Abstract
Objective
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which are hypoglycemic agents, have been shown to be cardioprotective through a variety of mechanisms, and the effect of lowering uric acid (UA) levels may be one of the mechanisms. In the present retrospective study, we investigated the changes in serum UA levels in patients with chronic kidney disease (CKD) treated with SGLT2 inhibitors.
Methods
We included 31 patients with CKD who were newly started on dapagliflozin for renal protection and evaluated trends in various parameters, including serum UA levels and UA excretion from urine.
Results
The patients’ median age was 71 years old, 20 patients were men, 7 patients had diabetes, and the median estimated glomerular filtration rate was 33.9 mL/min/1.73 m2 (CKD stage 3: 21 cases, stage 4: 10 cases). The differences in UA and fractional excretion of UA after three weeks and three months of prescription showed significantly decreased UA values and an increased fractional excretion of UA.
Conclusion
Our findings suggest that dapagliflozin can lower serum UA levels via increased UA excretion, even in patients with advanced CKD.
Keywords: dapagliflozin, uric acid, advanced CKD
Introduction
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are drugs that control blood glucose levels in patients with diabetes through increased urinary excretion of glucose. SGLT2 inhibitors have been reported to have not only glycemic effects but also cardioprotective (1-4) and renoprotective (5) effects that have not been identified with other diabetes drugs.
Hyperuricemia is common in patients with diabetes and chronic kidney disease (CKD) and may be a risk factor for hypertension (6,7) and CKD (8,9).
SGLT2 inhibitors have been reported to lower uric acid (UA) levels (10-12), but their effects in patients with CKD are unclear. In this study, we evaluated UA levels in patients with advanced CKD after the administration of an SGLT2 inhibitor.
Materials and Methods
This single-center observational study included individuals who visited the Department of Nephrology at Osaka Rosai Hospital as outpatients between September and December 2021. We enrolled patients (i) who were newly started on dapagliflozin for renal protection, (ii) who were ≥20 years old, and (iii) whose estimated glomerular filtration rate (eGFR) was 15-60 mL/min/1.73 m2. We excluded patients who had already received renal replacement therapy or had no urine samples analyzed at baseline. Patients were followed from the date of dapagliflozin administration to 12 weeks after administration. The dose of dapagliflozin (5 mg in 16 patients; 10 mg in 15 patients) was determined according to the clinical situation.
The baseline characteristics included age, sex, and primary CKD. Blood and urine samples for UA analyses were obtained before and 3 and 12 weeks after the prescription of dapagliflozin. Changes in the parameters were evaluated. In addition, we compared the values of body weight, blood urea nitrogen, serum creatinine, albumin, triglyceride, low-density lipoprotein cholesterol, bicarbonate, C-reactive protein, and urine biochemistry, including sodium, glucose, urea nitrogen, osmolality, protein excretion measured by spot urine, and beta-2-microglobulin. When we calculated the eGFR, a modified formula for the Japanese population was used, as follows (13): eGFR=194×serum creatinine level (mg/dL)-1.094×age-0.287 [×0.739 (for women)]. The value of each measurement is described as the median (interquartile range). Wilcoxon’s signed-rank test was used to compare parameters before and after prescription. Statistical significance was set at p<0.05. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University), a graphical user interface for R (R Foundation for Statistical Computing).
Results
Thirty-one patients were enrolled in this study, all of whom were outpatients. Table 1 shows the clinical characteristics of the study participants. Seven patients had diabetic kidney disease. The eGFR prior to the administration of dapagliflozin was 34 [27-44] mL/min/1.73 m2. The baseline UA level of the study participants was 6.3 [5.3-7.3] mg/dL. Ten patients had hyperuricemia (UA level >7.0 mg/dL). Before dapagliflozin was prescribed, the number of patients who were administered drug therapy for hyperuricemia was as follows: febuxostat, 17 patients; allopurinol, 1 patient; and benzbromarone, 1 patient. None of the patients were prescribed more than one UA-lowering drug. Prior to the administration of dapagliflozin, 5 patients were on diuretics, and 30 were on antihypertensive drugs. No changes were observed in these medications after the initiation of dapagliflozin.
Table 1.
