CHOlesterol Lowering and Residual Risk in Type 2 Diabetes

Phase 4

Completed

• Conditions: Type 2 Diabetes
• Interventions: Drug: Statin; Drug: PCSK9 inhibitor; Drug: Ezetimibe 10mg

• Registration Number: NCT04369664
• Lead Sponsor: NYU Langone Health

Brief Summary

The purpose of this study is to investigate why individuals with type 2 diabetes are at increased risk for heart disease and stroke. This study will investigate risk factors for heart disease and stroke, including platelet (involved in clotting) activity, inflammation, blood vessel wall function, and genetic information (blueprints of your cells), in participants with type 2 diabetes and elevated cholesterol. This study will also include a control group - subjects with elevated cholesterol who do not have diabetes. All participants will be given cholesterol-lowering medicines (PCSK9 inhibitor and statin or ezetimibe) for 1 month with the same risk factors being measured following cholesterol reduction. This study will help understand why individuals with type 2 diabetes are at higher risk for heart disease and stroke before and even after cholesterol reduction.

Detailed Description

As part of this SFRN investigating REPAIR (non-progression of clinical events or regression of atherosclerosis) in T2D, this project will reveal mechanisms behind the platelet mediated increased cardiovascular risk in patients with T2D by focusing on the platelet transcriptome in those with clinical progression and subsequent cardiovascular events versus those without clinical progression. A prospective clinical study will investigate platelet activity and transcriptome before and after significant cholesterol reduction to better understand mechanisms of increased residual risk observed in patients with T2D, even when cholesterol is not elevated. By combining prospective studies on the platelet phenotype in humans with T2D, mechanistic mouse models of diabetes-accelerated atherosclerosis in the Fisher, Basic Project, and the human plaque and genomic data available data from the Giannarelli, Population Project, the investigators believe the research will fill an important and clinically significant gap in the understanding of how diabetes attenuates cardiovascular repair and to identify new treatment and prevention strategies.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2020-04-27
• Study First Submitted QC: 2020-04-28
• Study First Posted: 2020-04-30
• Study Start: 2020-08-12
• Primary Completion: 2023-09-25
• Study Completion: 2023-10-19
• Results First Submitted: 2024-09-25
• Status Verified: 2024-10
• Results First Submitted QC: 2024-10-16
• Last Update Submitted: 2024-10-16
• Results First Posted: 2024-10-17
• Last Update Posted: 2024-10-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 151

Inclusion Criteria

Subjects with type 2 diabetes:

• Age ≥ 18 & < 90
• LDL-C >100mg/dl
• Able and willing to provide written informed consent for the study

Control subjects without known diabetes:

• Age ≥ 18 & < 90
• LDL-C >100mg/dl or lp(a) >50 mg/dl
• Able and willing to provide written informed consent for the study

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Exclusion Criteria

Subjects with type 2 diabetes:

• Established cardiovascular disease on antithrombotic therapy
• Triglycerides >250mg/dl
• Use of a PCSK9 inhibitor
• HbA1c >10%
• 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 severe bleeding or bleeding disorders
• Chronic kidney disease (CrCl < 30ml/min)

Control subjects without known diabetes:

