Graphical Abstract: Cardiovascular disease and gout
High serum uric acid (SUA) or urate levels have long been associated with adverse cardiovascular outcomes including congestive heart failure. The question has always been whether this association is causal or simply due to epiphenomena such as cardiovascular disease being causally associated with renal dysfunction or other metabolic abnormalities and thus higher urate levels.
Lowering SUA concentrations with medication has been associated with possible cardiovascular benefit in observational studies, including in patients with heart failure.[3,4] Interventional studies of urate-lowering therapies have shown improvements in angina symptoms, left ventricular mass regression, and endothelial function with high dose allopurinol therapy.[5–7] Gliflozins are known to improve outcomes in a number of cardiovascular conditions and conditions associated with increased cardiovascular risk, including type 2 diabetes mellitus, heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction, and effects in renal disease look promising, with further data on empagliflozin regarding renal disease progression expected later this year.
In the current issue of the European Heart Journal, Doehner et al. present a post-hoc analysis of the relationship between SUA levels and outcomes in patients with heart failure with reduced ejection fraction randomized to the sodium–glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin 10 mg vs. placebo in the EMPEROR-Reduced trial. In the placebo-treated group, as might be expected, clinical heart failure outcomes increased along with higher SUA levels, as did clinically relevant hyperuricaemic events including acute gout, gouty arthritis, or initiation of anti-gout therapy; these findings are consistent with those of previous studies.
SUA was reduced by an average of 1.12 mg/dL (66.2 μmol/L) with empagliflozin vs. placebo in this study, a relatively modest reduction compared with that achievable with xanthine oxidase inhibitors such as allopurinol. However, the modest reduction in urate in EMPEROR-Reduced was associated with a significant 32% reduction in adverse gout outcomes. This is important because hyperuricaemia, and also clinical gout, often co-exist with heart failure, and this causes difficulties with therapeutic choices in the management of patients, particularly with diuretics that can worsen hyperuricaemia. Empagliflozin treatment in EMPEROR-Reduced was also associated with an impressive 30% reduction in hospitalizations for heart failure, which was the main driver of the 25% reduction in the primary outcome of first hospitalization for heart failure or cardiovascular death. However, interestingly, this finding was independent of the decrease in SUA observed with empagliflozin therapy.
Further slicing of the data salami showed that the one-third of subjects with the highest SUA levels at baseline (taking into account the different ranges in males and females) appeared to have reduced cardiovascular and all-cause mortality when treated with empagliflozin. From this, a hypothesis could be generated that patients with higher baseline SUA might have more favourable outcomes from empagliflozin therapy.
A similar reduction in SUA [0.84 mg/dL, 95% confidence interval (CI) −0.93 to −0.74] was seen with another SGLT-2 inhibitor, dapagliflozin, compared with placebo in the DAPA-HF trial. In DAPA-HF, dapagliflozin improved outcomes (the composite of cardiovascular death or worsening heart failure, its components, and all-cause mortality) irrespective of the baseline SUA level.
In the Febuxostat vs. Allopurinol Streamlined Trial (FAST), the xanthine oxidase inhibitor febuxostat reduced SUA to a much greater extent than allopurinol, and the secondary endpoint of all-cause mortality was lower in the febuxostat-treated subjects. So perhaps a large fall in SUA may have other benefits, lending some consistency to the signal observed here.
As with all post-hoc analyses, a judgement call must be made about how much weight to attach to these exploratory findings, but it does not, at present, seem unreasonable to consider that a high SUA in patients with heart failure might strengthen the case for the use of empagliflozin.
Whether lowering SUA with medication is in itself beneficial must await evidence from large prospective cardiovascular outcome trials, such as the Allopurinol and cardiovascular outcomes in patients with ischaemic heart disease (ALL-HEART) study. This is a large, randomized trial of allopurinol therapy vs. usual care in people with ischaemic heart disease that will report soon and will provide more definitive evidence on the potential role of urate-lowering therapy in patients with cardiovascular disease who are free from clinical gout.
The place of empagliflozin or dapagliflozin therapy in patients already treated for gout but without heart failure could also be explored further. Perhaps future studies should investigate whether these SGLT-2 inhibitors improve outcomes in patients with treated gout and high cardiovascular risk. Added to best gout prophylaxis therapy, SGLT-2 inhibitors may improve gout outcomes in the most common inflammatory arthritis in men. Might they also improve cardiovascular outcomes?
Once the investigators have been given the opportunity to publish further analyses of the FAST and ALLHEART studies, the investigators/steering committees will be happy to consider applications for access to de-identified data. Applications should be made to the corresponding authors.
Eur Heart J. 2022;43(36):3447-3449. © 2022 Oxford University Press
Copyright 2007 European Society of Cardiology. Published by Oxford University Press. All rights reserved.