Cholesterol Lowering and Residual Risk in Diabetes, Type 1

Official title

CHORD1 - CHOlesterol Lowering and Residual Risk in Diabetes, Type 1

Overview

This is a prospective, interventional, cohort study, meaning that researchers will follow and observe a group of enrolled study participants over a period of time (one to two months) to gather information and record any developments of the outcomes in question. This study will recruit 125 participants with Type 1 Diabetes (T1D) to: 1. Analyze the effect of reducing the cholesterol levels in the blood on platelet function. (Platelets are small cells in the blood which help form blood clots to slow or stop bleeding and to help wounds heal 2. Analyze the effect of reducing the cholesterol levels in the blood on While Blood Cell (WBC) gene expression, (White Blood Cells are part of the body's immune system which help the body fight infection and other diseases) and 3. Analyze the effect of reducing the cholesterol levels in the blood on vascular or blood vessel function.

Detailed description

Participants will receive weekly injections of PCSK9i (evolocumab) plus daily, oral pills of atorvastatin or ezetimibe for 1 month.

Participants will undergo blood draw, and optional vascular studies that include:

* Glycocalyx testing (A non-invasive test where a video microscope camera is placed under the tongue to capture images of the movement of red blood cells as they travel through the micro-blood vessels) * PET/CT for vascular imaging - to assess any inflammation of blood vessels and to evaluate increased metabolism in related tissues, and * Endothelial cell collection before cholesterol reduction and 1-month after cholesterol reduction to measure any genetic changes in in the endothelial cells before and after collection

Glycemic Variability (GV), the amount one's blood sugar changes throughout the day, will be analyzed from continuous glucose monitoring (CGM) data.

Interventions

• Drug Evolocumab Cartridge
  Injectable PCSK9 inhibitor.
• Drug Atorvastatin Calcium Tablets
  HMG-CoA reductase inhibitor for oral use.
• Drug Ezetimibe Tablets
  Will only be distributed to patients with statin intolerance; replacement for both Atorvastatin and Evolocumab. Inhibitor of intestinal cholesterol for oral use.
• Drug 18F-FDG
  Optional procedure. Positron emission tomography (PET) and computed tomography (CT) imaging to assess vascular inflammation and related anatomy requires injection of the PET tracer 18F-FDG. 18F-FDG is an FDA-approved analogue of sugar, routinely used to evaluate elevated metabolism in tissues, including increased metabolism due to inflammatory cells. A standard dose of 7.0 mSv will be administered.
• Device Angiocatheter 20IV
  Optional procedure (endothelial cell harvesting). An angiocatheter ≤ 21 gauge will be inserted into a peripheral vein on the upper extremity using aseptic technique. A 0.018in. diameter J-shaped wire (Arrow, Reading, PA) will be then advanced into the angiocatheter, to a distance of 4cm beyond the end of the angiocatheter.
• Device J-Wire
  Optional procedure (endothelial cell harvesting). Either a 0.021in. diameter J-shaped wire (Daig, Minnetonka, MN) or a 0.018in. diameter J-shaped wire (Arrow, Reading, PA) will be used.
• Device GlycoCheck Glycocalyx Measurement Software
  Optional procedure (assessment of vascular function). Video microscope developed by GlycoCheck.

Primary outcome measures

• Change in Monocyte Platelet Aggregation (MPA) from Baseline [Time frame: Baseline, Week 4]
• Change in Light Transmission Aggregation (LTA) from Baseline [Time frame: Baseline, Week 4]

Secondary outcome measures (3)

• Percent Change in Natural Killer (NK) Cell Population from Baseline [Time frame: Baseline, Week 4]
• Percent Change in Dendritic Cell Population from Baseline [Time frame: Baseline, Week 4]
• Percent Change in CD8 Cell Population from Baseline [Time frame: Baseline, Week 4]

Eligibility criteria

Inclusion criteria

• Participants with previous diagnosis of T1D (as defined by American Diabetes Association or judgment of physician for at least 1 year)

• American Diabetes Association Criteria for diagnosis of diabetes (Must meet at least 1 of the following criteria):

• i. FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hours, OR;
• ii. 2-h PG ≥200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water, OR;
• iii. A1C ≥6.5% (48 mmol/mol), OR;
• iv. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L), AND;
• History of T1D (due to autoimmune β-cell destruction, usually leading to absolute insulin deficiency, including latent autoimmune diabetes of adulthood). Autoimmune markers include islet cell autoantibodies and autoantibodies to GAD (glutamic acid decarboxylase, GAD65), insulin, the tyrosine phosphatases islet antigen 2 (IA-2) and IA-2β, and zinc transporter 8, OR;
• Diagnosis of T1D and confirmed by review of records by 2 separate clinical members of the study team
• Age ≥ 18 \& < 90
• LDL-C >100mg/dl
• Able and willing to provide written informed consent for the study

Exclusion criteria

• Established cardiovascular disease on antithrombotic therapy
• Triglycerides >400mg/dl
• Use of a PCSK9 inhibitor
• Recent infection in the past 30 days
• Any hospitalization in the past 30 days
• Use of immunosuppressive therapy
• Use of any antithrombotic therapy
• Use of aspirin
• Use of NSAID within the past 72 hours
• Pregnancy
• Anemia (hemoglobin < 9 g/dl) or thrombocytopenia (platelet count <75), or thrombocytosis (platelet count >600)
• A history of hemorrhagic diathesis
• Chronic kidney disease (CrCl < 30ml/min)
• T2D, monogenic diabetes syndromes, or diabetes in the context of disease of the exocrine pancreas (such as pancreatitis, trauma or pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Other

Study locations

United States · 4 centers

• New York VA Hospital — New York
• NYC Health + Hospitals/Bellevue — New York
• NYU Langone Health — New York
• Mount Sinai School of Medicine — New York

Identifiers

NCT: NCT05641753 · 22-01095

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