Patients with chronic kidney disease (CKD) exhibit an elevated cardiovascular risk manifesting as coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. Although the incidence and prevalence of cardiovascular events is already significantly higher in patients with early CKD stages (CKD stages 1–3) compared with the general population, patients with advanced CKD stages (CKD stages 4–5) exhibit a markedly elevated risk. Cardiovascular rather than end-stage kidney disease (CKD stage 5) is the leading cause of death in this high-risk population. CKD causes a systemic, chronic proinflammatory state contributing to vascular and myocardial remodeling processes resulting in atherosclerotic lesions, vascular calcification, and vascular senescence as well as myocardial fibrosis and calcification of cardiac valves. In this respect, CKD mimics an accelerated aging of the cardiovascular system. This overview article summarizes the current understanding and clinical consequences of cardiovascular disease in CKD.

Background: Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events. Methods: Patients with Class II–IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes. Results: Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (hemoglobin A1c [HbA1c] 5.7–6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 [95% CI, 0.60–0.87] and 0.78 [95% CI, 0.64–0.97], respectively, P -interaction=0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome ( P -interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia. Conclusions: In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03057977.

Background: Many patients with heart failure and reduced ejection fraction (HFrEF) have chronic kidney disease that complicates pharmacological management and is associated with worse outcomes. We assessed the safety and efficacy of dapagliflozin in patients with HFrEF, according to baseline kidney function, in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure). We also examined the effect of dapagliflozin on kidney function after randomization. Methods: Patients who have HFrEF with or without type 2 diabetes and an estimated glomerular filtration rate (eGFR) ≥30 mL·min ^–1 ·1.73 m ^–2 were enrolled in DAPA-HF. We calculated the incidence of the primary outcome (cardiovascular death or worsening heart failure) according to eGFR category at baseline (<60 and ≥60 mL·min ^–1 ·1.73 m ^–2 ) and used eGFR at baseline as a continuous measure, as well. Secondary cardiovascular outcomes and a prespecified composite renal outcome (≥50% sustained decline eGFR, end-stage renal disease, or renal death) were also examined, along with a decline in eGFR over time. Results: Of 4742 patients with a baseline eGFR, 1926 (41%) had eGFR <60 mL·min ^–1 ·1.73 m ^–2 . The effect of dapagliflozin on the primary and secondary outcomes did not differ by eGFR category or examining eGFR as a continuous measurement. The hazard ratio (95% CI) for the primary end point in patients with chronic kidney disease was 0.71 (0.59–0.86) versus 0.77 (0.64–0.93) in those with an eGFR ≥60 mL·min ^–1 ·1.73 m ^–2 (interaction P =0.54). The composite renal outcome was not reduced by dapagliflozin (hazard ratio=0.71 [95% CI, 0.44–1.16]; P =0.17) but the rate of decline in eGFR between day 14 and 720 was less with dapagliflozin, –1.09 (–1.40 to –0.77) versus placebo –2.85 (–3.17 to –2.53) mL·min ^–1 ·1.73 m ^–2 per year ( P <0.001). This was observed in those with and without type 2 diabetes ( P for interaction=0.92). Conclusions: Baseline kidney function did not modify the benefits of dapagliflozin on morbidity and mortality in HFrEF, and dapagliflozin slowed the rate of decline in eGFR, including in patients without diabetes. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03036124.