Region-specific Adipose Tissues and Liver Changes Associated With Semaglutide Treatment in Chronic Kidney Disease Patients
Conditions: Chronic Kidney Disease in Type 2 Diabetes, Obesity & Overweight
Sponsor: University of Alberta

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PROTOCOL IDENTIFICATION 
 
Protocol Title 
Region-specific Adipose Tissues and Liver Changes 
Associated With Semaglutide Treatment in Chronic 
Kidney Disease Patients (ADIPOLIVE) 
Unique Protocol Id 
U1111-1328-1600 
Therapeutic Area 
CKD, Liver, and Cardiovascular  
Primary Product 
Semaglutide (drug not requested) 
Requested Support (i.e., 
type of support, dollar 
amount) 
$125,000 

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INVESTIGATOR IDENTIFICATION 
 
Department Name 
Medicine-Cardiology 
Institution Name 
University of Alberta 
Institution Address 
8840 112 Street, Edmonton, AB, 
T6G 2B7 
 
 
PROTOCOL SCHEDULE 
 
Study Duration 
12 months 
Recruitment Rate Per Month [if applicable] 
6-8 
Study Start Date* 
September 1, 2025 
First Patient First Visit (FPFV) [if applicable] 
September 15, 2025 
First Patient Last Visit (FPLV) [if applicable] 
September 15, 2026 
Last Patient Last Visit (LPLV) [if applicable] 
November 2027 
Study Completion Date 
November 2027 
Date of Final Study Report Submission to NNCI January  2028 
Anticipated Publication Submission Date 
February 2028 

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TABLE OF CONTENTS 
PROTOCOL SUMMARY .......................................................................................................... 6 
Section 1 .................................................................................................................................. 6 
1.1 Protocol Summary ........................................................................................................................ 6 
PROTOCOL BACKGROUND AND SPECIFIC AIMS ..................................................... 6 
Section 2 .................................................................................................................................. 6 
2.1 Background, Purpose, and Study Aims/Objective(s) ................................................................ 6 
PROTOCOL SIGNIFICANCE .......................................................................................... 7 
Section 3 .................................................................................................................................. 7 
3.1 Protocol Significance ................................................................................................................... 7 
PROTOCOL RESEARCH STRATEGY: STUDY DESIGN AND STUDY POPULATION7 
Section 4 ................................................................................................................................ 12 
4.1 Endpoints .................................................................................................................................... 12 
4.2 Study Type ................................................................................................................................... 12 
4.3 Study Design Rationale .............................................................................................................. 13 
4.4 Study Population ........................................................................................................................ 13 
4.5 Inclusion Criteria ......................................................................................................................... 14 
4.6 Exclusion Criteria ....................................................................................................................... 14 
4.7 Withdrawal Criteria ..................................................................................................................... 14 
4.8 Diversity and Inclusion ............................................................................................................... 14 
Section 5 ................................................................................................................................ 15 
5.1 Study Procedures/Assessments ............................................................................................... 15 
5.2 Assessments for Safety ............................................................................................................. 16 
5.3 Other Assessments (if applicable) ............................................................................................ 17 
5.4 Study Flowchart .......................................................................................................................... 17 
PROTOCOL RESEARCH STRATEGY: STATISTICAL CONSIDERATIONS .............. 17 
Section 6 ................................................................................................................................ 17 
6.1 Sample Size Calculation ............................................................................................................. 17 
6.2 Statistical Methods ..................................................................................................................... 18 
6.3 Interim Analyses (if applicable) ................................................................................................. 19 
PROTOCOL ETHICS .................................................................................................... 19 
Section 7 ................................................................................................................................ 19 
7.1 Data Handling and Recordkeeping ............................................................................................ 19 
7.2 Ethics ........................................................................................................................................... 19 
PROTOCOL ADVERSE EVENTS ................................................................................. 20 
Section 8 ................................................................................................................................ 20 
8.1 Adverse Event Reporting ........................................................................................................... 20 
8.2 Adverse Event Definitions ......................................................................................................... 20 
8.3 Adverse Event Follow-Up ........................................................................................................... 20 
PROTOCOL PREMATURE STUDY TERMINATION .................................................... 20 
Section 9 ................................................................................................................................ 20 
9.1 Early Study Termination ............................................................................................................. 20 

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PROTOCOL PUBLICATION PLAN .............................................................................. 20 
Section 10 .............................................................................................................................. 20 
10.1 Publication Plan ........................................................................................................................ 20 
PROTOCOL REFERENCES ......................................................................................... 21 
Section 11 .............................................................................................................................. 21 
 

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PROTOCOL SUMMARY 
Section 1 
1.1 Protocol Summary 
 
