Sitagliptin and HIV
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Inflammation Macrophage Infiltration Cardiovascular Disease |
Drug: Sitagliptin Drug: Placebo |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator) Primary Purpose: Treatment |
| 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. |
- inflammatory biomarkers [ Time Frame: 2 months ] [ Designated as safety issue: No ]Fasting serum and plasma samples obtained at baseline, week 4 and 8 are batched for ELISA analysis (end of sudy) of hsCRP, IL-6 and D-dimer concentrations.
- adipose inflammation [ Time Frame: 2 months ] [ Designated as safety issue: No ]Adipose tissue from obese, insulin resistant subjects is characterized by increased macrophage infiltration and overexpression of inflammatory cytokines/chemokines. In obese humans, the presence of CD68+ macrophages in direct contact with mature adipocytes has been noted in histologic sections of adipose tissue, and these appear as a macrophage "crown" around individual adipocytes. In adipocyte sections, we will use positive immunohistochemical staining for CD68 to quantify the density of macrophages and the frequency of "crown' like structures.
- Blood endothelial progenitor cells [ Time Frame: 2 months ] [ Designated as safety issue: No ]Monocytes are isolated from 20 mL blood. CD34+/VEGFR2+ and CD133+/CD34+/VEGFR2+ monocytes are counted (flow cytometry) and represent markers for endothelial progenitor cell number.
| Estimated Enrollment: | 36 |
| Study Start Date: | October 2012 |
| Estimated Study Completion Date: | January 2015 |
| Estimated Primary Completion Date: | October 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Sitagliptin
100 mg sitagliptin/day for 2 months
|
Drug: Sitagliptin
Oral, 100 mg/day for 2 months
Other Name: Januvia
|
|
Placebo Comparator: Placebo
Matching placebo daily for 2 months
|
Drug: Placebo
oral, matching placebo daily for 2 months
|
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| Ages Eligible for Study: | 18 Years to 65 Years |
| Genders Eligible for Study: | Both |
| Accepts 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.
Contacts and Locations| Contact: Kevin E Yarasheski, PhD | 3143628173 | key@wustl.edu |
| Contact: Erin Laciny, MSEd | 3147475371 | elaciny@wustl.edu |
| United States, Missouri | |
| Washington University School of Medicine | Recruiting |
| Saint Louis, Missouri, United States, 63110 | |
| Contact: Erin Laciny, MSEd 314-747-5371 elaciny@wustl.edu | |
| Sub-Investigator: Dominic N Reeds, MD | |
| Principal Investigator: | Kevin E Yarasheski, PhD | Washington University School of Medicine |
More Information
Additional Information:
No publications provided
| Responsible Party: | Kevin Yarasheski, PhD, Professor of Medicine, Washington University School of Medicine |
| ClinicalTrials.gov Identifier: | NCT01552694 History of Changes |
| Other Study ID Numbers: | 41052, 41052 |
| Study First Received: | March 8, 2012 |
| Last Updated: | May 13, 2013 |
| Health Authority: | United States: Food and Drug Administration United States: Institutional Review Board |
Keywords provided by Washington University School of Medicine:
|
cardiometabolic complications |
Additional relevant MeSH terms:
|
Acquired Immunodeficiency Syndrome HIV Infections Cardiovascular Diseases Inflammation Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Slow Virus Diseases |
Immunologic Deficiency Syndromes Immune System Diseases Pathologic Processes Sitagliptin Dipeptidyl-Peptidase IV Inhibitors Protease Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Hypoglycemic Agents Physiological Effects of Drugs |
ClinicalTrials.gov processed this record on May 19, 2013