Semaglutide and Vascular Regeneration (SEMA-VR)

July 22, 2023 updated by: Canadian Medical and Surgical Knowledge Translation Research Group

Semaglutide and Vascular Regeneration in People With Diabetes and/or Obesity

SEMA-VR is a prospective, randomized, 6-month long, open-label study of semaglutide. Approximately 100 participants with type 2 diabetes and/or obesity will be randomized (1:1) to receive semaglutide at escalating doses (up to 1.0 mg/week) or usual care without semaglutide for 6 months.

The goal of this trial is to understand how semaglutide exerts cardio-protective effects in people with type 2 diabetes and/or obesity. The main question it aims to answer is:

• Does semaglutide treatment preserve or increase the number of vessel-repairing cells circulating in the blood?

Participants will:

  • Be allocated to receive either semaglutide or usual care for 6 months
  • Provide a blood sample at the baseline visit and another blood sample at the 6-month visit

Researchers will compare participants receiving semaglutide to those receiving usual care for any differences in the 6-month change in the number of vessel-repairing cells in the blood.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The leading cause of death in people with type 2 diabetes (T2D) and/or obesity is atherosclerotic cardiovascular disease (ASCVD). Arterial damage and repair are regulated by mechanisms of vessel homeostasis, which include vasculogenesis (de novo blood vessel synthesis), angiogenesis (vessel formation from pre-existing vessels), and arteriogenesis (re-modelling of collateral vessels). Key cellular modulators of these processes include hematopoietic stem/progenitor cells (HPC) and their myeloid progenies, together referred to as vascular regenerative cells.

An established and innovative multi-parametric flow cytometry assay that utilizes lineage-specific cell surface marker expression and aldehyde dehydrogenase (ALDH) activity will be used to characterize and quantify vascular regenerative cells from peripheral blood samples. Using this assay, three distinct populations of vascular regenerative cells within the hematopoietic hierarchy have been previously identified:

  • ALDHhiSSClow (high ALDH activity, low side scatter/granular complexity) represent primitive progenitor cells, such as HPCs, that secrete chemo-attractant cytokines to recruit other circulating vascular regenerative cells to sites of vessel damage and ischemia.
  • ALDHhiSSCmid cells represent macrophage precursor cells (i.e. monocytes) classified along a spectrum of pro-inflammatory subtypes versus pro-vascular subtypes that remodel arterial occlusions.
  • ALDHhiSSChi cells represent granulocyte precursors, consisting of a heterogeneous group of pro-inflammatory subtypes that aggravate atherosclerosis and endothelial damage, along with pro-angiogenic subtypes that reduce inflammation and support vessel repair.

Using this multi-parametric flow cytometry assay, it has been previously reported that people with T2D presented lower frequencies of vascular regenerative cells in their peripheral blood compared to people without T2D. In addition, these frequencies were increased in response to the antihyperglycemic agent empagliflozin and bariatric surgery, suggesting that this regenerative cell deficiency can be reversed. Specifically, three months after bariatric surgery, frequencies of ALDHhiSSClow primitive progenitor cells and pro-vascular ALDHhiSSCmid monocytes in the peripheral blood were increased, whereas frequencies of pro-inflammatory monocytes and ALDHhiSSChi granulocyte precursors were decreased. These studies established circulating vascular regenerative cells as key mechanistic constituents of vessel homeostasis that can be quantified from readily available blood samples, and highlighted the utility of the multi-parametric flow cytometry assay in providing high-throughput, real-time biological readouts of vascular repair potential or deficiency.

Semaglutide belongs to a drug class known as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RA). Semaglutide mimics the actions of GLP-1, a gut hormone that is released after a meal and triggers a range of metabotropic effects such as elevating insulin release, reducing food motility, and increasing satiety. In landmark clinical trials, weekly semaglutide injections led to a 1.9% reduction in HbA1c, 16% weight loss in adults and teens, and a 26% reduction in major ASCVD events.

The precise mechanism(s) underlying the effect of semaglutide on ASCVD reduction remain poorly defined. In light of previous observations (described above), the investigators hypothesize that in people with T2D, semaglutide add-on to usual care will be superior to usual care alone in the restoration of vascular regenerative cell frequency. Specifically, the investigators predict significantly greater baseline to 6 month increases in the frequency of ALDHhiSSClow primitive progenitor cells and pro-vascular ALDHhiSSCmid monocytes, along with decreases in pro-inflammatory monocytes and ALDHhiSSChi granulocyte precursors in the semaglutide-assigned group compared to the usual care group.

Findings from this study will reveal whether semaglutide affects the quantity of circulating vascular regenerative cells responsible for vessel repair, thereby providing a potential mechanism of action behind the reduction of ASCVD events observed in GLP-1RA cardiovascular outcome trials.