Cardio-kidney-liver metabolic disorders (CKLMD) are highly prevalent in western 
societies and are associated with increased risk of cardiovascular disease. Visceral 
adipose tissue and accumulation of lipids in the liver are phenotypical changes often 
seen in patients with CKLMD.  
The proposed focus of our project is to phenotype the visceral adipose tissue (AT) of 
patients with chronic kidney disease (CKD) and assess the prevalence and severity 
of metabolic associated steatotic liver disease (MASLD), as they correlate with 
cardiovascular disease (CVD) complications, in patients receiving and not receiving 
semaglutide. GLP-1RAs represent a very important advancement in the 
management of diabetes mellitus and the frequently associated CKD. A few 
investigations suggested that GLP-1RAs have a remodelling effect on AT. Ours will 
be the first study to link changes in organ-specific AT deposits (epicardial and 
perirenal) associated with GLP-1RAs therapy to stages of renal function and 
cardiometabolic load; we will identify different adiposopathy profiles within each CKD 
stage.  
The proposal has two specific objectives, divided into precise tasks related to the 
general purpose of this project.  
In the short-term, our project will contribute to increasing our knowledge of the 
potential mechanisms of actions of GLP-1RA (i.e modification of AT deposits) and 
may provide a new way to classify CKD patients as far as their CV risk is concerned. 
In the medium to long term, the results derived from this project will bring physicians 
and healthcare staff closer to a personalized treatment approach, to reduce not only 
the progression of renal failure but also a set of associated cardiometabolic 
complications. 
 
PROTOCOL BACKGROUND AND SPECIFIC AIMS 
Section 2 
2.1 Background, Purpose, and Study Aims/Objective(s) 
 
Chronic kidney disease (CKD) is one of the most prevalent non-communicable chronic 
diseases, affecting more than 10% of the worldwide population, ie more than 800 million 
individuals (1,2). According to the WHO, CKD is among the leading causes of morbidity 
and mortality worldwide, and it is expected to become the 5th most common chronic 
disease by 2040 (3,4). The progression to end-stage kidney disease (ESKD) is associated 
with a substantial increase in the risk for cardiovascular disease (CVD), such as stroke, 
myocardial infarction and heart failure (5,6), which translates into a poor prognosis for 
affected patients, with annual mortality rates higher than 10% and an estimated five-year 
survival around 50% (7,8). Similarly, MASLD is the most frequent form of liver disease in 

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the world and the most frequent cause of cirrhosis and liver transplant. Diabetes mellitus 
(DM), particularly type 2 (T2DM), arterial hypertension and obesity are well-known risk 
factors for CKD and MASLD (9-11). In the recent past, visceral AT has garnered attention 
as the organ potentially connecting these risk factors and underlying cardiovascular risk in 
patients with CKD. Various methodologies have been used to explore the role of AT 
dysfunction as a cardiovascular risk and mortality indicator in patients diagnosed with 
different stages of CKD. Body composition assessment through bioimpedance revealed 
that the percentage of total body fat has an inverse correlation to kidney function (12) and 
is an independent risk factor for all-cause mortality in patients with CKD (13). Imaging 
methods (computed tomography, magnetic resonance and ultrasonography) were also 
used by diverse research groups, ours amongst others, to evaluate differences in the AT 
accumulated in specific body areas (region-specific AT), such as the intrabdominal, 
thoracic (epicardial) and around the kidneys (perirenal), in patients with CKD. Their 
augmented radiodensity and thickness/volume are associated with an increased 
cardiovascular risk and a worse prognosis in CKD (14-17). From a proteomic point of 
view, the cytokines secreted by AT, known as adipokines, have both anti- and pro-
inflammatory both locally and systemically. An imbalance in the actions of adipokines in 
favor of those with a pro-inflammatory function, also associated with insulin resistance and 
cardiometabolic injury, has been reported in patients with CKD and MASLD (18,19).The 
aforementioned highlights that obesity, T2DM, CVD, CKD and MASLD are strongly linked 
through AT dysfunction (adiposopathy) and should be considered different aspects of the 
same spectrum of diseases newly termed adiposity-based chronic diseases (ABCD) 
(20,21). Accordingly, new trends in CKD management are focusing efforts on adopting an 
adipocentric approach, in which the identification of AT alteration serves as an earlier 
diagnosis of kidney dysfunction, allowing a more precise categorization of the 
cardiometabolic risk in patients with CKD and the implementation of personalized 
therapeutic plans that prioritize targeting the AT to effectively reduce the morbidity and 
mortality of this disease (22). Glucagon-like peptide 1 receptor agonists (GLP-1RA) are 
recommended for patients with T2DM and obesity, and are well suited to address this 
adipocentric view point in light of their ability to induce weight loss and provide 
cardiometabolic and renal protection beyond glycemic control (23-25).  
The purpose of the study is to explore the link between adiposity and cardio-renal-liver 
metabolic dysfunction, within a multidisciplinary adipocentric approach (using clinical, 
imaging and biochemical markers of adiposopathy) across different stages of CKD in 
patients treated and not treated with semaglutide, both oral and injectable. This study will 
unveil the association of AT, renal dysfunction and MASLD and provide a view on the 
potential mechanism of action of GLP-1RA. This may pave the way toward new 
adipocentric diagnostic and therapeutic models in CKD. 
 
