Mosenzon O, Wiviott SD, Cahn A, 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. Lancet Diabetes Endocrinol. 2019 Aug;7(8):606-617. doi: 10.1016/S2213-8587(19)30180-9. Epub 2019 Jun 10. (Original study)

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors have shown beneficial effects on renal outcomes mainly in patients with established atherosclerotic cardiovascular disease. Here we report analyses of renal outcomes with the SGLT2 inhibitor dapagliflozin in the DECLARE-TIMI 58 cardiovascular outcomes trial, which included patients with type 2 diabetes both with and without established atherosclerotic cardiovascular disease and mostly with preserved renal function.

METHODS: In DECLARE-TIMI 58, patients with type 2 diabetes, HbA1c 6·5-12·0% (47·5-113·1 mmol/mol), with either established atherosclerotic cardiovascular disease or multiple risk factors, and creatinine clearance of at least 60 mL/min were randomly assigned (1:1) to 10 mg dapagliflozin or placebo once daily. A prespecified secondary cardiorenal composite outcome was defined as a sustained decline of at least 40% in estimated glomerular filtration rate [eGFR] to less than 60 mL/min per 1·73m2, end-stage renal disease (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR <15mL/min per 1·73 m2), or death from renal or cardiovascular causes; a prespecified renal-specific composite outcome was the same but excluding death from cardiovascular causes. In this renal analysis, we report findings for the components of these composite outcomes, subgroup analysis of these composite outcomes, and changes in eGFR at different timepoints. DECLARE-TIMI 58 is registered with ClinicalTrials.gov, number NCT01730534.

FINDINGS: The trial took place between April 25, 2013, and Sept 18, 2018; median follow-up was 4·2 years (IQR 3·9-4·4). Of the 17?160 participants who were randomly assigned, 8162 (47·6%) had an eGFR of at least 90 mL/min per 1·73 m2, 7732 (45·1%) had an eGFR of 60 to less than 90 mL/min per 1·73 m2, and 1265 (7·4%) had an eGFR of less than 60 mL/min per 1·73 m2 at baseline (one participant had missing data for eGFR); 6974 (40·6%) had established atherosclerotic cardiovascular disease and 10?186 (59·4%) had multiple risk factors. As previously reported, the cardiorenal secondary composite outcome was significantly reduced with dapagliflozin versus placebo (hazard ratio [HR] 0·76, 95% CI 0·67-0.87; p<0·0001); excluding death from cardiovascular causes, the HR for the renal-specific outcome was 0·53 (0·43-0·66; p<0·0001). We identified a 46% reduction in sustained decline in eGFR by at least 40% to less than 60 mL/min per 1·73 m2 (120 [1·4% vs 221 [2·6%]; HR 0·54 [95% CI 0·43-0·67]; p<0·0001). The risk of end-stage renal disease or renal death was lower in the dapagliflozin group than in the placebo group (11 [0·1%] vs 27 [0·3%]; HR 0·41 [95% CI 0·20-0·82]; p=0·012). Both the cardiorenal and renal-specific composite outcomes were improved with dapagliflozin versus placebo across various prespecified subgroups, including those defined by baseline eGFR (cardiorenal outcome pinteraction=0·97; renal-specific outcome pinteraction=0·87) and the presence or absence of established atherosclerotic cardiovascular disease (cardiorenal outcome pinteraction=0·67; renal-specific outcome pinteraction=0·72). 6 months after randomisation, the mean decrease in eGFR was larger in the dapagliflozin group than in the placebo group. The mean change equalised by 2 years, and at 3 and 4 years the mean decrease in eGFR was less with dapagliflozin than with placebo.

INTERPRETATION: Dapagliflozin seemed to prevent and reduce progression of kidney disease compared with placebo in this large and diverse population of patients with type 2 diabetes with and without established atherosclerotic cardiovascular disease, most of whom had preserved renal function.

FUNDING: AstraZeneca.

Discipline Area Score
Internal Medicine 7 / 7
Nephrology 7 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Endocrine 6 / 7
Cardiology 5 / 7
Comments from MORE raters

Cardiology rater

"Dapagliflozin seemed to prevent and reduce progression of kidney disease compared with placebo"..."seemed" just does not belong in a medical journal.

Endocrine rater

Results are consistent with trials of other SGLT2 inhibitors, showing benefit on renal outcomes in patients with diabetes.

Endocrine rater

This is more evolving evidence that SGLT-2 inhibitors are renal protective.

Endocrine rater

This double-blind, randomized, placebo-controlled trial clearly shows a reduction in the progression of diabetic renal disease and a reduction in the risk for its development with dapagliflozin vs placebo. It adds to the cardiac risk reduction trial seen with SGLT2 inhibitors, (EMPA-Reg, Canvas), and the Credence trial, which demonstrated a reduction in the progression of diabetic kidney disease with canagliflozin vs placebo. This study adds to the benefits seen with this class, and, in particular, showed the renal benefits of dapagliflozin.

Endocrine rater

This is a very good trial and I should say a good review of frequently used SGLT-2 R blockers: empagliflozin, canagliflozin, and dapagliflozin. My practice shows that a significant number of patients with T2DM are already at earlier stages of asymptomatic diabetic nephropathy (DN) at diagnosis. According to natural history, DN is a progressive disease in nature and there is no cure. Reduction of progression (decline of eGFR) is the only treatment option. We actually do not have any specific treatment option for DN. Apart from ACEIs or ARBs, SGLT-2R blockers have given us excellent treatment options for reducing progression of DN to end-stage renal disease. According to result of DECLARE-TIMI-58, dapagliflozin is found to offer excellent treatment options in patients with T2DM complicated with DN with or without established ASCVD. I think promising renal outcomes of this study should have good practical implications.

Family Medicine (FM)/General Practice (GP) rater

This work will shape a new path toward the care of patients with diabetes.

General Internal Medicine-Primary Care(US) rater

This is additional evidence for clinical benefit of STLG2 inhibitors in patients with diabetes who are already at higher risk for atherosclerotic disease. Renal outcomes are improved with use of dapaglifozin, although the exact mechanisms are unknown. Hemodynamic enhancements have been postulated. Clinicians must weigh these anticipated benefits for renal function with the potential adverse effects of this drug class.
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