Lower serum uric acid and hyperuricemia events with SGLT2i in HFrEF
Uric acid and sodium-glucose cotransporter-2 inhibition with empagliflozin in heart failure with reduced ejection fraction: the EMPEROR-reduced trial
Introduction and methods
Hyperuricemia is common in patients with HF and is related to advanced disease severity, higher concentrations of natriuretic peptides, higher ventricular filling pressure, and lower cardiac output [1,2]. In addition, gout is a common comorbidity in patients with HF that accounts for an increased mortality and a higher risk of hospitalization for HF [3-5]. Consequently, serum uric acid concentration is an independent risk factor for HF in various prediction models [4,6,7]. SGLT2 inhibitors, such as empagliflozin, decrease serum uric acid concentration , but clinical relevance of this effect in patients with HF is unclear [9,10].
Aim of the study
This secondary analysis of the EMPEROR-Reduced trial examined the effect of empagliflozin on serum uric acid concentration and how this effect is related to hospitalizations, mortality, and renal function in patients with HFrEF. The effect of empagliflozin on clinical events of hyperuricemia was also assessed.
The EMPEROR-Reduced trial is an international, multicenter, double-blind, placebo-controlled phase 3 study in which patients with chronic heart failure (NYHA class II-IV) with reduced ejection fraction (EF ≤40%) were randomized to empagliflozin 10 mg daily or placebo in addition to their usual treatment . In this analysis, 3676 patients with a baseline serum acid measurement were included. Serum uric acid concentration was determined in a central laboratory at baseline, after 4 and 12 weeks, and every 6 months for the duration of treatment. Hyperuricemia was defined as a serum uric acid concentration >5.7 mg/dL (for women) or >7.0 mg/dL (for men). In the analyses, patients were divided in serum uric acid tertiles.
The primary outcome was a composite of cardiovascular mortality or hospitalization for HF, analyzed as time to first event. Secondary outcome measures included hospitalizations for HF (first and subsequent events), cardiovascular mortality, all-cause mortality, time to first hospitalization for HF, and a composite renal outcome measure. Clinical events of hyperuricemia, defined as investigator-reported episodes of acute gout, gouty arthritis or de-novo initiation of serum uric acid-lowering therapy, were aggregated into one outcome measure.
- Hyperuricemia occurred in 53% of patients and was associated with advanced disease severity, as reflected by NYHA class, risk of hospitalization, NT-proBNP concentration and LVEF.
Uric acid and clinical outcomes
- In the placebo group, patients with a serum uric acid concentration in the highest tertile (mean: 9.38 mg/dL ± 1.49) had an increased cardiovascular mortality or risk of hospitalization for HF (HR: 1.64; 95%CI: 1.28-2.10), cardiovascular mortality (HR: 1.98; 95%CI: 1.35-2.91) and all-cause mortality (HR: 1.80; 95%CI: 1.29-2.49), compared with patients with a serum uric acid concentration in the lowest tertile (mean: 4,99 mg/dL ± 0,84).
Effect of empagliflozin on uric acid and hyperuricemia
- After 4 weeks of treatment, serum uric acid concentration was lower in patients treated with empagliflozin than in patients receiving placebo (mean difference: -1.11 ± 0.03 vs. 0.01 ± 0.03 mg/dL; P <0.001); this difference persisted throughout the follow-up period.
- Treatment with empagliflozin reduced the number of clinical events of hyperuricemia by 32% (HR: 0.68; 95%CI: 0.52-0.89; P=0.004).
Benefit of empagliflozin in relation to serum uric acid levels
- Patients treated with empagliflozin had a reduced cardiovascular mortality or risk of hospitalization for HF (HR: 0.75; 95%CI: 0.65-0.86); this effect was independent of serum uric acid concentration at baseline and after 4 weeks of treatment.
- There was a significant interaction between the uric acid concentration at baseline and the therapeutic effect of empagliflozin for both cardiovascular mortality (P=0.005) and all-cause mortality (P=0.011).
Hyperuricemia is common in patients with HFrEF and is an independent predictor of disease severity and mortality. In addition, treatment with empagliflozin results in a rapid and sustained reduction in serum uric acid concentration and in fewer clinical events of hyperuricemia. The beneficial effect of empagliflozin on the primary outcome measure is independent of serum uric acid concentration.