diabetes and high cardiovascular risk,” he announced, adding that this effect was primarily driven by a reduction in new-onset macroalbuminuria (hazard ratio [HR], 0.62 for those treated with empagliflozin compared with placebo; P < .001).
He pointed out that kidney disease is “a growing concern” in patients with type 2 diabetes, with 35% of patients eventually developing it, and noted that almost half (44%) of the renal-dialysis population at any current time is made up of those with diabetes, primarily type 2.
“In the placebo group you see the natural progression of kidney disease [as would be expected in type 2 diabetes] whereas the [estimated glomerular filtration rate] eGFR in the empagliflozin group remained stable,” he observed.
Important Addition to Original Findings, but More Work Needed
Dr Wanner noted, however, that the EMPA-REG trial lasted only 3 years, “so we are certainly looking to the future for more on this.”
And both he and discussant of the findings at ADA, endocrinologist and epidemiologist, William Herman, MD, MPH, of the University of Michigan, Ann Arbor, stressed that the results are applicable only “to the population studied in the EMPA-REG trial” (ie, older patients with type 2 diabetes at high cardiovascular risk).
Currently, about a third of the population of type 2 diabetes fall into that category, Dr Herman said.
Nevertheless, Dr Wanner observed in his presentation: “There have been no new diabetic kidney-disease–specific treatments in the past 15 years, until today.”
And he hinted that the agent may well be used in those who don’t yet have overt cardiovascular disease (CVD). “Nephrologists are waiting for this drug for patients with albuminuria,” he told Medscape Medical News.
They and endocrinologists “maybe will not wait until the patient has survived a myocardial infarction — there are some patients without cardiovascular disease but already with nephropathy, so I think we are all going to use this drug in the nephropathy patients with albuminuria.”
But Dr Herman pointed out in his talk that “the absolute differences are relatively small” in EMPA-REG and the number needed to treat with empagliflozin to achieve the renal benefits was 200.
In addition, it’s possible that the findings “had to do with medications not administered,” he said. “So it may not be a benefit of empagliflozin but the fact that those in the empagliflozin group did not receive medications causing harm [as patients in the trial were also allowed certain other standard therapies for diabetes].”
Overall, as well as the demonstrated renal effects, empagliflozin is “moderately effective” at lowering HbA1c and results in a 2- to 3-kg reduction in body weight, with no issue with hypoglycemia, although it does increase the risk of genitourinary infections, Dr Herman surmised.
He concluded that empagliflozin is “a reasonable therapy, but we still don’t know its exact role or exact mechanisms of action.”
Chair of the session in which the EMPA-REG renal findings were presented at ADA, Matthew Riddle, MD, from Oregon Health & Science University, Portland, said the renal outcomes from EMPA-REF are “an important addition to the original findings,” which nevertheless require further analysis.
Cost Is a Huge Issue
Of key importance, said both Drs Herman and Riddle, is the fact that empagliflozin and other SGLT2 inhibitors — like the other newer agents for type 2 diabetes (dipeptidyl peptidase-4 [DPP-4] inhibitors, glucagonlike peptide-1 [GLP-1] agonists, and insulin analogues) —are expensive, costing, in the US, in the region of $500 per month, as compared with a few dollars for metformin, the recommended first-line agent for type 2 diabetes and some other generically available drugs, such as sulfonylureas and pioglitazone.
Another trial with one of these newer agents, the GLP-1 agonist liraglutide (Victoza, Novo Nordisk), stole the headlines here yesterday with the results of the LEADER trial indicating that it significantly reduced the rates of major adverse cardiovascular events in a patient population similar to those in EMPA-REG, type 2 diabetes patients at elevated cardiovascular risk. This has prompted some experts to predict “a new era” in the management of type 2 diabetes.
Dr Riddle, however, believes this is a premature conclusion to draw: “I don’t think the regulatory agencies’ and the professional societies’ recommendations are going to change immediately; we are going to have to digest these findings,” he told Medscape Medical News.
And, he added, “The cost [of newer diabetes drugs] is a huge issue in the US. It’s one of the things I’m very interested in and very disturbed by.
