Cholesterol Lowering and Residual Risk in Diabetes, Type 1

Phase 4

Recruiting

• Conditions: Type 1 Diabetes
• Interventions: Drug: Evolocumab Cartridge; Drug: Atorvastatin Calcium Tablets; Drug: Ezetimibe Tablets; Drug: 18F-FDG; Device: Angiocatheter 20IV; Device: J-Wire; Device: GlycoCheck Glycocalyx Measurement Software

• Registration Number: NCT05641753
• Lead Sponsor: NYU Langone Health

Brief Summary

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.

Study Timeline

• Study First Submitted: 2022-11-29
• Study First Submitted QC: 2022-11-29
• Study Start: 2022-12-06
• Study First Posted: 2022-12-08
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-28
• Last Update Posted: 2025-03-03
• Primary Completion: 2027-07-01
• Study Completion: 2027-07-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 125

Inclusion Criteria

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

   1. 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;

   2. 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;

   3. Diagnosis of T1D and confirmed by review of records by 2 separate clinical members of the study team

2. Age ≥ 18 & < 90

3. LDL-C >100mg/dl

4. Able and willing to provide written informed consent for the study

Exclusion Criteria

1. Established cardiovascular disease on antithrombotic therapy
2. Triglycerides >400mg/dl
3. Use of a PCSK9 inhibitor
4. Recent infection in the past 30 days
5. Any hospitalization in the past 30 days
6. Use of immunosuppressive therapy
7. Use of any antithrombotic therapy
8. Use of aspirin
9. Use of NSAID within the past 72 hours
10. Pregnancy
11. Anemia (hemoglobin < 9 g/dl) or thrombocytopenia (platelet count <75), or thrombocytosis (platelet count >600)
12. A history of hemorrhagic diathesis
13. Chronic kidney disease (CrCl < 30ml/min)
14. 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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
4-Week LDL-Cholesterol (LDL-C)-Reduction Treatment	Evolocumab Cartridge	Treatment consists of: Evolocumab (140 mg; 2 injections, one administered at baseline visit and another self-administered 2 weeks later), and; Atorvastatin (up to 80mg dose; 1 tab per day for 30 days, starting at baseline visit post-assessment). Participants with statin intolerance will be provided with a 1-month supply of ezetimibe 10 mg to replace Evolocumab and Atorvastatin. * Additional procedures: Blood draws. * Optional procedures: Glycocalyx testing, PET/CT, or Endothelial Cell Collection.
4-Week LDL-Cholesterol (LDL-C)-Reduction Treatment	Ezetimibe Tablets	Treatment consists of: Evolocumab (140 mg; 2 injections, one administered at baseline visit and another self-administered 2 weeks later), and; Atorvastatin (up to 80mg dose; 1 tab per day for 30 days, starting at baseline visit post-assessment). Participants with statin intolerance will be provided with a 1-month supply of ezetimibe 10 mg to replace Evolocumab and Atorvastatin. * Additional procedures: Blood draws. * Optional procedures: Glycocalyx testing, PET/CT, or Endothelial Cell Collection.
4-Week LDL-Cholesterol (LDL-C)-Reduction Treatment	Atorvastatin Calcium Tablets	Treatment consists of: Evolocumab (140 mg; 2 injections, one administered at baseline visit and another self-administered 2 weeks later), and; Atorvastatin (up to 80mg dose; 1 tab per day for 30 days, starting at baseline visit post-assessment). Participants with statin intolerance will be provided with a 1-month supply of ezetimibe 10 mg to replace Evolocumab and Atorvastatin. * Additional procedures: Blood draws. * Optional procedures: Glycocalyx testing, PET/CT, or Endothelial Cell Collection.
4-Week LDL-Cholesterol (LDL-C)-Reduction Treatment	J-Wire	Treatment consists of: Evolocumab (140 mg; 2 injections, one administered at baseline visit and another self-administered 2 weeks later), and; Atorvastatin (up to 80mg dose; 1 tab per day for 30 days, starting at baseline visit post-assessment). Participants with statin intolerance will be provided with a 1-month supply of ezetimibe 10 mg to replace Evolocumab and Atorvastatin. * Additional procedures: Blood draws. * Optional procedures: Glycocalyx testing, PET/CT, or Endothelial Cell Collection.
4-Week LDL-Cholesterol (LDL-C)-Reduction Treatment	GlycoCheck Glycocalyx Measurement Software	Treatment consists of: Evolocumab (140 mg; 2 injections, one administered at baseline visit and another self-administered 2 weeks later), and; Atorvastatin (up to 80mg dose; 1 tab per day for 30 days, starting at baseline visit post-assessment). Participants with statin intolerance will be provided with a 1-month supply of ezetimibe 10 mg to replace Evolocumab and Atorvastatin. * Additional procedures: Blood draws. * Optional procedures: Glycocalyx testing, PET/CT, or Endothelial Cell Collection.
4-Week LDL-Cholesterol (LDL-C)-Reduction Treatment	Angiocatheter 20IV	Treatment consists of: Evolocumab (140 mg; 2 injections, one administered at baseline visit and another self-administered 2 weeks later), and; Atorvastatin (up to 80mg dose; 1 tab per day for 30 days, starting at baseline visit post-assessment). Participants with statin intolerance will be provided with a 1-month supply of ezetimibe 10 mg to replace Evolocumab and Atorvastatin. * Additional procedures: Blood draws. * Optional procedures: Glycocalyx testing, PET/CT, or Endothelial Cell Collection.
4-Week LDL-Cholesterol (LDL-C)-Reduction Treatment	18F-FDG	Treatment consists of: Evolocumab (140 mg; 2 injections, one administered at baseline visit and another self-administered 2 weeks later), and; Atorvastatin (up to 80mg dose; 1 tab per day for 30 days, starting at baseline visit post-assessment). Participants with statin intolerance will be provided with a 1-month supply of ezetimibe 10 mg to replace Evolocumab and Atorvastatin. * Additional procedures: Blood draws. * Optional procedures: Glycocalyx testing, PET/CT, or Endothelial Cell Collection.

Primary Outcome Measures

Name	Time	Method
Change in Monocyte Platelet Aggregation (MPA) from Baseline	Baseline, Week 4	Measurement of platelet activity. Assessed via patient blood sample.
Change in Light Transmission Aggregation (LTA) from Baseline	Baseline, Week 4	Measurement of platelet activity. Assessed via patient blood sample.

Secondary Outcome Measures

Name	Time	Method
Percent Change in Natural Killer (NK) Cell Population from Baseline	Baseline, Week 4	Assessed via patient blood sample.
Percent Change in Dendritic Cell Population from Baseline	Baseline, Week 4	Assessed via patient blood sample.
Percent Change in CD8 Cell Population from Baseline	Baseline, Week 4	Assessed via patient blood sample.

Trial Locations

Locations (4)

New York VA Hospital; 🇺🇸 New York, New York, United States

NYC Health + Hospitals/Bellevue; 🇺🇸 New York, New York, United States

Mount Sinai School of Medicine; 🇺🇸 New York, New York, United States

NYU Langone Health; 🇺🇸 New York, New York, United States