Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05071417 |
| Other study ID # |
SEPLA |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
November 2021 |
| Est. completion date |
December 2025 |
Study information
| Verified date |
September 2021 |
| Source |
Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León |
| Contact |
Leopoldo Pérez de Isla, MD |
| Phone |
+34609084225 |
| Email |
leopisla[@]hotmail.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The main objective of this trial is to evaluate the effect of Semaglutide on the burden of
coronary atherosclerosis, based on the change in Percent Atheroma Volume (PAV) by quantifying
atheroma plaque throughout the coronary tree based on the analysis of CCTA in asymptomatic
subjects with T2D in optimized and stable treatment with Semaglutide.
Description:
Patients with type 2 diabetes mellitus (DM2) are considered to be at high vascular risk (VR).
However, the VR risk may vary, depending on the presence of other cardiovascular risk factors
(CVRFs), particularly dyslipidemia, smoking habit, hypertension, and obesity. High blood
glucose levels are part of the etiopathogenic basis of atherosclerosis, whose vascular
complications are the leading cause of death and disability in developed countries.
Atherosclerosis is considered a chronic immunoinflammatory process with a polygenic and
multifactorial origin that begins early due to vascular endothelial dysfunction.
Atherosclerosis is a dynamic process that develops intermittently over time; periods of
inactivity and rapid evolution are interspersed and modulated by environmental and genetic
factors. As a result of a series of etiopathogenic and environmental factors, lesions
(plaques) develop with greater or lesser lipid content, collagen, elastic fibers, and
calcium. The location and degree of development of atherosclerotic plaques give rise to
different forms of atherosclerotic disease, which is characterized by symptoms and signs that
correspond to the obstruction of the vascular lumen with decreased flow and the consequent
occurrence of (possibly chronic) ischemia. Atherosclerotic disease can also be characterized
by the rupture of the plaque and the appearance of thrombotic phenomena (because the lipid
nucleus of the plaque is highly thrombogenic and triggers the activation of the coagulation
and platelet adhesion and aggregation cascades), with manifestations of acute ischemia.
The relationship between the composition of the atheroma plaque and the occurrence of
cardiovascular events, revealed the need for imaging techniques that could identify not only
the degree of stenosis of atherosclerotic lesions, but also their volume, composition and
levels of inflammation, and thus being able to identify the possible high-risk plaques
(vulnerable plaques). Within imaging techniques, there are invasive ones such as coronary
angiography or coronary angiography, ultrasound or intravascular ultrasound (IVUS) and
optical coherence tomography (OCT); and non-invasive, such as magnetic resonance imaging
(MRI), positron emission tomography (PET), and computed tomography.
Invasive coronary angiography has traditionally been the reference imaging test to determine
the degree of stenosis and continues to be the procedure of choice for the evaluation of
coronary anatomy and the identification of atherosclerotic lesions. Angiography provides
information on the number and size of vascular stenosis but does not allow to know the plaque
composition. Provides Simply an image of the internal arterial lumen but lacks the ability to
adequately represent the vessel wall with its developing atherosclerotic plaque.
Intravascular ultrasound (IVUS) is considered the reference method for the evaluation of
atherosclerotic plaque burden and plaque characteristics. However, IVUS is an invasive method
that has risks, cannot be used to study the entire coronary tree, only in one segment of the
arterial tree and is not indicated for asymptomatic individuals.
The IVUS technique plus virtual histology allows the identification of atheroma plaques in
the vascular tree, and can quantify the size, volume, composition and distribution of the
plaque. However, a limitation of this technique is the ability of the ultrasound signal to
penetrate the calcified tissue, resulting in an acoustic shadow after the calcified tissue.
Currently, with the new advances in the development of cardiac imaging techniques, coronary
computed tomographic angiography (CCTA) has been incorporated as a non-invasive and easily
applied method for direct visualization of coronary arteries without the need to introduce a
catheter The image study of the coronary vessels by CCTA has been proposed as a suitable
method for the qualitative detection of changes in the vessel wall, allowing the evaluation
of the coronary arteries and the characterization of the atherosclerotic plaque.
In the last decade, several advances have been seen in CCTA that have made it one of the key
diagnostic instruments for the non-invasive evaluation of coronary atherosclerosis in
patients with a low to intermediate probability of coronary heart disease. CCTA may be useful
for prognostic classification together with classic CVRF in patients with intermediate
cardiovascular risk, for more accurate reclassification and as a screening for the early
diagnosis of coronary atherosclerotic disease in certain groups of patients at special risk.
Previous studies have shown that CCTA is comparable to IVUS for the classification of
atheroma plaques. CCTA, therefore, emerges as a non-invasive alternative for plaque
characterization compared to other techniques such as IVUS.
