Dapagliflozin in Patients with Chronic Kidney Disease Heerspink, Hiddo J.L; Stefánsson, Bergur V; Correa-Rotter, Ricardo ...
The New England journal of medicine,
10/2020, Letnik:
383, Številka:
15
Journal Article
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In this trial, patients with CKD (with or without type 2 diabetes) were randomly assigned to receive dapagliflozin or placebo. The primary composite outcome — a sustained decline in the estimated GFR ...of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes — was less frequent with dapagliflozin.
Immunoglobulin A (IgA) nephropathy is a common form of glomerulonephritis, which despite use of renin-angiotensin-aldosterone-system blockers and immunosuppressants, often progresses to kidney ...failure. In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial, dapagliflozin reduced the risk of kidney failure and prolonged survival in participants with chronic kidney disease with and without type 2 diabetes, including those with IgA nephropathy. Participants with estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio 200-5000 mg/g (22.6-565 mg/mol) were randomized to dapagliflozin 10mg or placebo, as adjunct to standard care. The primary composite endpoint was a sustained decline in eGFR of 50% or more, end-stage kidney disease, or death from a kidney disease-related or cardiovascular cause. Of 270 participants with IgA nephropathy (254 94% confirmed by previous biopsy), 137 were randomized to dapagliflozin and 133 to placebo, and followed for median 2.1 years. Overall, mean age was 51.2 years; mean eGFR, 43.8 mL/min/1.73m2; and median urinary albumin-to-creatinine ratio, 900 mg/g. The primary outcome occurred in six (4%) participants on dapagliflozin and 20 (15%) on placebo (hazard ratio, 0.29; 95% confidence interval, 0.12, 0.73). Mean rates of eGFR decline with dapagliflozin and placebo were −3.5 and −4.7 mL/min/1.73m2/year, respectively. Dapagliflozin reduced the urinary albumin-to-creatinine ratio by 26% relative to placebo. Adverse events leading to study drug discontinuation were similar with dapagliflozin and placebo. There were fewer serious adverse events with dapagliflozin, and no new safety findings in this population. Thus, in participants with IgA nephropathy, dapagliflozin reduced the risk of chronic kidney disease progression with a favorable safety profile.
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In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized, placebo-controlled trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin ...significantly reduced risk of kidney failure and prolonged survival in patients with CKD with or without type 2 diabetes.
Adults with eGFR of 25-75 ml/min per 1.73 m
and urinary albumin-to-creatinine ratio of 200-5000 mg/g had been randomized to receive dapagliflozin 10 mg/d or placebo. Here, we conducted a prespecified analysis of dapagliflozin's effects in patients with stage 4 CKD (eGFR,30 ml/min per 1.73 m
) at baseline. The primary end point was a composite of time to ≥50% sustained decline in eGFR, ESKD, or kidney or cardiovascular death. Secondary end points were a kidney composite (same as the primary end point but without cardiovascular death), a composite of cardiovascular death or heart failure hospitalization, and all-cause death.
A total of 293 participants with stage 4 CKD received dapagliflozin and 331 received placebo. Patients with stage 4 CKD randomized to dapagliflozin experienced a 27% (95% confidence interval 95% CI: -2 to 47%) reduction in the primary composite endpoint, and 29% (-2 to 51%), 17% (-53 to 55%), and 32% (-21 to 61%) reductions in the kidney, cardiovascular and mortality endpoints, respectively, relative to placebo. Interaction P-values were 0.22, 0.13, 0.63, and 0.95, respectively, comparing CKD stages 4 versus 2/3. The eGFR slope declined by 2.15 and 3.38 ml/min per 1.73 m
per year in the dapagliflozin and placebo groups, respectively (
=0.005). Patients treated with dapagliflozin or placebo had similar rates of serious adverse events and adverse events of interest.
Among patients with stage 4 CKD and albuminuria, the effects of dapagliflozin were consistent with those observed in the DAPA-CKD trial overall, with no evidence of increased risks.
Patients undergoing hemodialysis have an elevated risk of cardiovascular disease-related morbidity and mortality compared with the general population. Intradialytic hypotension (IDH) is estimated to ...occur during 20%-30% of hemodialysis sessions. To date, no large studies have examined whether IDH is associated with cardiovascular outcomes. This study determined the prevalence of IDH according to interdialytic weight gain (IDWG) and studied the association between IDH and outcomes for cardiovascular events and mortality to better understand its role.
