Effectiveness of Sitagliptin for HIV Insulin Resistance and Inflammation
Effectiveness of Sitagliptin for HIV Insulin Resistance and Inflammation
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.
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.
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.