Hyperuricemia is defined as an elevated serum uric acid (UA) level, typically exceeding 357 μmol/L in women and 416 μmol/L in men (1). Its prevalence varies widely worldwide, ranging from 2.6% to 36%, with a reported rate of 8.4% in Saudi Arabia (2–4). This condition arises from either increased UA synthesis or impaired excretion, ultimately leading to deposition of urate crystals in joints (gout) and kidneys (nephrolithiasis) (5, 6).

Hyperuricemia presents along a clinical spectrum, ranging from asymptomatic elevation of serum UA to manifestations such as gout and nephrolithiasis (7, 8). Importantly, elevated serum UA is independently associated with an increased risk of cardiovascular morbidity and mortality, even in the absence of gout (8–10). Non-pharmacologic interventions play a critical role in managing asymptomatic hyperuricemia, focusing on dietary and lifestyle modifications (11, 12). For symptomatic cases, xanthine oxidase inhibitors remain the first-line pharmacological treatment (13). However, the effectiveness of current urate-lowering therapies is often limited by dosing challenges, adverse effects, and patient nonadherence (14). This underscores the need for exploring alternative therapies that are both safer and more effective.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i), recommended for patients with type 2 diabetes (T2D), heart failure (HF), or chronic kidney disease (CKD), have been shown to reduce serum uric acid (UA) levels through enhanced urinary urate excretion and modulation of metabolic pathways, potentially lowering the risk of incident gout (15–17). However, the magnitude and clinical relevance of this effect, particularly in patients with cardiovascular–kidney–metabolic syndrome, remain uncertain. Although mechanistic and clinical studies suggest that SGLT2i may lower UA through pathways distinct from conventional urate-lowering therapies, findings have not been consistently replicated across diverse populations or real-world settings. Moreover, while large, randomized trials have primarily focused on cardiovascular and renal outcomes, data on the impact of SGLT2i on UA levels in routine clinical practice—especially among patients with multiple comorbidities—remain limited (10, 16). Thus, robust, population-based evidence is needed to clarify the role of SGLT2i in managing hyperuricemia.

Despite advances in hyperuricemia management and a deeper understanding of its relationship with cardiovascular and renal comorbidities, data remain limited regarding the practical effects of SGLT2i on UA levels in real-world patient populations. Observational studies and clinical trials have hinted at the potential of SGLT2i to reduce hyperuricemia through mechanisms distinct from traditional urate-lowering therapies, yet these findings have not been consistently replicated in diverse healthcare settings or in patients with multiple comorbidities such as diabetes, HF, and CKD. Furthermore, while randomized trials have typically focused on cardiovascular and renal endpoints, the impact of SGLT2i on UA levels in routine clinical practice is not fully established, underscoring the need for robust, population-based data in this area. To address this knowledge gap, this study conducted a comprehensive multicenter retrospective cohort utilizing electronic medical records from diverse healthcare institutions across the Kingdom of Saudi Arabia. The primary aim of this study was to evaluate the effect of SGLT2i on serum UA levels in patients with diabetes, heart failure and chronic kidney diseases in different healthcare settings.

This study examines the effect of SGLT2i on UA levels in a real-world, multicenter cohort in Saudi Arabia. Conducted across four major medical centers, this analysis demonstrated that SGLT2i therapy reduced UA levels regardless of the indication for use. Although patients with elevated baseline UA experienced the most pronounced reductions, UA-lowering effects were consistent across multiple subgroups. Additionally, the presence of both DM and HF emerged as an independent predictor of a favorable UA response. Given the high prevalence of hyperuricemia in patients with DM, HF, and CKD, - and its known association with worse outcomes - these findings support the use of SGLT2i in these patient populations (22–24).

