medwireNews: Detailed analysis of renal outcomes in the DECLARE-TIMI 58 trial confirms that treatment with the sodium-glucose cotransporter (SGLT)2 inhibitor dapagliflozin is renoprotective in patients with type 2 diabetes and preserved kidney function.
Presenting the findings to reporters at the 79th ADA Scientific Sessions in San Francisco, California, USA, Itamar Raz (Hebrew University of Jerusalem, Israel) stressed that other SGLT2 inhibitor cardiovascular outcomes trials that have demonstrated a protective effect on kidney function involved patient populations with a degree of baseline kidney dysfunction, with an average estimated glomerular filtration rate (eGFR) of around 75 mL/min per 1.73 m2 and existing micro- or macroalbuminuria. And the recent CREDENCE trial specifically recruited patients with renal dysfunction.
The majority of DECLARE participants, by contrast, had preserved renal function, with an average eGFR of 85.2 mL/min per 1.73 m2. They were aged 64 years, on average, with a median diabetes duration of 10–11 years, and 41% had established cardiovascular disease.
Raz stressed that, in a given population, around 50% of those who eventually progress to end-stage renal disease will have no evidence of kidney dysfunction at baseline. “So we don’t know who these patients are and we don’t treat them on time to prevent this deterioration.”
The researchers previously reported the composite renal endpoint, the risk for which was “tremendously reduced by 47%” in patients taking dapagliflozin versus placebo, said Raz.
And the individual endpoint components followed a similar pattern. The risk for a sustained eGFR reduction of more than 40% to less than 60 mL/min per 1.73 m2 occurred in 1.4% versus 2.6% in the dapagliflozin versus placebo groups, respectively, amounting to a significant 46% reduction. And for end-stage renal disease it was a corresponding 0.1% versus 0.2% and a 69% reduction.
“These patients were healthy patients, followed for only 4 years,” says Raz, “and yet 19 of them lost their kidney on placebo and only six lost their kidney when they were on dapagliflozin.”
Patients taking dapagliflozin experienced a larger fall in eGFR over the first 6 months than patients in the placebo group, but the two crossed over at the 2-year mark so that by 4 years eGFR had fallen significantly further in patients taking placebo than in those taking dapagliflozin, although the between-group difference was fairly small.
Raz believes that current practice is to initiate renoprotective treatment too late in the pathogenesis of the disease.
“Today we have to think, because of the outstanding effect of the drug, of starting giving this drug at the very early stage, even the hyperfiltration stage, which is eGFR more than the normal, in order to prevent deterioration,” he said.
The findings were simultaneously published in The Lancet Diabetes and Endocrinology, in which the author of a linked commentary, Ian de Boer (University of Washington, Seattle, USA) notes that although these were secondary outcomes that DECLARE was not powered to assess, “their internal validity is now supported by CREDENCE.”
The combined findings of CREDENCE and the cardiovascular outcomes trials demonstrate the renoprotective effects of SGLT2 inhibitors “across a wide range of patients with type 2 diabetes,” he writes.
De Boer stresses that more data are needed on a number of issues, including whether the benefits of SGTL2 inhibition are sustained in the longer term, and the potential adverse effects of taking these medications over many years.
However, overall he believes that there is “a strong argument in favour of expanding the population in which use of this drug class could be recommended.”
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Lancet Diabetes Endocrinol 2019; doi: 10.1016/S2213-8587(19)30180-9
Lancet Diabetes Endocrinol 2019; doi: 10.1016/S2213-8587(19)30183-4