“The range of cost between a generic established evidence-based oral therapy like metformin, the sulfonylureas, and now pioglitazone and the new agents is 100-fold. That is a big increase for, in some cases, a modest theoretical or practical advantage. So it’s a problem for physicians and patients in the US.”
Drilling Down Into Renal Outcomes
In the overall EMPA-REG trial, first reported last September to much acclaim, more than 6000 patients with type 2 diabetes at high risk of cardiovascular events were randomly assigned to one of two doses of empagliflozin or placebo on top of standard therapy. Empagliflozin reduced the risk of major adverse cardiovascular events by 38% relative to placebo.
In this new analysis of microvascular outcomes, incident or worsening nephropathy occurred in 525 of 4124 patients taking empagliflozin and 388 of 2061 in the placebo group (12.7% vs 18.8%; HR, 0.61; P< .001).
This renal end point consisted of a combination of progression to macroalbuminuria, a doubling of serum creatinine, the start of renal-replacement therapy, or renal death.
However, the benefit was primarily driven by the reduction in new-onset albuminuria, which occurred in 459 of 4091 patients taking empagliflozin compared with 330 of 2033 patients on placebo (11.2% vs 16.2%; HR, 0.62; P < .001).
Kidney dialysis was also reduced by more than half among those taking empagliflozin, although the absolute numbers affected were small (HR, 0.45; P = .0409).
In an editorial accompanying the renal findings in the published paper, Julie R Ingelfinger, MD, from Massachusetts General Hospital, Boston, Massachusetts, and Clifford J Rosen, MD, from the Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, say: “This new report indicates that empagliflozin was associated with a slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care in [type 2 diabetes] patients at high cardiovascular risk.”
And commenting on both EMPA-REG overall and LEADER, “We are left with differences that are encouraging yet are not a home run with regard to the management of diabetes,” they point out.
Is Empagliflozin a Renal Drug?
There was also some discussion at the ADA meeting about the mechanism of action of empagliflozin, both in lowering cardiovascular risk and now with regard to these renal benefits.
Most newer agent for diabetes will require dose adjustment in diabetic kidney disease because the majority are renally excreted; this includes DPP-4 inhibitors other than linagliptin, most GLP-1 agonists with the exception of liraglutide, and the SGLT2 inhibitors.
The latter, including empagliflozin, have required dose adjustment in patients with diabetic kidney disease. The current licenses for most SGLT-2 inhibitors precludes their use in patients with renal failure (eGFR < 60 mL/min/1.73 m2 in some cases or < 45 mL/min/1.73 m2 in others).
Dr Wanner said that 25% of the patients in EMPA-REG had eGFR < 60 mL/min/1.73 m2, more than a third already had albuminuria, and almost a third already had prevalent kidney damage.
Yet, paradoxically, they seem to provide some renal protection. These newest findings from EMPA-REG bolster excitement about the potential for SGLT2 inhibitors to provide a renoprotective effect, despite being metabolized by the kidney.
“The effect of empagliflozin on renal outcomes was there early and continued for the whole of the study, with both doses showing an effect. Empagliflozin works at lower stages of kidney function too,” Dr Wanner stressed.
Silvio Inzucchi, MD, of Yale University, New Haven, Connecticut, the lead investigator of EMPA-REG, added also that, regarding the overall cardiovascular benefit of empagliflozin seen in the trial, “there was no heterogeneity of effect based on eGFR; cardiovascular disease was reduced even in stage 3b renal-disease [eGFR 30–45 mL/min/1.73 m2] patients.”
Another SGLT2 inhibitor, canagliflozin (Invokana, Janssen) is being specifically tested in a diabetic kidney-disease population in the large multicenter randomized Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial.
This will enroll 3000 patients with stage 2 or 3 chronic kidney disease and macroalbuminuria already receiving standard of care. They will be randomized to canagliflozin 100 mg daily or placebo for 5 years, and results are not expected until 2019.
It is not known whether the latest caution from the Food and Drug Administration, strengthening the warning regarding acute kidney injury for canagliflozin and dapagliflozin, will affect this trial. This states that healthcare providers should consider factors that might predispose patients to acute kidney injury prior to starting them on canagliflozin or dapagliflozin.