Clinical, Morphometric and Biochemical Effects on Adiposopathy Associated With the Use of GLP-1RA in CKD

Официальное название

Clinical, Morphometric and Biochemical Effects on Adiposopathy Associated With the Use of GLP-1 Receptor Agonists in Chronic Kidney Disease

Обзор

Chronic kidney disease (CKD) is the progressive damage to kidney function, associated with an increased risk of cardiovascular diseases, such as stroke or myocardial infarct, particularly in the most severe stages of CKD, in which the patient requires dialysis. Several risk factors are reported for CKD, such as diabetes mellitus, obesity and hypertension. One of the most increasingly recognized risk factors is the fat tissue malfunction, known as adiposopathy. The accumulation of fat tissue around the organs in conditions of obesity or diabetes accelerates the production of pro-inflammatory factors that may worsen the kidney and heart damage. New antidiabetic medications, such as glucagon-like peptide-1 receptor agonists (GLP-1RA), have proven beneficial effects on the kidney and heart due to several mechanisms, including anti-inflammatory actions and a potential action on the fat tissue. The aim of this study is to assess the link between adiposopathy and CKD, by investigating the changes in adiposopathy measures throughout treatment with GLP-1RA to a sample of patients with CKD.

Подробное описание

Chronic kidney disease (CKD) is defined as an irreversible abnormality of kidney structure and/or function lasting for more than three months. CKD is a major global health burden, affecting over 10% of the worldwide population and representing a leading cause of morbidity and mortality. Its progression to end-stage kidney disease (ESKD) drastically increases cardiovascular risk and is associated with a five-year survival rate of only approximately 50%. The principal risk factors for CKD-hypertension, obesity and type 2 diabetes (T2DM) in particular-are intrinsically linked through the dysfunction of fat/adipose tissue (AT), also known as adiposopathy.

Adiposopathy is a key driver of cardiorenal risk in CKD. Evidence from bioimpedance, imaging techniques (CT, MRI), and molecular biology studies confirm that alterations in adipose tissue-including its quantity, distribution (e.g., perirenal, epicardial), radiodensity, and the secretion of pro-inflammatory adipokines-are powerful triggers of cardiorenal damage and mortality in these patients. This understanding frames obesity, T2DM, cardiovascular diseases (CVDs), and CKD as different manifestations of a shared spectrum, now termed adiposity-based chronic disease (ABCD), necessitating an "adipocentric" therapeutic approach.

One hallmark feature of adiposopathy is the reprogramming and increase in size of certain region-specific adipose tissue. Perivisceral adipose tissue plays a pivotal role in adiposity-based chronic diseases as it releases adipokines and cytokines that not only contribute to the systemic pro-inflammatory and oxidative stress processes but may also influence the function of the organs surrounded by this tissue.

GLP-1RA stimulates the receptor for glucagon-like peptide-1 (GLP-1), an incretin-like hormone released in the large intestine that reduces serum glucose concentrations by stimulating the glucose-dependent release of insulin, inhibiting the hypersecretion of glucagon (except in hypoglycemia periods) and promoting satiety. GLP-1RA reduced the incidence of cardiovascular death in patients with T2DM compared with placebo and decreased the incidence of major kidney events, also reducing the progression of kidney dysfunction and the risk of death. In animals, the observed morphological changes generated by GLP-1RA could be underlined by potential actions on adipose tissue remodeling, as these drugs upregulated the expression of AT-browning related genes in perivisceral white adipose tissue from murine models, although the transcriptomic effects from GLP-1RA on the adiposopathy process are still unknown.

Вмешательства

• Препарат GLP-1 receptor agonist
  Semaglutide: weekly subcutaneous administration, starting dose 0.25mg, maintenance dose 1mg
• Препарат SGLT2 inhibitor
  dapagliflozin: oral administration from 5 to 10mg/day
• Препарат Tirzepatide
  subcutaneous injection: starting dose 2.5 mg, maintenance 5mg (weekly administration)
• Препарат Other drugs
  Patients not under SGLT2i or GLP-1RA influence, but receiving other treatments which are part of CKD standard care: mineralocorticoid receptor agonists, metformin, ACE inhibitors, ARBs...

Первичные конечные точки

• Ultrasonography change in perirenal adipose tissue thickness [Срок оценки: 16 months]
• Change in estimated glomerular filtration rate [Срок оценки: 16 months]

Вторичные конечные точки (10)

• Ultrasonographic Change in epicardial adipose tissue thickness [Срок оценки: 16 months]
• Change in serum leptin levels [Срок оценки: 16 months]
• Change in visceral fat area [Срок оценки: 16 months]
• Ultrasonographic Change in subcutaneous adipose tissue [Срок оценки: 16 months]
• Ultrasonographic Change in preperitoneal adipose tissue thickness [Срок оценки: 16 months]
• Ultrasonographic Change in intrahepatic adipose tissue [Срок оценки: 16 months]
• Change in subcutaneous fat area [Срок оценки: 16 months]
• Changes in muscle mass (kg) [Срок оценки: 16 months]
• Change in serum adiponectin levels [Срок оценки: 16 months]
• Change in urinary levels of Kidney Injury Molecule-1 [Срок оценки: 16 months]

Критерии участия

Критерии включения

• > or = 18 years of age
• diagnosed with CKD in stages G1, G2, G3a, G3b, and G4, not candidate for dialysis
• had uncontrolled T2DM, CVDs and/or obesity
• willing to participate in the study and sign informed consent

Критерии исключения

• Age <18 years
• pregnancy
• CKD in stage G5 or G4 candidate for dialysis
• neuropsychiatric diseases preventing the patient from understanding the benefits/risks associated with the project
• refusal to participate and/or consent revocation were considered as exclusion criteria

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Испания · 1 центр

• Vithas Valencia Consuelo — Valencia

Публикации

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Идентификаторы

NCT: NCT07309094 · 23/424

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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