PROTOCOL SIGNIFICANCE 
Section 3 
3.1 Protocol Significance 
a) Adipose tissue as a dynamic endocrine organ 

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AT is a connective tissue mainly composed of adipocyte cells, which can be divided into 
three different types according to structure, location and functions. AT should be 
considered a dynamic tissue, as its cells are in a continuous state of remodeling 
depending on many factors, such as insulin sensitivity, energy expenditure and 
inflammatory status (26). Thus, white adipocytes, which contain large globules of fat (lipid 
droplets), are mainly energy-storing cells that give rise to the white AT (WAT), mainly 
located in the subcutaneous layer and around the organs (perivisceral), such as the 
epicardial and perirenal AT (27). On the contrary, brown adipocytes contain smaller lipid 
droplets and a higher number of mitochondria, that are capable of thermogenic activities 
via the uncoupling protein-1 (UCP-1). Brown AT (BAT) is located in small depots in the 
sub-clavicular and axillary areas (28). Beige adipocytes (BeAT) are white AT (WAT) 
adipocytes that have undergone partial “browning”. Browning is induced by exposure to 
cold, sympathetic stimulation and certain drugs (29). Some diseases or metabolic 
disorders could generate the opposite effect, known as whitening, in which BAT becomes 
white or more pathologic, as described further on.   
AT secretes multiple adipokines involved in glucose metabolism, appetite regulation and 
inflammation, which exert their functions on nearby (paracrine actions) and distant organs 
(endocrine actions) (26). Leptin and adiponectin are the best known adipokines. Whereas 
adiponectin is cardioprotective and has anti-inflammatory and antioxidant properties, by 
inhibiting the expression of inducible nitric oxide synthase (iNOS) and stimulating 
cyclooxygenase-2 (COX-2) production (30,31), leptin induces cardiac cell hypertrophy, the 
production of reactive oxygen species (ROS) and macrophage infiltration among 
endothelial cells, leading to atherosclerosis (32,33). Other less commonly studied 
adipokines are resistin, visfatin and omentin. Resistin and visfatin behave similarly to 
leptin, whereas omentin has properties analogous to adiponectin (34-36).  
 
b) The link between adiposity, cardiometabolic dysfunction and kidney disease 
As previously mentioned, ABCD is a new concept used to encapsulate the diverse 
conditions related to adiposopathy, which includes the process of hypertrophy, 
inflammation and fibrosis of the AT. This process, which ultimately has a negative impact 
on cardiovascular health, is shared by metabolic diseases (obesity, T2DM) MASLD and 
CKD (20,21). The adiposopathy process initiates with the expansion of the AT 
(hypertrophy) via increased accumulation of lipids in the adipocytes, which in the process 
of gaining volume compress adjacent cells leading to reduced regional blood flow and 
hypoxia. The hypoxic process activates ROS production and the nuclear factor kappa B 
(NF-kB). This initiates a pro-inflammatory cascade, with release of interferon-gamma (IF-
γ), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), 
interleukin-6 (IL)-6 and IL-1β (37). These factors activate macrophages, which shift to a 
pro-inflammatory M1 phenotype and infiltrate the vascular endothelium via the expression 
of adhesion molecules and selectins (38), leading to endothelial dysfunction and, 
eventually, atherosclerosis, thrombosis and cardiovascular injury. Chronic inflammation 
and immune cell infiltration among adipocytes eventually lead to the deposit of fibroblasts 
(fibrosis) (26). The hypoxia secondary to cellular hypertrophy that initiates the the 
phenotypical adiposopathy transformation, involves a process of transcriptomic and 