• Diabetes (type 1 or type 2)
• All other exclusions are identical to the type 2 diabetes group.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Type 2 Diabetes group	Statin	All participants with type 2 diabetes will be given cholesterol-lowering medicine (evolocumab (PCSK9 inhibitor) plus atorvastatin (statin) or ezetimibe (zetia)) for 1 month with the same risk factors being measured following cholesterol reduction. They will be asked to undergo blood draw, to receive study medication, and to undergo additional optional vascular health testing including endothelial cell harvesting and glycocalyx (tongue probe).
Control group	Ezetimibe 10mg	The participants in the control group are subjects with elevated cholesterol who do not have diabetes. All participants will be given cholesterol-lowering medicines (evolocumab (PCSK9 inhibitor) plus atorvastatin (statin) or ezetimibe (zetia)) for 1 month with the same risk factors being measured following cholesterol reduction. They will be asked to undergo blood draw, to receive study medication, and to undergo additional optional vascular health testing including endothelial cell harvesting and glycocalyx (tongue probe).
Type 2 Diabetes group	Ezetimibe 10mg	All participants with type 2 diabetes will be given cholesterol-lowering medicine (evolocumab (PCSK9 inhibitor) plus atorvastatin (statin) or ezetimibe (zetia)) for 1 month with the same risk factors being measured following cholesterol reduction. They will be asked to undergo blood draw, to receive study medication, and to undergo additional optional vascular health testing including endothelial cell harvesting and glycocalyx (tongue probe).
Control group	PCSK9 inhibitor	The participants in the control group are subjects with elevated cholesterol who do not have diabetes. All participants will be given cholesterol-lowering medicines (evolocumab (PCSK9 inhibitor) plus atorvastatin (statin) or ezetimibe (zetia)) for 1 month with the same risk factors being measured following cholesterol reduction. They will be asked to undergo blood draw, to receive study medication, and to undergo additional optional vascular health testing including endothelial cell harvesting and glycocalyx (tongue probe).
Type 2 Diabetes group	PCSK9 inhibitor	All participants with type 2 diabetes will be given cholesterol-lowering medicine (evolocumab (PCSK9 inhibitor) plus atorvastatin (statin) or ezetimibe (zetia)) for 1 month with the same risk factors being measured following cholesterol reduction. They will be asked to undergo blood draw, to receive study medication, and to undergo additional optional vascular health testing including endothelial cell harvesting and glycocalyx (tongue probe).
Control group	Statin	The participants in the control group are subjects with elevated cholesterol who do not have diabetes. All participants will be given cholesterol-lowering medicines (evolocumab (PCSK9 inhibitor) plus atorvastatin (statin) or ezetimibe (zetia)) for 1 month with the same risk factors being measured following cholesterol reduction. They will be asked to undergo blood draw, to receive study medication, and to undergo additional optional vascular health testing including endothelial cell harvesting and glycocalyx (tongue probe).

Primary Outcome Measures

Name	Time	Method
Percent Change in Platelet Activity (MPA) Before and After Cholesterol Reduction	Baseline visit, Follow up visit (4 weeks)	The difference in platelet activity will be assessed by measuring changes in monocyte-platelet aggregates. Monocyte platelet aggregates (MPA) are a robust marker of platelet activity and inflammatory monocytes. The difference in platelet activity before and after cholesterol reduction will be compared using paired t-test or Wilcoxon signed-rank test. The study will also perform a linear mixed model for the multivariate analysis; the primary outcome will be the change in platelet activity (MPA) before and after cholesterol reduction. All tests will be 2-tailed, and a P \<0.05 will be considered as statistically significant. A positive MPA value indicates increased platelet activity, while a negative MPA value indicates decreased platelet activity.
Percent Change in Platelet Activity (LTA) Before and After Cholesterol Reduction	Baseline visit, Follow up visit (4 weeks)	The difference in platelet activity will be assessed by using the light transmission aggregometry test (LTA). Light Transmission Aggregometry \[LTA\] is frequently undertaken as the first test of platelet function, as a screening test for a bleeding disorder and in addition for monitoring of anti-platelet drugs using platelet rich plasma (PRP). The difference in platelet activity before and after cholesterol reduction will be compared using paired t-test or Wilcoxon signed-rank test. We will also perform a linear mixed model for the multivariate analysis; the primary outcome will be the change in platelet activity (LTA) before and after cholesterol reduction. All tests will be 2-tailed, and a P \<0.05 will be considered as statistically significant. A positive value indicates increased platelet activity, while a negative value indicates decreased platelet activity.

Trial Locations

Locations (1)

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