Introduction
Liver cirrhosis is a considerable healthcare problem globally [1]. Ascites are a common consequence of cirrhosis, which is coupled with a significant increase in morbidity and death [2]. Cirrhotic ascites results from a vicious circle of splanchnic vasodilation, decreased effective blood volume, renal vasoconstriction, and stimulation of the rennin-angiotensin-aldosterone system (RAAS), leading to sodium and extracellular fluid retention [3].
Moderate salt restriction and oral diuretics are the main lines of cirrhotic ascites management. Oral diuretics in the form of a mineralocorticoid receptor antagonist alone or combined with a loop diuretic are used [4, 5]. Nearly 5–10% of patients with cirrhotic ascites will develop refractoriness to medical treatment, which has a remarkably high mortality rate [6]. Refractory ascites (RA) refers to the inability to respond to medical and dietary management or rapid reaccumulation of ascites after large-volume paracentesis (LVP). Liver transplantation is the only curative choice for refractory ascites; however, it is not available for all patients. Other available options include LVP associated with intravenous human albumin infusion, transjugular intrahepatic portosystemic shunt placement (TIPS), and an automated low-flow ascites pump (alpha pump). However, each approach is associated with significant drawbacks and restrictions [6]. A novel treatment for cirrhotic RA is needed.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of drugs used for managing type 2 diabetes mellitus (DM). This group of drugs targets SGLT2 in the nephron’s proximal tubule, causing greater excretion of sodium and glucose in the urine, ending up with enhanced natriuresis and osmotic diuresis [7, 8]. Moreover, when sodium reabsorption is blocked in the proximal tubule, downstream sodium availability to the macula densa increases, and as a result, RAAS activity is inhibited [9]. Other mechanisms include the effect of empagliflozin on glomerular hemodynamics and tubular-glomerular feedback [7, 8]. The capacity of SGLT2 inhibitors to increase urinary excretion of sodium led to their authorization for the treatment of heart failure even in nondiabetic patients [10, 11]. The purpose of this trial was to investigate the role of SGLT2 inhibitors in the management of RA.
Methods
Study design
This is a randomized, parallel-group investigator/outcome assessor-blinded controlled phase II trial of patients with cirrhotic RA that was conducted at the Hepatology Unit, Internal Medicine Department, Faculty of Medicine, Alexandria University, Egypt.
Sample size and study population
There was no solid data on the effect of empagliflozin in patients with refractory ascites apart from case reports [12–14] that showed no need for LVP in all patients who received SGLT2 inhibitors. The sample size calculation was based on the presumption that 50% of patients in the empagliflozin group might not need LVP during the study period, while the need for LVP in the SoC group would be 90%, according to an earlier study [15] with a margin of error of 0.05, a significance level of 0.05, power (1-β) = 0.8, and an expected dropout rate of 10%. The study’s minimum required sample size was 21 patients per group.
Participants in the trial were to be 18 years of age or older, with a diagnosis of decompensated liver cirrhosis complicated by RA made 3 months or more before recruitment.
Patients were excluded if they had a previous history of hypoglycemia, had low blood pressure (less than 90/60) or required a dose of midodrine greater than 15 mg/day, were taking nonselective B-blockers, had a previous history of repeated urinary tract infection (UTI) (more than a 2 infections within 6 months), were pregnant or lactating females, had a previous history of hypersensitivity to any SGLT2 inhibitor, had an estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease study (MDRD) less than 30 ml/min, consumed alcohol, had a previous history of diabetic ketoacidosis, had a Child–Pugh score of 12 or more and had hepatocellular carcinoma or any malignancy.
Randomization and masking
Randomization and allocation concealment were carried out at the High Institute of Public Health to randomize participants to receive either a fixed daily dose of 10 mg of empagliflozin in addition to standard-of-care (SoC) therapy (empagliflozin group) or SoC therapy consisting of diuretics and LVP (SoC group). The study employed a 1:1 block-randomized method, with block sizes of 6 and 7 blocks in total, to ensure a balanced sample size across groups over time. Furthermore, the allocation sequence was concealed from the enrolling investigator using the sequentially numbered, opaque, and sealed envelope (SNOSE) technique.