Study Type

Interventional

Enrollment (Estimated)

100

Phase

  • Phase 4

Contacts and Locations

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

Study Contact

Study Locations

  • Canada
    • Ontario
      • North York, Ontario, Canada, M6B 1N6
        • Recruiting
        • North York Diagnostic and Cardiac Centre
        • Contact:
          • Subodh Verma, MD, PhD
      • Scarborough, Ontario, Canada, M1S4N6
        • Recruiting
        • Diagnostic Assessment Centre
        • Contact:
          • Subodh Verma, MD, PhD

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

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Adults ≥ 18 years of age who meet one of the following Health Canada indications to receive subcutaneous semaglutide injections:

    • Documented T2D with inadequate glycemic control
    • Body mass index (BMI) ≥ 30 kg/m^2 (obesity)
    • BMI ≥ 27 kg/m^2 (overweight) and at least one weight-related comorbidity, such as hypertension, dyslipidemia, or obstructive sleep apnea

  2. AND meet one of the following ASCVD criteria:

    • History of ASCVD:

      • Documented coronary artery disease
      • Documented cerebrovascular or carotid disease
      • Documented peripheral artery disease

    • No ASCVD but has 2 or more of the following risk factors:

      • Cigarette smoker or stopped smoking within 3 months of screening
      • Persistent hypertension (defined as office blood pressure ≥ 140/90 mmHg) or currently on antihypertensive medications
      • BMI ≥ 27 kg/m^2
      • estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73m^2
      • Treated or untreated dyslipidemia
      • Triglyceride ≥ 2.0 mmol/L
      • HDL-C ≤ 1.0 mmol/L for men or ≤ 1.3 mmol/L for women
      • High sensitivity C-reactive protein (hsCRP) ≥ 2.0 mg/L
      • Documented micro- or macro-albuminuria
      • Self-identified South Asian ethnicity

Exclusion Criteria:

  • Female subjects who are pregnant, planning pregnancy, or breastfeeding
  • HbA1c > 11.0 %
  • Currently on a GLP-1RA or previously taken a GLP-1RA
  • Personal or family history of medullary thyroid carcinoma
  • Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
  • New York Heart Association class IV symptoms of heart failure
  • Known history of severe liver disease (e.g. Child-Pugh Class B or C)
  • White blood cell count ≥ 15 x 10^9/L
  • Active infectious disease requiring antibiotic or anti-viral agents
  • Known acquired immunodeficiency syndrome such as HIV
  • On oral steroid therapy (e.g. prednisone or other corticosteroids) or other immunosuppressive agents (e.g. methotrexate)
  • Any malignancy not considered cured (except basal cell carcinoma of the skin). A subject is considered cured if there has been no evidence of cancer recurrence for the 5 years prior to screening
  • Any clinically significant or unstable medical condition that might limit one's ability to complete the study or comply with the requirements of the protocol, including: dermatologic disease, hematological disease, pulmonary disease, hepatic disease, gastrointestinal disease, genitourinary disease, endocrine disease, neurological disease, and psychiatric disease

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

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Semaglutide
Participants will receive once-weekly semaglutide subcutaneous injection [Ozempic] at escalating doses from 0.25 mg/week, 0.5 mg/week, to 1.0 mg/week.
Drug: Semaglutide Pen Injector
  • 0.25 mg/week (non-therapeutic dose) during Weeks 1-4
  • 0.50 mg/week during Weeks 5-8
  • 1.0 mg/week during Weeks 9-24

Participants experiencing side effects (e.g. nausea, stomach pain, constipation, diarrhea, vomiting) at the maximum dose (1.0 mg/week) may be down-titrated to 0.50 mg/week.

Participants who had been receiving a dipeptidyl peptidase 4 (DPP-4) inhibitor (sitagliptin, saxagliptin, linagliptin, alogliptin) will stop taking their DPP-4 inhibitor upon randomization to this arm.

Other Names:
  • Ozempic
  • Wegovy
No Intervention: Usual care
Participants will continue to receive other usual medications, rehabilitation, procedures, and interventions as recommended by their healthcare providers.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Changes in the mean frequency (%) of circulating ALDHhiSSClow primitive progenitor cells in individuals treated with semaglutide versus usual care for 6 months
Time Frame: Baseline to 6 months post-randomization
Baseline to 6 months post-randomization

Secondary Outcome Measures

Outcome Measure
Time Frame
Changes in the mean frequency (%) of circulating ALDHhiSSCmid pro-vascular monocytes in individuals treated with semaglutide versus usual care for 6 months
Time Frame: Baseline to 6 months post-randomization
Baseline to 6 months post-randomization
Changes in the frequency (%) of circulating ALDHhiSSCmid pro-inflammatory monocytes in individuals treated with semaglutide versus usual care for 6 months
Time Frame: Baseline to 6 months post-randomization
Baseline to 6 months post-randomization
Changes in the frequency (%) of circulating ALDHhiSSChi pro-inflammatory granulocyte precursors in individuals treated with semaglutide versus usual care for 6 months
Time Frame: Baseline to 6 months post-randomization
Baseline to 6 months post-randomization

Collaborators and Investigators

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

Sponsor

Canadian Medical and Surgical Knowledge Translation Research Group

Collaborators

Unity Health Toronto
Western University, Canada

Investigators

  • Principal Investigator: Subodh Verma, MD, PhD, Unity Health Toronto
  • Principal Investigator: David A Hess, PhD, Robarts Research Institute, London, Ontario
  • Study Chair: David Mazer, MD, Unity Health Toronto
  • Study Chair: Hwee Teoh, PhD, Unity Health Toronto

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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)

April 29, 2023

Primary Completion (Estimated)

December 1, 2024

Study Completion (Estimated)

December 1, 2024

Study Registration Dates

First Submitted

April 28, 2023

First Submitted That Met QC Criteria

May 12, 2023

First Posted (Actual)

May 23, 2023

Study Record Updates

Last Update Posted (Actual)

July 25, 2023

Last Update Submitted That Met QC Criteria

July 22, 2023

Last Verified

July 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pro00068765

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

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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