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Dapagliflozin Boosts Renal Function in T2D

<ѻý class="mpt-content-deck">— Secondary outcomes build on previously reported cardiovascular benefit from SGLT2 inhibitors
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SAN FRANCISCO -- Dapagliflozin (Farxiga) halved incidence of serious kidney disease for patients with type 2 diabetes irrespective of baseline cardiovascular disease, according to a secondary analysis of DECLARE-TIMI trial data reported here.

In a group of more than 17,000 patients, those treated with 10 mg daily dapagliflozin had a reduced risk of composite renal outcomes by 47% compared with patients in the placebo group (hazard ratio 0.53, 95% CI 0.43-0.66, P<0.0001) when deaths by cardiovascular causes were excluded, reported Ofri Mosenzon, MD, of the Hebrew University of Jerusalem, at the American Diabetes Association annual meeting.

This composite outcome included:

  • At least a 40% reduction in estimated glomerular filtration rate (eGFR) to less than 60 mL/min per 1.73 m2
  • End-stage renal outcomes requiring dialysis for at least 90 days
  • Kidney transplantation
  • eGFR less than 14 mL/min per 1.73 m2
  • Renal death

Furthermore, just 7.4% of the patients in this sample had moderate renal impairment (less than 60 mL/min per 1.73 m²), and most had preserved renal function (mean eGFR 85.2 mL/min per 1.73 m²), indicating that the sodium-glucose co-transporter-2 (SGLT2) inhibitor can be effective regardless of baseline renal function, Mosenzon explained.

"These results emphasize the value of SGLT2 inhibitors and their importance not just in the treatment, but also in the prevention of chronic kidney disease in type 2 diabetes," she said in her presentation at the meeting.

The findings, also published in as DECLARE–TIMI 58, were presented as a secondary analysis to the main DECLARE-TIMI trial reported last November, which found that dapagliflozin reduced the rate of cardiovascular death or hospitalization for heart failure, but did not improve overall major adverse cardiovascular events. However, because only half of the primary outcomes demonstrated superiority in the original trial, the secondary outcomes presented should be viewed as "hypothesis-generating," she said.

SGLT2 inhibitors like empagliflozin, canagliflozin, and dapagliflozin have been shown to reduce cardiovascular events and common complications like kidney disease in this population, wrote Ian de Boer, MD, MS, of the University of Washington in Seattle, in an .

The results of the trial are validated by recent studies such as CREDENCE, which showed a 30% reduction in the doubling of serum creatinine concentration, end-stage renal disease, or death from renal or cardiovascular causes in patients given canagliflozin versus placebo, de Boer noted. However, CREDENCE involved patients with albuminuric chronic kidney disease, whereas 69.1% of patients in the study by Mosenzon, et al. had normoalbuminuria.

Despite the relatively long follow-up in the trial (mean 4.2 years), it's not clear what the lifetime effects of dapagliflozin will be in type 2 diabetes, de Boer emphasized, particularly since the results of both trials indicate that eGFR may begin to increase long-term. He cautioned against potential long-term adverse events associated with SGLT2 inhibitors, such as amputations and increased risk of fractures.

In 2018, the mandating new labeling for SGLT2 inhibitors due to reported cases of Fournier's gangrene associated with the new class of the drug.

In the study, five cases of Fournier's gangrene were recorded in the placebo arm and one occurred with dapagliflozin. Further, the risk for acute kidney injury was actually reduced by 31% for patients in the intervention arm versus placebo (HR 0.69, 95% CI 0.55-0.87, P=0.002), the authors reported.

"Despite the FDA warning for the risk of acute kidney injury, kidney injury in this trial was lower in the dapagliflozin arm than the placebo arm," Mosenzon said.

Still, acute kidney injury may have been underestimated due to the infrequent urine albumin-to-creatinine ratio measurements performed (four in the first year and annually thereafter), and since the researchers included only confirmed sustained changes in eGFR.

In the trial, the mean eGFR decrease was larger for patients on dapagliflozin versus placebo at 6 months, equalized by 2 years, and was then smaller than placebo by years 3 and 4, the researchers reported, attributing this trend towards the well-preserved renal function of the cohort.

The dapagliflozin and placebo groups did not differ significantly in the incidence of other serious adverse events such as amputations (123 vs 113), fractures, and symptoms of volume depletion like hypotension, dehydration, or syncope, the authors reported.

Study Details

The trial involved a patient population with type 2 diabetes with developed cardiovascular disease or who were at high-risk for developing it. Eligible participants were required to have HbA1c levels of 6.5-12% and creatinine clearance of at least 60 mL/min before being blinded to either the dapagliflozin or placebo group.

Not surprisingly, patients with lower eGFR measures were older, had diabetes for a longer time, and tended to have more cardiovascular risk factors than those with higher measures, Mosenzon and co-authors noted. Individuals with higher eGFR more commonly used metformin and sulfonylurea as well, while those with lower eGFR had more insulin use.

A cardiorenal composite outcome including death from cardiovascular causes was also significantly lower for patients on dapagliflozin than placebo (HR 0.76, 95% CI 0.67-0.87, P<0.0001), and patients on dapagliflozin had a significantly lower risk for having sustained decreases in eGFR of more than 40% as well (HR 0.54, 95% CI 0.43-0.67, P<0.0001).

Specifically, patients on the SGLT2 inhibitor had a reduced risk of end-stage renal disease and renal death versus those on placebo (0.1% vs 0.3%, HR 0.41, 95% CI 0.2-0.82, P=0.01), although the incidence of end-stage renal disease was rare, Mosenzon noted.

The risk of at least a 40% reduction in eGFR to less than 60 mL/min per 1.73 m2 was also significantly lower in the dapagliflozin group than in the placebo group (HR 0.54, 95% CI 0.43–0.67, P<0·0001).

Most subgroups, based on patient characteristics or the presence of atherosclerotic cardiovascular disease, did not have a mitigated risk across the placebo and intervention arms. However, dapagliflozin appeared to be more effective in patients not using diuretics at baseline, the authors said.

De Boer emphasized that future studies should investigate the effects of other glucose-lowering drugs with SGLT2 inhibitors, since secondary drugs may need to be paired with this new class.

"Cost permitting, and pending the emergence of data for the issues that remain to be addressed (additional trials are underway), there is a strong argument in favor of expanding the population in which use of this drug class could be recommended," he concluded.

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    Elizabeth Hlavinka covers clinical news, features, and investigative pieces for ѻý. She also produces episodes for the Anamnesis podcast.

Disclosures

The study received initial funding from AstraZeneca and Bristol-Myers Squibb, but by its publication AstraZeneca was the sole funder.

Mosenzon reported financial relationships with AstraZeneca, Bristol-Myers Squibb, Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Johnson & Johnson, and Novartis.

De Boer reported financial relations with Boehringer-Ingelheim, Ironwood, Medtronic, and Abbott.

Primary Source

The Lancet Diabetes and Endocrinology

Mosenzon O, et al "Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial" The Lancet Diabetes and Endocrinology2019; DOI: 10.1016/S2213-8587(19)30180-9.

Secondary Source

The Lancet Diabetes and Endocrinology

Boer I "The expanding résumé of SGLT2 inhibitors" The Lancet Diabetes and Endocrinology 2019; DOI: 10.1016/ S2213-8587(19)30183-4.