The study protocol and follow-up
All patients underwent an evaluation for their demographic data, symptoms, signs of chronic liver diseases, and symptoms of complications from diuretics or LVP. Baseline laboratory data were recorded, including fasting blood glucose, urine analysis, serum creatinine, serum sodium, albumin, aspartate aminotransferase, alanine aminotransferase, total serum bilirubin, complete blood count, international normalized ratio, and serum alpha-fetoprotein. An ultrasonography was performed to assess the liver parenchyma and the degree of ascites. The Child–Pugh score and model for end-stage liver disease were calculated for every patient.
Patients were followed up every week initially in the 1 month and then every 4 weeks throughout the study (3 months). They underwent clinical and laboratory evaluations with regard to the degree of ascites, need for LVP, change in body weight (body weight was measured at the scheduled visits at the same time of the day regardless of the time of the last LVP), possible side effects of empagliflozin or diuretics, and symptoms and signs of decompensation of liver cirrhosis. Ultrasonography of the abdomen and pelvis was performed to assess the degree of ascites. LVP was done when the amount of ascites caused significant discomfort or respiratory distress. Albumin administration was given for the following indications: (a) LVP at a dose of 8 gm/L fluid withdrawn; (b) spontaneous bacterial peritonitis and acute kidney injury (AKI) according to EASL guidelines [4]. Midodrine was added or up-titrated if the blood pressure fell below 100/70 mmHg [16], and the dose was adjusted according to the blood pressure [17].
Operational definitions
RA was defined as one of the following:
Diuretic-resistant refractory ascites: ascites that cannot be mobilized or that reoccur quickly regardless of moderate salt restriction and maximum dose of diuretics (400 mg of spironolactone and 160 mg of furosemide, or equivalent) [4].
Intractable refractory ascites: ascites that are immobile or that reoccur quickly due to the occurrence of adverse events that make it impossible to employ an appropriate dosage of diuretics [4].
Acute kidney injury (AKI) was diagnosed in patients who had a rise in serum creatinine ≥ 0.3 mg/dL within 48 h or more than a 50% increase from the baseline within the prior 7 days:
Stage I referred to an increase in serum creatinine by 1.5–1.9 times from the baseline within 7 days.
Stage II, when serum creatinine increased by 2 to 2.9 times the baseline within 7 days [4].
The LVP was defined as removing 5 L or more of the ascetic fluid from the peritoneal cavity [4].
Management of adverse events
Mild to moderate asymptomatic hyponatremia, either new onset or worsening of preexisting hyponatremia, was managed conservatively without modifying or stopping either empagliflozin or standard diuretics. Severe asymptomatic hyponatremia (serum Na < 125 mEq/L) was managed by stopping the standard diuretics and fluid restriction [4].
Mild transient muscle cramps were managed conservatively without modifying or stopping either empagliflozin or standard diuretics. Persistent or significant muscle cramps were managed by decreasing the dose of diuretics and/or adding baclofen at a dose of 10 mg/day [4].
The diuretics were temporarily stopped if any of the following occurred: renal impairment, an attack of HE, or significant electrolyte disturbance (serum sodium < 125 mEq/L, serum potassium < 3 or > 6 mEq/L). They were stopped permanently if urine sodium was < 30 mEq per day in cirrhotic-resistant RA and in patients not tolerating any dose of diuretics. Empagliflozin was planned to be discontinued if the patient experienced any of the following: episodes of symptomatic hypoglycemia, hypotension not responding to midodrine, a complicated urinary tract infection, renal impairment that did not respond to decreasing diuretics or diabetic ketoacidosis.
Endpoints
The primary endpoint of the study was the avoidance of the need for LVP. We also reported the safety and adverse effects of empagliflozin in cirrhotic patients with RA. Post-hoc analysis was done to determine the change in body weight at 1 month and 3 months and the complete resolution of ascites by the end of the study.
Ethics
The study was conducted in accordance with the principles of the Declaration of Helsinki, and ethical approval was obtained on 20/01/2022 from the Ethics Committee at the Faculty of Medicine, Alexandria University (IRB number 00012098) and given a serial number of 0305418. The trial was also registered at www.clinicaltrials.gov under the identifier NCT05430243. Every patient who took part in the trial gave written informed consent.
