How does the level of uric acid affect the incidence of cardiorenal events in patients with T2DM and CVD?
One of the post hoc analyses of the well-known EMPA-REG OUTCOME study provided data on the relationship between uric acid levels and the incidence of cardiorenal events in type 2 diabetics with existing cardiovascular disease.
Introduction
The authors based their study on the knowledge that uric acid acts as an antioxidant, especially in the extracellular environment (estimated to provide about half of the total antioxidant capacity of biological fluids in humans). However, in the cytoplasm or the acidic/hydrophobic environment of atherosclerotic plaques, it is converted into a pro-oxidative agent that promotes oxidative stress and can accelerate the development of cardiovascular disease (CVD).
Furthermore, they relied on the conclusions of several epidemiological studies, which suggested that there is a connection between elevated serum uric acid levels and an increased risk of cardiovascular events, metabolic syndrome, diabetes mellitus (DM), and chronic kidney disease (CKD). Until now, it was unclear whether uric acid concentration in patients with established CVD had prognostic significance. And since it was found that treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors, i.e., antidiabetic drugs with cardiovascular benefits, can reduce uric acid levels, it seemed interesting to explore the relationship between this parameter and clinical outcomes when administering SGLT2 inhibitors or placebo.
Data Evaluated
Post hoc, participants were divided into tertiles based on uric acid levels measured before randomization (< 309.30; 309.30 to < 387.21; ≥ 387.21 μmol/l), and differences in outcomes between patients in the highest and lowest tertiles were assessed. Factors such as age, gender, body mass index (BMI), baseline glycosylated hemoglobin (HbA1c) level, baseline estimated glomerular filtration rate (eGFR), use of diuretics, gout medication, presence of heart failure (HF), and uric acid concentration were considered.
Evaluated parameters included CV mortality, hospitalization for heart failure (HHF), a composite parameter involving HHF and CV death, overall mortality, major adverse cardiovascular events (MACE), and the onset or worsening of nephropathy. Additionally, the therapeutic effects of empagliflozin (compared to placebo) were analyzed according to the tertile of baseline uric acid levels.
Key Findings
The median baseline plasma uric acid concentration in the cohort (n = 7017) was 344.98 μmol/l (286.10–409.82). Baseline characteristics of patients were generally balanced across tertiles of this parameter. Empagliflozin reduced uricemia compared to placebo.
The analysis confirmed the relationship between uric acid levels and cardiorenal events. In the placebo group, patients in the highest tertile compared to the lowest tertile had a significantly higher incidence of hospitalizations for heart failure or CV mortality (composite parameter; hazard ratio [HR] 1.51; 95% confidence interval [CI] 1.02–2.23; p = 0.0396) and significantly higher onset or worsening of nephropathy (HR 1.77; 95% CI 1.33–2.34; p < 0.0001).
When baseline uric acid levels were evaluated as a continuous variable, a statistically significant association with hospitalization for heart failure, CV mortality, and onset or worsening of nephropathy was found in patients with placebo (HR 1.17; 95% CI 1.09–1.25; p < 0.0001). Empagliflozin reduced the risk of all evaluated cardiorenal events across tertiles of baseline uric acid levels.
Conclusion
The cited post hoc analysis of the EMPA-REG OUTCOME study shows that baseline uric acid levels are an independent predictor of cardiorenal events in patients with T2DM and CVD. Empagliflozin reduced the risk of cardiorenal events regardless of baseline uric acid concentration. Given that the study did not have sufficient power to demonstrate statistical significance in the difference between some cardiorenal parameters based on uric acid levels, the authors suggest conducting further clinical research.
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Source: Verma S., Ji Q., Bhatt D. L. et al. Association between uric acid levels and cardio‐renal outcomes and death in patients with type 2 diabetes: a subanalysis of EMPA‐REG OUTCOME. Diabetes Obes Metab 2020; 22 (7): 1207–1214, doi: 10.1111/dom.13991.
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