Cardiovascular Disease, Inflammation, Macrophage Infiltration
Conditions
Keywords
cardiometabolic complications
Brief summary
People living with human immunodeficiency virus infection (HIV) have 2-4fold greater risk for developing diabetes and heart disease than the general population. They need safe and effective treatments that reduce the risk for developing diabetes and heart disease, and improve their quality of life. This project will explore whether a new anti-diabetes medication (Januvia) with a novel mechanism of action reduces inflammation, and improves blood vessel function in HIV infected men and women with several risk factors for developing cardiovascular disease.
Detailed description
People living with human immunodeficiency virus (HIV+) infection have a 2-fold greater prevalence and incidence of T2DM and cardiovascular disease (CVD) than the general population. The investigators lack safe and effective treatments for these HIV related cardiometabolic complications despite the fact that HIV infected adults represent an ideal clinical population in which to study interactions among chronic low-grade pro-inflammatory processes that are linked to the development of adipose accumulation, insulin resistance, ß-cell secretory failure, vascular endothelial dysfunction, atherosclerosis and CVD. Dipeptidyl peptidase-IV (DPP4)-inhibitors represent a new drug class that safely and effectively regulate glycemia in T2DM, but have not been adequately tested in HIV. Of note, pre-clinical studies suggest that DPP4-inhibitors have several pleiotropic actions that may specifically benefit people living with HIV infection. For example, DPP4 inhibition reduced adipose macrophage infiltration & inflammation and increased the number of bone-derived endothelial progenitor cells in the circulation. Our preliminary findings indicate that DPP4 inhibition is virologically and immunologically safe in non-diabetic HIV+ adults taking combination antiretroviral therapy (in preparation), but the potential pleiotropic benefits have not been examined in HIV. The investigators propose a randomized, double blind, placebo controlled physiological study to test 2 potential pleiotropic benefits of DPP4 inhibition (100 mg sitagliptin/d, 8 wk): reduce circulating and adipose-specific markers of inflammation; and increase endothelial progenitor cell numbers used for vascular repair in 36 HIV+ adults with insulin resistance, central adiposity and CVD risk factors. The investigators hypothesize that sitagliptin will reduce circulating cytokine levels, reduce adipose tissue macrophage number and inflammation, and increase the number of circulating endothelial progenitor cells in HIV infected men and women. These physiological studies will advance our understanding about the efficacy of DPP4 inhibition in this high-risk group, and may help prevent the inexorable transition from insulin resistance to T2DM and CVD in HIV infected men and women.
Interventions
DRUGSitagliptin
Oral, 100 mg/day for 2 months
DRUGPlacebo
oral, matching placebo daily for 2 months
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 18-65 yr old HIV infected men and women. * Stable (at least the past 6 months) on combined antiretroviral therapy (cART). * Stable immune (\> 300 CD4+ T-cells/µL) and virologic (\< 50 copies HIV RNA/mL) status. * Insulin resistant/impaired glucose tolerance (fasting glucose 100-125mg/dL, or 2-hr glucose 140-200mg/dL or fasting HOMA-IR= 2.5-6.0). * Waist circumference \> 102 cm (men), \> 88 cm (women). * BMI \> 20 kg/m2. * Fasting hypertriglyceridemia \> 150 mg/dL. * Low HDL-cholesterol (\< 40 mg/dL in men or \< 50 mg/dL in women). * Platelet count \> 30,000/mm3. * Absolute neutrophil count \> 750/mm3. * Transaminases \< 2.5x the upper limit of normal. * Long-term non-progressors (not taking anti-HIV medications) are not eligible.