This study retrospectively examined records of 39,497 hemodialysis patients during 2007 and 2008. US Renal Data System claims and dialysis provider data were used to determine outcomes. IDH was defined by current Kidney Disease Outcomes Quality Initiative guidelines (≥20 mmHg fall in systolic BP from predialysis to nadir intradialytic levels plus ≥2 responsive measures dialysis stopped, saline administered, etc.). IDWG was measured absolutely (in kilograms) and relatively (in percentages).
IDH occurred in 31.1% of patients during the 90-day exposure assessment period. At baseline, the higher the IDWG (relative or absolute), the greater the frequency of IDH (P<0.001). For all-cause mortality, the median follow-up was 398 days (interquartile range, 231-602 days). Compared with patients without IDH, IDH was associated with all-cause mortality (7646 events; adjusted hazard ratio, 1.07 95% confidence interval, 1.01 to 1.14), myocardial infarction (2396 events; 1.20 1.10 to 1.31), hospitalization for heart failure/volume overload (8896 events; 1.13 1.08 to 1.18), composite hospitalization for heart failure/volume overload or cardiovascular mortality (10,805 events; 1.12 1.08 to 1.17), major adverse cardiac events (MACEs; myocardial infarction, stroke, cardiovascular mortality) (4994 events, 1.10 1.03 to 1.17), and MACEs+ (MACEs plus arrhythmia or hospitalization for heart failure/volume overload) (12,221 events; 1.14 1.09 to 1.19).
IDH was potently associated with cardiovascular morbidity and mortality. Clinical trials to ascertain causality are needed and should consider reduction in IDWG as a potential means to reduce IDH.
The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD; NCT03036150) trial was designed to assess the effect of the sodium-glucose co-transporter 2 (SGLT2) inhibitor ...dapagliflozin on kidney and cardiovascular events in participants with CKD with and without type 2 diabetes (T2D). This analysis reports the baseline characteristics of those recruited, comparing them with those enrolled in other trials.
In DAPA-CKD, 4304 participants with a urinary albumin:creatinine ratio (UACR) ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 were randomized to dapagliflozin 10 mg once daily or placebo. Mean eGFR was 43.1 mL/min/1.73 m2 and median UACR was 949 mg/g (108 mg/mmol).
Overall, 2906 participants (68%) had a diagnosis of T2D and of these, 396 had CKD ascribed to a cause other than diabetes. The most common causes of CKD after diabetes (n = 2510) were ischaemic/hypertensive nephropathy (n = 687) and chronic glomerulonephritis (n = 695), of which immunoglobulin A nephropathy (n = 270) was the most common. A total of 4174 participants (97%) were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 1882 (43.7%) diuretics, 229 (5.3%) mineralocorticoid receptor antagonists and 122 (2.8%) glucagon-like peptide 1 receptor agonists. In contrast to the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), the DAPA-CKD trial enrolled participants with CKD due to diabetes and to causes other than diabetes. The mean eGFR of participants in the DAPA-CKD trial was 13.1 mL/min/1.73 m2 lower than in CREDENCE, similar to that in the Finerenone in Reducing Kidney Failure and Disease Progression in DKD (FIDELIO-DKD) trial and the Study Of diabetic Nephropathy with AtRasentan (SONAR).
Participants with a wide range of underlying kidney diseases receiving renin-angiotensin system blocking therapy have been enrolled in the DAPA-CKD trial. The trial will examine the efficacy and safety of dapagliflozin in participants with CKD Stages 2-4 and increased albuminuria, with and without T2D.
Dapagliflozin reduces the risk of kidney failure and heart failure in patients with chronic kidney disease. We aimed to investigate the effects of dapagliflozin on kidney, cardiovascular, and ...mortality outcomes according to presence or absence of type 2 diabetes and according to underlying cause of chronic kidney disease, reported as diabetic nephropathy, chronic glomerulonephritides, ischaemic or hypertensive chronic kidney disease, or chronic kidney disease of other or unknown cause.
DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 study sites in 21 countries, in which participants with a urinary albumin-to-creatinine ratio of 200-5000 mg/g and an estimated glomerular filtration rate (eGFR) of 25-75 mL/min per 1·73m
were randomly assigned (1:1) to dapagliflozin 10 mg once daily or matching placebo, as an adjunct to standard care. The primary outcome was a composite of sustained decline in eGFR of at least 50%, end-stage kidney disease, or kidney-related or cardiovascular death. Secondary efficacy outcomes were a kidney-specific composite (the same as the primary outcome but excluding cardiovascular death), a composite of cardiovascular death or hospital admission for heart failure, and all-cause mortality. In this study, we conducted a prespecified subgroup analysis of the DAPA-CKD primary and secondary endpoints by presence or absence of type 2 diabetes and by aetiology of chronic kidney disease. DAPA-CKD is registered with ClinicalTrials.gov, NCT03036150.