Statistical analysis
Version 20.0 of the IBM SPSS software program (Armonk, NY: IBM Corp.) was used to analyze the data. Numbers and percentages were employed to represent the categorical data, and the chi-square test was used to compare the two studied groups. The Fisher exact correction test was used if more than 20% of the cells had an anticipated count of less than 5. The Shapiro–Wilk test was utilized to check for normalcy in continuous data. To express quantitative data, the mean, standard deviation, median, and interquartile range were utilized. For the quantitative variables, the Mann–Whitney test was employed. Intention-to-treat (ITT) analysis was done. A significant level of 5% was used to evaluate the obtained results.
Results
We assessed 70 patients with cirrhotic RA for eligibility in the study. Initially, 28 patients were excluded from the study, leaving 42 patients who met the eligibility criteria, were randomized, and constituted the ITT population. After randomization, all patients were equally allocated to both groups and received the designated treatment. Of these patients, 18/21 in the empagliflozin group and 19/21 in the SoC group completed all follow-up. Details are provided in the CONSORT flowchart (Fig. 1).
Fig. 1 [Images not available. See PDF.]
Consort flow diagram for the study population
Baseline patients’ characteristics
There was no significant difference between the empagliflozin group and the SoC group in any of the sociodemographic, clinical, or laboratory data at the baseline phase (Table 1).
Table 1. Comparison between the two studied groups according to baseline characteristics
Empagliflozin group (n = 21) | SoC group (n = 21) | p | |
|---|---|---|---|
Age (years), mean (SD) | 65.7(5) | 65.1(5.4) | tp = 0.703 |
Sex Male, n (%) | 9 (42.9%) | 11 (52.4%) | χ2p = 0.537 |
Type of refractory ascites, n (%) | |||
Intractable ascites | 16 (76.2%) | 15 (71.4%) | χ2p = 0.726 |
Resistant ascites | 5 (23.8%) | 6 (28.6%) | |
Diabetes, n (%) | 9 (42.9%) | 11 (52.4%) | χ2p = 0.537 |
Need for midodrine, n (%) | 11 (52.4%) | 9 (42.9%) | χ2p = 0.537 |
Weight: kg, mean (SD) | 95 (10.2) | 88.5 (12.2) | tp = 0.068 |
Etiology of liver cirrhosis, n (%) | |||
HCV | 10 (47.6%) | 9 (42.9%) | χ2p = 0.757 |
Steatocirrhosis | 11 (52.4%) | 12 (57.1%) | |
Previous historyof, n (%) | |||
AKI | 6 (28.6%) | 6 (28.6%) | χ2p = 1.000 |
Leg cramps | 12 (57.1%) | 9 (42.9%) | χ2p = 0.355 |
Hepatic encephalopathy | 10 (47.6%) | 9 (42.9%) | χ2p = 0.757 |
Lower limb edema, n (%) | 19 (90.5%) | 14 (66.7%) | FEp = 0.130 |
Pleural effusion, n (%) | 7 (33.3%) | 3 (14.3%) | χ2p = 0.147 |
Platelets 109/L, median (IQR) | 73 (66–170) | 100 (70–210) | Up = 0.290 |
Total bilirubin mg/dl, median (IQR) | 1.7 (1.1–3.1) | 1.4 (0.8–1.9) | Up = 0.115 |
Serum albumin mg/dl, mean (SD) | 3.0 (0.3) | 2.9 (0.3) | tp = 0.179 |
FBG, median (IQR) | 97 (87–180) | 98 (78–190) | Up = 0.615 |
Serum creatinine (mg/dl), mean (SD) | 1.3 (0.3) | 1.1 (0.3) | tp = 0.100 |
Na (mEq/L), mean (SD) | 135.3(3.7) | 134.7 (5.2) | tp = 0.631 |
INR, mean (SD) | 1.5 (0.3) | 1.4 (0.2) | tp = 0.079 |
AFP (ng/ml), median (IQR) | 5 (3.4–6.3) | 4 (2.4–7.1) | Up = 0.614 |
eGFR by MDRD (ml/min), median (IQR) | 58 (43–69) | 64 (53–72) | Up = 0.102 |
Child score, mean (SD) | 9.3 (1.5) | 9.2 (1.1) | tp = 0.815 |
Child class, n (%) | |||
B | 11 (52.4%) | 12 (57.1%) | χ2p = 0.757 |
C (up to score 11) | 10 (47.6%) | 9 (42.9%) | |
MELD-Na median (IQR) | 18 (14–20) | 14 (11–19) | Up = 0.306 |
AKI acute kidney injury, AFP alpha-fetoprotein, eGFR estimated glomerular filtration rate, FBG fasting blood glucose, HCV hepatitis C virus, INR international normalized ratio, IQR interquartile range, MELD-Na model for end-stage liver disease MDRD Modification of Diet in Renal Disease Study, Na sodium, SD standard deviation, TSB total serum bilirubin, PLT platelet, p p value for comparing between the two studied groups, t Student t-test, U Mann–Whitney test, χ2 chi-square test, FE Fisher exact
Efficacy
The number of patients who required LVP was significantly lower in the empagliflozin group than in the SoC group: 21 (100%) patients in the SoC group versus 9 (42.9%) patients in the empagliflozin group (p < 0.001) (Fig. 2). The calculated post-hoc power of the study was estimated to exceed 99% for the primary outcome.