Exclusion criteria
* Diabetes (T2DM, IDDM or diabetic ketoacidosis) or taking any glucose-lowering medication (e.g., insulin, TZDs, metformin, sulfonylurea). * Any agent that might artifactually alter glycemic control (e.g., glucocorticoids, megace, rhGH, GH-secretagogue, testosterone derivatives, creatine monohydrate, chromium picolinate, AA/protein supplements, medium- or long-chain fatty acids) during 6 months prior to or during enrollment. * History of serious CV disease. NYHA Functional Class III or IV (e.g., recent MI, unstable angina, edema, CHF, CAD, CABG, stroke, resting hypertension \> 160/95 mmHg), irregular heart rhythm, resting ST-segment depression \> 1mm). Treatment with medications for CV condition (e.g., α- or ß-blockers). Some BP-lowering medications (Ca++channel blocker, diuretic, or ACE inhibitor) are permitted. * Moderate to severe renal insufficiency. Serum creatinine \> 1.7 mg/dL (men) \> 1.5 mg/dL (women). * Plan or anticipate a change in anti-HIV medications during the study. * Lipid-lowering medications are permitted (fibrate or statin or niacin), but must be stable on that agent for at least 6 months prior to enrollment. Lipid-lowering agents cannot be started during the treatment period. * Chronic hepatitis B (HBV-surface antigen positive). Active hepatitis C (detectable Hep C RNA). * Positive urine drug test for opiates, methamphetamine, heroin, cocaine. Active substance abuse that the MD-scientist believes may compromise safety, compliance, interfere with study drug or data interpretation. * Hematocrit \< 34% in men or \< 25% in women with symptoms (fatigue, tired-legs, shortness of breath). Hemoglobin \< 10 gm/dL with symptoms. * Pregnant or nursing mothers. Women must agree to use an acceptable form of birth control during the study. If using birth control pills-must be stable on this medication for at least 6 months prior to enrollment. * Active malignancy or treatment with chemotherapeutic agents or radiation therapy or any cytokine or anti-cytokine therapy during 6 months prior to enrollment. * History of pancreatitis * \> 10% unintentional weight loss during the 6 months prior to enrollment. * Reduced cognitive function/unable to provide voluntary informed consent. Prisoners are excluded. * Blinded investigational drugs for 3 months prior to enrollment that will not be unblinded before enrollment. * Nausea, vomiting, diarrhea (\> 4 loose stools/day) that are unresponsive to treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Inflammatory Biomarker 1: Plasma hsCRP Concentration | 2 months | Fasting serum and plasma samples obtained at baseline and week 8 are batched for ELISA analysis (end of sudy) of hsCRP, IL-6 and D-dimer concentrations. |
| Inflammatory Biomarker 2: Plasma IL-6 Concentration | 2 months | There are 3 levels of the primary outcome measure; hsCRP, IL-6, and D-dimer concentrations measured at baseline and week 8 |
| Inflammatory Biomarker 3: Serum D-dimer Concentration | 2 months | There are 3 levels of the primary outcome measure, hsCRP, IL-6, and D-dimer |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fold Change in Adipose Inflammation Marker CCL2 (MCP-1) mRNA Expression | Baseline to 2 months | Adipose tissue from obese, insulin resistant subjects is characterized by increased macrophage infiltration and overexpression of inflammatory cytokines/chemokines. In adipose samples, mRNA expression for the macrophage inflammation marker CCL2 (MCP-1) was quantified. Fold change between population averages from baseline to 2 months for adipose macrophage CCL2 (MCP-1) mRNA expression is the outcome measure. |
| Percent Change in Blood Endothelial Progenitor Cells | Baseline to 2 months | Monocytes (PBMC) are isolated from 20 mL blood. CD34+/VEGFR2+/KDR+ monocytes represent cell markers for endothelial progenitor cells (EPC). CD34+/VEGFR2+/KDR+ monocytes are counted (flow cytometry) and expressed as a percentage of PBMC number. Percent change between population averages from baseline to 2 months for the EPC/PBMC ratio is calculated and reported as the outcome measure. |
Countries
United States
Participant flow
Recruitment details
38 participants were initially enrolled. 1 was lost to follow-up; 1 started a personal exercise training program while enrolled in the study. Any data collected on these 2 participants were excluded from the analysis. Both were initially enrolled in the placebo group.
Pre-assignment details
36 participants completed the trial with complete data.
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin 100 mg sitagliptin/day for 2 months
Sitagliptin: Oral, 100 mg/day for 2 months | 18 |
| Placebo Matching placebo daily for 2 months
Placebo: oral, matching placebo daily for 2 months | 18 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Sitagliptin | Placebo |
|---|---|---|---|
| Age, Continuous | 51 years STANDARD_DEVIATION 7 | 49 years STANDARD_DEVIATION 9 | 52 years STANDARD_DEVIATION 6 |
| Body mass index | 32.9 kg/m^2 STANDARD_DEVIATION 8.2 | 32.7 kg/m^2 STANDARD_DEVIATION 8.2 | 33.1 kg/m^2 STANDARD_DEVIATION 8.2 |
| CD4+ T-cell count | 668 cells/µL STANDARD_DEVIATION 219 | 731 cells/µL STANDARD_DEVIATION 220 | 606 cells/µL STANDARD_DEVIATION 218 |
| CD8+ T-cell count | 909 cells/µL STANDARD_DEVIATION 418 | 1017 cells/µL STANDARD_DEVIATION 542 | 801 cells/µL STANDARD_DEVIATION 294 |
| Diastolic blood pressure | 76 mmHg STANDARD_DEVIATION 10 | 74 mmHg STANDARD_DEVIATION 9 | 78 mmHg STANDARD_DEVIATION 10 |
| HIV duration | 14.6 years STANDARD_DEVIATION 6.2 | 14.9 years STANDARD_DEVIATION 5.8 | 14.2 years STANDARD_DEVIATION 7.5 |
| Race/Ethnicity, Customized African American | 23 participants | 16 participants | 7 participants |
| Race/Ethnicity, Customized Caucasian | 13 participants | 2 participants | 11 participants |
| Region of Enrollment United States | 36 participants | 18 participants | 18 participants |
| Sex: Female, Male Female | 10 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Male | 26 Participants | 13 Participants | 13 Participants |
| Systolic blood pressure | 125 mmHg STANDARD_DEVIATION 14 | 124 mmHg STANDARD_DEVIATION 15 | 127 mmHg STANDARD_DEVIATION 14 |
| Waist circumference | 109 cm STANDARD_DEVIATION 22 | 106 cm STANDARD_DEVIATION 19 | 112 cm STANDARD_DEVIATION 23 |
| Weight | 100 kg STANDARD_DEVIATION 25 | 97 kg STANDARD_DEVIATION 21 | 102 kg STANDARD_DEVIATION 29 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 18 | 8 / 20 |
| serious Total, serious adverse events | 0 / 18 | 0 / 20 |
Outcome results
Primary
Inflammatory Biomarker 1: Plasma hsCRP Concentration
Fasting serum and plasma samples obtained at baseline and week 8 are batched for ELISA analysis (end of sudy) of hsCRP, IL-6 and D-dimer concentrations.