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proteomic conversion (reprogramming) of the AT, by which the secretion of anti-
inflammatory adipokines, such as adiponectin and omentin, is reduced, together with an 
upregulation of the pro-inflammatory leptin, visfatin and resistin, further contributing to the 
dysfunctional AT state (15,39). AT reprogramming also affects the brown and beige 
adipocytes, that lose their thermogenic properties through autophagic degradation of 
mitochondria and reduced expression of UCP-1, to end up exhibiting characteristics 
typical of white adipocytes in a whitening process (40,41).  
In patients with CKD, the adiposopathy process is both induced and aggravated by a 
chronic low-grade systemic inflammation secondary to the progressive accumulation of 
uremic toxins in the circulation derived from kidney dysfunction (42). This pro-
inflammatory state is supported by the early elevation of biomarkers of inflammation and 
kidney damage, such as the soluble urokinase-type plasminogen activator receptor 
(suPAR) and/or kidney injury molecule 1 (KIM-1) in initial CKD stages, even before the 
estimated glomerular filtration rate (eGFR) decreases or other classical risk markers, such 
as microalbuminuria, emerge (43,44). Hence, adipokines in patients with CKD seem to 
behave slightly differently from patients with obesity, T2DM and other related conditions. 
Unlike what happens in these three situations (15), adiponectin levels in patients with CKD 
are increased up to three-fold in relation to physiological conditions, and their 
concentrations correlate with the progression of kidney dysfunction, so that patients with 
ESKD are found to have the highest levels of adiponectin (45). Along with high serum 
levels of adiponectin, in patients with CKD there is an increased production of adiponectin 
by the AT and its receptor, marking a state of adiponectin resistance and altered 
adiponectin signaling induced by uremia (19,46). What is still unclear is the role of 
adiponectin as a cardiovascular risk marker in patients with CKD, as certain studies 
revealed that lower levels of this adipokine are predictive of CVD in renal populations 
(47,48), whereas others found that cardiovascular mortality increases with the rise in 
adiponectin concentrations (49). As expected, given their pro-inflammatory status, patients 
with CKD show elevated leptin levels, with up to a four-fold increase in ESKD. The 
reasons for hyperleptinemia in kidney failure are multifactorial, including reduced renal 
elimination and increased production of leptin by the adipocytes (15,50), as demonstrated 
by an upregulated expression of the leptin gene in the subcutaneous AT from patients with 
CKD (18). Only rare studies focused on the role of less common adipokines in CKD: 
visfatin and resistin levels increase with declining renal function and they appear to actas 
independent CVD risk markers (51,52). Simultaneously, whereas significantly lower 
concentrations of omentin concentrations have been reported in CKD, particularly in the 
subgroup of patients with T2DM (53). 
One hallmark feature of adiposopathy is the reprogramming and increase in size of certain 
region-specific AT. Perivisceral AT plays a pivotal role in ABCD 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 (54). Epicardial AT (EAT) is located below the visceral pericardium (epicardium), in 
direct contact with the coronary arteries and the myocardium. Patients with CKD show 
increased EAT thickness (ultrasonography evaluation) and volume (measured through 
computed tomography or magnetic resonance) (55). This increase in size serves as an 

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independent predictor for myocardial perfusion defects (56), as well as an independent 
predictor for mortality in patients on dialysis (57). These findings were later corroborated 
by other authors (16), who highlighted that not only an augmented size but also a higher 
EAT radiodensity are predictors of mortality in CKD populations (58). Perirenal AT (PAT) 
is in the retroperitoneal space surrounding the kidneys (54); therefore, its accumulation 
may mechanically compress the kidney with renal and/or cardiovascular consequences 
(59). Nonetheless, the consideration of its role as an endocrine organ influencing kidney 
function is relatively new. PAT thickness has been reported to have a negative correlation 
with eGFR, and to be associated with renal functional decline and cardiometabolic risk 
factors (14,60). MASLD (61) is the ultimate liver manifestation of cardiometabolic 
disorders, and potentially closely associated with CKD.  Intrahepatic fat may act as a 
mediator in the pro-inflammatory signaling pathway activation that occurs in patients with 
CKD, rendering it a potential independent predictor of kidney damage (62,63). Non-
perivisceral AT, such as the subcutaneous AT (SAT) and the preperitoneal AT (pPAT), 
have also been associated with CKD. SAT is the fat accumulated subcutaneously in the 
anterior abdominal wall. Its volume is positively correlated with leptin levels and insulin 
resistance measures in non-dialysis populations (64). An increase in its radiodensity is 
also considered an independent predictor of kidney damage progression (65). A less 
explored abdominal depot in CKD populations is the pPAT, which is AT located between 
the liver surface and the linea alba situated between the two recti abdominal muscles. 
Classically associated with arterial stiffness (vascular aging) and cardiometabolic risk 
markers, such as hypertension, T2DM and high triglyceride levels (66,67), it appears that 
certain non-coding microRNA (miRNAs 17-5p and 130b) secreted by the pPAT are 
predictors of survival and cardiovascular events in candidates for dialysis (68).  
As described, region-specific AT seems to be a risk factor for CVD and kidney disease 
progression in CKD. However, no study to date has simultaneously explored region-
specific Ats, such as EAT and PAT, MASLD and adiposopathy biomarkers in the CKD 
population to generate knowledge of how they vary across different stages of the disease 
and to distinguish those region-specific AT with a strongest association with renal function. 
Also, no studies have observed these adiposopathy markers during   treatment with GLP-
1RA.  
 
c) GLP-1 receptor agonists: first steps towards an adipocentric therapeutic 
approach 
The new antidiabetic GLP-1RAs, together with the sodium-glucose cotransporter inhibitors 
(SGLT-2i), have made a revolution in the comprehensive management of diabetic 
patients. Besides their glucose-lowering effects, both medications have weight-loss effects 
beneficial in obesity, they slow diabetic kidney disease progression, and exert anti-
inflammatory actions that would alleviate the pro-inflammatory state associated with 
ABCD (69). However, the beneficial mechanisms of both drugs beyond their glycemic 
control are complex and not completely understood; in particular, their effects on AT 
remodeling and adiposopathy are still under evaluation. With the proposal we present 
here, we intend to take a step forward into the global assessment of these antidiabetic 
medication effects on adiposopathy by evaluating the changes triggered by GLP-1RA on 

