Molecular Mechanisms and Carotid Atherosclerosis

• ClinicalTrials.gov Identifier: NCT03962686
• Recruitment Status: Completed
• First Posted: May 24, 2019
• Last Update Posted: July 26, 2021
• Sponsor: University of Campania "Luigi Vanvitelli"
• Information provided by (Responsible Party): Celestino Sardu, University of Campania "Luigi Vanvitelli"

Study Description

Brief Summary:

The role of methylase system in the accelerated atherosclerotic progression of diabetic patients is unclear. Authors will evaluate methylase activity in carotid plaques of asymptomatic diabetic and non diabetic patients, as well as the effect of metformin added to sodium glucose transporter 2 inhibitors (SLGT2i) therapy vs. metformin 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 1000 mg of metformin (n 23) or 1000 mg of metformin plus SGLT2i (100 mg of canagliflozin; 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 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.

Condition or disease	Intervention/treatment
Diabetes Mellitus, Type 2; Atherosclerosis of Artery; Atherosclerotic Plaque	Drug: MetFORMIN 1000 Mg Oral Tablet plus SLGT2i

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 hypoglycemic drugs as SLGT2i. However, in the present study authors hypothesized that by increasing methylase activity, diabetes may enhance the inflammatory potential of atherosclerotic plaques favoring instability. Therefore, authors designed this study to identify differences in inflammatory infiltration as well as methylase activity 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 metformin added to SLGT2i (vs. metformin alone) on methylase activity in carotid plaques of diabetic patients.

Study Design

• Study Type: Observational
• Actual Enrollment: 76 participants
• Observational Model: Case-Control
• Time Perspective: Prospective
• Official Title: Molecular Mechanisms Implied in Carotid Atherosclerosis and Atherosclerotic Plaque Progression in Patients Normoglycemics vs. Patients With Diabetes Mellitus
• Actual Study Start Date: January 1, 2015
• Actual Primary Completion Date: January 1, 2017
• Actual Study Completion Date: January 1, 2018

Groups and Cohorts

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 metformin; 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 metformin plus SLGT2i; 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 metformin 1000 mg daily (n 20) added to SLGT2i, 100 mg daily (n 30).	Drug: MetFORMIN 1000 Mg Oral Tablet plus SLGT2i; Patients in the third study cohort will receive for 4 months a 1000 mg metformin oral therapy plus 100 mg SLGT2i oral therapy before to practice surgical intervention for carotid artery obstruction.

Outcome Measures

Primary Outcome Measures :

1. 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 vs. DM patients previous treated by metformin.

Biospecimen Retention:   Samples With DNA

samples of atherosclerotic plaques obtained during revascularization of carotid arteries.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• 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 1000 mg daily of metformin (23 patients) vs. DM patients (n 20) previous treated by 1000 mg daily of metformin plus 100 mg daily of SLGT2i. All patients will be affected by severe obstructive carotid artery atherosclerosis.

Criteria

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 SLGT2i treatment;
• neoplastic diseases;

Contacts and Locations

Locations

Italy

Raffaele Marfella

Naples, Italy, 80138

Sponsors and Collaborators

University of Campania "Luigi Vanvitelli"

More Information

• Responsible Party: Celestino Sardu, clinical professor, University of Campania "Luigi Vanvitelli"
• ClinicalTrials.gov Identifier: NCT03962686
• Other Study ID Numbers: SecondUNI 22.05.2019
• First Posted: May 24, 2019
• Last Update Posted: July 26, 2021
• Last Verified: July 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Carotid Artery Diseases; Atherosclerosis; Diabetes Mellitus; Diabetes Mellitus, Type 2; Plaque, Atherosclerotic; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metformin; Hypoglycemic Agents; Physiological Effects of Drugs