Patients’ Baseline Characteristics.
| Value | ||
|---|---|---|
| Number of patients | 31 | |
| Age (years) (mean±standard deviation) | 67±15 | |
| Male (%) | 20 (65) | |
| Body weight (kg) [median, IQR] | 65.0 [53.8, 78.0] | |
| Body mass index (kg/m2) [median, IQR] | 23.9 [22.4, 27.7] | |
| Comorbidity (%) | ||
| Hypertension | 30 (97) | |
| Diabetes mellitus | 7 (23) | |
| Primary disease (%) | ||
| Chronic glomerular nephritis | 13 (42) | |
| Diabetic kidney disease | 7 (23) | |
| Others | 11 (35) | |
| Blood pressure (mmHg) [median, IQR] | ||
| Systolic | 130 [120, 135] | |
| Diastolic | 75 [65, 85] | |
| Chronic kidney disease stage (%) | ||
| Stage G3 | 21 (68) | |
| Stage G4 | 10 (32) | |
| Stage G5 | 0 (0) | |
| Hemoglobin (g/dL) [median, IQR] | 12.3 [11.5, 13.6] | |
| Blood urea nitrogen (mg/dL) [median, IQR] | 26 [19, 40] | |
| Creatinine (mg/dL) [median, IQR] | 1.55 [1.17, 1.91] | |
| eGFR (mL/min/1.71 m2) [median, IQR] | 34 [27, 44] | |
| Albumin (g/dL) [median, IQR] | 4.0 [3.9, 4.3] | |
| Uric acid (mg/dL) [median, IQR] | 6.3 [5.3, 7.3] | |
| Urine osmolality (mmHg/kg H2O) [median, IQR] | 457 [345, 568] | |
| Urinary protein (g/gCr) [median, IQR] | 0.95 [0.19, 1.79] | |
| Urinary beta-2-microglolin [median, IQR] | 220 [60, 818] |
IQR: interquartile range, eGFR: estimated glomerular filtration rate
Only age was normally distributed in the distribution study of each parameter using the Kolmogorov-Smirnov test.
The serum UA levels decreased after dapagliflozin administration (p<0.05) (Table 2). The body weight, serum albumin, and lipid profiles remained unchanged during the first three months of oral dapagliflozin therapy. The patients’ hemoglobin levels increased significantly. Furthermore, we analyzed changes in urinary parameters after the initiation of dapagliflozin. While serum UA levels decreased, the fractional excretion of UA increased significantly. A regression analysis using the change in the serum UA level as the objective variable and change in the UA excretion as the explanatory variable confirmed that an increase in UA excretion decreased serum UA levels (regression coefficient: -0.15). Figure shows the changes in the UA levels and UA excretion in patients with hyperuricemia (UA level >7.0 mg/dL). Despite the increase in urinary glucose levels after oral administration, there was no marked increase in urine osmolality or urinary sodium excretion. No adverse effects, such as loss of appetite, were observed throughout the study period.
Table 2.
Changes in Laboratory Parameters
| Before | 3 weeks | 12 weeks | ||||
|---|---|---|---|---|---|---|
| Body weight (kg) | 65.0 [53.8, 78.0] | 63.3 [52.5, 72.3] | 63.3 [52.4, 74.3] * | |||
| Blood pressure (mmHg) | ||||||
| Systolic | 130 [120, 135] | 132 [121, 135] | 130 [125, 135] | |||
| Diastolic | 75 [65, 85] | 75 [68, 82] | 80 [70, 83] | |||
| Hemoglobin (g/dL) | 12.3 [11.5, 13.6] | 12.8 [12.0, 13.9] * | 13.4 [12.1, 14.2] * | |||
| Mean corpuscular volume (fL) | 91.7 [90.1, 94.0] | 92.0 [90.5, 94.5] | 93.0 [90.6, 94.8] | |||
| LDL-cholesterol (mg/dL) | 92 [82, 109] | 100 [79, 122] | 99 [84, 123] | |||
| Triglyceride (mg/dL) | 145 [94, 174] | 144 [118, 174] | 142 [109, 166] | |||
| Blood urea nitrogen (mg/dL) | 26 [19, 40] | 27 [21, 35] | 28 [24, 34] | |||
| Creatinine (mg/dL) | 1.55 [1.17, 1.91] | 1.60 [1.25, 1.92] * | 1.66 [1.35, 2.10] * | |||
| eGFR (mL/min/1.71 m2) | 33.9 [26.9, 44.0] | 32.4 [24.4, 40.5] * | 31.2 [24.8, 35.7] * | |||
| Albumin (g/dL) | 4.0 [3.9, 4.3] | 4.1 [4.0, 4.3] | 4.1 [3.9, 4.3] | |||
| Uric acid (mg/dL) | 6.3 [5.3, 7.3] | 5.4 [4.9, 5.9] * | 5.8 [5.3, 6.6] * | |||
| Urine osmolality (mmHg/kg H2O) | 457 [345, 568] | 483 [373, 545] | 486 [388, 600] | |||
| Urinary glucose (mg/gCr) | 0.04 [0.04, 0.07] | 14 [8, 19] | 13 [10, 22] | |||
| Urinary protein (g/gCr) | 0.95 [0.19, 1.79] | 0.44 [0.18, 1.35] | 0.62 [0.28, 1.61] | |||
| Fractional excretion of sodium (%) | 1.01 [0.62, 1.71] | 1.12 [0.83, 1.75] | 1.27 [0.83, 2.07] | |||