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different AT depots from a clinical, biochemical and imaging perspective. 
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 hypoglycemic periods) and promoting satiety (70). There are different 
GLP-1RAs released to the market, such as exenatide, liraglutide, dulaglutide, and 
semaglutide; the latter has the longest duration of action allowing once weekly dosing 
(71). GLP-1RA reduced the incidence of CVD and cardiovascular death in patients with 
T2DM compared with placebo (72). In the randomized placebo-controlled FLOW trial 
(NCT03819153), that addressed the effects of semaglutide on CKD populations, this GLP-
1RA significantly decreased the incidence of major kidney events, also reducing the 
progression of kidney dysfunction and the risk of death (73). The cardiorenal protective 
effects from GLP-1RA derive not only from glycemic and weight control, but also from 
direct involvement in the regulation of the apoptotic process of myocardial cells (74), and 
from inhibition of the sodium-hydrogen antiporter 3 (NH3) in the renal proximal tubule, 
increasing natriuresis and reducing pressure on the glomerulus (75). In animals, the 
observed morphological changes generated by GLP-1RA could be underlined by potential 
actions on AT remodeling, as these drugs upregulated the expression of AT-browning 
related genes in perivisceral WAT from murine models (76), although the transcriptomic 
effects from GLP-1RA on the adiposopathy process are still unknown. At the same time, 
semaglutide has been shown to reduce liver inflammation, fibrosis and lipid accumulation 
in patients to MASH (77). Whether the beneficial effects on AT, liver and kidney proceed 
together has not been studies yet.

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PROTOCOL RESEARCH STRATEGY: STUDY DESIGN AND STUDY POPULATION 
Section 4 
a. Endpoints 
a) Primary and Secondary Endpoints 
The primary endpoint of this proposal is to establish a connection between kidney 
disease progression and cardiometabolic changes, focusing on region-specific adipose 
tissues such as perirenal, epicardial and hepatic steatosis in patients with or without 
semaglutide treatment. Additionally, adiposopathy biomarker comparisons between 
different CKD severity stages will be investigated. Given the current indication of GLP-
1RA, the sample will comprise patients with T2DM and CKD (diabetic kidney disease 
or DKD). Thus, this endpoint can be split into two secondary endpoints, also identified 
as Work Packages (WP) 1 & 2, each one divided into different tasks: 
 
WP1. To distinguish cardiometabolic profiles within each CKD mild to moderate 
severity stage (1 to 4). Patients will already be classified into their corresponding 
stages based on their eGFR and albuminuria. Patients on semaglutide or standard of 
care (SoC) regimen, within each CKD stage, will be categorized based on clinical, 
imaging and biochemical markers of adiposopathy. These markers will be associated 
with variables of both renal function and cardiometabolic risk. Creatinine, urea, cystatin 
C, intact parathyroid hormone (iPTH), vitamin D, calcium/phosphate, and uric acid will 
be used as markers of renal function in serum; in urine, microalbuminuria, 
albumin/creatinine ratio, and microalbuminuria/creatinine ratio will be measured. 
Serum 
total 
cholesterol, 
LDL-cholesterol, 
HDL-cholesterol, 
VLDL-cholesterol, 
apolipoprotein A, triglycerides, glycated hemoglobin (HbA1C) and N-terminal pro b-
type natriuretic peptide (NT-proBNP) will be considered cardiometabolic risk markers. 
Hepatic steatosis will be assessed using various non-invasive serum biomarkers. 
These include the Fatty Liver Index (FLI), NAFLD Liver Fat Score (NAFLD-LFS), 
Hepatic Steatosis Index (HSI), FIB-4 score and the TyG index (triglyceride × glucose). 
 
Task 
1a. 
To 
connect 
clinical 
markers 
of 
adiposopathy 
with 
renal/hepatic/cardiometabolic function. The clinical markers of adiposopathy will be 
based on anthropometric measures such as weight and body mass index, among 
others.  
 
Task 1b. To establish associations between biochemical (proteomics) biomarkers of 
adiposopathy/inflammation 
and 
renal/hepatic/cardiometabolic 
function. 
The 
biochemical markers will include serum and urinary profile of kidney function 
(creatinine, eGFR, urea, microalbuminuria, protein-creatinine ratio, KIM1, the protein 
Klotho); 
adipokines 
(leptin, 
adiponectin, 
visfatin, 
omentin, 
resistin). 
Serum 
inflammatory markers, such as TNF-α, INF-γ, interleukins (IL-6, IL-8 and IL-10) and 
suPAR, will also be measured. Additionally, the SteatoTest and Fibromax panel will be 
used for a more comprehensive assessment.  
 
• 
Task 1c. To establish a link between imaging (MRI) markers of adiposopathy via 

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assessment of region-specific adipose tissue and renal/hepatic/cardiometabolic 
function. Three region-specific AT will be assessed (perirenal, epicardial and 
steatotic liver), measuring their total volume, fatty acid composition (78) and 
vascularization (79). 
 
