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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Type 2 Diabetes group | Experimental | 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 | Other | 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Statin | Drug | Participants will be given up to 80 mg oral tablets daily for the entire study period preferably at the same time each day. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change in Platelet Activity (MPA) Before and After Cholesterol Reduction | 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. | Baseline visit, Follow up visit (4 weeks) |
| Percent Change in Platelet Activity (LTA) Before and After Cholesterol Reduction | 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. | Baseline visit, Follow up visit (4 weeks) |
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Inclusion Criteria:
Subjects with type 2 diabetes:
Control subjects without known diabetes:
Exclusion Criteria:
Subjects with type 2 diabetes:
Control subjects without known diabetes:
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| Name | Affiliation | Role |
|---|---|---|
| Jeffrey Berger, MD | NYU Langone Health | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| NYU Langone Health | New York | New York | 10016 | United States |
Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
The investigator who proposed to use the data and upon reasonable request. Requests should be directed to jeffrey.berger@nyulangone.org. To gain access, data requestors will need to sign a data access agreement.
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| ID | Title | Description |
|---|---|---|
| FG000 | Type 2 Diabetes Group | 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). Statin: Participants will be given up to 80 mg oral tablets daily for the entire study period preferably at the same time each day. PCSK9 inhibitor: Participants will receive 2 injections of 140 mg of PCSK9 inhibitor, one will be administered at baseline visit and the other will be self-administered 2 weeks later at home. Ezetimibe 10mg: Participants who are not able to or not willing to take atorvastatin will be given 10 mg ezetimibe oral tablets daily for the entire study period preferably at the same time each day. |
| FG001 | Control Group | 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). Statin: Participants will be given up to 80 mg oral tablets daily for the entire study period preferably at the same time each day. PCSK9 inhibitor: Participants will receive 2 injections of 140 mg of PCSK9 inhibitor, one will be administered at baseline visit and the other will be self-administered 2 weeks later at home. Ezetimibe 10mg: Participants who are not able to or not willing to take atorvastatin will be given 10 mg ezetimibe oral tablets daily for the entire study period preferably at the same time each day. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Type 2 Diabetes Group | 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). Statin: Participants will be given up to 80 mg oral tablets daily for the entire study period preferably at the same time each day. PCSK9 inhibitor: Participants will receive 2 injections of 140 mg of PCSK9 inhibitor, one will be administered at baseline visit and the other will be self-administered 2 weeks later at home. Ezetimibe 10mg: Participants who are not able to or not willing to take atorvastatin will be given 10 mg ezetimibe oral tablets daily for the entire study period preferably at the same time each day. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percent Change in Platelet Activity (MPA) Before and After Cholesterol Reduction | 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. | Posted | Median | Inter-Quartile Range | percent change in platelet aggregation | Baseline visit, Follow up visit (4 weeks) |
|
1 month
Participants were asked about side effects/any changes in health during weekly follow-up phone calls and during follow-up visit(s). Feedback from participants was recorded in the case report form and discussed with PI during weekly team meetings and/or immediately if participant had an urgent concern.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Type 2 Diabetes Group | 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). Statin: Participants will be given up to 80 mg oral tablets daily for the entire study period preferably at the same time each day. PCSK9 inhibitor: Participants will receive 2 injections of 140 mg of PCSK9 inhibitor, one will be administered at baseline visit and the other will be self-administered 2 weeks later at home. Ezetimibe 10mg: Participants who are not able to or not willing to take atorvastatin will be given 10 mg ezetimibe oral tablets daily for the entire study period preferably at the same time each day. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jeffrey Berger, MD | NYU Langone Health | 212-263-4004 | jeffrey.berger@nyulangone.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 28, 2023 | Sep 24, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D019161 | Hydroxymethylglutaryl-CoA Reductase Inhibitors |
| D000069059 | Atorvastatin |
| C577155 | evolocumab |
| D000069438 | Ezetimibe |
| ID | Term |
|---|---|
| D000924 | Anticholesteremic Agents |
| D000960 | Hypolipidemic Agents |
| D000963 | Antimetabolites |
| D045504 | Molecular Mechanisms of Pharmacological Action |
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|
| PCSK9 inhibitor | Drug | Participants will receive 2 injections of 140 mg of PCSK9 inhibitor, one will be administered at baseline visit and the other will be self-administered 2 weeks later at home. |
|
|
| Ezetimibe 10mg | Drug | Participants who are not able to or not willing to take atorvastatin will be given 10 mg ezetimibe oral tablets daily for the entire study period preferably at the same time each day. |
|
|
| BG001 | Control Group | 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). Statin: Participants will be given up to 80 mg oral tablets daily for the entire study period preferably at the same time each day. PCSK9 inhibitor: Participants will receive 2 injections of 140 mg of PCSK9 inhibitor, one will be administered at baseline visit and the other will be self-administered 2 weeks later at home. Ezetimibe 10mg: Participants who are not able to or not willing to take atorvastatin will be given 10 mg ezetimibe oral tablets daily for the entire study period preferably at the same time each day. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
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).
