A Randomized, Open-label, Clinical Trial Evaluating the Anti-atherosclerotic Efficacy of Selected Antidiabetic Drugs in Patients With Coronary Artery Disease and Pre-diabetes
Phase: PHASE4
Conditions: Coronary Artery Disease, PreDiabetes
Sponsor: National Institute of Cardiology, Warsaw, Poland

 
 
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 “CASCADES” CLINICAL TRIAL PROTOCOL SUMMARY 
 
"A randomized, open-label, clinical trial evaluating the anti-atherosclerotic efficacy of selected 
antidiabetic drugs in patients with coronary artery disease and pre-diabetic conditions. CASCADES 
Trial" 
 
 
 
 
 
Date and version number 
Version 2.1 dated 06/09/2024 
Protocol symbol 
CSDS.IV/VIII/2023 
EU CT number 
2023-508525-27-00 
 
Type of test 
non-commercial clinical trial 
Center 
Cardinal Stefan Wyszyński National Institute of Cardiology – 
National Research Institute 
 
Principal investigator 
dr n. med Jan Henzel 
 
Clinic of Coronary Artery Disease and Structural Heart Diseases – 
National Research Institute, ul. Alpejska 42, 04-628 Warsaw, tel. 
+48 22 343-43-42 
Sponsor  
Cardinal Stefan Wyszyński National Institute of Cardiology – 
National Research Institute, ul. Alpejska 42, 04-628 Warsaw, tel. 
+48 22 343-43-42 
Funding organization 
Medical Research Agency, ul. Stanisława Moniuszki 1A, 00-014 
Warsaw 
Project management 
 
Clinical Research Support Center, Cardinal Stefan Wyszyński 
National Institute of Cardiology – National Research Institute, 42 
Alpejska St., 04-628 Warsaw, tel. +48 22 343-40-80; e-mail: 
kkotlinska@ikard.pl 

 
 
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Study title 
A randomized, open-label, clinical trial evaluating the anti-
atherosclerotic 
efficacy 
of 
selected 
antidiabetic 
drugs  
in 
patients 
with 
coronary 
artery 
disease 
and 
pre-diabetic  
conditions. CASCADES Trial. 
Acronym 
CASCADES  
EU CT: 
2023-508525-27 
Sponsor 
Cardinal Stefan Wyszyński National Institute of Cardiology – National 
Research Institute, ul. Alpejska 42, 04-628 Warsaw. 
Researcher 
 
dr n. med. Jan Henzel, Department of Coronary Artery Disease and 
Structural Heart Diseases, Cardinal Stefan Wyszyński National Institute 
of Cardiology – National Research Institute, ul. Alpejska 42, 04-628 
Warsaw, tel. 22 343 34 42, e-mail: jhenzel@ikard.pl 
Research center 
Cardinal Stefan Wyszyński National Institute of Cardiology – National 
Research Institute, ul. Alpejska 42, 04-628 Warsaw. Single-center study. 
Study rationale 
The purpose of the study is to compare the anti-atherosclerotic efficacy 
of oral treatment with a GLP-1 analogue (semaglutide) or an SGLT-2 (so-
called “flozin”) inhibitor (dapagliflozin) versus routine treatment 
(metformin) in patients with pre-diabetes and diagnosed coronary 
artery disease at 24 months.  
The diagnosis of coronary artery disease will be defined as the presence 
of coronary atherosclerosis confirmed by coronary artery computed 
tomography (coronary CT). 
Clinical phase 
IV 
Study 
methodology 
Randomized controlled, open, with two arms of therapeutic 
intervention 
Measurements 
and procedures 
Evaluation of coronary arteries by computed tomography scanning   of 
coronary arteries with contrast 
Pharmacological intervention: flozin 10 mg vs. semaglutide 3 mg – 7 mg, 
14 mg vs. metformin 500 mg – 1000 mg (1:1:1) 
Physical examination 
Laboratory tests (venous blood draw, general urinalysis) 
Measurement of weight, height, blood pressure 
Assessment of body composition by bioimpedance 
Resting 12-lead electrocardiogram 
Non-pharmacological control of coronary heart disease risk factors 
(dietary, anti-smoking and appropriate physical activity counseling) 

 
 
