Clinical trial NCT05999773: SGLT-2 Inhibitors in the Treatment of Ascites
Official title: Potential Role of Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Ascites in Cirrhotic Patients
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Ascites Hepatic
Cirrhosis, Liver
Diabete Type 2
Keywords: Ascites
Liver Cirrhosis
Diabete Type 2
Sodium Glucose Cotransporter 2 (SGLT-2) Inhibitors
Glyphozines
Lead sponsor: University of Palermo
Sponsor class: OTHER
Collaborators: name: Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello
First posted: 2023-08-21
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: We will enroll subjects with complicated liver cirrhosis and type II diabetes mellitus consecutively, in two centers: Internal Medicine Unit of the "Policlinico Paolo Giaccone", University Hospital of Palermo, Italy and Internal Medicine Unit of the "Ospedali Riuniti Villa Sofia- Cervello" Hospital of Palermo, Italy.

Patients will be assigned to intervention or control group according diabetology indications to start SGLT-2 inhibitors.

Patients included in the two study groups will be sex, age and race matched.

Brief summary: The goal of this observational study is to test the efficacy of glyphozines (SGLT-2 inhibitors) in the control of ascites in patients with liver cirrhosis in class A6-B9, according to the Child-Pugh classification, and type 2 diabetes mellitus. The investigators will compare patients belonging to the intervention group (A), who will be given SGLT-2 inhibitors according to diabetology indications in addition to standard medical therapy for 6, with patients of the control group (B), who will, instead, continue with the standard medical therapy for 6 months. Standard medical therapy will include dietary sodium restriction, treatment with diuretics (furosemide and spironolactone), hypoglycemic therapy (metformin, insulin, or both) and other supportive care.

The main questions aims of this study are:

1. Compare the efficacy and safety of a therapeutic approach based on the administration of SGLT-2 inhibitors in addition to optimal medical therapy (MRA and loop diuretic) compared to traditional diuretic therapy only, in cirrhotic patients with saline retention and diabetes.
2. Demonstrate better control of the glycemic profile in cirrhotic diabetic patients using SGLT-2 inhibitors.

Detailed description: Background The occurrence of ascites and saline retention is the most common complication in patients affected by liver cirrhosis and it is associated with poor prognosis.

It is well-known that in liver cirrhosis the underlying pathogenetic events responsible of ascites are portal hypertension and splanchnic vasodilation. These mechanisms reduce the effective circulating blood volume, triggering counter-regulatory systems such as the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS), that leading to renal sodium and water retention.

Therefore, considering pathogenetic knowledge, the cornerstones of ascites treatment are sodium restriction and drugs such as mineralocorticoid receptor antagonists (MRA) and loop diuretics, reserving more invasive techniques, like paracentesis with administration of human albumin, for more severe patients with grade 3 ascites unresponsive to diuretics. However, even though diuretics have proven to be among the most efficient drugs in controlling ascites, patients with liver cirrhosis and ascites treated with diuretics develop adverse drug reactions in 20-40% of cases.

One of the most common comorbidities of liver cirrhosis is type-2 diabetes mellitus (DM2), which affects approximately one-third of cirrhotic patients. The connection between liver cirrhosis and DM2 is complex. DM2 can be a secondary effect or, conversely, a casual factor of liver dysfunction.

Sodium glucose cotransporter 2 inhibitors (SGLT-2i) are a relatively new class of drugs for the management of type-2 diabetes mellitus. They inhibit the reabsorption of sodium and glucose in the proximal convoluted tubule of the nephron, leading to a significant natriuresis and have proven to be effective and safe drugs for the control of the glycemic profile in patients with liver dysfunction.

In recently published case reports, SGLT-2i have also proven to be safe and effective in controlling the glycemic profile in patients with liver dysfunction. In these patients, in addition to better control the glycemic profile, they led to saline retention improvement and to weight loss, without inducing encephalopathy or acute kidney injury. Other studies have hypothesized that, similarly to the previously demonstrated beneficial effect of glyphozines in patients with acute heart failure, SGLT-2i may also lead to the improvement of complicated liver cirrhosis acting as "neuromodulators", suppressing the RAAS axis and inducing better mobilization of ascites and reduction of saline retention.

Currently, there are no randomized controlled trials supporting these evidences.

In this observational study the investigators intend to evaluate the efficacy and safety of SGLT-2i in cirrhotic and diabetic patients with saline retention.

Aims

* Comparing the efficacy and safety of a therapeutic approach based on the administration of SGLT-2i in addition to optimal medical therapy (MRA and loop diuretic) compared to traditional diuretic therapy only, in cirrhotic patients with saline retention and diabetes.
* Demonstrating better control of the glycemic profile in cirrhotic diabetic patients using SGLT-2i.

Sample and study design Our study will be a clinical, prospective, observational multicenter study. The investigators will enroll subjects with complicated liver cirrhosis and type II diabetes mellitus consecutively, in two centers: Internal Medicine Unit of the "Policlinico Paolo Giaccone", University Hospital of Palermo, Italy and Internal Medicine Unit of the "Ospedali Riuniti Villa Sofia- Cervello" Hospital of Palermo, Italy.

Sample size The sample size is difficult to determine as there are no studies that have evaluated the efficacy of SGLT-2i treatment in addition to diuretic therapy in the patient with liver cirrhosis and saline retention. To date, there are only a few case reports in the literature that have demonstrated its effectiveness. Considering the prospective and pilot nature of this study the investigators decided to enroll at least 40 patients.