The study took place between Feb 2, 2017, and June 12, 2020. 4304 participants were randomly assigned (2152 to dapagliflozin and 2152 to placebo) and were followed up for a median of 2·4 years (IQR 2·0-2·7). Overall, 2906 (68%) participants had a diagnosis of type 2 diabetes, of whom 396 (14%) had chronic kidney disease ascribed to causes other than diabetic nephropathy. The relative risk reduction for the primary composite outcome with dapagliflozin was consistent in participants with type 2 diabetes (hazard ratio HR 0·64, 95% CI 0·52-0·79) and those without diabetes (0·50, 0·35-0·72; p
=0·24). Similar findings were seen for the secondary outcomes: kidney-specific composite outcome (0·57 0·45-0·73 vs 0·51 0·34-0·75; P
=0·57), cardiovascular death or hospital admission for heart failure (0·70 0·53-0·92 vs 0·79 0·40-1·55; P
=0·78), and all-cause mortality (0·74 0·56-0·98 vs 0·52 0·29-0·93; P
=0·25). The effect of dapagliflozin on the primary outcome was also consistent among patients with diabetic nephropathy (n=2510; HR 0·63, 95% CI 0·51-0·78), glomerulonephritides (n=695; 0·43, 0·26-0·71), ischaemic or hypertensive chronic kidney disease (n=687; 0·75, 0·44-1·26), and chronic kidney disease of other or unknown cause (n=412; 0·58, 0·29-1·19; P
=0·53), with similar consistency seen across the secondary outcomes. The proportions of participants in the dapagliflozin and placebo groups who had serious adverse events or discontinued study drug due to adverse events did not vary between those with and those without type 2 diabetes.
Dapagliflozin reduces the risks of major adverse kidney and cardiovascular events and all-cause mortality in patients with diabetic and non-diabetic chronic kidney disease.
AstraZeneca.
Dapagliflozin reduces the risk of end-stage renal disease in patients with chronic kidney disease. We examined the relative risk of cardiovascular and renal events in these patients and the effect of ...dapagliflozin on either type of event, taking account of history of cardiovascular disease.
In the DAPA-CKD trial (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease), 4304 participants with chronic kidney disease were randomly assigned to dapagliflozin 10 mg once daily or placebo. The primary end point was a composite of sustained decline in estimated glomerular filtration rate ≥50%, end-stage kidney disease, or kidney or cardiovascular death. The secondary end points were a kidney composite outcome (primary end point, minus cardiovascular death), the composite of hospitalization for heart failure or cardiovascular death, and all-cause death. In a prespecified subgroup analysis, we divided patients into primary and secondary prevention subgroups according to history of cardiovascular disease.
Secondary prevention patients (n=1610; 37.4%) were older, were more often male, had a higher blood pressure and body mass index, and were more likely to have diabetes. Mean estimated glomerular filtration rate and median urinary albumin-to-creatinine ratio were similar in the primary and secondary prevention groups. The rates of adverse cardiovascular outcomes were higher in the secondary prevention group, but kidney failure occurred at the same rate in the primary and secondary prevention groups. Dapagliflozin reduced the risk of the primary composite outcome to a similar extent in both the primary (hazard ratio, 0.61 95% CI, 0.48-0.78) and secondary (0.61 0.47-0.79) prevention groups (
-interaction=0.90). This was also true for the composite of heart failure hospitalization or cardiovascular death (0.67 0.40-1.13 versus 0.70 0.52-0.94, respectively;
-interaction=0.88), and all-cause mortality (0.63 0.41-0.98 versus 0.70 0.51-0.95, respectively;
-interaction=0.71). Rates of adverse events were low overall and did not differ between patients with and without cardiovascular disease.
Dapagliflozin reduced the risk of kidney failure, death from cardiovascular causes or hospitalization for heart failure, and prolonged survival in people with chronic kidney disease, with or without type 2 diabetes, independently of the presence of concomitant cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036150.
Anemia is common in type 2 diabetes (T2D), particularly in patients with kidney impairment, and often goes unrecognized. Dapagliflozin treatment increases hemoglobin and serum erythropoietin levels. ...We investigated the effect of dapagliflozin 10-mg/day on hemoglobin in T2D patients with and without anemia.