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Inclusion and 
exclusion 
criteria 
Inclusion criteria: 
• Age 18 – 80 
• Diagnosed coronary artery disease (coronary artery stenosis of at 
least 20% with a reference diameter of >2.5 mm or status after 
percutaneous coronary revascularization procedure found on 
coronary CT scan) 
• Coronary CT scan performed <3 months after inclusion in the 
study, at least of good quality 
• Pre-diabetic status defined as fasting blood glucose 100-125 mg% 
or Hba1c 5.70-6.49% (measurement documented at the 
screening/randomization appointment or within 30 days prior to 
the screening/randomization appointment) or documented, 
positive result of an oral glucose load test (fasting blood glucose 
100-125 mg% and 140-199 mg% 2h after a 75 g oral glucose load) 
performed up to 30 days before the screening/randomization 
appointment  
• Stable treatment and control of cardiovascular risk factors, 
including dietary and lifestyle management for at least 4 weeks 
• Willing and able to give informed consent to participate in the study 
• Willing and able, according to the researcher, to comply with all the 
requirements of the study 
 
Exclusion criteria: 
• Severe valvular defect 
• Clinical condition requiring surgical treatment of coronary artery 
disease 
• Status after coronary artery bypass surgery 
• Diagnosed diabetes or Hba1c>=6.5% at screening/randomization 
appointment 
• Other severe medical conditions requiring scheduled hospital 
treatment at the time of the study 
• Severe musculoskeletal conditions requiring specific rehabilitation 
recommendations 
• Diagnosed heart failure 
• Presence of an artificial valve, cardiac pacing system or other 
implantable device (such as a cardioverter defibrillator) 

 
 
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• Severe arrhythmia/unexplained loss of consciousness 
• Other contraindications to physical activity 
• No consent to participate in the study 
• Use of glucose-lowering drugs other than metformin 
• Use of weight-loss drugs 
• Condition after bariatric surgery 
• Diagnosed liver disease or ALT, AST above three times the upper 
limit of normal at screening appointment 
• Uncompensated hyperthyroidism   
• Pancreatic cancer 
• Medullary thyroid cancer 
• History of anaphylactic shock after iodine contrast administration  
• Chronic kidney disease (eGFR <45 ml/min/1.73 m2)  
• History of pancreatitis or active pancreatitis 
• Body mass index (BMI) >40 kg/m2 
• Pregnancy/lactation 
• Participation in another clinical trial 
• Other known contraindications to treatment with metformin, 
dapagliflozin or semaglutide 
Sample size 
300 patients 
Statistical issues The study is exploratory, and the primary analysis is designed to 
separately compare each of the two active groups (treatment: 
semaglutide or dapagliflozin) with the control group (routine treatment 
– metformin). According to the scientific literature, the size of the study 
group was calculated based on a separate comparison of each active 
group with the control group, without adjusting the power ratios 
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534018/). 
We hypothesized that the % change in the volume of non-calcified 
atherosclerotic plaque (final values versus initial values) in each active 
group differed from the control group.  
To determine the sample size, the following assumptions were made 
about treatment efficacy as measured by % change in non-calcified 
plaque volume compared to baseline values:  
Standard deviation of 2.5% for the primary variable.  
Treatment difference of at least 1.2% in non-calcified plaque in favor of 
each study drug compared with the control group.  

 
 
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Taking into account the 7% of patients excluded from the study (no 
follow-up CT scan at month 24), a total sample size of 300 participants 
(282 after withdrawals), with 93 in the semaglutide group, 93 in the 
dapagliflozin group, and 93 in the control group, provides a power of 
0.90 with a two-sided alpha level of 0.05. 
Planned 
study 
duration 
Single participant observation period: 24 months 
 
Project start date 01/09/2023  
Enrolment start date 01/06/2024 
Completion of treatment and observation 01/06/2028 
 
Project completion date 01/08/2029 
Planned 
enrolment 
period 
01/06/2024 – 01/06/2026 
 
Purposes 
Endpoints  
Time 
points 
Co-primary 
Evaluation of the effect of 
GLP-1 analogue treatment on 
coronary 
artery 
disease 
progression 
 
 
 
Evaluation of the effect of 
flozin 
treatment 
on 
the 
progression 
of 
coronary 
artery disease 
Change in % volume of non-
calcified 
atherosclerotic 
plaque in the coronary 
arteries 
assessed 
by 
coronary CT versus routine 
management (intention-to-
treat) 
 
