Overview

Type II diabetes mellitus (T2DM) is a chronic disease associated with a very high risk of developing cardiovascular (CV) events, especially because of its long-term effects. Glucagon-like-peptide-1 receptor agonists (GLP1-RAs) are recommended in subjects suffering from T2DM with a history or at risk for CV disease; however there is a lack of evidence on local actions of GLP1-RAs on inflammation and endothelial function.

The STABLE-GLP1 study aims to evaluate, in patients with T2DM without atherosclerotic cardiovascular disease (ASCVD) or severe target-organ damage (TOD), the possible beneficial effect of semaglutide, a GLP1-AR, on clinical prognosis, inflammatory and endothelial biomarkers.

The STABLE-GLP1 trial is a phase IV interventional, national, multicenter, randomized, pragmatic study, aiming at enrolling 80 patients with T2DM and no ASCVD. Participants will be randomized in 1:1 ratio to receive semaglutide in addition to standard therapy or standard therapy alone, according to body mass index (BMI) category (BMI \<30 vs. ≥30 kg/m²). All patients will perform clinical visit, ECG, echocardiography, blood sample collection for endothelial and inflammatory biomarkers dosage at baseline, at 26 weeks, and after 52 weeks of treatment. Data from CTA, performed according to clinical practice before enrollment, will be recorded and retrospectively evaluated to test secondary outcomes.

Eligibility

Inclusion Criteria:

• Age ≥ 18 years.
• Diagnosis of T2DM in patients without ASCVD or severe TOD but with SCORE2-Diabetes ≥10% with clinical indication in accordance with current guidelines \[1\] to initiate semaglutide therapy (level of evidence IIa).
• Evaluable, pre-randomization CTA with no evidence of stenosis ≥50% of epicardial coronary vessels, as confirmed by the core laboratory, performed within 2 years prior to inclusion.
• Stable clinical conditions, with controlled blood pressure, lipid profile, and glycemic values, based on assessments performed within 4 weeks prior to inclusion.
• Stable antidiabetic treatment for at least 6 weeks.
• Left ventricular ejection fraction ≥50%.
• For female participants, the participant must not be pregnant or lactating and must be of non-childbearing potential, confirmed at enrollment by one of the following:

  (a) Postmenopausal, defined as amenorrhea for ≥12 months following cessation of fall exogenous hormonal treatments, and with luteinizing hormone and follicle stimulating hormone levels in the postmenopausal range. (b) Documentation of irreversible surgical sterilization by hysterectomy bilateral oophorectomy, or bilateral salpingectomy. Tubal ligation is not considered as irreversible surgical sterilization.

• Ability to understand study procedures and sign informed consent.

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

• Age \> 85 years.
• Previous treatment with semaglutide or GLP1-RAs.
• Patients with stenosis of epicardial coronary arteries ≥50%.
• eGFR \<45 mL/min/1.73 m2 irrespective of albuminuria or eGFR 45-59 mL/min/1.73 m2 and microalbuminuria (UACR 30-300 mg/g; stage A2) or proteinuria (UACR \>300 mg/g; stage A3) or presence of microvascular disease in at least three different sites \[e.g. microalbuminuria (stage A2) plus retinopathy plus neuropathy\], based on assessments performed within 4 weeks prior to inclusion.
• History of any clinically important disease or disorder which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, or influence the results or the participant's ability to participate in the study.
• Any history of ASCVD.
• Ongoing New York Heart Association Class IV (heart failure (HF).
• Significant valvulopathy.
• Type 1 diabetes mellitus.
• Hypersensitivity to the active substance or to any of the excipients.
• Known or suspected liver disease, defined by serum transaminase and alkaline phosphatase levels 3 times the normal level.
• Patients with acute inflammatory or infectious diseases during the 3 months prior to inclusion in the study.
• Patients with chronic inflammatory, immune or infectious diseases.
• Patients with a history of cancer within the past 5 years.
• History of alcohol, drug or medication abuse.
• Patients exposed to any other type of radiation, medical or professional.
• Clinically relevant haematological disorders.
• Decompensated metabolic disorders.
• Abuse of alcohol or drugs in the previous 3 months.