Study design and outcome evaluation Our project has been approved by the ethics committee of the University Hospital of Palermo.

Patients enrolled on the basis of the inclusion and exclusion criteria and who agreed to enter the study, after signing the informed consent, will be assigned to intervention group (group A) or control group (group B).

Patients belonging to the intervention group (A) will be given SGLT-2 inhibitors, according diabetology indications, in addition to standard medical therapy for 6 months; the patients of the control group (B) will instead continue with the only standard medical therapy for 6 months, according diabetology indications.

Standard medical therapy will include dietary sodium restriction, treatment with diuretics (furosemide and spironolactone), hypoglycemic therapy (metformin, insulin, or both) and other supportive care. Patients taking non-selective beta-blockers will continue to do.

Patients in group A and group B will be evaluated for specific clinical and laboratory parameters before the start of the study (T0) and they will subsequently be evaluated again at 4 weeks, 3 months and 6 months (T1, T2, T3).

Eligibility criteria: Inclusion Criteria:

* Age between 18 and 80 years
* Patients diagnosed with Child-Turcotte-Pugh A6-B class Hepatic Cirrhosis (moderately impaired liver function)
* Patients diagnosed with Hepatic Cirrhosis of viral etiology (if previous hepatitis C virus (HCV) infection they must be in Sustained Virological Response (SVR); if previous hepatitis B virus (HBV) infection they must have undetectable viral genome)
* Patients diagnosed with hepatic cirrhosis of metabolic etiology
* Patients diagnosed with liver cirrhosis of alcoholic etiology (non active potus)
* Patients with grade 1 ascites: ascites detectable only ultrasound that can be fully mobilized or controlled with diuretic therapy associated with or without moderate dietary sodium restriction
* Grade 2 ascites: ascites that leads to a moderate abdominal distension and that recurs on at least 3 occasions within a 12-month period despite sodium restriction and adequate diuretic therapy (23)
* Patients diagnosed with type II diabetes mellitus defined according to 2022 American Diabetes Association (ADA) guidelines.

Exclusion Criteria:

* Inability to obtain informed consent
* Ascites of non-cirrhotic origin
* Patients diagnosed with heart failure Heart (NYHA) class =\> 2
* Patients diagnosed with acute renal failure
* Patients diagnosed with chronic renal failure and glomerular filtration rate (eGFR) below 25ml/min
* Patients with hepatocellular carcinoma (diagnosed according to the Barcelona criteria) or other active tumors (25)
* Grade 3 ascites: ascites that causes marked distention of the abdomen and that cannot be mobilized or whose early recurrence (i.e. after large volume paracentesis) cannot be satisfactorily prevented by medical therapy
* Patients diagnosed with acute Spontaneous Bacterial Peritonitis (26)
* Patients diagnosed with severe hepatic encephalopathy
* Patients diagnosed with autoimmune diseases on active steroid treatment
* Patients diagnosed with liver cirrhosis due to storage diseases
* Patients diagnosed with cirrhosis of the liver due to enzyme deficiency
* Patients diagnosed with complete portal thrombosis
* Patients with active sepsis
* Pregnant or breastfeeding women
* Patients who use drugs
* Patients with active alcohol consumption

Primary outcomes:
measure: Ascites control
timeFrame: Day 0, 4 weeks, 3 months, 6 months
measure: Glycemic control
timeFrame: Day 0, 4 weeks, 3 months, 6 months
measure: SGLT-2 inhibitors related adverse events
timeFrame: Day 0, 4 weeks, 3 months, 6 months
Secondary outcomes:
measure: Fasting glucose control
timeFrame: Day 0, 4 weeks, 3 months, 6 months
measure: Weight loss
timeFrame: Day 0, 4 weeks, 3 months, 6 months
measure: 24-hour diuresis
timeFrame: Day 0, 4 weeks, 3 months, 6 months
measure: Sodium excretion in the urine
timeFrame: From day 0 to day 180
measure: Natremia
timeFrame: Day 0, 4 weeks, 3 months, 6 months
measure: Mean arterial pressure
timeFrame: Day 0, 4 weeks, 3 months, 6 months
measure: Glomerular filtration rate
timeFrame: Day 0, 4 weeks, 3 months, 6 months
measure: Child-Turcotte-Pugh (CTP) score
timeFrame: Day 0, 4 weeks, 3 months, 6 months
measure: Survival
timeFrame: 6 months
measure: Loop diuretics posology
timeFrame: Day 0, 4 weeks, 3 months, 6 months
measure: Mineralocorticoid receptor antagonists posology
timeFrame: Day 0, 4 weeks, 3 months, 6 months
measure: Metformin posology
timeFrame: Day 0, 4 weeks, 3 months, 6 months
measure: Insulin bolus posology
timeFrame: Day 0, 4 weeks, 3 months, 6 months
measure: Insulin basal posology
timeFrame: Day 0, 4 weeks, 3 months, 6 months
measure: Adverse events classification
timeFrame: 4 weeks, 3 months, 6 months
Other outcomes:
Locations:
city: Palermo
country: Italy
facility: Internal Medicine Unit, V. Cervello Hospital
city: Palermo
country: Italy
facility: Department of Internal Medicine, University Hospital of Palermo
Study officials:
affiliation: University of Palermo
name: Lydia Giannitrapani, MD
role: PRINCIPAL_INVESTIGATOR
References:
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