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). 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
300
Semaglutide 3 mg daily - up-titrated to 7 mg daily if well tolerated - up-titrated to 14 mg daily if well tolerated
Dapagliflozin 10 mg daily
Metformin 500 mg daily (up-titrated to 1000 mg daily if indicated)
* cardiological counselling aiming to reduce risk factors of atherosclerosis progression (LDL target, optimal medical therapy, comorbidities management, electrocardiogram) in accordance with current European Society of Cardiology guidelines * dietary counselling * body weight management * advice on optimizing physical activity levels * advice on how to quit smoking if applicable * psychological counselling
National Institute of Cardiology, Department of Coronary Artery and Structural Heart Diseases
Warsaw, Poland
RECRUITINGEvaluation of the effect of GLP-1 analogue treatment on coronary artery disease progression AND Evaluation of the effect of flozin treatment on the progression of coronary artery disease (CO-PRIMARY ENDPOINTS)
Change in % volume of noncalcified atherosclerotic plaque in the coronary arteries assessed by coronary CT versus routine management (intention-to-treat) AND Change in % volume of noncalcified atherosclerotic plaque in the coronary arteries assessed by coronary CT versus routine management (intention-to-treat)
Time frame: 24 months
Evaluation of the effect of each of the tested drugs vs. control group on progression of coronary artery disease
% change in volume of noncalcified atherosclerotic plaque assessed by coronary CT (as treated) between baseline and end of study
Time frame: 24 months
Comparison of the effect of semaglutide vs. flozin on coronary artery disease progression
% change in volume of noncalcified atherosclerotic plaque assessed by coronary CT (intention to treat/as treated) between baseline and end of study
Time frame: 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
Time frame: 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
Time frame: 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 (plaque conversion)
Conversion of non-calcified plaque to calcified plaque assessed by coronary CT (intention to treat/as treated) between baseline and end of study
Time frame: 24 months
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
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
Time frame: 24 months
Evaluation of the effect of each of the tested drugs vs. control group/comparison of the effect of semaglutide vs. flozin on CV risk on pericoronary fat attenuation index
Change in the Pericoronary Fat Attenuation Index assessed by coronary TK (intention-to-treat/as treated) between baseline and end of study
Time frame: 24 months
Evaluation of changes in anthropometric measurements in patients treated with semaglutide vs. patients treated with flozin - body weight
Change in total body mass (expressed in kilograms) (intention-to-treat/as treated) between baseline and end of study
Time frame: 24 months
Evaluation of changes in anthropometric measurements in patients treated with semaglutide vs. patients treated with flozin - body mass index
Change in body mass index (BMI), calculated as following body mass index (BMI) = total body mass / (height)\^2 and expressed in kg/m2 (intention-to-treat/as treated) between baseline and end of study
Time frame: 24 months
Evaluation of changes in anthropometric measurements in patients treated with semaglutide vs. patients treated with flozin - total body fat
Change in totabl body fat mass (expressed in kilograms) measured by bioimpedance analysis (intention-to-treat/as treated) between baseline and end of study
Time frame: 24 months
Evaluation of changes in anthropometric measurements in patients treated with semaglutide vs. patients treated with flozin - body cell mass
Change in Body Cell Mass (BCM) (expressed in kilograms) measured by bioimpedance analysis (intention-to-treat/as treated) between baseline and end of study
Time frame: 24 months
Evaluation of changes in anthropometric measurements in patients treated with semaglutide vs. patients treated with flozin - fat to mass ratio
Change in fat to mass ratio (FMR), calculated as following fat to mass ratoi (FMR) = total body fat (TBF) / skeletal muscle mass measured by bioimpedance analysis (intention-to-treat/as treated) between baseline and end of study
Time frame: 24 months
Evaluation of changes in anthropometric measurements in patients treated with semaglutide vs. patients treated with flozin - visceral fat area
Change in visceral fat area (expressed in cm2) measured by bioimpedance analysis (intention-to-treat/as treated) between baseline and end of study
Time frame: 24 months
Evaluation of changes in anthropometric measurements in patients treated with semaglutide vs. patients treated with flozin - waist-to-hip index
Change in waist-to-hip index (WHI) measured by bioimpedance analysis between baseline and end of study
Time frame: 24 months
Evaluation of change in inflammatory parameters in patients treated with semaglutide vs. patients treated with flozin
Change in concentration of high-sensitivity C-reactive protein between baseline and end of the study
Time frame: 24 months
Evaluation of change in lipid levels in patients treated with semaglutide vs. patients treated with flozin
Change in * total cholesterol * low-density lipoproteins (LDL) * high-density lipoproteins (HDL) * non-HDL cholesterol * triglycerides * lipoprotein A concentrations between baseline and end of the study
Time frame: 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
Time frame: 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
Time frame: 24 months
Evaluation of change in the percentage of patients smoking tobacco or electronic cigarettes in patients treated with semaglutide vs. patients treated with flozin
Change in the percentage of patients smoking tobacco (cigarettes, pipe, cigar, tobacco heating products) or electronic cigarettes as defined by the study protocol between baseline and end of study
Time frame: 24 months
Evaluation of compliance with physical activity recommendations in patients treated with semaglutide vs. patients treated with flozin
Change in * Percentage of patients classified in the "high" physical activity category; * Percentage of patients classified in the "sufficient" physical activity category; * Percentage of patients classified in the "insufficient" physical activity category between baseline and end of study
Time frame: 24 months
Evaluation of dietary compliance in patients treated with semaglutide vs. patients treated with flozin
Change in the Dietary Approaches to Stop Hypertension (DASH) Index between baseline and end of study. For each of the 8 DASH food groups, a score of 10 is assigned when the DASH recommendation is met, lower intakes are scored proportionately, and the 8 individual scores are summed to create the overall DASH adherence score, which could range from 0 to 80. The higher the score, the better the adherence. Reference Günther AL, Liese AD, Bell RA, et al. Association between the dietary approaches to hypertension diet and hypertension in youth with diabetes mellitus. Hypertension. 2009 Jan;53(1):6-12
Time frame: 24 months
Type 2 diabetes diagnosis
Number of patients diagnosed with of diabetes based on the criteria of the Polish Diabetes Association during the study
Time frame: 24 months
Evaluation of the onset of heart failure requiring hospitalization
Number of patients hospitalized for heart failure during the study
Time frame: 24 months
Number of unscheduled hospitalizations
Number of unscheduled hospitalizations during the study
Time frame: 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) during the study
Time frame: 24 months
Homeostatic Model Change Assessment - Insulin Resistance (HOMA-IR)
Change in Homeostatic Model Assessment - Insulin Resistance (HOMA-IR) between baseline and of study
Time frame: 12 and 24 months
Evaluation of change in the concentration of selected oxidative stress markers - catalase
Change in plasma concentration of catalase between baseline and end of study
Time frame: 12 months and 24 months
Evaluation of change in the concentration of selected oxidative stress markers - superoxide dismutase (SOD)
Change in plasma concentration of superoxide dismutase (SOD) between baseline and end of study
Time frame: 12 months and 24 months
Evaluation of change in the concentration of selected oxidative stress markers - Oxygen Radical Absorbance Capacity (ORAC)
Change in concentration of Oxygen Radical Absorbance Capacity (ORAC) between baseline and end of study
Time frame: 12 months and 24 months
Evaluation of change in the concentration of selected oxidative stress markers - total antioxidant capacity (TAC)
Change in concentration of total antioxidant capacity (TAC) between baseline and end of study
Time frame: 12 months and 24 months
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