Time frame: 2 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sitagliptin | Inflammatory Biomarker 1: Plasma hsCRP Concentration | Baseline | 3.4 mg/L | Standard Deviation 3.2 |
| Sitagliptin | Inflammatory Biomarker 1: Plasma hsCRP Concentration | Week 8 | 2.9 mg/L | Standard Deviation 2.6 |
| Placebo | Inflammatory Biomarker 1: Plasma hsCRP Concentration | Baseline | 5.4 mg/L | Standard Deviation 4.5 |
| Placebo | Inflammatory Biomarker 1: Plasma hsCRP Concentration | Week 8 | 7.4 mg/L | Standard Deviation 5.8 |
p-value: 0.006t-test, 2 sided
Primary
Inflammatory Biomarker 2: Plasma IL-6 Concentration
There are 3 levels of the primary outcome measure; hsCRP, IL-6, and D-dimer concentrations measured at baseline and week 8
Time frame: 2 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sitagliptin | Inflammatory Biomarker 2: Plasma IL-6 Concentration | Baseline | 1.36 pg/mL | Standard Deviation 0.74 |
| Sitagliptin | Inflammatory Biomarker 2: Plasma IL-6 Concentration | Week 8 | 1.30 pg/mL | Standard Deviation 0.55 |
| Placebo | Inflammatory Biomarker 2: Plasma IL-6 Concentration | Baseline | 2.61 pg/mL | Standard Deviation 1.91 |
| Placebo | Inflammatory Biomarker 2: Plasma IL-6 Concentration | Week 8 | 2.65 pg/mL | Standard Deviation 1.83 |
p-value: 0.24t-test, 2 sided
Primary
Inflammatory Biomarker 3: Serum D-dimer Concentration
There are 3 levels of the primary outcome measure, hsCRP, IL-6, and D-dimer
Time frame: 2 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sitagliptin | Inflammatory Biomarker 3: Serum D-dimer Concentration | Baseline | 0.32 µg FEU/mL | Standard Deviation 0.2 |
| Sitagliptin | Inflammatory Biomarker 3: Serum D-dimer Concentration | Week 8 | 0.33 µg FEU/mL | Standard Deviation 0.24 |
| Placebo | Inflammatory Biomarker 3: Serum D-dimer Concentration | Baseline | 0.28 µg FEU/mL | Standard Deviation 0.15 |
| Placebo | Inflammatory Biomarker 3: Serum D-dimer Concentration | Week 8 | 0.31 µg FEU/mL | Standard Deviation 0.2 |
p-value: 0.78t-test, 2 sided
Secondary
Fold Change in Adipose Inflammation Marker CCL2 (MCP-1) mRNA Expression
Adipose tissue from obese, insulin resistant subjects is characterized by increased macrophage infiltration and overexpression of inflammatory cytokines/chemokines. In adipose samples, mRNA expression for the macrophage inflammation marker CCL2 (MCP-1) was quantified. Fold change between population averages from baseline to 2 months for adipose macrophage CCL2 (MCP-1) mRNA expression is the outcome measure.
Time frame: Baseline to 2 months
Population: Adipose tissue samples were not available from all participants. This secondary outcome includes fewer participants analyzed than the primary outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Fold Change in Adipose Inflammation Marker CCL2 (MCP-1) mRNA Expression | -2.5 fold change |
| Placebo | Fold Change in Adipose Inflammation Marker CCL2 (MCP-1) mRNA Expression | -0.4 fold change |
Secondary
Percent Change in Blood Endothelial Progenitor Cells
Monocytes (PBMC) are isolated from 20 mL blood. CD34+/VEGFR2+/KDR+ monocytes represent cell markers for endothelial progenitor cells (EPC). CD34+/VEGFR2+/KDR+ monocytes are counted (flow cytometry) and expressed as a percentage of PBMC number. Percent change between population averages from baseline to 2 months for the EPC/PBMC ratio is calculated and reported as the outcome measure.
Time frame: Baseline to 2 months
Population: CD34+/VEGFR2+/KDR+ monocytes (EPC) are a very rare cell type (\<1% of PBMC). Not all blood samples contain EPC cells, or there are too few to count reliably. This measure was obtained in a subset of the total participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Percent Change in Blood Endothelial Progenitor Cells | 0.3 Percent change |
| Placebo | Percent Change in Blood Endothelial Progenitor Cells | -0.2 Percent change |