Statin: Participants will be given up to 80 mg oral tablets daily for the entire study period preferably at the same time each day.
PCSK9 inhibitor: Participants will receive 2 injections of 140 mg of PCSK9 inhibitor, one will be administered at baseline visit and the other will be self-administered 2 weeks later at home.
Ezetimibe 10mg: Participants who are not able to or not willing to take atorvastatin will be given 10 mg ezetimibe oral tablets daily for the entire study period preferably at the same time each day.
| OG001 | Control Group | 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). Statin: Participants will be given up to 80 mg oral tablets daily for the entire study period preferably at the same time each day. PCSK9 inhibitor: Participants will receive 2 injections of 140 mg of PCSK9 inhibitor, one will be administered at baseline visit and the other will be self-administered 2 weeks later at home. Ezetimibe 10mg: Participants who are not able to or not willing to take atorvastatin will be given 10 mg ezetimibe oral tablets daily for the entire study period preferably at the same time each day. |
|
|
| Primary | Percent Change in Platelet Activity (LTA) Before and After Cholesterol Reduction | 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. | Posted | Median | Inter-Quartile Range | percent change in MPAs | Baseline visit, Follow up visit (4 weeks) |
|
|
|
| 0 |
| 75 |
| 0 |
| 75 |
| 37 |
| 75 |
| EG001 | Control Group | 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). Statin: Participants will be given up to 80 mg oral tablets daily for the entire study period preferably at the same time each day. PCSK9 inhibitor: Participants will receive 2 injections of 140 mg of PCSK9 inhibitor, one will be administered at baseline visit and the other will be self-administered 2 weeks later at home. Ezetimibe 10mg: Participants who are not able to or not willing to take atorvastatin will be given 10 mg ezetimibe oral tablets daily for the entire study period preferably at the same time each day. | 0 | 75 | 0 | 75 | 30 | 75 |
| Muscle Cramps | General disorders | Systematic Assessment |
|
| Site Injection Discomfort or Reaction | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Flu Like Symptoms | General disorders | Systematic Assessment |
|
| Headache | Nervous system disorders | Systematic Assessment |
|
| Dizziness | Ear and labyrinth disorders | Systematic Assessment |
|
| Other symptoms of upset stomach (Including nausea, indigestion or constipation) | General disorders | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Joint Pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Back Pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Leg pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Discomfort at site of IV insertion | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Increases in blood sugar | Endocrine disorders | Systematic Assessment |
|
| Hair loss | General disorders | Systematic Assessment |
|
| Trouble sleeping/vivid dreams | General disorders | Systematic Assessment |
|
| Brain fog | General disorders | Systematic Assessment |
|
| Bilateral leg swelling | General disorders | Systematic Assessment |
|
| Swollen lymph node reported | Immune system disorders | Systematic Assessment |
|
| Hand swelling | General disorders | Systematic Assessment |
|
| Tremors | Nervous system disorders | Systematic Assessment |
|
| Hives or Welts | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Sinus infection | Infections and infestations | Systematic Assessment |
|
| Strep infection | Infections and infestations | Systematic Assessment |
|
| Covid infection | Infections and infestations | Systematic Assessment |
|
| Migraine | Nervous system disorders | Systematic Assessment |
|
| ER visit due to work injury | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| ER visit/urgent care due to injury caused by fall | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Relapse of existing depression | Psychiatric disorders | Systematic Assessment |
|
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| D004700 | Endocrine System Diseases |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D004791 | Enzyme Inhibitors |
| D057847 | Lipid Regulating Agents |
| D045506 | Therapeutic Uses |
| D011758 | Pyrroles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006538 | Heptanoic Acids |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| D001384 | Azetidines |
| D001385 | Azetines |