Change in % volume of non-
calcified 
atherosclerotic 
plaque in the coronary 
arteries 
assessed 
by 
coronary CT versus routine 
management (intention-to-
treat) 
24 months 
 
 
 
 
 
 
24 months 

 
 
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Secondary 
Evaluation of the effect of 
each of the tested drugs vs. 
control 
group 
on 
progression 
of 
coronary 
artery disease 
% change in volume of non-
calcified 
atherosclerotic 
plaque 
assessed 
by 
coronary CT (as treated) 
between baseline and end 
of study 
24 months 
Comparison of the effect of 
semaglutide vs. flozin on 
coronary 
artery 
disease 
progression 
% change in volume of non-
calcified 
atherosclerotic 
plaque 
assessed  
by coronary CT (intention to 
treat/as treated) between 
baseline and end of study 
24 months 
Evaluation of the effect of 
each study drug vs. control 
group/comparison of the 
effect of semaglutide vs. 
flozin on progression of 
coronary artery disease 
% change in volume of the 
entire 
atherosclerotic 
plaque 
assessed 
by 
coronary CT) (intention to 
treat/as treated) between 
baseline and end of study 
24 months 
Evaluation of the effect of 
each of the tested drugs vs. 
control group/comparison 
of the effect of semaglutide 
vs. flozin on progression of 
coronary artery disease 
% change in volume of 
individual components of 
atherosclerotic 
plaque 
assessed by coronary CT 
(intention 
to 
treat/as 
treated) between baseline 
and end of study 
24 months 
Evaluation of the effect of 
each of the tested drugs vs. 
control group/comparison 
of the effect of semaglutide 
vs. flozin on progression of 
coronary artery disease   
Conversion of non-calcified 
plaque to calcified plaque 
(change in % volume of 
calcified plaque relative to 
% volume of non-calcified 
plaque) 
assessed 
by 
coronary CT (intention to 
treat/as treated) between 
baseline and end of study 
24 months 

 
 
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Evaluation of the effect of 
each of the tested drugs vs. 
control group/comparison 
of the effect of semaglutide 
vs. 
flozin 
on 
CV 
risk 
expressed as the dynamics 
of high-risk features 
1. Change in the number of 
high-risk 
atherosclerotic 
lesions 
defined 
as 
the 
presence of at least 2 high-
risk features among: 
- Spotty calcifications 
- Low attenuation plaques 
(low attenuation plaque), 
i.e. plaque density < 30 HU 
- positive remodeling 
- napkin ring sign  
assessed by coronary TK 
(intention-to-treat/as 
treated) between baseline 
and end of study; 
24 months 
2. 
Change 
in 
the 
Pericoronary 
Fat 
Attenuation Index assessed 
by coronary TK (intention-
to-treat/as 
treated) 
between baseline and end 
of study 
 
Evaluation 
of 
weight 
change, 
including 
body 
composition, 
in 
patients 
treated with semaglutide vs. 
patients treated with flozin 
- weight 
- body mass index (BMI). 
- fat mass 
- skeletal muscle mass 
- 
Fat-To-Muscle 
Ratio 
(FMR). 
- Body Cell Mass (BCM) 
- Visceral Fat Area (VFA) 
24 months 
Evaluation of waist-to-hip 
index 
(WHI) 
change 
in 
patients 
treated 
with 
semaglutide vs. patients 
treated with phlorizin 
Change in waist-to-hip index 
(WHI) between baseline and 
end of study 
24 months 
Evaluation of change in 
inflammatory parameters in 
patients 
treated 
with 
semaglutide vs. patients 
treated with phlorizin 
Concentration of hsCRP 
24 months 

 
 
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Evaluation of change in lipid 
levels in patients treated 
with 
semaglutide 
vs. 
patients treated with flozin 
- 
total 
cholesterol 
concentration 
- low-density lipoproteins 
(LDL) concentration 
- high-density lipoproteins 
(HDL) concentration 
- 
non-HDL 
cholesterol  
concentration 
- triglycerides concentration 
- 
lipoprotein 
A 
concentration 
24 months 
Evaluation of change in the 
percentage 
of 
glycated 
hemoglobin 
(HBA1c) 
in 
patients 
treated 
with 
semaglutide vs. patients 
treated with flozin 
Change in the percentage of 
glycated 
hemoglobin 
(HBA1c) between baseline 
and end of study 
24 months 
Evaluation of change in the 
percentage of patients with 
normal blood pressure in 
patients 
treated 
with 
semaglutide vs. patients 
treated with flozin 
Change in percentage of 
patients with normal blood 
pressure defined as systolic 
pressure <140 mmHg and 
diastolic 
pressure 
<90 
mmHg between baseline 
and end of study 
 