Fig. 2 [Images not available. See PDF.]
Number of patients who needed LVP in both groups. There was a significant reduction in the number of patients who needed large-volume paracentesis (LVP) in the empagliflozin group compared with the SoC group (p < 0.001, (chi-square test))
The median (interquartile range (IQR)) number of required LVP sessions during the study was significantly lower in the empagliflozin group than in the SoC group (0–3) LVP versus 7 (5–10) LVP, respectively (p < 0.001) (Fig. 3).
Fig. 3 [Images not available. See PDF.]
The median number of LVP sessions needed in both groups during the 3-month follow-up. Box and whisker plots of the median number of LVPs/patients in both groups; bold lines inside the box plot in the SoC group and forming the bottom in the empagliflozin group represent median levels; the box represents the interquartile range (from the 25th to 75th percentiles); and the extremes are represented by the whiskers. A significant difference between empagliflozin and SoC was noted, p < 0.001 (Mann–Whitney U test). LVP: large-volume paracentesis; EMPA: empagliflozin; SoC: standard of care
The median (IQR) volume of ascites removed throughout the study was significantly lower in the empagliflozin group than in the SoC group (0–19.7) liters/patient versus 39.7 (26.8–61.5) liters/patient, respectively (p < 0.001).
The median (IQR) change in body weight in kg was significantly higher in the empagliflozin group than in the SoC group by the end of the study (− 7.0 (− 11–1) versus − 1.00 (− 2.75–1) kg, respectively; p = 0.004), and most of this reduction occurred in the first month: − 8 (− 9.3–0.0) kg versus − 1.0 (− 1.5–1) kg, respectively; p = 0.015 (Fig. 4).
Fig. 4 [Images not available. See PDF.]
Overall change in body weight in both groups at the 1st month and at the end of the study compared to baseline body weight. Box and whisker plots of median change in the body weight (kg) in both groups at the first month and throughout the study period; bold lines inside the box plot represent median levels; the box represents the interquartile range (from 25 to 75th percentiles); and the extremes are represented by the whiskers. A significant difference between the empagliflozin and SoC groups was noted in all measures. *p significant p value < 0.05. (Mann–Whitney U test), EMPA empagliflozin, SoC standard of care
By the end of the study, 5 (23.8%) patients in the empagliflozin group had no ascites by ultrasound; 3 of them were off diuretics, and 2 were on spironolactone 50 mg/day.
Responders and non-responders to empagliflozin were compared according to baseline characteristics as shown in Supplementary material 1: Table S1. Half of the respondents were non-diabetic. The need for midodrine was noticeably higher in the non-responders, reflecting the higher incidence of hypotension among this sub-group.
Adverse events
The incidences of leg cramps (57.1% vs. 19.0%) and newly developed hyponatremia (42.9% vs. 9.6%) were more reported in the empagliflozin group than in the SoC group (p = 0.011, respectively), but most hyponatremia events were mild (> 130 mEq/L) (Table 2). Moreover, the decrease in the mean serum sodium between the baseline and end of therapy in the empagliflozin group was not statistically significant. The mean ± SD was (135.1 ± 3.9 vs. 133.1 ± 2.8) at the baseline and end of the study, respectively (p = 0.098) (Table 3). The incidence of UTI was also higher in the empagliflozin group, but the difference was not statistically significant (Table 3).
