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Sitagliptin and HIV

Information source: Washington University School of Medicine
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Inflammation; Macrophage Infiltration; Cardiovascular Disease

Intervention: Sitagliptin (Drug); Placebo (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Washington University School of Medicine

Official(s) and/or principal investigator(s):
Kevin E Yarasheski, PhD, Principal Investigator, Affiliation: Washington University School of Medicine

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.

Clinical Details

Official title: A Double Blind, Randomized, Placebo Controlled Study to Determine the Physiological Effectiveness of Januvia (100 mg/d) for Reducing Inflammation and Increasing Endothelial Progenitor Cell Number in Human Immunodeficiency Virus (HIV) Infected Men and Women With Insulin Resistance and Central Adiposity.

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Primary outcome:

Inflammatory Biomarker 1: Plasma hsCRP Concentration

Inflammatory Biomarker 2: Plasma IL-6 Concentration

Inflammatory Biomarker 3: Serum D-dimer Concentration

Secondary outcome:

Adipose Inflammation

Blood Endothelial Progenitor Cells

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.

Eligibility

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

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.

Locations and Contacts

Washington University School of Medicine, Saint Louis, Missouri 63110, United States
Additional Information

Center for Clinical Studies- Washington University

Starting date: October 2012
Last updated: May 13, 2015

Page last updated: August 23, 2015

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