A study analyzing the renal outcomes of the DECLARE-TIMI 58 trial were presented at ADA 2019 in San Francisco, CA.
Data on the renal outcomes and effects of dapagliflozin on diabetic kidney disease as observed through the DECLARE-TIMI 58 trial were presented at the American Diabetes Association 2019 Scientific Sessions in San Francisco, CA.
Investigators found that dapagliflozin was associated with reduced progression of kidney disease and lower rates of clinically relevant renal events compared with placebo.
Lead author Ofri Mosenzon, MD, MSc, professor of internal medicine at Hadassah Hebrew University Hospital in Israel, presented the findings and spoke with MD Magazine afterwards to discuss the implications of the findings.
MD Mag: What were the findings of the study and what are the clinical implications of those findings?
Mosenzon: The DECLARE-TIMI 58 Trial is the cardiovascular outcome trial of dapagliflozin or Farxiga in different parts of the world, which is a drug from the SGLT2 inhibitors group of drugs. As you probably know we randomized 17,160 patients, who were patients with type 2 diabetes and either establish cardiovascular disease or risk factors for established cardiovascular disease — which were actually the majority with around 60% of patients just with risk factors without established cardiovascular disease risk factors.
The primary outcomes of the trials, as a whole, were reported during the American Heart Association meeting in November 2018 and we showed the safety outcome of 3-point MACE and we showed also, in the efficacy outcome, cardiovascular death and hospitalization for heart failure — there was a superiority with the topography loss in versus placebo. While, with the 3-point MACE, there was non-inferiority. There was a safety, but not a superiority endpoints achieved. Another important outcome of the trial, which were actually defined as the first secondary outcome, was the renal outcome.
We must remember that, due to a hierarchy of testing, since only 1 of the 2 co-primary efficacy endpoints was achieved all of these endpoints have to be seen as hypothesis-generating not as final results. Still, what have we found, first of all, we defined 2 important renal outcomes. The first one, was a cardio renal composite outcome, which included 4 components and all of them as you will see are important clinical components and do not include change in urinary ACR as was used in previous cardiovascular outcome trials, and these components are a reduction by 40% or more in EGFR to a level of less than 60 repeated in 2 measurements at a central laboratory at least 4 weeks apart. The second one was end-stage renal disease defined as, once again, dialysis or any kind of replacement therapy or in a replacement therapy or reduction in EGFR to less than 15 into repeated tests. The third one was cardiovascular death and the fourth one was renal death. The renal specific outcome was all of the above without cardiovascular death.
So, it's showing really only renal outcomes. There was significant reduction with dapagliflozin versus placebo in both cardiovascular renal outcome and in the renal specific outcome. Actually, a 47% reduction in the realm of specific outcome if we look into components we can actually see that both the reduction in EGFR of more than 40 percent was significantly reduced and achievement of end-stage renal disease was very significant reduce with dapagliflozin. Now, this reduction in clinical outcomes was also joined by a reduction in the rate of deterioration of EGFR in the entire study group and in pre-specified subgroups.
So, you could see, as can be expected with SGLT2 inhibitors, an initial reduction in EGFR. So, therefore, after half a year the reduction in the EGFR was larger, there was more reduction in dapagliflozin compared to the placebo but the two graphs met after 2 years and in years 3 and 4 the reduction in EGFR was greater in the placebo arm than in the dapagliflozin arms — showing safety, showing the fact that deterioration in rebel function was reduced by dapagliflozin and this was apparent in the entire population and also in the sub population like patients with EGFR above 90 and that's the amazing part, because the not many trials with such a population of healthy individuals, patients with normal renal function at baseline at the group of 60 to 90 EGFR. So, mildly reduce renal function and in a considerably smaller group of EGFR less than 60, we also did sub analysis according to all kind of prespecified subgroups. Sex, age, ethnicity, and so on and so on. Basic renal function, use of a ACR but the baseline and so and so on and in all these subgroups there was a significant reduction with dapagliflozin, both in the of the cardio renal and under the renal-specific outcome, showing the robustness of this reduction.
Why is that clinically important? Because most trial, most large trials, like the EMPA-REG, the CANVAS, and, now most recently, the CREDENCE trial we're looking mainly into a population of patients with reduced EGFR at baseline and also with a high percentage of patient pre or at a risk of preatherosclerotic cardiovascular disease. Here, we were able to show the superiority and the renal protective effect of dapagliflozin in a population of patient, which are mostly what we see in our clinics every day. We see patients that are mostly with preserved renal function with preserved EGFR and most of them are not even with albuminuria and we were able to prove that, in this population of considerably healthy patients, the dapagliflozin reduced the risk of a progression into renal insufficiency and even to end-stage renal disease.