Molecular Mechanisms and Carotid Atherosclerosis

August 1, 2022 updated by: Celestino Sardu, University of Campania "Luigi Vanvitelli"

Molecular Mechanisms Implied in Carotid Atherosclerosis and Atherosclerotic Plaque Progression in Patients Normoglycemics vs. Patients With Diabetes Mellitus

The role of methylase system and Proprotein convertase subtilisin/kexin type 9 (PCSK9) in the accelerated atherosclerotic progression of diabetic patients is unclear. Authors will evaluate methylase activity and PCSK9 in carotid plaques of asymptomatic diabetic and non diabetic patients, as well as the effect of statin added to PCSK9 inhibitors (PCSK9i) therapy vs. statin alone in diabetic plaques. Plaques will be obtained from 43 type 2 diabetic and 30 non diabetic patients undergoing carotid endarterectomy. Diabetic patients will receive statin therapy (n 23) or statin plus PCSK9i (140 mg of evolocumab; n 20) or placebo (n 23) for 4 months before scheduled endarterectomy. Plaques will be analyzed for macrophages (CD68), T-cells (CD3), inflammatory cells (HLADR), methylase activity, nuclear factor (NF)-KB, tumor necrosis factor (TNF)-alpha, nitrotyrosine, matrix metalloproteinase (MMP) and collagen content (immunohistochemistry and enzyme- linked immunosorbent assay. Authors' study hypothesis is that methylase and PCSK9 over-activity will be associated with enhanced inflammatory reaction and NF-KB expression in diabetic plaques. Secondly, the inhibition of methylase activity in atherosclerotic lesions of diabetic patients by metformin plus SLGT2i might be associated with morphological and compositional characteristics of a potential stable plaque phenotype, possibly by down regulating NF-KB-mediated inflammatory pathways.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Diabetes Mellitus (DM) leads to increased vulnerability for plaque disruption and mediates increased incidence and severity of clinical events. Inflammation, particularly in diabetes, plays a central role in the cascade of events that result in plaque erosion and fissuring. There is emerging evidence that the methylase system might be involved in both initial stage and progression of atherosclerosis. Moreover, the methylase system might be involved in inflammatory/oxidative stress pathway, involved for activation of nuclear factor kappa B (NF-KB), and other proteins linked to over inflammation/oxidative stress. Although it has been demonstrated that diabetes may up regulate these inflammatory/oxidative pathway, still no evidence exists about the potential role of methylase system in the evolution of atherosclerotic plaques of diabetic patients. Conversely, less data have been reported about the possible modulation of these pathways by drugs as PCSK9i. However, in the present study authors hypothesized that by increasing methylase activity, diabetes may enhance the inflammatory potential of atherosclerotic plaques favoring instability, and its relation with the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9). Therefore, authors designed this study to identify differences in inflammatory infiltration as well as methylase activity and PCSK9 expression between carotid plaques of asymptomatic diabetic and non diabetic (normoglycemics) patients. Because experimental and pathological studies suggest that activation of methylase system might control inflammation/oxidative stress, the present study also evaluated the effect of the statin added to PCSK9i (vs. statin alone) on methylase activity and PCSK9 expression in carotid plaques of diabetic patients.

Study Type

Observational

Enrollment (Actual)

76

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Naples, Italy, 80138
        • Raffaele Marfella

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Study population will be divided in 30 normoglycemics patients vs. 46 DM patients. DM patients will be divided in patients previous treated by oral daily statin therapy (23 patients) vs. DM patients (n 20) previous treated by daily statin therapy plus 140 mg twice a month of PCSK9i. All patients will be affected by severe obstructive carotid artery atherosclerosis.

Description

Inclusion Criteria:

  • evidence of carotid artery atherosclerosis with endoluminal stenosis > 60%;
  • aged >18 years.
  • aged <75 years

Exclusion Criteria:

  • insulin dependent DM;
  • absence of carotid artery atherosclerosis with endoluminal stenosis > 60%;

  • contraindication to receive a carotid artery revascularization treatment;

    --contraindication to receive metformin treatment;

  • controindication to receive PCSK9i treatment;
  • neoplastic diseases;

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
normoglycemics
In this cohort will be enrolled 30 normoglycemics patients affected by carotid artery atherosclerotic and evidence of atherosclerotic plaque causing an endolumninal stenosis > 60%. These patients will receive a surgical intervention to remove the atherosclerotic plaque and to revascularize the obstructed coronary artery vessel.
patients with diabetes mellitus (DM) treated with statin
In this cohort will be enrolled 23 DM patients affected by carotid artery atherosclerotic and evidence of atherosclerotic plaque causing an endolumninal stenosis > 60%. These patients will receive a surgical intervention to remove the atherosclerotic plaque and to revascularize the obstructed coronary artery vessel.
patients with diabetes mellitus (DM) treated with statin plus PCSK9i
In this cohort will be enrolled 20 DM patients affected by carotid artery atherosclerotic and evidence of atherosclerotic plaque causing an endolumninal stenosis > 60%. These patients will receive a surgical intervention to remove the atherosclerotic plaque and to revascularize the obstructed coronary artery vessel. These patients were treated before the surgical intervention by statin therapy daily (n 20) added to PCSK9i, 140 mg twice a month (n 30).
Drug: statin Oral Tablet plus PCSK9i
Patients in the third study cohort will receive for statin oral therapy plus 140 mg twice a month PCSK9i therapy via subcutaneous injection before to practice surgical intervention for carotid artery obstruction.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
methylase status
Time Frame: 12 months
to evaluate the activity (over vs. hypo activation) of methylase complex in atherosclerotic carotid plaques of normoglycemics vs. DM patients, and of DM patients treated with statin vs. DM patients previous treated by statin plus PCSK9i
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Campania "Luigi Vanvitelli"

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

January 1, 2015

Primary Completion (ACTUAL)

January 1, 2017

Study Completion (ACTUAL)

January 1, 2018

Study Registration Dates

First Submitted

May 22, 2019

First Submitted That Met QC Criteria

May 22, 2019

First Posted (ACTUAL)

May 24, 2019

Study Record Updates

Last Update Posted (ACTUAL)

August 3, 2022

Last Update Submitted That Met QC Criteria

August 1, 2022

Last Verified

August 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SecondUNI 22.05.2019

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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