Effects of Dapagliflozin in Patients With Kidney Disease, With and Without HeartFailure

ISS Fro Re L Sw Gr nin of of Ch Co D OBJECTIVES The purpose of this paper was to investigate the effects of dapagliflozin in chronic kidney disease (CKD) patients, with and without heart failure (HF). BACKGROUND Patients with CKD, with and without type 2 diabetes, were enrolled in the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial. Some patients had HF at baseline. METHODS A total of 4,304 participants were randomized to dapagliflozin 10 mg daily or placebo. The primary composite endpoint was $50% decline in estimated glomerular filtration rate, end-stage kidney disease, or kidney/ cardiovascular death. Secondary endpoints were a kidney composite (primary endpoint minus cardiovascular death), the composite of cardiovascular death/HF hospitalization, and all-cause death. Analysis of outcomes according to HF history was prespecified. RESULTS HF patients (n 1⁄4 468; 11%) were older and had more coronary disease, atrial fibrillation, and type 2 diabetes. Mean estimated glomerular filtration rate was similar in patients with and without HF. Rates of HF hospitalization/cardiovascular death and death from any cause were higher in HF patients, but the secondary kidney failure outcome occurred at the same rate in people with and without HF. Dapagliflozin reduced the risk of the primary outcome equally in patients with HF (HR: 0.58 [95% CI: 0.37-0.91]) and without HF (HR: 0.62 [95% CI: 0.51-0.75]) (P interaction 1⁄4 0.59). The proportional risk-reductions were similar in patients with and without HF for the cardiovascular death/HF hospitalization composite (HR: 0.68 [95% CI: 0.44-1.05] vs HR: 0.70 [95% CI: 0.51-0.97], respectively; P interaction 1⁄4 0.90), and all-cause death (HR: 0.56 [95% CI: 0.34-0.93] vs HR: 0.73 [95% CI: 0.54-0.97], respectively; P interaction 1⁄4 0.39), although absolute risk reductions were larger in HF patients. Adverse event rates were low and did not differ among patients with or without HF. CONCLUSIONS Dapagliflozin reduced the risk of kidney failure and cardiovascular death/HF hospitalization and prolonged survival in CKD patients with or without type 2 diabetes, independently of history of HF. (A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease [DAPA-CKD]; NCT03036150) (J Am Coll Cardiol HF 2021;-:-–-) © 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). N 2213-1779 https://doi.org/10.1016/j.jchf.2021.06.017 m the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom; Department of nal Medicine, University College London, London, United Kingdom; The George Institute for Global Health, Sydney, Australia; ate-stage Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gothenburg, eden; Department Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, oningen, the Netherlands; Department Epidemiology, University of Groningen, University Medical Center Groningen, Grogen, the Netherlands; National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico; Departments Medicine and Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA; Division Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, Guangzhou, ina; Steno Diabetes Center Copenhagen, Gentofte, Denmark; Department of Clinical Medicine, University of Copenhagen, penhagen, Denmark; Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA; and the epartment of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA. ABBR EV I A T I ON S

H eart failure (HF) is common in patients with chronic kidney disease (CKD), reflecting the high prevalence of hypertension and diabetes in these individuals. These, along with premature and extensive atherosclerotic disease, impaired sodium and water homeostasis, and anemia, cause or aggravate cardiac and vascular hypertrophy and fibrosis as well as myocardial ischemia, leading to left ventricular diastolic and systolic dysfunction. HF is an important cause of hospitalization and a powerful and independent predictor of death in this population (1)(2)(3)(4)(5)(6)(7). In the ARIC (Atherosclerosis Risk In Communities) study, the adjusted incidence of HF was 3-fold higher in people with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 compared with those with eGFR >90 mL/ min/1.73 m 2 (1,4). Additional epidemiological studies confirmed these findings, showing that the magnitude of risk of HF in people with CKD was as high as that for coronary disease and higher than that for stroke (1)(2)(3)(4)(5)(6)(7). The incidence and prevalence of HF is higher in patients with more severe CKD; recent reports from the US Renal Data System suggest that up to 30% of patients with CKD have concomitant HF, a much higher prevalence than in the general population (6,7). . HF is associated with a particularly poor survival in patients with CKD. Consequently, both prevention and treatment of HF in patients with CKD is a priority.
A series of large randomized controlled trials have demonstrated that sodium glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of HF hospitalization in patients with type 2 diabetes mellitus, including those with CKD (8-12). More recently, this benefit of SGLT2 inhibitors was expanded to patients with CKD without type 2 diabetes in the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial (13). Whereas the SGLT2 inhibitor trials in patients with type 2 diabetes largely described prevention of incident HF, the effect of SGLT2 inhibitors in patients with CKD, diabetes, and prevalent HF was reported in the CREDENCE

