Sodium-Glucose Cotransporter-2 Inhibitors and Uric Acid

A recent exploratory analysis of the 2-year EMPA-KIDNEY Trial reported that the use of empagliflozin (10 mg daily) in subjects with chronic kidney disease (CKD) with eGFR varying from 20 mL/min/1.73 m2 to 90 mL/min/1.73 m2 resulted in an approximately 30 μm (0.5 mg/dL) decrease in serum uric acid level from a baseline of 420 μm (7.2 mg/dL) but did not reduce episodes of gout (HR 0.87, 95% CI 0.79–1.02) nor was there a relationship between baseline serum uric acid with kidney outcomes [1]. One interpretation of this study is that lowering uric acid by empagliflozin may not be clinically relevant, especially in subjects with CKD. However, concluding this based on this study may be premature.Sodium-glucose cotransporter-2 (SGLT2) inhibitors have had spectacular success in subjects with CKD and have been found to help slow the progression of kidney disease, decrease admissions for heart failure, and reduce cardiovascular mortality [2, 3]. While initially there were reports suggesting that they might carry an increased risk for acute kidney injury, such as from osmotic nephrosis [4], subsequent studies suggested that while many subjects show an initial worsening in kidney function, it is commonly from volume depletion due to the glycosuria and osmotic diuresis. Indeed, epidemiological studies strongly suggest SGLT2 inhibitors may actually protect against AKI, even in subjects with CKD [3].The mechanisms by which SGLT2 inhibitors provide kidney protection are not fully understood. The main action of SGLT2 inhibitors would be to reduce the uptake of glucose and sodium into the S1 and S2 segments of the proximal tubule, which in turn results in glycosuria and osmotic diuresis. This diuretic-like action not only reduces blood pressure slightly but also may help control the expansion of the extracellular fluid, which could account for some of the benefits in reducing flares of heart failure and admissions. In turn, it may also result in enhanced sodium delivery to the macula densa, resulting in enhanced tubule-glomerular feedback that might lead to afferent arteriolar vasoconstriction that may reduce glomerular hydrostatic pressure that is often high in subjects with reduced nephron number. However, one of the most striking protective mechanisms appears to be an alteration in metabolism in the kidney tissues, in which there is a shift from glycolysis to oxidative metabolism, with a reduction in local oxidative stress, attenuation of mTOR activation, stimulation of AMP-activated protein kinase, a stimulation of sirtuins, and an inhibition of the pentose phosphate pathway (that generates NADPH oxidase and uric acid) [5‒7]. Packer has suggested that physiology is similar to switching into starvation mode despite nutrient surplus [5‒7] (Fig. 1).One additional consequence of SGLT2 inhibition is a decrease in serum uric acid. One mechanism is from the glycosuria, as this is known to induce uricosuria, likely from effects on urate transporters, such as by downregulating URAT1 (which reabsorbs uric acid) and upregulating ABCG2 (which secretes uric acid) (reviewed in [6]). In addition, by downregulating the pentose phosphate pathway, SGLT2 inhibitors also inhibit uric acid synthesis [6]. The net effect is that SGLT2 inhibitors reduce serum uric acid by 30 μm–60 μm (0.5 mg/dL–1 mg/dL) (Fig. 1).While this represents a relatively small reduction in serum uric acid, one must remember that gout is common in CKD and that treatment is often suboptimal [8]. Indeed, there are now several clinical trials in subjects without CKD that have reported a significant decrease in gout flares in subjects receiving SGLT2 inhibitors, including in subjects with diabetes or heart failure [9‒11] with an overall effect (based on a meta-analysis) of about 45 percent [12]. Likewise, while the induction of uricosuria might be expected to lead to an increase in uric acid kidney stones, the SGLT2 inhibitors markedly increase urinary citrate, an effect perhaps mediated by the activation of ATP citrate lyase [13, 14], and are associated with a reduced risk for both calcium- and uric acid-containing kidney stones in nondiabetic subjects with a history of kidney stones [15] (Fig. 1). These studies suggest that SGLT2 inhibitors might be an ancillary treatment for gout and kidney stones, and while the benefit is likely to be dampened in subjects with CKD, it might still add benefit.Another aspect related to SGLT2 inhibitors and uric acid relates to the mechanism by which SGLT2 inhibitors are protective. Studies of diabetic animals have shown that glucose uptake into the proximal tubule can activate aldose reductase, the rate-limiting enzyme in the polyol pathway that converts glucose to sorbitol and then fructose [16]. The fructose produced can then be metabolized by fructokinase, which is present in the proximal tubule [17], that leads to a cascade of events that stimulate glycolysis and the pentose phosphate pathway, induce oxidative stress, and lead to the degradation of ATP to uric acid [18]. The aldose reductase-uric acid pathway activation may also have a role in reducing NAD+ and, thereby, the activity of sirtuins, with a potential role in CKD injury and progression [19, 20]. Knocking down fructokinase can improve kidney inflammation and tissue injury in diabetic mice [18]. SGLT2 inhibitors may replicate these effects by preventing excess glucose absorption (Fig. 2).In conclusion, it remains possible that the lowering of serum uric acid by SGLT2 inhibitors in subjects with CKD could confer benefit on gout and kidney outcomes. Indeed, the study conclusions of Mayne et al. [1], although interesting, are tentative due to the substantial missing baseline uric acid data (in 1,445 participants), the specific empagliflozin findings in certain subgroups (those with uric acid <380 µmol/L and females), and the previously reported relationship between uric acid reduction and improved outcomes in heart failure and CKD [21, 22].Richard J. Johnson has received honoraria from Horizon Pharma. Richard J. Johnson, Laura G. Sánchez-Lozada, and Miguel A. Lanaspa also have equity with Colorado Research Partners, LLC.Portions of the research described here were funded by the Science, Humanities, Technology, and Innovation Secretariat of the Mexican Government (Grant No. CF-2023-I-1083). The funder was not involved in the design, data collection, analysis, or reporting of these studies.R.J.J. wrote the first draft, and L.G.S.-L. created the figures. All authors critically reviewed and edited the manuscript, approved the final version, and contributed equally to this work.