WP2. To establish a link between the clinical improvement observed in patients 
receiving GLP-1RA (Semaglutide) and the changes in adiposopathy markers. Patients 
receiving semaglutide or SoC will be invited to participate.  
 
Task 2a. To compare the changes in clinical (anthropometric) markers of 
adiposopathy with GLP-1RA or SoC and correlated with the improvement observed in 
renal, hepatic and cardiometabolic variables. Comparisons will be made at one point in 
time, in which the total body composition measures mentioned above will also be 
correlated with the renal, hepatic and cardiometabolic risk markers.  
 
Task 2b. To make comparisons in biochemical markers of adiposopathy/inflammation 
throughout GLP-1RA or SoC treatment and establish correlations with the changes in 
renal function and cardiometabolic variables. The biochemical markers measured in 
urine and serum will be compared to correlate these differences with the ones in the 
cardiometabolic, hepatic, and renal profile of the patient. 
 
Task 2c. To compare the imaging aspect of each region-specific AT in GLP-1RA or 
SoC regimens and how each one associates with kidney and liver function and 
cardiometabolic markers.  
b. Study Type  
We propose cross sectional, real-life, single-center, and observational study. We will enroll 
patients with diabetic kidney disease at different stages of CKD receiving the GLP-1RA 
Semaglutide or SoC regimen, depending on their medical indication and cardiometabolic 
and hepatic steatosis stage.  
c. Study Population  
Patients will be recruited from the Divisions of Family Medicine, Cardiology, Nephrology, 
Internal Medicine and Endocrinology at the University of Alberta by PR (PI), and 
associates, according to the following selection criteria:

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Inclusion Criteria 
• Patients ≥ 18 years of age. 
• Patients diagnosed with T2DM (>18 months) and CKD in stages G1, G2, G3a, G3b and 
G4; the CKD staging will be established according to the eGFR as per the KDIGO 
guidelines (G1: eGFR ≥90 ml/min/1.73m2; G2: 60-89 ml/min/1.73m2; G3a: 45-59 
ml/min/1.73m2; G3b: 30-44 ml/ min/1.73m2; G4: 15-29 ml/ min/1.73m2).  
• Patients with T2DM and CKD, with or without semaglutide treatment.   
• Patients who voluntarily agree to participate and sign informed consent. 
 
Exclusion Criteria 
• Patients <18 years of age. 
• Pregnant, breastfeeding, or an intention of becoming pregnant or not using adequate 
contraceptive measures (including country-specific adequate measures, if any) 
• Patients diagnosed with T2DM and CKD in stage G5 or stage G4 requiring dialysis as 
per KDIGO guidelines. 
• Previous participation in this trial (screened or randomized)   
• Patients diagnosed with neuropsychiatric diseases that prevent them from understanding 
the benefits/risks associated with the project or voluntarily choosing to participate. 
• Known or suspected allergy to trial medication(s), excipients, or related products  
• Contraindications to study medication(s), worded specifically as stated in the Product 
Monograph 
• Refusal to participate or consent revocation. 
 
d. Withdrawal Criteria  
• The subject may withdraw at will at any time. 
• Consent revocation 
• Patient dies 
e. Diversity and Inclusion  
Effects of gender inclusion in the 
content of the proposal  
• Research focus: The prevalence of T2DM is slightly higher in men than in women. 
However, the latter have a higher risk of suffering cardiovascular events. Nonetheless, the 
effect of GLP-1RA, in terms of glycaemic control and weight loss, is greater in women 
(80). Therefore, the impact of the results derived from this project in terms of improving 
the metabolic profile and adiposopathy and prevention strategies will benefit both sexes 
and genders.  
• Literature review: the literature review carried out on the scientific framework of this 
project includes, for the most part, clinical and preclinical studies with participants of both 
sexes. Some of them also investigate differences in the levels of adipokines linked to 
gender (81), and differences in the effects of GLP-1RA related to sex (80). 

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• Research hypothesis: Our research hypothesis, based on the ability of Semaglutide to 
modify adiposopathy markers and the metabolic profile of patients with T2DM and CKD, is 
aimed at both sexes, being aware that the effects of these drugs may vary in men and 
women. Hormonal variations during the female life stage (menstrual and postmenopausal) 
can influence the metabolic effects derived from Semaglutide. Once the global results of 
the study population have been obtained, a stratified analysis will be carried out 
concerning sex, which will allow us to observe differences in the results between men and 
women. 
• Research methods: the recruitment of patients will ensure that similar populations of 
men and women are obtained, so that solid results differentiated in their magnitude can be 
obtained for both sexes if required. The analytical extractions will have a volume 
proportional to the patient's weight. The participant's hormonal stage will be considered in 
the interpretation of the values of certain parameters, such as adipokines, parathyroid 
hormone, and inflammation parameters. 
• Ethical issues: the particular implications for certain life stages of women have been 
considered, such as pregnancy, which has been excluded from the study due to the 
possible risks of GLP-1RA on the mother and foetus. 
• Dissemination of results: the dissemination of results will be performed in a truthful 
manner, reporting all differences in the results between men and women, providing 
evidence-based explanations related to biological (sex), cultural variations and social 
(gender) status that can justify the observed differences. 
 
