Title: URIC ACID LEVELS PREDICT CARDIORENAL OUTCOMES AND CARDIOVASCULAR DEATH IN PATIENTS WITH TYPE 2 DIABETES: A SUB-ANALYSIS OF EMPA-REG OUTCOME
Abstract: Although plasma uric acid (UA) has been proposed as a biomarker of cardiovascular (CV) risk, there are limited data from large prospective studies to evaluate this rigorously. Furthermore, it is unknown if UA levels might modulate the effectiveness of CV risk reduction therapies. In the EMPA-REG OUTCOME trial, a total of 7020 patients with type 2 diabetes (T2D) and established CV disease were randomized to empagliflozin 10 mg, 25 mg, or placebo with a median follow-up of 3.1 years. In a post-hoc analysis of 7017 patients with available UA levels, we explored the association of tertiles of pre-randomization UA ( < 5.20, 5.20 to < 6.51, and ≥6.51 mg/dl) with CV death, hospitalization for heart failure (HHF), the composite of CV death/HHF, total mortality, and incident/worsening nephropathy by Cox regression, adjusting for baseline risk factors. In the overall population, the median baseline plasma UA concentration was 5.80 mg/dl (IQR: 4.81–6.89 mg/dl). Baseline characteristics were mostly balanced among tertiles, although the highest tertile had more men (77.8 vs 63.5% in the first tertile), more prevalent history of HF (14.4 vs 8.1%), and diuretic use (58.9 vs 30.6%). In the placebo group, for patients in the highest vs lowest UA tertile, the multivariable adjusted HRs for HHF, CV death, composite of CV death/HHF, and new/worsening nephropathy were 1.73 (95% CI 0.97–3.10; p=0.0638), 1.59 (0.99–2.54; p=0.0534), 1.51 (1.02–2.23; p=0.0396), and 1.77 (1.33–2.34; p < 0.0001), respectively. In univariable analysis, higher UA levels were significantly associated with increased all-cause mortality (HR 1.60; 1.11–2.29; p=0.0112), but this association was no longer statistically significant after multivariable adjustment (HR 1.36; 0.91–2.03; p=0.1302). When baseline UA was evaluated as a continuous variable, CV death/HHF (HR 1.17; 1.08–1.28; p=0.0003) and nephropathy (HR 1.18; 1.11–1.26; p < 0.0001) remained significant. Empagliflozin improved cardiorenal outcomes consistently across the three UA tertiles with HRs of 0.60 (0.41–0.88), 0.53 (0.38–0.76), and 0.78 (0.60–1.02) for CV death/HHF (interaction P=0.1937), and 0.72 (0.55–0.93), 0.57 (0.45–0.72), and 0.59 (0.49–0.73) for the renal outcome (interaction P=0.4169). However, given the higher baseline risk, the absolute risk reductions for cardiorenal outcomes and CV mortality with empagliflozin is larger in patients with higher vs lower UA. In this large, multinational, randomized controlled trial, we demonstrate that plasma UA appears to be an independent predictor of HHF, CV death, and new/worsening nephropathy in patients with T2D and CV disease. Empagliflozin consistently reduces adverse CV and renal outcomes across the spectrum of baseline UA.