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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

https://doi.org/10.1016/S2213-8587(19)30180-9Get rights and content

Summary

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.

Introduction

For many years, optimal glucose control plus blood pressure control with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs)1, 2 has been the basis of treatment of diabetic kidney disease.3, 4, 5 Early identification of renal impairment and appropriate interventions are more effective than later interventions for the prevention of adverse renal outcomes.3 Even if patients with type 2 diabetes are treated with ACE inhibitors or ARBs, their residual risk of adverse renal and cardiovascular outcomes remains higher than that in age-matched and sex-matched counterparts without diabetes,4, 5 and diabetes remains the leading cause of end-stage renal disease in most parts of the world.6, 7 Novel treatments are therefore needed to both prevent and slow progression of chronic kidney disease in patients with type 2 diabetes.

Research in context

Evidence before this study

We searched PubMed for all English-language publications from Jan 1, 2000, to May 28, 2019, using the search terms “SGLT2”, “CKD”, “kidney disease”, “diabetic nephropathy”, and “eGFR”. Previous trials have shown that the sodium-glucose co-transporter-2 (SGLT2) inhibitors empagliflozin and canagliflozin slowed the progression of nephropathy in patients with type 2 diabetes. However, most of the patients in these trials had established atherosclerotic cardiovascular disease or mild to moderate chronic kidney disease, or both. In the primary report of the DECLARE–TIMI 58 trial, a cardiorenal secondary composite outcome (≥40% decrease in estimated glomerular filtration rate [eGFR] to <60 mL/min per 1·73 m2, new end-stage renal disease, or death from renal or cardiovascular causes) was reduced by 24%, and a renal-specific composite outcome excluding cardiovascular death was reduced by 47%.

Added value of this study

In this renal analysis of the DECLARE–TIMI 58 trial, we identified a 46% reduction in sustained decline in eGFR by at least 40% to less than 60 mL/min per 1·73m2 (hazard ratio 0·54 [95% CI 0·43–0·67]; p<0·0001). Despite small numbers of events, we also showed a reduction in the combined risk of end-stage renal disease or renal death (0·41 [95% CI 0·20–0·82]; p=0·012). Furthermore, we have shown the consistent beneficial effects of dapagliflozin on composite renal outcomes compared with placebo in predefined subgroups of patients, including those defined by eGFR status and the presence or absence of atherosclerotic cardiovascular disease at baseline. Thereby, our results show the effect of an SGLT2 inhibitor on both early prevention and reduction in progression of chronic kidney disease in patients with type 2 diabetes. DECLARE–TIMI 58 is the first study to show the effects of an SGLT2 inhibitor on clinically important renal outcomes and on changes in eGFR in a large cohort of patients with type 2 diabetes with and without previous atherosclerotic cardiovascular disease, most of whom had normal or only mildly reduced renal function.