24 months 
Evaluation of change in the 
percentage 
of 
patients 
currently smoking tobacco 
or electronic cigarettes in 
patients 
treated 
with 
semaglutide vs. patients 
treated with flozin 
Change in the percentage of 
patients currently  smoking 
tobacco (cigarettes, pipe, 
cigar, 
tobacco 
heating 
products) 
or 
electronic 
cigarettes as defined in 
section 
8.7.a 
between 
baseline and end of study 
24 months 
Evaluation of compliance 
with 
physical 
activity 
recommendations 
in 
patients 
treated 
with 
semaglutide vs. patients 
treated with flozin 
- Percentage of patients 
classified in the "high" 
physical activity category; 
- Percentage of patients 
classified in the "sufficient" 
physical activity category; 
24 months 

 
 
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- Percentage of patients 
classified 
in 
the 
"insufficient" 
physical 
activity category 
Evaluation 
of 
dietary 
compliance 
in 
patients 
treated with semaglutide vs. 
patients treated with flozin 
Change in the DASH Index 
between baseline and end 
of study 
24 months 
Type 2 diabetes diagnosis 
Number 
of 
patients 
diagnosed with diabetes-  
based on the criteria of the 
Polish Diabetes Association 
24 months 
Evaluation of the onset of 
heart 
failure 
requiring 
hospitalization 
Number 
of 
hospitalized 
patients for heart failure 
24 months 
Number 
of 
unplanned 
hospitalizations 
Number 
of 
unplanned 
hospitalizations  
24 months 
Number 
of 
major 
cardiovascular events and 
strokes  
(MACCE: death/myocardial 
infarction/revascularization
/stroke) 
separately 
and 
combined 
Number of cardiovascular 
events and strokes (MACCE: 
death/myocardial 
infarction/revascularization
/stroke)  
24 months 
Homeostatic Model Change 
Assessment 
– 
Insulin 
Resistance (HOMA-IR). 
Homeostatic 
Model 
Assessment 
– 
Insulin 
Resistance 
(HOMA-IR) 
Change. 
12-24 
months 
Evaluation of change in the 
concentration of selected 
oxidative stress markers  
Change in concentration of 
selected oxidative stress 
markers: catalase, 
superoxide dismutase 
(SOD), Oxygen Radical 
Absorbance Capacity 
(ORAC), total antioxidant 
capacity (TAC) 
12-24 
months 

 
 
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Results 
The study will evaluate the effect of treatment with flozin vs. 
semaglutide compared to treatment with metformin on the 
progression/regression of coronary atherosclerosis, change in plaque 
character, and control of cardiovascular risk factors in patients with 
non-obstructive coronary artery disease and pre-diabetic status 
Interventions: 
Tested 
medicinal 
product #1 
Dapagliflozin (Forxiga), 10 mg film-coated tablets, oral 
Tested 
drug 
product #2 
Semaglutide (Rybelsus), 3 mg tablets, 7 mg tablets, 14 mg tablets (target 
dose), oral 
Other 
interventions  
Dietary, anti-smoking and appropriate physical activity counseling 
Comparator 
Metformin (Formetic), 500 mg film-coated tablets or 1000 mg film-
coated tablets, oral 
Study schedule 
Month and year of inclusion of the first participant: June 2024 
Month and year of completion of the last participant’s participation: 
June 2028  
A pictorial diagram of the study is shown in Figure 1. A detailed schedule 
of appointments is provided in Section 8.6 (Table 1). 
 