Table 2. Comparison between the two studied groups according to the side effects developed
Side effects | Empagliflozin group (n = 21) | SoC group (n = 21) | p |
|---|---|---|---|
Hypotension | 7 (33.3%) | 8 (38.1%) | χ2p = 0.747 |
Hepatic encephalopathy | 9/21 (42.9%) | 6/21 (28.6%) | χ2p = 0.334 |
AKI | 7/21 (33.3%) | 12/21 (57.1%) | χ2p = 0.121 |
UTI | 7/21 (33.3%) | 2/21 (9.5%) | FEp = 0.130 |
Leg cramps | 12/21 (57.1%) | 4/21 (19.0%) | χ2p = 0.011* |
Electrolyte disturbances | |||
Hypokalemia | 2 (9.5%) | 0 (0.0%) | FEp = 0.488 |
Hyperkalemia | 2 (9.5%) | 0 (0.0%) | FEp = 0.488 |
Newly developed hyponatremia | 9 (42.9%) | 2 (9.6%) | χ2p = 0.015* |
AKI acute kidney injury, UTI urinary tract infection, χ2 chi square test, FE Fisher exact, p p value for comparing with empagliflozin and SoC
*Statistically significant at p ≤ 0.05
Table 3. Changes in different laboratory parameters between baseline and the end of the study
Empagliflozin group | SoC group | |||||
|---|---|---|---|---|---|---|
Baseline (n = 18) | After 3 months (n = 18) | p | Baseline (n = 19) | After 3 months (n = 19) | p | |
HB (g/dl), mean (SD) | 10.2 (1.4) | 9.9 (1.2) | tp = 0.113 | 10.5 (1.7) | 10.1 (1.4) | tp = 0.090 |
PLT (× 109/L), median (IQR) | 71.5 (65–170) | 91 (85–110) | Zp = 0.845 | 100(68.5–223.5) | 85 (65–181) | Zp = 0.205 |
TSB mg/dl, median (IQR) | 1.9 (1.1–3.2) | 1.8 (1.7–2.6) | Zp = 0.434 | 1.3 (0.8–1.7) | 1.4 (0.9–1.7) | Zp = 0.711 |
Serum albumin (mg/dl), mean (SD) | 3 (0.3) | 2.9 (0.5) | tp = 0.202 | 2.9 (0.3) | 2.8 (0.3) | tp = 0.539 |
FBG (mg/dl), median (IQR) | 92.5 (87–209) | 99.5 (97–143) | Zp = 0.687 | 130 (82–215) | 94 (81–187.5) | Zp = 0.214 |
Serum creatinine (mg/dl), mean (SD) | 1.3 (0.3) | 1.3 (0.4) | tp = 0.891 | 1.1 (0.3) | 1.4 (0.6) | tp = 0.026* |
Na (mEq/L), mean (SD) | 135.1 (3.9) | 133.1 (2.8) | tp = 0.098 | 134.8 (5.4) | 134.2 (5.6) | tp = 0.490 |
eGFR by MDRD (ml/min) and median (IQR) | 56 (42–65) | 57 (32–71) | Zp = 0.224 | 64 (53.5–72) | 52 (47–66) | Zp = 0.008* |
Child score, mean (SD) | 9.4 (1.5) | 9.1 (1.8) | tp = 0.231 | 9.2 (1.2) | 9.1 (0.9) | tp = 0.682 |
Child class no. (%) | ||||||
A | 0 (0%) | 2 (11.1%) | MHp = 0.180 | 0 (0%) | 0 (0%) | McNp = 1.000 |
B | 9 (50%) | 8 (44.4%) | 11 (57.9%) | 12 (63.2%) | ||
C | 9 (50%) | 8 (44.4%) | 8 (42.1%) | 7 (36.8%) | ||
MELD-Na, median (IQR) | 19 (15–22) | 18 (16–25) | Zp = 0.585 | 14 (11–18.5) | 17 (13–19.5) | Zp = 0.135 |
eGFR estimated glomerular filtration rate, HB hemoglobin, FBG fasting blood glucose, IQR interquartile range, Na sodium, MELD-Na model for end-stage liver disease, MDRD Modification of Diet in Renal Disease Study, PLT platelet, SD standard deviation, SoC standard of care, TSB total serum bilirubin, p value for comparing between the two studied groups, McN McNemartest, MH marginal homogeneity test, t paired t-test, Z Wilcoxon signed rank test, p p value for comparing between baseline and after 3 months
*Statistically significant at p ≤ 0.05
The incidence of AKI events was higher in the SoC group (57.1%) than in the empagliflozin group (33.3%); however, this was not statistically significant. All AKI events in the empagliflozin group were reversible; 5 patients improved after decreasing the dose of diuretics, and the other 2 patients necessitated stopping the empagliflozin. Despite the improvement in renal function, we did not resume empagliflozin for these two patients. Both asked to withdraw from the study, and one of them underwent TIPS. In the SoC group, the AKI was reversible in 8 patients, 3 patients showed partial response, and 1 patient died with progressive renal failure and septic shock secondary to spontaneous bacterial peritonitis.