PROTOCOL RESEARCH STRATEGY: METHODS 
Section 5 
5.1 Study Procedures/Assessments 
Collection of the following data by research assistants and PI will occur at the time of MRI 
imaging appointment or within 10 days of the imaging visit: 
• Clinical data collection from participants and institutional clinical databases, including 
age, sex, cause and duration of CKD  
• Mean blood pressure value after three consecutive blood pressure measurements. 
• Fasting blood sample collection will be performed by the nursing staff at the hospital 
hospital to measure serum levels of routine renal biomarkers (creatinine, urea, iPTH, 
vitamin D, calcium/phosphate, cystatin C, renin and uric acid) and cardiometabolic 
markers, such as serum total cholesterol, LDL-cholesterol, HDL-cholesterol, VLDL-
cholesterol, apolipoprotein A, triglycerides, glycated hemoglobin (HbA1C), Pro-
adrenomedullin and N-terminal pro b-type natriuretic peptide (NT-proBNP). 
• An additional blood volume (~10mL) will be taken from the same extraction to be 
transported, upon centrifugation, to the laboratories at the University of Alberta to be 
frozen at -80ºC.  
• Morning urinary sample collection to measure standard urinary markers of kidney 
function, 
such 
as 
the 
albumin/creatinine 
ratio, 
microalbuminuria 
and 
the 

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microalbuminuria/creatinine ratio. An additional urine volume is stored at -80ºC in the 
University of Alberta laboratories.The samples from serum/urine stored at University of 
Alberta will be further processed and prepared under the Co-PI’s lead. Aliquots from the 
serum samples will be separated for proteomic analyses through proximity extension 
assay via the Olink® Target 96 (metabolic & cardiovascular panels). This technique will 
allow us to simultaneously obtain a variety of measures, adipokines (adiponectin, leptin, 
visfatin, resistin, omentin), fatty acid-binding protein and inflammatory markers (IL-6, IL-8, 
IL-10, IFN-γ, TNF-α) amongst others. In addition, the Olink® proteomic technique allows 
us to customize a selection of protein biomarkers (Flexi panels) spanning a wide range of 
target areas to evaluate metabolic connections between adiposopathy-related proteins 
and kidney dysfunction. 
The remaining serum aliquots and urine samples will be processed and analyzed at 
University of Alberta to determine the concentrations of Klotho, suPAR and KIM-1 (urine) 
through enzyme-linked immunosorbent assay (ELISA), with the use of commercially 
available kits. 
Imaging methods: 
• Patients will be referred to the University of Alberta imaging centre for the MRI scan. 
Image interpretation will be conducted by experienced radiologists in the field.  
• T1 imaging of the epicardial and PAT and proton density fat fraction (PDFF) imaging of 
the liver will be performed on all patients.  Considering that a decrease in the oxygen 
supply may be related to adipose tissue hypoxia observed in CKD and dysfunctional fat, 
BOLD imaging will also be attempted (this technique is used to measure oxygen 
saturation in the myocardium and has never been attempted on visceral fat before).   
• MRI images will be obtained using a 1.5 Tesla unit (Magnetom Avanto; Siemens 
Medical Solutions, Erlangen, Germany) and a 16-channel body coil with the patient in 
the supine position without sedation. Imaging will be performed in a T2-weighted turbo 
axial and coronal plane (T2W TSE) without fat saturation or apnoea, and a volumetric 
interpolated breath-hold examination (VIBE) with T1 fat-saturated gradient echo 
sequence.  
• All images will be processed with OsiriX MD v.10.0.2 software (UCLA, Pixmeo, Bernex, 
Switzerland) on a MacOS-X radiology workstation (Apple Inc., Cupertino, USA). Slicing 
will be performed on the T2W images to remove artifacts. Measurements in the axial 
plane will be performed in Dixon Fat (DF) and Dixon Water (DW) sequences from an 
appropriate single slice passing through the level of the renal hilum to quantify the PAT.   
• The estimated total radiation dose for MRI is zero and no intravenous or oral contrast 
will be administered to patients. All the MRI images resulting from the study will be 
stored in standard DICOM format for medical imaging information for further processing 
and evaluation. 
5.2 Assessments for Safety  
The proposal has two clear, specific objectives, divided into precise activities (tasks) 
related to the general purpose of this project. The work plan is accordingly divided into two 

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closely related but independent WPs, so that the execution of a WP is not dependent on 
results originating from the other WP, which increases the success of the project. Most of 
the material and technological resources are already available. The research and working 
team are composed of competent professionals with whom the PI and Co-PI, particularly 
the PI, have previously worked as per their joint publications. Continuous monitoring of the 
research progress will be carried out. There are always several people involved in each 
task, with more than one as task leader, ensuring there is always one person available to 
take over the work in case of maternity or sick leave. To ensure homogeneous patient 
recruitment and sample processing, every study member has received proper previous 
training in the selection criteria, study protocol and sample identification for further 
anonymization. A route of action has been laid out (verbally and in written form with 
leaflets) for the laboratory staff to homogenize the sample processing, identification and 
storage process. 
5.3 Study Flowchart  
 
