Effectiveness of Sitagliptin for HIV Insulin Resistance and Inflammation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01552694
Recruitment Status : Completed
First Posted : March 13, 2012
Results First Posted : March 5, 2015
Last Update Posted : May 8, 2018
Information provided by (Responsible Party):
Kevin Yarasheski, PhD, Washington University School of Medicine

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.

Condition or disease Intervention/treatment Phase
Inflammation Macrophage Infiltration Cardiovascular Disease Drug: Sitagliptin Drug: Placebo Phase 3

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 38 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Double Blind, Randomized, Placebo Controlled Study to Determine the Physiological Effectiveness of Januvia for Reducing Inflammation and Increasing EPC Number in HIV Infected Men and Women With Insulin Resistance and Central Adiposity.
Study Start Date : October 2012
Actual Primary Completion Date : October 2014
Actual Study Completion Date : December 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. Inflammatory Biomarker 1: Plasma hsCRP Concentration [ Time Frame: 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.

  2. Inflammatory Biomarker 2: Plasma IL-6 Concentration [ Time Frame: 2 months ]
    There are 3 levels of the primary outcome measure; hsCRP, IL-6, and D-dimer concentrations measured at baseline and week 8

  3. Inflammatory Biomarker 3: Serum D-dimer Concentration [ Time Frame: 2 months ]
    There are 3 levels of the primary outcome measure, hsCRP, IL-6, and D-dimer

Secondary Outcome Measures :
  1. Fold Change in Adipose Inflammation Marker CCL2 (MCP-1) mRNA Expression [ Time Frame: 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.

  2. Percent Change in Blood Endothelial Progenitor Cells [ Time Frame: 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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01552694

United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Principal Investigator: Kevin E Yarasheski, PhD Washington University School of Medicine

Additional Information:
Publications of Results:
Responsible Party: Kevin Yarasheski, PhD, Professor of Medicine, Washington University School of Medicine Identifier: NCT01552694     History of Changes
Other Study ID Numbers: 41052
41052 ( Other Grant/Funding Number: Merck )
First Posted: March 13, 2012    Key Record Dates
Results First Posted: March 5, 2015
Last Update Posted: May 8, 2018
Last Verified: March 2018

Keywords provided by Kevin Yarasheski, PhD, Washington University School of Medicine:
cardiometabolic complications

Additional relevant MeSH terms:
Cardiovascular Diseases
Insulin Resistance
Pathologic Processes
Glucose Metabolism Disorders
Metabolic Diseases
Sitagliptin Phosphate
Hypoglycemic Agents
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action