Implications of all the available evidence

On the basis of available evidence, SGLT2 inhibitors seem to reduce the risk of both progression and development of nephropathy in patients with type 2 diabetes, irrespective of the presence of atherosclerotic cardiovascular disease or baseline renal function. The effect of SGLT2 inhibitors on nephropathy is being examined in dedicated studies of renal outcomes, both in patients with and without type 2 diabetes. However, these trials focus on populations with nephropathy at baseline, and therefore should be considered as complementary to our findings.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a class of drugs that have been shown to decrease the rate of decline in renal function in patients with type 2 diabetes and cardiovascular disease. In the EMPA-REG OUTCOME cardiovascular outcomes trial,8 treatment with the SGLT2 inhibitor empagliflozin reduced the risk of the main composite renal outcome (defined as progression to macroalbuminuria; a doubling of the serum creatinine level accompanied by an eGFR of ≤45 mL/min per 1·73 m2; initiation of renal-replacement therapy; or death from renal disease) by 39% compared with placebo in a high-risk population of patients with previous atherosclerotic cardiovascular disease and a high prevalence of chronic kidney disease (baseline median estimated glomerular filtration rate [eGFR] 74·1 mL/min per 1·73 m2, with 25·9% [1819/7020] with an eGFR below 60 mL/min per 1·73 m2 and 39·6% [2782/7020] with microalbuminuria or macroalbuminuria).9 In the CANVAS trial Program,10, 11, 12 the SGLT2 inhibitor canagliflozin improved renal outcomes compared with placebo in a population of patients predominantly with atherosclerotic cardiovascular disease (65·6% [6656/10 142]) and with renal function similar to that of the EMPA-REG OUTCOME population (mean eGFR 76·5 mL/min per 1·73 m2 and median urinary albumin-to-creatinine ratio [UACR] 12·3 mg/g). In the CREDENCE trial,13 patients with type 2 diabetes and albuminuric chronic kidney disease (eGFR 30 to <90 mL/min per 1·73 m2 and UACR >300 to 5000 mg/g) were randomly assigned to canagliflozin or placebo. Canagliflozin was associated with a 30% reduction in the primary composite outcome of end-stage renal disease (ie, dialysis, transplantation, or a sustained eGFR <15 mL/min per 1·73 m2), doubling of serum creatinine concentrations, or death from renal or cardiovascular causes.13

In the placebo-controlled Dapagliflozin Effect on Cardiovascular Events (DECLARE)–TIMI 58 trial,14 the SGLT2 inhibitor dapagliflozin reduced the frequency of one of the dual primary composite outcomes (cardiovascular death or hospital admission for heart failure) but did not significantly reduce the frequency of the other (major adverse cardiovascular events). As previously reported,14 a cardiorenal secondary composite outcome (≥40% decrease in eGFR to <60 mL/min per 1·73 m2, new end-stage renal disease, or death from renal or cardiovascular causes) was reduced by 24% and the same composite outcome excluding cardiovascular death (renal-specific outcome) was reduced by 47%. Notably, the study population of DECLARE–TIMI 58 included a mixture of patients with established atherosclerotic cardiovascular disease and those multiple risk factors for cardiovascular disease; additionally, most of the participants had preserved renal function (mean eGFR 85·2 mL/min per 1·73 m2). Here we report results of detailed analyses of renal outcomes of the DECLARE–TIMI 58 trial, including components of the cardiorenal and renal-specific composite outcomes, subgroup analysis of these composite outcomes, and change in eGFR at different timepoints, in order to investigate the renal effects of dapagliflozin in this large and diverse study population.

Section snippets

Study design and participants

The DECLARE–TIMI 58 trial design, baseline characteristics of participants, and main results have been previously reported.14, 15, 16 Briefly, patients with type 2 diabetes and either established atherosclerotic cardiovascular disease (age ≥40 years and either ischaemic heart disease, cerebrovascular disease, or peripheral arterial disease), or multiple risk factors for atherosclerotic cardiovascular disease (age ≥55 years for men or ≥60 years for women plus at least one of dyslipidaemia,

Results

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, 6974 (40·6%) had established atherosclerotic cardiovascular disease and 10 186 (59·4%) had multiple risk factors for atherosclerotic cardiovascular disease.

Of the 17 159 participants with available baseline eGFR data (one participant had missing data for eGFR), 8162 (47·6%) had an eGFR of at least 90 mL/min per 1·73 m2 and 7732

Discussion

In the DECLARE–TIMI 58 trial, patients randomly assigned to dapagliflozin had significantly reduced frequencies of composite cardiorenal and renal-specific outcomes compared with those in the placebo group.14 Components of the composite outcomes were also significant reduced with dapagliflozin, including a sustained decrease in eGFR by at least 40% to less than 60 mL/min per 1·73 m2. End-stage renal disease, although a rare event in the trial, as would be expected in a population with

Data sharing

Individual participant data will not be made available. However, we encourage parties interested in collaboration to contact the corresponding author directly for further discussions.

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