Researchers Study the Potential Impact of Dapagliflozin on Diabetic Kidney Disease

Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), was found to have a favorable effect on both urinary albumin-to-creatinine ratio (UACR) and renal-specific outcomes across baseline UACR categories, suggesting a potential role for the drug in the primary prevention of diabetic kidney disease. This is according to research results published in Diabetes Care.

Researchers conducted a secondary exploratory analysis of data from the DECLARE-TIMI 58 trial (ClinicalTrials.gov Identifier: NCT01730534) in order to evaluate the effect of dapagliflozin on UACR in the entire trial population and by baseline UACR and estimated glomerular filtration rate (eGFR) categories.

DECLARE-TIMI 58 included adults with type 2 diabetes and either multiple risk factors for atherosclerotic cardiovascular disease or established atherosclerotic cardiovascular disease; additional inclusion criteria were glycated hemoglobin (HbA_1c) between 6.5% and 12% and creatinine clearance of ≥60 mL/min estimated by the Cockcroft-Gault equation.

Participants were randomly assigned in a double-blinded, 1:1 fashion to receive either dapagliflozin 10 mg/d or placebo. The cardiorenal outcome was defined as the time to first event of a composite of sustained confirmed decrease in eFGR by at least 40%.

Of the 17,160 study participants, 98.15% (n=16,843) had baseline UACR data available. Just over 50% of participants (n=9067; 53.83%) had baseline UACR ≤15 mg/g, of which 551 (3.30%) had albumin below detectible levels. A total of 15.30% of participants had UCAR >15 to <30 mg/g, 23.93% had baseline UACR ≥30 to ≤300 mg/g, and 6.94% had baseline UACR >300 mg/g.

Participants in lower baseline UACR categories were more likely to be White women with shorter diabetes duration and were less likely to have a history of established atherosclerotic cardiovascular disease, heart failure, or hypertension. Those with a higher baseline UACR had higher mean HbA_1c, lower eGFR, and higher systolic blood pressure. The use of angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) was common in all baseline UACR categories.

The dapagliflozin arm had statistically significantly lower mean UACR vs placebo in all UACR subgroups. Between 6 months and 4 years, UACR in the UACR >15 mg/g subgroup was lower in the dapagliflozin arm. At separation of the curves as a marker for effect in the lowest UACR category was seen after 36 months.

In the high-risk category — patients with baseline proteinuria (UACR >300 mg/g) — mean UACR remained stable to decreased through 48 months of treatment with dapagliflozin after a large mean decrease during the first 6 months.

Among all 3 eGFR subgroups — eGFR ≥90, <90 to ≥60, and <60 mL/min/1.73 m² — at baseline and all time points after, the dapagliflozin arm had a statistically significantly lower mean UACR vs placebo.

Results of an analysis confirmed the sustained change in categorical UACR from baseline through the end of the trial, which demonstrated an improvement in UACR in all subgroups with dapagliflozin treatment vs placebo. The improvement seen with dapagliflozin was statistically significant in each UACR category, both separately and as the sum of patients who improved by at least 1 and 2 UACR categories (hazard ratios, 1.45 and 1.43, respectively). The investigators also noted that treatment with dapagliflozin was associated with a statistically significant reduction in deterioration in most UACR categories from baseline to the end of the trial.

When looking specifically at the change in distribution of UACR categories from randomization to 6 months by treatment arm, there were statistically significant differences between patients treated with dapagliflozin and those receiving placebo. At 6 months, there was a higher percentage of patients treated with dapagliflozin in the UACR ≤15 mg/g category (56% vs 52%), with the opposite being true for the ≥30 to ≤300 mg/g category and the >300 mg/g category (23% vs 25% and 5% vs 7%).

In the placebo arm, cardiorenal event rates for UACR ≤15 mg/g vs UCAR >15 mg/g to <30 mg/g were 3.1% and 4.9%, respectively; renal-specific event rates were 1.3% and 2.4% in the same groups. “Together,” the researchers wrote, “these findings demonstrate an increased risk for both outcomes with higher baseline UACR categories, even in the normoalbuminuria range.” Cardiorenal outcomes were reduced with dapagliflozin for all UACR ≥30 mg/g subgroups, while renal-specific outcomes were reduced with dapagliflozin for all UACR subgroups.

Study limitations include the need for analyses to be viewed as hypothesis generating, as the dual primary efficacy outcome of major adverse cardiovascular events was not achieved and because the DECLARE-TIMI 58 trial was a cardiovascular, not renal, outcome trial. Other limitations include the limited number of African American and Hispanic patients enrolled, the testing of UACR as a single sample instead of as an average of 2 to 3 samples, and the relatively low number of patients in the highest-risk albuminuria category.

“This reduction in UACR and renal outcomes with dapagliflozin was achieved on top of >80% use of ACEi and ARBs,” the researchers concluded. “The possible association between the positive effect of dapagliflozin on albuminuria and its positive effect on the cardiorenal and renal-specific outcomes in DECLARE-TIMI 58 remain to be further analyzed.”

Disclosure: This clinical trial was supported by AstraZeneca and Bristol-Myers Squibb. Please see the original reference for a full list of authors’ disclosures.

Reference

Mosenzon O, Wiviott SD, Heerspink HJL, et al. The effect of dapagliflozin on albuminuria in DECLARE-TIMI 58. Diabetes Care. 2021;44(8):1805-1815. doi:10.2337/dc21-0076