 
 
PROTOCOL RESEARCH STRATEGY: STATISTICAL CONSIDERATIONS 
Section 6 
6.1 Sample Size Calculation 
For the sample size calculation, we assumed a 25% difference in region-specific AT 
(epicardial, hepatic, and perirenal) in patients in treatment with Semaglutide or SoC to be 
clinically relevant. In a two-sided paired-sample T-test, a minimum sample of 48 

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participants achieved 80% power to detect this difference, with a significance level (alpha) 
of 0.05. Considering an estimated 10% dropout rate, 62 participants would be needed. 
The sample size was calculated with the Power Module for JASP software version 
0.19.0.0 (The JASP© Team, Amsterdam, The Netherlands).

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6.2 Statistical Methods 
Descriptive measures will be analyzed using mean (standard deviation) or median 
(standard error), based on their parametric/non-parametric distribution. Analysis of 
variance (ANOVA) tests and/or their non-parametric alternative will be used for 
comparisons, as well as linear regression measures for variable association studies. The 
results will be stratified according to sex and CKD staging, given that the effects observed 
may be greatly influenced by the severity of renal damage. Statistical significance will be 
set for an α-value <0.05. The SPSS for Windows software version 29 (SPSS Inc, 
Chicago, IL, USA) will be used for statistical analysis.  
 
PROTOCOL ETHICS 
Section 7 
7.1 Data Handling and Recordkeeping 
All data is processed anonymously and stored in a central database. All personal data is 
handled in accordance with appropriate national regulations. 
 
7.2 Ethics 
The inclusion of patients and procedures will be carried out in accordance with the 2013 
revision of the Declaration of Helsinki, after signing and accepting the informed consent by 
the patient. 
The SoC and or Semaglutide treatments will be prescribed by the physician in charge in 
accordance with current guidelines and following strict dosage escalation as per Canadian 
medication agency, hence the observational nature of the study. 
Analytical/urinary extractions and other procedures are scheduled at one specific time 
point given that we are recruiting a heterogeneous sample in terms of CKD staging; 
however, they will try to coincide in time with the routine extractions prescribed by the 
physician. Imaging studies will use a non-invasive procedure (MRI) which implies no 
radiation to patients.

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PROTOCOL ADVERSE EVENTS 
Section 8 
8.1 Adverse Event Reporting 
The investigator will inform the subjects and the reviewing accredited medical research 
ethics committee (MREC) if anything occurs, based on which it appears that the 
disadvantages of participation may be significantly greater than were foreseen in the 
research proposal. The study will be suspended pending further review by the accredited 
MREC, except insofar as suspension would jeopardise the subjects’ health. The 
investigator will take care that all subjects are kept informed. 
 
8.2 Adverse Event Definitions  
Adverse events are defined as any undesirable experience occurring to a subject during 
the study, whether or not considered related to the investigational product or 
intervention. Adverse events reported spontaneously by the subject or observed by the 
investigator or his staff will be recorded. 
8.3 Adverse Event Follow-Up  
All AEs will be followed up until they have abated or until a stable situation has been 
reached. Depending on the event, follow-up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist.  
SAEs need to be reported till the end of the study, as defined in the protocol. 
Pregnancy 
Women of childbearing potential will be asked to perform a pregnancy test prior to 
performing the MRI. This test will be provided to each patient.  
 
PROTOCOL PREMATURE STUDY TERMINATION 
Section 9 
9.1 Early Study Termination 
The sponsor will notify the accredited METC and the competent authority of the end of the 
study within a period of 90 days. The end of the study is defined as the last patient’s last 
visit. In case the study is ended prematurely, the sponsor will notify the accredited METC 
and the competent authority within 15 days, including the reasons for the premature 
termination. 
PROTOCOL PUBLICATION PLAN 
Section 10 
10.1 Publication Plan 
 
After the first year of the study, we plan to present our preliminary results in regional 
and national scientific meetings and congresses. The group will also aim to present 

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their preliminary results at the annual World Congress of Nephrology of the International 
Society of Nephrology, Canadian Congress of Cardiology, and American Heart 
Congress, among others. Additionally, we anticipate participation in the European Renal 
Association (ERA) and its weekly bulletin (ERA Renal Week), opening new avenues for 
international collaborations with other research institutions.   
The preliminary results obtained at the end of the first year will be submitted as 
manuscripts to Q1-Q2 ranked open-access journals in the area. The submission of 
manuscripts to D1/Q1-ranked open-access journals, such as Nephrology Dialysis & 
Transplantation and Clinical Kidney Journal, is anticipated between the 2nd and 3rd 
year of the project. 
 
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