There was a notable deterioration of the renal functions (serum creatinine and eGFR by MDRD) in the SoC group between baseline and the end of the study (p = 0.026, p = 0.008, respectively), while there was no statistically significant change in the renal functions in the empagliflozin group (Table 3).
Discussion
To the best of our knowledge, this is the first randomized controlled trial to investigate the safety and efficacy of empagliflozin as a novel add-on therapy for patients with cirrhotic RA with or without DM. In recent years, there have been limited case reports showing that SGLT2 inhibitor use in patients with type 2 DM and cirrhotic RA significantly led to improved ascites and decreased doses of conventional diuretics [12–14]. The use of SGLT2 inhibitors is considered well-tolerated in persons with mild to moderate liver impairment [18].
This trial showed that the use of empagliflozin effectively eliminated the need for LVP in approximately 57.1% of patients with lower doses of diuretics or without diuretics in a few patients and successfully led to total elimination of ascites in approximately one-quarter of the patients. Even beyond the planned trial period, 11 patients in the empagliflozin group did not require LVP during a 6-month period from empagliflozin initiation, and 9 patients did not require LVP till the end of 1 year of its usage. Total elimination of ascites was maintained in 4 patients (19%) by the end of the first year. These findings are consistent with those of previous case reports [12–14]. It can be considered a safe and inexpensive treatment option for patients with cirrhotic RA.
In the current study, we attribute the ascites control to the diuretic effect of empagliflozin (either osmotic diuresis or natriuresis), which was supported by the significant weight loss in the empagliflozin group that occurred early in the first month. The increased incidence of newly developed hyponatremia observed in the empagliflozin group may be due to excessive natriuresis or a compensatory mechanism to osmotic diuresis [19]. We recommend measuring urinary sodium excretion and neurohormonal alterations to investigate the underlying mechanisms of empagliflozin on RA in future studies.
Most of the patients who achieved the primary endpoint in the empagliflozin group were diuretic-intractable, 92% (11/12 patients). Patients who were treated with empagliflozin needed lower doses of their conventional diuretics, which sequentially decreased the incidence of diuretic-related adverse effects, especially AKI, and allowed continued adherence to the treatment without frequent interruptions. The lower incidence of AKI in the empagliflozin group may also be attributed to the potential additional reno-protective effect of SGLT2 inhibitors through inhibiting renin-mediated hyperfiltration damage caused by afferent arteriole vasodilation [20].
No hypoglycemic episodes occurred in the empagliflozin group. UTI was more frequently reported in the empagliflozin group, but it was reversible with oral antibiotics [20]. Newly developed hyponatremia was more frequently encountered among patients treated with empagliflozin. This finding was not completely understood, but short-term hyponatremia was also reported with dapagliflozin and was improved with long-term usage [21]. The initial osmotic diuresis caused by SGLT2 inhibitors can result in increased vasopressin release with a subsequent decrease in free-water excretion, which might account for the early reduction in serum sodium concentration [8, 20, 22]. Muscle cramps were reported more frequently in the empagliflozin group, which may be attributed to hyponatremia, but they were usually mild and tolerable.
One of the limitations of our study was the small sample size. Before we performed this trial, data about the use of empagliflozin in patients with RA was limited. Therefore, we decided to perform a study on a small but effective number of patients. The power of our study exceeds 99% for the proposed outcome. We recommend studying empagliflozin in the management of RA on a larger sample size and for a longer duration.
