Effectiveness of Sitagliptin for HIV Insulin Resistance and Inflammation

NCT ID: NCT01552694

Last Updated: 2018-05-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 38 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-10-31
• Study Completion Date: 2014-12-31

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.

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.

Conditions

Inflammation; Macrophage Infiltration; Cardiovascular Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Sitagliptin

100 mg sitagliptin/day for 2 months

Group Type: EXPERIMENTAL

Sitagliptin

Intervention Type: DRUG

Oral, 100 mg/day for 2 months

Placebo

Matching placebo daily for 2 months

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

oral, matching placebo daily for 2 months

Interventions

Sitagliptin

Oral, 100 mg/day for 2 months

Intervention Type: DRUG

Placebo

oral, matching placebo daily for 2 months

Intervention Type: DRUG

Other Intervention Names

Januvia

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Kevin Yarasheski, PhD

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Kevin E Yarasheski, PhD

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Locations

Washington University School of Medicine

St Louis, Missouri, United States

Countries

United States

References

Best C, Struthers H, Laciny E, Royal M, Reeds DN, Yarasheski KE. Sitagliptin Reduces Inflammation and Chronic Immune Cell Activation in HIV+ Adults With Impaired Glucose Tolerance. J Clin Endocrinol Metab. 2015 Jul;100(7):2621-9. doi: 10.1210/jc.2015-1531. Epub 2015 May 4.

Reference Type: RESULT

PMID: 25938633 (View on PubMed)

Related Links

https://ccs.wustl.edu/

Center for Clinical Studies- Washington University

Other Identifiers

41052

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

41052

Identifier Type: -

Identifier Source: org_study_id