| Fractional excretion of urea nitrogen (%) | 35.9 [29.5, 41.1] | 36.1 [28.3, 42.5] | 38.3 [30.7, 42.4] | |||
| Fractional excretion of uric acid (%) | 5.87 [4.03, 8.27] | 7.94 [5.10, 10.88] * | 7.49 [5.83, 9.45] * | |||
| Urinary beta-2-microglobrin (%) | 220 [60, 818] | 380 [73, 608] | 490 [130, 750] |
Continuous variables were described as median with interquartile range
LDL: low density lipoprotein, eGFR: estimated glomerular filtration rate
* p<0.05
Figure.
Comparisons of the degree of change in serum uric acid levels and fractional excretion of uric acid after the administration of dapagliflozin in patients with hyperuricemia. The graph shows the amount by which the actual serum uric acid levels and fractional excretion of uric acid changed after treatment. Within each box, horizontal lines denote median values; boxes extend from the 25th percentile to the 75th percentile of each group’s distribution of values; vertical extending lines denote adjacent values.
Discussion
This study was conducted on patients with advanced CKD. Management of hyperuricemia is often difficult in these patients. In the present study, we demonstrated that dapagliflozin lowered serum UA levels by promoting urinary UA excretion, even in patients with severe renal insufficiency. This suggests that dehydration is unlikely to occur because of osmotic diuresis after dapagliflozin administration. These data suggest that changes in UA levels were not related to the fluid or nutritional status. There was a decrease in the renal function after administering the SGLT2 inhibitor, but this was assumed to reflect an “initial dip” possible due to decrease in intraglomerular pressure following the drug administration (5). Furthermore, our data showed an elevation in hemoglobin levels. This change is assumed to be due to the recovery of the tubulointerstitial function (14) and not due to dehydration because of the lack of findings suggestive of dehydration.
Several reports indicate that SGLT2 inhibitors reduce serum UA levels (10-12). Regarding the underlying mechanism, glucose transporter 9 (GLUT9) isoform 2, a transporter that absorbs glucose and excretes UA, is present in the proximal tubules. It is suspected that the administration of SGLT2 inhibitors may promote UA excretion via this transporter in the presence of increased glucose levels in the tubules. Furthermore, GLUT9 isoform 2 is also present in the collecting ducts and is responsible for UA reabsorption; however, its action is inhibited by glucose stimulation, resulting in accelerated UA excretion in urine (10). An association between poor glycemic control and hypouricemia has been reported (15), suggesting that a similar mechanism is involved.
Regarding whether or not a reduction in UA levels due to increased glucose excretion leads to any prognostic improvement, it has been reported that patients with type 2 diabetes treated with SGLT2 inhibitors have a significantly lower risk of gout than patients treated with GLP-1 receptor agonists (16). Future studies are needed to investigate the gout-preventive and cardiorenal-protective effects of SGLT2 inhibitors in patients with CKD via their UA-lowering effects.
The limitations of our study include its observational, one-arm design. Furthermore, long-term follow-up data are not available, and future studies are warranted to confirm this finding. Moreover, since this was not a randomized intervention trial, the effects of selection bias, Hawthorne effect, etc., cannot be completely ruled out. In addition, hyperuricemia is generally more problematic in men than in women; therefore, this study should also have been divided by sex; however, the small sample size made it difficult to further divide by sex.
In conclusion, even in patients with a relatively impaired renal function, dapagliflozin can reduce serum UA levels via increased UA excretion.
The authors state that they have no Conflict of Interest (COI).
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