Dual benefits of sodium-glucose cotransporter 2 inhibitors in metabolic diseases: Diabetes control and gout management

Abstract

The study by Lin et al delves into the clinical impact of dapagliflozin, a representative sodium-glucose cotransporter 2 (SGLT2) inhibitor, on chronic heart failure complicated by hyperuricemia. This investigation highlights dapagliflozin’s efficacy in lowering serum uric acid levels, enhancing cardiac function, and reducing cardiovascular events. This work not only provides a comprehensive analysis of dapagliflozin’s sustained benefits in these patients but also introduces novel insights for managing chronic heart failure exacerbated by elevated uric acid. Furthermore, this review examines the potential role of SGLT2 inhibitor in the context of gout, evaluating its mechanisms and clinical application prospects in the management of hyperuricemia, thereby further enriching the medical community’s understanding of SGLT2 inhibitor.

Key Words: Sodium-glucose cotransporter 2 inhibitors; Hyperuricemia; Gout; Uric acid reduction; Chronic heart failure

Core Tip: This article explores the dual benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in managing hyperuricemia and gout, particularly in patients with type 2 diabetes and cardiovascular complications. By highlighting the ability of SGLT2 inhibitors to lower uric acid levels and reduce the risk of gout flare-ups, this article provides insights into their potential as a comprehensive treatment option. The review also emphasizes the importance of understanding the underlying mechanisms, offering a new perspective on optimizing the clinical application of SGLT2 inhibitors in high-risk patients.

TO THE EDITOR

We recently read the article by Lin et al[1] which was published recently. In this study, the researchers conducted a 24-month randomized double-blind trial, that included 200 patients with chronic heart failure and hyperuricemia. The results demonstrated that dapagliflozin significantly reduced uric acid levels, enhanced cardiac function and quality of life, and decreased the risk of cardiovascular mortality and hospitalization, suggesting that it may be an effective treatment option for patients with chronic heart failure complicated by hyperuricemia. The study’s experimental design was robust, offering a valuable reference for the application of dapagliflozin in such patients[1]. Notably, this research highlights therapeutic strategies beyond conventional urate-lowering drugs, which is particularly pertinent for patients with hyperuricemia or gout, especially when comorbid with other conditions[1]. However, as the article highlights, the study lacks sufficient discussion on issues such as varying uric acid levels and the management of gout attacks. In this article, we provide a fresh perspective by integrating recent findings to underscore the dual benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in managing diabetes and gout. This review delves into mechanistic pathways, including the stabilization of serum uric acid levels and modulation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, offering novel insights into their anti-inflammatory effects. Furthermore, it emphasizes practical implications for high-risk populations, such as patients with metabolic and cardiovascular comorbidities, offering a clinical framework for optimizing SGLT2 inhibitor use in these populations. A comprehensive understanding of their clinical application and mechanisms of action will further aid in optimizing their use in practice.

APPLICATION AND MECHANISMS OF SGLT2 INHIBITORS IN THE MANAGEMENT OF HYPERURICEMIA AND GOUT

Diabetes is a common complication associated with hyperuricemia, which, beyond causing gout, has been recognized as an independent risk factor for various diseases[2]. Previous studies have indicated that hyperuricemia frequently occurs in patients with type 2 diabetes and is an independent risk factor for cardiovascular disease and chronic kidney disease[1-2]. SGLT2 inhibitors, in addition to lowering blood glucose, have shown efficacy in reducing body weight and blood pressure. A clinical study involving 14520 patients revealed that canagliflozin not only significantly reduced the risk of cardiovascular events and kidney disease across different body mass index subgroups, but also contributed to weight loss and blood pressure reductions[3]. These findings suggest that SGLT2 inhibitors are especially suitable for patients with gout and cardiovascular complications.

In addition to lowering blood uric acid, various SGLT2 inhibitors have been found to reduce the risk of gout attacks[4]. A post hoc analysis involving 10142 patients with type 2 diabetes, followed over 3.6 years, evaluated the effectiveness of canagliflozin in reducing serum uric acid concentrations and the risk of gout attacks[5]. The results demonstrated that participants treated with canagliflozin had mean serum uric acid concentrations 23.3 μmol/L lower than those in the placebo group, and the rate of colchicine initiation during follow-up was lower in the dapagliflozin group than in the control group. This indicates that SGLT2 inhibitors, exemplified by dapagliflozin, can effectively reduce the risk of gout attacks.

In addition, recent evidence highlights that dapagliflozin exerts unique anti-inflammatory effects beyond uric acid reduction. Studies have shown that dapagliflozin increases circulating hydroxybutyrate levels, which modulate NLRP3 inflammasome activation, a key inflammatory pathway in gout. This dual mechanism “stabilizing serum uric acid and reducing inflammation” makes dapagliflozin particularly beneficial for high-risk patients with metabolic and inflammatory comorbidities[6-8]. Furthermore, evidence suggests that reducing gout flares through SGLT2 inhibitors may also improve long-term outcomes. In a large cohort study, SGLT2 inhibitor treatment in patients with type 2 diabetes and gout significantly reduced the frequency of gout flares and was associated with lower mortality compared to those not receiving these inhibitors[7].

Acute gout attacks are triggered by fluctuations in blood uric acid levels, so when selecting uric acid-lowering drugs, it is important to choose those with stable effects. Meta-analyses suggest that the uric acid-lowering effect of various SGLT2 inhibitors can be sustained for over 2 years, indicating a long-lasting and stable uric acid-lowering capacity[6,8]. It is currently believed that the mechanism by which SGLT2 inhibitors reduce the risk of gout is primarily related to the consistent lowering of uric acid. Additionally, SGLT2 inhibitors may mitigate the activation of NLRP3 in high-risk hyperuricemic patients by increasing circulating hydroxybutyrate levels, further suggesting that SGLT2 inhibitors can reduce inflammation and thereby lower the risk of gout attacks[8].

CONCLUSION

In addition to lowering blood uric acid, numerous SGLT2 inhibitors have been found to reduce the risk of gout attacks[4]. A post hoc analysis involving 10142 patients with type 2 diabetes, followed over 3.6 years, evaluated the effectiveness of canagliflozin in reducing serum uric acid concentrations and the risk of gout attacks[5]. The results demonstrated that participants treated with canagliflozin had mean serum uric acid concentrations 23.3 μmol/L lower than those in the placebo group, and the rate of colchicine initiation during follow-up remained lower among the dapagliflozin group than in the control group. This indicates that SGLT2 inhibitors, exemplified by dapagliflozin, can effectively reduce the risk of gout attacks. Acute gout attacks are triggered by fluctuations in blood uric acid levels, so when selecting uric acid-lowering drugs, it is important to choose those with stable effects. Meta-analyses suggest that the uric acid-lowering effect of certain SGLT2 inhibitors can be sustained for over 2 years, indicating a long-lasting and stable uric acid-lowering capacity[6]. It is currently believed that the mechanism by which SGLT2 inhibitors reduce the risk of gout is primarily related to the stable reduction of serum uric acid[6]. Additionally, SGLT2 inhibitors may also mitigate the activation of NLRP3 in high-risk hyperuricemic patients by increasing circulating hydroxybutyrate levels, further suggesting that SGLT2 inhibitors can reduce inflammation and thereby lower the risk of gout attacks[8]. Recent studies have further demonstrated that SGLT2 inhibitors not only lower uric acid and reduce gout flares but also improve cardiovascular outcomes and overall mortality, especially in patients with type 2 diabetes and gout[9,10].