We used only one concentration of empagliflozin (10 mg) for all patients, and it is unknown whether higher or lower dosages might provide different results. We recommend further multicentric, large-scale trials that use different doses of empagliflozin and measures of urinary sodium excretion and neurohormonal alterations to investigate the efficacy, safety, and underlying mechanisms of empagliflozin in RA.
Conclusions
The current trial would suggest that empagliflozin is a good option when added to SoC therapy for patients with RA. This trial contributes to the current body of evidence showing that the use of empagliflozin is relatively safe in patients with moderate hepatic impairment up to Child–Pugh C11.
Acknowledgements
The authors would like to thank all patients who participated in this study, Dr. Cinaria Albadri, Dnirpo Medical Institute, Ukraine, for English language editing, and Dr. Sameh Shehata, Alexandria University, for statistical consultation.
We acknowledge the Mind the Graph platform where we created the graphical abstract (www.mindthegraph.com).
Authors' contributions
Conceptualization: M.B. and A.K. Methodology: R.G., M.B., and A.K. Randomization: R.G. Recruitment and outcome assessment of participants: A.K. Formal analysis and investigation: R.G. Data Interpretation: all authors. Writing—original draft preparation: M.B, R.G, and A.K. Writing—review and editing: All authors. Patients and care provision: M.B., and W.E. Supervision: A.K. All authors read and approved the final manuscript.
Funding
The authors declare that this study was fully investigator-driven and did not receive grants or other financial support from the industry.
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study was conducted in accordance with the principles of the World Medical Association's Declaration of Helsinki, and ethical approval was obtained on 20/01/2022 from the Ethics Committee at the Faculty of Medicine, Alexandria University (IRB number 00012098) and given a serial number of 0305418. The trial was also registered at www.clinicaltrials.gov under the identifier NCT05430243. (Available at https://clinicaltrials.gov/study/NCT05430243). Written informed consent was obtained from all patients who participated in the study.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Abbreviations
Refractory ascites
Standard of care
Large volume paracentecis
Renin-angiotensin-aldosterone system
Trans-jugular intrahepatic porto-systemic shunt
European Association for the Study of the Liver
Sodium-glucose cotransporter-2
Urinary tract infection
Estimated glomerular filtration rate
Modification of Diet in Renal Disease
Acute kidney injury
Intention to treat
Interquartile range
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Abstract
Background
Cirrhotic refractory ascites (RA) patients have few alternatives for treatment. Empagliflozin is now known to have natriuretic and neurohormonal modulatory effects. This research investigated the safety and efficacy of empagliflozin in the management of RA when added to the standard of care (SoC) compared to SoC alone.
Methods
Patients were randomized to receive either a fixed dose of 10 mg of empagliflozin plus standard of care (SoC) or SoC alone. Patients were followed up for 3 months. The primary endpoint was achieving no need for large-volume paracentesis (LVP).
Results
Forty-two patients were randomized equally, and intention-to-treat was performed. There was a statistically significant decrease in the need for LVP in the empagliflozin group compared to the SoC group (100% in the SoC vs. 42.9% in the empagliflozin group, p < 0.001). By the end of the study, the total resolution of ascites was reported in approximately 24% of patients. Muscle cramps and newly developed hyponatremia were more common in the empagliflozin group, but they were mild. Acute kidney injury was more common in the SoC group.
Conclusions
Empagliflozin may be an effective option for use as an add-on therapy in the management of RA, with an accepted safety profile.
Trial registration
The trial was registered at www.clinicaltrials.gov under the identifier NCT05430243. The registration was submitted on 18/06/2022. It is available at https://clinicaltrials.gov/study/NCT05430243.
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Details
1 Alexandria University, Hepatology Unit, Internal Medicine Department, Faculty of Medicine, Alexandria, Egypt (GRID:grid.7155.6) (ISNI:0000 0001 2260 6941)
2 High Institute of Public Health, Alexandria University, Tropical Health Department, Alexandria, Egypt (GRID:grid.7155.6) (ISNI:0000 0001 2260 6941)
3 Alexandria University, Tropical Medicine Department, Faculty of Medicine, Alexandria, Egypt (GRID:grid.7155.6) (ISNI:0000 0001 2260 6941)