Effectiveness of Sitagliptin for HIV Insulin Resistance and Inflammation

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.