(Canagliflozin and Renal Events in Diabetes With
Established Nephropathy Clinical Evaluation) trial (12,14). Here we extend these findings to patients with CKD and HF, with and without type 2 diabetes, reporting the effects of dapagliflozin on HF hospitalization, kidney outcomes, and mortality in patients with HF at baseline in DAPA-CKD (13,15). This analysis is clinically relevant, given the suggestion that development of HF may accelerate the rate of decline in glomerular filtration rate, leading to a vicious circle whereby one condition exacerbates the other (1)(2)(3)(4)(5)(6)(7). In addition, the greater concomitant use of diuretic therapy in patients with HF is also relevant here, given that these drugs can also worsen kidney function and that their action might be augmented by the diuresis caused by SGLT2 inhibitors.

METHODS
DAPA-CKD was a randomized, double-blind, placebocontrolled, multicenter trial, and the protocol and primary results are published (13). The study was registered at clinicaltrials.gov (NCT03036150). All participants provided written informed consent, and the trial was approved by an ethics committee at each site. Data supporting the findings described in this paper may be obtained in accordance with AstraZeneca's data sharing policy. PATIENTS. Adults with or without type 2 diabetes, an estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m 2 , and a urinary albumin-tocreatinine ratio (UACR) between 200 and 5,000 mg/g were eligible. Unless intolerant, participants were required to be prescribed an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in a stable dose for at least 4 weeks before screening.
The full inclusion and exclusion criteria are described elsewhere (13). Participants were randomized to dapagliflozin 10 mg once daily or placebo, with stratification by diagnosis of type 2 diabetes and UACR (#1,000 or >1,000 mg/g Nearly all patients with and without HF were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, as required by protocol. Dapagliflozin and Heart Failure in CKD -  Figure 1, Central Illustration). The reduction in risk was largely driven by HF hospitalization, which Values are n (%), mean AE SD, or median (interquartile range).

Effect of Dapagliflozin, Compared with Placebo, in DAPA-CKD
Overall and According to Baseline Heart Failure Status    following: $50% decline in eGFR (confirmed by a second serum creatinine measurement after at least 28 d), onset of end-stage kidney disease (defined as maintenance dialysis for more than 28 d, kidney transplantation, or eGFR <15 mL/min/1.73 m 2 confirmed by a second measurement after at least 28 d), or death from kidney or cardiovascular cause, according to history of heart failure at baseline. One prespecified secondary outcome is not shown and was a kidney composite outcome identical to the primary endpoint, excepting death from cardiovascular causes. CV ¼ cardiovascular.
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SAFETY OUTCOMES AND ADVERSE EVENTS.
Rates of all prespecified adverse events of interest were low overall and were generally similar in the HF and no HF subgroups ( Table 3). Adverse event rates were similar, overall, in patients assigned to dapagliflozin and placebo, irrespective of history of HF ( Table 3).

DISCUSSION
Among participants with CKD with and without type 2 diabetes, in DAPA-CKD, 11% had a history of HF.
Although the risk of HF hospitalization or cardiovascular death and all-cause death differed markedly according to history of HF, risk of progressive kidney disease did not. Dapagliflozin was equally efficacious Values are n (%). a The following criteria were confirmed by the investigator: symptoms of severe impairment in consciousness or behavior, need of external assistance, intervention to treat hypoglycemia, and prompt recovery from acute symptoms after the intervention. Definite or probable ketoacidosis occurred in 2 patients without heart failure randomly allocated to placebo; there were no cases of ketoacidosis in the dapagliflozin group.
AE ¼ adverse event; CV ¼ cardiovascular.    (17,18). The same consideration applies to the difference in all-cause mortality between the 2 trials. Another difference between the 2 trials was the reduction in death from any cause in DAPA-CKD, which was not observed in CREDENCE.
The reason for this difference is unknown. In DAPA-CKD, the effect of dapagliflozin on all-cause mortality was similar in patients with and without a history of HF, which was consistent with the findings of DAPA-HF (19).