In this cohort, about 35% of patients with DM also had CKD, aligning with previous findings in the Saudi population (25). Similarly, approximately 25% of patients with DM in this study also had HF, reflecting the well-documented bidirectional relationship between these conditions, where diabetes can contribute to structural and functional changes in the heart, and HF can exacerbate metabolic abnormalities, further increasing diabetes risk (26). For patients with combined diabetes, HF, and CKD, the prevalence was estimated at around 15–20% in this cohort, consistent with the concept of the “cardiorenal-metabolic syndrome,” where these interconnected conditions significantly worsen outcomes due to shared pathophysiological mechanisms (27). Additionally, among patients with HF, CKD prevalence in this study was 23%, which is within the reported range in previous epidemiological studies (28).

In this study, SGLT2i treatment led to a 4.5% reduction in UA levels over a 10-month follow-up. While this reduction is modest, it aligns with previous post hoc analyses of randomized clinical trials that reported approximately 13% reduction in UA levels with canagliflozin compared to placebo in type 2 DM patients (29). Similarly, empagliflozin lowered UA levels in the EMPA-REG OUTCOME study (30). A recent meta-analysis of patients with and without type 2 diabetes (n ≈ 464,009) showed that SGLT2i reduce the risk of clinically relevant hyperuricemic events by 33% (HR, 0.67; 95% CI, 0.59–0.77), reinforcing the UA-lowering effects beyond diabetic populations (31). Real-world studies have also confirmed these effects, and empagliflozin has demonstrated UA-lowering benefits in HF patients regardless of ejection fraction phenotype (24, 29).

Although this study did not assess gout incidence directly, prior analyses of trials such as EMPA-REG OUTCOME, EMPEROR-Reduced, CANVAS, and EMPEROR-Preserved—as well as real-world data—have shown that SGLT2i use reduces gout incidence (24, 32–34). Notably, SGLT2i have also been associated with lower risk of recurrent gout flares compared to GLP-1 receptor agonists and DPP-4 inhibitors in type 2 DM patients (35).

The UA-lowering effects of SGLT2i likely extend beyond their uricosuric action, involving reductions in UA synthesis via downregulation of pentose phosphate pathway enzymes (17, 36). Although some studies suggest that urate-lowering therapies like allopurinol can reduce cardiovascular events in hypertension, this effect has not consistently translated to HF populations (37, 38). Thus, the UA-lowering properties of SGLT2i may contribute to—but not solely account for—their cardiovascular benefits.

It is noteworthy that most patients with DM in this cohort initiated SGLT2i approximately 5 years after diagnosis. Earlier initiation may help prevent complications such as CKD, highlighting the importance of timely adherence to current guidelines (15, 39, 40). Given the high prevalence and adverse outcomes of hyperuricemia in patients with DM, HF, and CKD, the UA-lowering effect of SGLT2i may represent an additional pleiotropic benefit in these populations. While this study did not assess gout incidence or flare reduction, future prospective studies are warranted to determine whether these metabolic effects translate into improved gout-related outcomes (15, 39).

This study’s real-world, multicenter design across four major healthcare centers in Saudi Arabia enhances generalizability. The main limitation is the absence of a comparator group. As SGLT2i are now guideline-recommended for patients with diabetes, heart failure, and chronic kidney disease, an untreated control group was not feasible retrospectively. Instead, a pre–post design was used, allowing patients to serve as their own controls and reducing inter-individual variability. While this does not replace a formal comparator, the findings remain consistent with prior randomized trials. Another limitation is the lack of detailed data on diet and concomitant medications (e.g., diuretics), although we excluded patients with recent changes in urate-lowering therapy to minimize confounding. Moreover, the high exclusion rate, largely reflecting patients lost to follow-up. These exclusions were necessary to preserve data quality and ensure valid assessment of uric acid changes, but they may still introduce selection bias and affect generalizability.

SGLT2i were associated with a modest but consistent reduction in uric acid, most pronounced in patients with elevated baseline levels and those with both diabetes and heart failure. These findings suggest potential metabolic benefits and should be regarded as hypothesis-generating, warranting further prospective studies to confirm and clarify their implications for long-term patient management.