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Jardiance slows kidney disease progression in adults with type 2 diabetes
NEW ORLEANS — The SGLT2 inhibitor Jardiance was associated with slower progression of kidney disease and fewer clinically relevant renal events compared with placebo, according to new data from the EMPA-REG OUTCOME study.
“Kidney disease is developed in approximately 35% of the population with type 2 diabetes. … In the last 15 years, we have had no new diabetes-specific kidney treatment until today,” Christoph Wanner, MD, from the department of medicine, division of nephrology at Würzburg University Clinic, Würzburg, Germany, said during his presentation of results of the secondary outcome subanalysis of the EMPA-REG OUTCOME trial presented at the American Diabetes Association Scientific Sessions. Results were also published simultaneously in The New England Journal of Medicine.
Christoph Wanner
In EMPA-REG OUTCOME, the primary objective was assessment of cardiovascular outcomes. Researchers found significantly reduced risk for CV death and all-cause mortality in adults with type 2 diabetes and an established history of CV disease.
Participants included 7,020 adults with type 2 diabetes, a BMI of 45 kg/m² or less, an HbA1c between 7% and 10%, and an established history of CVD (mean age, 63 years; 72% men; mean HbA1c, 8%; mean BMI, 30.6 kg/m²). Within the cohort, 76% of participants had an established history of coronary artery disease; 46% had a history of myocardial infarction; and between 9.5% and 10.5% of participants had a history of cardiac failure. About 80% of participants were using ACE inhibitors; between 75% and 78% of participants were using statins.
Participants were randomly assigned empagliflozin 10 mg (n = 2,345) or 25 mg (n = 2,342) or placebo (n = 2,333) added to standard of care, including glucose-lowering agents and antihypertensive and cholesterol-lowering drugs. Primary endpoint was defined as the time to first occurrence of CV death, nonfatal MI or nonfatal stroke; the trial continued until at least 691 participants experienced a primary outcome event. Researchers used Cox proportional hazards to analyze CV outcomes, following participants for an average of 3.1 years. Prespecified secondary microvascular endpoints of the trial included diabetic retinopathy and nephropathy.
Researchers reported renal outcomes in a subgroup of participants with an estimated glomerular filtration rate of 30 to 59 mL/min/1.73 m2; 4,124 participants were assigned to empaglifozin and 2,061 to placebo. Renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine level, starting renal-replacement therapy or death from kidney disease) and incident albuminuria. Results were similar for both empagliflozin doses studied. In the overall empagliflozin group compared with the placebo group, incident or worsening nephropathy occurred in 12.7% vs. 18.8%, respectively (HR = .61; 95% CI: 0.53-0.70; P < .001). The composite endpoint of incident or worsening nephropathy or CV death was lower in the empagliflozin group vs. the placebo group (HR = 0.61; 95% CI: 0.55-0.69; P < .001). Progression to macroalbuminuria occurred in 11.2% vs. 16.2%, respectively (relative risk reduction [RRR] = 38%); doubling of serum creatinine level occurred in 1.5% vs. 2.6%, respectively (RRR = 44%); and initiation of renal-replacement therapy occurred in 0.3% vs. 0.6%, respectively (RRR = 55%). Rates of incident albuminuria were similar across groups.
William H. Herman
Furthermore, empagliflozin was noninferior to placebo with respect to incident or worsening nephropathy regardless of eGFR, urinary albumin-to-creatinine ratio, sex, age older or younger than 65 years, race, diabetes duration, HbA1c level, BMI, blood pressure control, and use of other diabetes and antihypertensive medications. In participants with prevalent kidney disease, those assigned empagliflozin vs. placebo had an HR of 0.58 (95% CI: 0.47-0.71; P < .001) for incident or worsening nephropathy.
Rates of adverse events, serious adverse events and adverse events leading to study discontinuation were similar for those with eGFR above and below 60 mL/min/1.73 m2.
Kidney function results indicate a possible mechanism of action for empagliflozin’s renal effects, Wanner said during his presentation. Empagliflozin produced a short-term decrease in eGFR and then stabilization over time. When treatment was stopped, eGFR rates improved.
“A hemodynamic effect of empagliflozin has been reported, and lowering of glomerular hypertension is considered to play a key role in its renal effects,” Wanner said.
“One key message and one question arise from the EMPA-REG Outcome study,” Wanner told Endocrine Today. “Empagliflozin demonstrated slowing of kidney disease progression in lower ranges of kidney function (eGFR 30 to 60 mL/min/1.73m2). Can empagliflozin be used in type 2 diabetics with albuminuric kidney disease, but not yet diagnosed cardiovascular disease?”
William H. Herman, MD, MPH, professor of epidemiology and of internal medicine at University of Michigan, provided reaction to the cardiovascular and renal results of EMPA-REG OUTCOME. “Empagliflozin in combination with metformin is a reasonable option for initial dual therapy in patients with type 2 diabetes and CVD, though we still don’t know its exact role,” Herman said. “But I think it is clear that empagliflozin may be a preferred treatment for older adults with type 2 diabetes and CVD. Mechanistically we don’t know why, but the results, I think, speak for themselves.” – by Jill Rollet
References:
Wanner C, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1515920.
Wanner C. 3-CT-SY29.
Disclosure: EMPA-REG OUTCOME was funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Wanner reports serving as a speaker for Boehringer Ingelheim Pharmaceuticals, Inc. Herman reports serving as a board member and speaker for Lexicon Pharmaceuticals and Merck Sharp & Dohme. Please see the full study for the authors’ relevant financial disclosures.
Perspective
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I think most of us were shocked at the power of the EMPA-REG kidney analysis, how statistically strong it was, showing that empagliflozin improves acute renal injury. I think this report will translate to practice, but I don’t know if it’s going to translate as fast as one might predict.
If you’re going to choose an SGLT2 inhibitor, how could you not choose empagliflozin? In light of the recent FDA action strengthening kidney warnings on dapagliflozin (AstraZeneca) and canagliflozin (Janssen), we are seeing stark differences between SGLT2 inhibitors. I don’t know the FDA’s basis for the warning.
It may just be that they got an excess of reported cases with dapagliflozin and canagliflozin, but not with empagliflozin. Still, the EMPA-REG data were so impressive with the reduction in renal injury with empagliflozin that it’s hard to believe that sometimes it can cause injury and sometimes not. So, I’m perplexed — unless empagliflozin really is just that much better of an SGLT2 inhibitor. The drugs were not compared head to head. We should know more when the DECLARE and CANVAS trials come out in another year or two.