Data from 5325 patients from 14 placebo-controlled, dapagliflozin-treatment studies of at least 24-weeks duration were pooled. Dapagliflozin's effects (vs. placebo) on hemoglobin, serum albumin, estimated glomerular filtration rate (eGFR), systolic blood pressure, body weight, and safety in patients with and without anemia were evaluated.
At baseline, 13% of all T2D patients and 28% of those with chronic kidney disease (eGFR <60 mL/min/1.73 m2) had anemia. Hemoglobin increased continuously to at least week 8 and was sustained throughout 24-weeks follow-up in dapagliflozin-treated patients. Serum albumin increased in dapagliflozin-treated patients at week 4 and remained stable thereafter. Dapagliflozin was well tolerated and corrected anemia in 52% of patients with anemia at baseline (placebo: 26%). Incidences of new-onset anemia were lower in dapagliflozin-treated (2.3%) versus placebo-treated (6.5%) patients.
Treatment with dapagliflozin can correct and prevent anemia in T2D patients. A gradual increase in hemoglobin beyond week 4 may indicate an erythropoiesis-stimulating effect of sodium-glucose cotransporter 2 inhibition.
•14 placebo-controlled, dapagliflozin (DAPA)-treatment studies (N = 5325) were pooled.•Hemoglobin increase was sustained through 24-weeks follow-up in DAPA-treated patients.•DAPA corrected anemia in 52% of patients with anemia at baseline (placebo: 26%).•Incidences of new-onset anemia were lower in DAPA (2.3%) vs placebo (6.5%).•Treatment with DAPA can correct and prevent anemia in patients with type 2 diabetes.
OBJECTIVE
The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) study demonstrated risk reduction for kidney and cardiovascular outcomes with dapagliflozin versus ...placebo in participants with chronic kidney disease (CKD) with and without diabetes. We compared outcomes according to baseline glycemic status.
RESEARCH DESIGN AND METHODS
We enrolled participants with CKD, estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2, and urinary albumin-to-creatinine ratio 200–5,000 mg/g. The primary composite end point was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death.
RESULTS
Of 4,304 participants, 738 had normoglycemia, 660 had prediabetes, and 2,906 had type 2 diabetes. The effect of dapagliflozin on the primary outcome was consistent (P for interaction = 0.19) in normoglycemia (hazard ratio HR 0.62 95% CI 0.39, 1.01), prediabetes (HR 0.37 0.21, 0.66), and type 2 diabetes (HR 0.64 0.52, 0.79). We found no evidence for effect modification on any outcome. Adverse events were similar, with no major hypoglycemia or ketoacidosis in participants with normoglycemia or prediabetes.
CONCLUSIONS
Dapagliflozin safely reduced kidney and cardiovascular events independent of baseline glycemic status.
Dapagliflozin reduces kidney failure risk in patients with CKD but can result in a reversible acute reduction in eGFR upon treatment initiation. Determinants of this eGFR reduction and its ...associations with efficacy and safety outcomes are unknown.
The DAPA-CKD trial randomized 4304 adults with CKD and albuminuria to once-daily dapagliflozin 10 mg or placebo, added to standard care. We prespecified an analysis comparing the effects of dapagliflozin among patients who experienced relative reductions in eGFR (>10% or >0%-10%) or an increase in eGFR from baseline to 2 weeks and assessed long-term efficacy and safety thereafter.
A total of 4157 (96.6%) patients had eGFR data available at baseline and at 2 weeks. In the dapagliflozin and placebo groups, 1026 (49.4%) and 494 (23.7%), respectively, experienced an acute reduction in eGFR >10%. Among patients receiving dapagliflozin, those with an acute reduction in eGFR >10% experienced a long-term eGFR decline of -1.58 ml/min per 1.73 m
per year compared with -2.44 and -2.48 ml/min per 1.73 m
per year among those experiencing a less pronounced reduction or increase in eGFR, respectively (
-interaction=0.05). In the placebo group, long-term eGFR decline was -3.27, -3.84, and -3.77 ml/min per 1.73 m
per year for acute eGFR reduction subgroups of >10%, >0%-10%, or increase in eGFR (
-interaction=0.48). Rates of serious adverse events and adverse events of special interest in patients randomized to dapagliflozin were unrelated to the acute eGFR change.
Among patients with CKD and albuminuria treated with dapagliflozin, an acute reduction in eGFR (from baseline to 2 weeks) is not associated with higher rates of CKD progression.
A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (Dapa-CKD) NCT03036150.
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