Coronary CCTA has established itself as a reliable and accurate tool for the detection of
coronary atherosclerotic plaque and stenosis. Since CCTA provides information about plaque
burden and the characteristics of high-risk plaques, the addition of these parameters to the
traditional interpretation of CCTA, which is limited to the detection of stenosis, could
improve the efficiency of this method for the early detection of coronary heart disease.
Plaque characteristics are usually analyzed in a qualitative (subjective) way. This
limitation can be solved through the use of new analytical platforms that allow automated
quantification of the characteristics of the coronary plaque with high accuracy and
reproducibility. In this context, software tools have been developed for the automated
quantification of atheroma plaques in CCTA images. In this area, the QAngio CT (Medis medical
imaging system, the netherlans) stands out, a software tool designed to perform quantitative
analysis of images in CCTA data sets. In the CCTA data sets, the software is able to detect
the contours of the vessel wall and the lumen, which are used for automated quantitative
evaluations of coronary plaques. As for the characterization of the atherosclerotic plaque,
the software is able to analyze virtual histology, differentiating between what is the mean,
fibrous plaque, fibro-fatty, necrotic and calcified, with its consequent prognostic
implication. The parameters of the entire coronary tree are obtained independently: vessel
length, plaque burden, plaque volume, maximum thickness of the plaque, volume and percentage
of fibrous plaque, fibro-fatty plaque, necrotic plaque and calcium plaque, maximum stenosis
by area and by diameter. This software tool has a number of advantages over the analysis
based on the IVUS. First, the non-invasiveness of the CCTA technique based on which this tool
performs quantitative plaque analysis allows a consecutive analysis with a lower risk than
that of IVUS. In addition, previous studies have demonstrated the correlation between QAngio
CT and IVUS-based analysis regarding the area of lumen stenosis, plaque burden and remodeling
index. On the other hand, although IVUS is the reference method for plaque quantification, it
has the limitation of analyzing only a specific segment of the coronary tree, while QAngio CT
allows the complete analysis of the coronary tree. In an evaluation study of atheroma plaque,
this method could provide information not only on the size of the plaque, but also on the
characteristics of the plaque.
The change in plaque volume has been used successfully to monitor plaque progression in
studies with IVUS. Using IVUS, plaque volumes are calculated as the difference between the
area of the outer elastic membrane and the lumen area for successive cross sections of a
coronary artery. The difference between the volume of the vessel and the volume of the lumen
constitutes the total volume of the plaque. From these volumes, other parameters such as the
plaque burden or percentage of atheroma volume (PVA) or the total volume of atheroma (VTA)
can be derived, being PVA the most reproducible and the molt related to cardiovascular
prognosis.
Furthermore, recent studies have correlated the evaluation of the radiographic
characteristics of plaque (Virtual histology) with the patient's prognosis. The QAngio CT
provides an automated evaluation of the characteristics of the complete coronary tree plate
based on radiological densities.
The prevention and treatment of DM2 should be considered an essential part of atherosclerotic
disease. Throughout numerous and extensive clinical trials, it has been shown that reductions
in blood glucose and HbA1c levels lead to reductions in cardiovascular risks. This knowledge
suggests that atherosclerosis can be influenced by DM2 treatment.
Numerous studies have shown the beneficial effects of Glucagon-like peptide-1 (GLP-1) in the
control of different cardiovascular pathologies and other effects beyond glycemic control,
such as high blood pressure, weight control, and lipid metabolism. In addition to effects
that are tangible in clinical practice, drugs that affect GLP-1 have been shown to have
anti-atherosclerotic effects, due to the control of VR factors, or direct effects at the
endothelial level. GLP-1-mediated decreases in atherosclerosis biomarkers, e.g., B-type
natriuretic peptide (BNP), plasminogen activator inhibitor (PAI-1) and C- reactive protein
(PCR), among others, have been observed. One of the parameters studied to validate this
improvement in the progression of atherosclerosis has been the improvement in the control of
the thickness of the carotid intima, which has clear benefits; however, studies in other
vascular beds, such as the coronary, are more limited in terms of both numbers of
participants and results.
The effect of semaglutide, a GLP-1 agonist, on the progression of atheroma plaque lesions has
been published. Studies in animal models have shown that semaglutide treatment reduced
progression by anti-inflammatory mechanisms, independent of weight loss and glycemic control.
Semaglutide treatment in SUSTAIN6, as well as liraglutide treatment in LEADER, showed a
benefit against placebo in major adverse cardiac events (MACE) (HR [95% confidence interval
(CI)]: 0.87 [0.78; 0.97] LEADER and 0.74 [0.58; 0.95] SUSTAIN 6) in patients with
atherosclerotic disease with or without previous ischemic events. The authors can affirm,
after reviewing the literature, that the effect of GLP-1 on atheroma plaque is not
definitively known but instead speculated on based on results in animal models and derived,
to a large extent, from cardiovascular findings in clinical trials.