 
 
 
 
 
 
 
 

 
 
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Detailed schedule of appointments 
 
Appointment 
V1 
V2 
V3  
V4  
V5 
V6 
V7  
V8  
V9 
V10 
V11 
V12 
Time window 
(D-Day/W-Week/M-
Month) 
D0 
W2 
(±3 
D) 
M1  
(±3 
D) 
W6 
(±3 
D) 
M2 
(±3 
D) 
M6 
(±3 
D) 
M9 
(±3 
D) 
M12 
(±9D
)  
M15 
(±9D
)  
M18 
(±9D
) 
M21 
(±9D
) 
M24 
(±9D
) 
Clinical 
(K) 
/ 
Prescription 
(R) 
/ 
Telephone (T). 
K 
T 
K 
T 
K 
K 
R 
K 
R 
K 
R 
K 
Cardiology 
consultation  
● 
 
● 
 
● 
● 
 
● 
 
● 
 
● 
Physical examination 
● 
 
● 
 
● 
● 
 
● 
 
● 
 
● 
Presenting 
the 
patient with an offer 
to participate in the 
study. Discussing the 
risks and procedures 
involved 
in 
participating in the 
study. Providing the 
patient 
with 
an 
informed 
consent 
form for participation 
in the study 
● 
 
 
 
 
 
 
 
 
 
 
 
Obtaining consent to 
participate 
in 
the 
study 
● 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Performing an ECG 
● 
 
 
 
 
● 
 
● 
 
● 
 
● 
Collection of blood for 
determination 
of 
blood 
count, 
creatinine/GFR, lipid 
profile, 
glucose, 
Hba1c, 
insulin, 
lipoprotein A, ALT, 
AST, determination of 
TSH 
in 
selected 
patients 
(appointment 
V12); 
determination 
of 
hsCRP, 
HOMA-IR 
oxidative 
stress 
markers 
(appointment V1, V8, 
V12) 
● 
 
● 
 
● 
● 
 
● 
 
● 
 
● 
General urinalysis 
● 
 
● 
 
● 
● 
 
● 
 
● 
 
● 
Taking measurements 
of 
weight, 
height, 
blood pressure, body 
composition, 
abdominal/hip 
circumference 
measurements 
● 
 
● 
 
● 
● 
 
● 
 
● 
 
● 
Assessment 
of 
comorbidities, 
diet 
(history) 
● 
 
● 
 
● 
● 
 
● 
 
● 
 
● 
Assessment 
of 
physical activity levels 
(e.g., using an app 
that 
measures 
physical activity levels 
on 
the 
patient’s 
smartphone or other 
mobile device) 
● 
 
● 
 
● 
● 
 
● 
 
● 
 
● 
Advice 
on 
dietary ● 
 
● 
 
● 
● 
 
● 
 
● 
 
 

 
 
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goals and how to 
achieve them 
Advice on optimizing 
physical activity levels ● 
 
● 
 
● 
● 
 
● 
 
● 
 
 
Advice on how to quit 
smoking 
● 
 
 
 
 
 
 
 
 
 
 
 
Quality-of-life 
assessment – EQ5D-
5L,Seattle 
Angina 
Questionnaire,  
● 
 
● 
 
● 
● 
 
● 
 
● 
 
● 
Randomization 
– 
allocation to the arm 
(experimental 
or 
control, 2:1) and, in 
the 
case 
of 
the 
experimental arm, to 
the appropriate drug 
group 
(flozin 
or 
semaglutide, 
1:1), 
dispensing of the drug 
by support staff 
● 
 
 
 
 
 
 
 
 
 
 
 
Transfer of CT imaging 
data records to the 
central 
imaging 
laboratory (Core Lab) 
for 
independent 
analysis  
● 
 
 
 
 
 
 
 
 
 
 
● 
Evaluation 
of 
the 
occurrence 
of 
endpoints (according 
to the description of 
endpoints, Chapter 6) 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Collection of packages 
of 
drugs 
assigned 
during the previous 
appointment. 
Dispensing of new 
 
 
● 
 
● 
● 
 
● 
 
● 
 
● 

 
 
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drugs (except V12) 
Assessment of the 
regularity 
of 
the 
patient’s drug intake  
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Evaluation 
of 
the 
tolerability 
of 
the 
assigned drugs, taking 
into account potential 
side effects  
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Reminder to follow 
dietary 
recommendations 
and 
maintain 
adequate levels of 
physical activity 
 
● 
 
● 
 
 
● 
 
● 
 
● 
 
Pregnancy test 
● 
 
 
 
 
 
 
 
 
 
 
● 
Coronary CT study 
 
 
 
 
 
 
 
 
 
 
 
● 
Providing 
recommendations for 
treatment 
after 
participation in the 
study 
 
 
 
 
 
 
 
 
 
 
 
● 
Table 1. Detailed scope of activities and procedures performed during appointments