Type 2 Diabetes
Conditions
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.
Interventions
DRUGStatin
Participants will be given up to 80 mg oral tablets daily for the entire study period preferably at the same time each day.
DRUGPCSK9 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.
DRUGEzetimibe 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.
Sponsors
NYU Langone Health
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 89 Years
Healthy volunteers
Yes
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
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 75 |
| 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. | 75 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Type 2 Diabetes Group | Total | Control Group |
|---|---|---|---|
| Age, Continuous | 52.2 years STANDARD_DEVIATION 13.88 | 49.96 years STANDARD_DEVIATION 14.68 | 47.72 years STANDARD_DEVIATION 15.49 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants | 26 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 60 Participants | 124 Participants | 64 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 23 Participants | 15 Participants |
| Race (NIH/OMB) Black or African American | 31 Participants | 39 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 8 Participants | 2 Participants |
| Race (NIH/OMB) White | 27 Participants | 75 Participants | 48 Participants |
| Region of Enrollment United States | 75 participants | 150 participants | 75 participants |
| Sex: Female, Male Female | 47 Participants | 87 Participants | 40 Participants |
| Sex: Female, Male Male | 28 Participants | 63 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 75 |
| other Total, other adverse events | 37 / 75 | 30 / 75 |
| serious Total, serious adverse events | 0 / 75 | 0 / 75 |
Outcome results
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.
Time frame: Baseline visit, Follow up visit (4 weeks)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Type 2 Diabetes Group | Percent Change in Platelet Activity (LTA) Before and After Cholesterol Reduction | -74 percent change in MPAs |
| Control Group | Percent Change in Platelet Activity (LTA) Before and After Cholesterol Reduction | -76 percent change in MPAs |
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.
Time frame: Baseline visit, Follow up visit (4 weeks)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Type 2 Diabetes Group | Percent Change in Platelet Activity (MPA) Before and After Cholesterol Reduction | -5 percent change in platelet aggregation |
| Control Group | Percent Change in Platelet Activity (MPA) Before and After Cholesterol Reduction | -7 percent change in platelet aggregation |