Effectiveness of Sitagliptin for HIV Insulin Resistance and Inflammation

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT01552694
• Collaborator: (none)
• Enrollment: 38
• Location: 1
• Arms: 2
• Duration (Months): 26
• Patients Per Site Per Month: 1.5

Study Details

Study Description

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 Design

• Study Type: Interventional
• 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: Oct 1, 2012
• Actual Primary Completion Date: Oct 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sitagliptin 100 mg sitagliptin/day for 2 months	Drug: Sitagliptin; Oral, 100 mg/day for 2 months; Other Names: Januvia
Placebo Comparator: Placebo Matching placebo daily for 2 months	Drug: Placebo; oral, matching placebo daily for 2 months

Outcome Measures

Primary Outcome Measures

1. Inflammatory Biomarker 1: Plasma hsCRP Concentration [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 [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 [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 [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 [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine

Investigators

• Principal Investigator: Kevin E Yarasheski, PhD, Washington University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Center for Clinical Studies- Washington University

Publications

None provided.

• Responsible Party: Kevin Yarasheski, PhD, Professor of Medicine, Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT01552694
• Other Study ID Numbers: 41052; 41052
• First Posted: Mar 13, 2012
• Last Update Posted: May 8, 2018
• Last Verified: Mar 1, 2018

• Keywords provided by Kevin Yarasheski, PhD, Professor of Medicine, Washington University School of Medicine: cardiometabolic complications
• Additional relevant MeSH terms: Cardiovascular Diseases; Insulin Resistance; Inflammation; Sitagliptin Phosphate

Study Results

Participant Flow

Recruitment Details	38 participants were initially enrolled. 1 was lost to follow-up; 1 started a personal exercise training program while enrolled in the study. Any data collected on these 2 participants were excluded from the analysis. Both were initially enrolled in the placebo group.
Pre-assignment Detail	36 participants completed the trial with complete data.

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	100 mg sitagliptin/day for 2 months Sitagliptin: Oral, 100 mg/day for 2 months	Matching placebo daily for 2 months Placebo: oral, matching placebo daily for 2 months
Period Title: Overall Study
STARTED	18	20
COMPLETED	18	18
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Sitagliptin	Placebo	Total
Arm/Group Description	100 mg sitagliptin/day for 2 months Sitagliptin: Oral, 100 mg/day for 2 months	Matching placebo daily for 2 months Placebo: oral, matching placebo daily for 2 months	Total of all reporting groups
Overall Participants	18	18	36
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49 (9)	52 (6)	51 (7)
Sex: Female, Male (Count of Participants)
Female	5 27.8%	5 27.8%	10 27.8%
Male	13 72.2%	13 72.2%	26 72.2%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	2 11.1%	11 61.1%	13 36.1%
African American	16 88.9%	7 38.9%	23 63.9%
Region of Enrollment (participants) [Number]
United States	18 100%	18 100%	36 100%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	97 (21)	102 (29)	100 (25)
Body mass index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	32.7 (8.2)	33.1 (8.2)	32.9 (8.2)
Waist circumference (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	106 (19)	112 (23)	109 (22)
Systolic blood pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	124 (15)	127 (14)	125 (14)
Diastolic blood pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	74 (9)	78 (10)	76 (10)
HIV duration (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.9 (5.8)	14.2 (7.5)	14.6 (6.2)
CD4+ T-cell count (cells/µL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cells/µL]	731 (220)	606 (218)	668 (219)
CD8+ T-cell count (cells/µL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cells/µL]	1017 (542)	801 (294)	909 (418)

Outcome Measures

1. Primary Outcome

Title	Inflammatory Biomarker 1: Plasma hsCRP Concentration
Description	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.
Time Frame	2 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	100 mg sitagliptin/day for 2 months Sitagliptin: Oral, 100 mg/day for 2 months	Matching placebo daily for 2 months Placebo: oral, matching placebo daily for 2 months
Measure Participants	18	18
Baseline	3.4 (3.2)	5.4 (4.5)
Week 8	2.9 (2.6)	7.4 (5.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sitagliptin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	A priori threshold for statistical significance was p<0.05. Unadjusted p-value compares the change (week 8 - baseline) for plasma hsCRP between the 2 groups.
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	100 mg sitagliptin/day for 2 months Sitagliptin: Oral, 100 mg/day for 2 months	Matching placebo daily for 2 months Placebo: oral, matching placebo daily for 2 months
Measure Participants	18	18
Baseline	1.36 (0.74)	2.61 (1.91)
Week 8	1.30 (0.55)	2.65 (1.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sitagliptin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.24
	Comments	A priori threshold for statistical significance was p<0.05. Unadjusted analysis.
	Method	t-test, 2 sided
	Comments

3. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	100 mg sitagliptin/day for 2 months Sitagliptin: Oral, 100 mg/day for 2 months	Matching placebo daily for 2 months Placebo: oral, matching placebo daily for 2 months
Measure Participants	18	18
Baseline	0.32 (0.20)	0.28 (0.15)
Week 8	0.33 (0.24)	0.31 (0.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sitagliptin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments	A priori threshold for statistical significance was p<0.05. Unadjusted analysis
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	Fold Change in Adipose Inflammation Marker CCL2 (MCP-1) mRNA Expression
Description	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.
Time Frame	Baseline to 2 months

Outcome Measure Data

Analysis Population Description

Adipose tissue samples were not available from all participants. This secondary outcome includes fewer participants analyzed than the primary outcome.

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	100 mg sitagliptin/day for 2 months Sitagliptin: Oral, 100 mg/day for 2 months	Matching placebo daily for 2 months Placebo: oral, matching placebo daily for 2 months
Measure Participants	11	7
Number [fold change]	-2.5	-0.4

5. Secondary Outcome

Title	Percent Change in Blood Endothelial Progenitor Cells
Description	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.
Time Frame	Baseline to 2 months

Outcome Measure Data

Analysis Population Description

CD34+/VEGFR2+/KDR+ monocytes (EPC) are a very rare cell type (<1% of PBMC). Not all blood samples contain EPC cells, or there are too few to count reliably. This measure was obtained in a subset of the total participants.

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	100 mg sitagliptin/day for 2 months Sitagliptin: Oral, 100 mg/day for 2 months	Matching placebo daily for 2 months Placebo: oral, matching placebo daily for 2 months
Measure Participants	12	11
Number [Percent change]	0.3	-0.2

Adverse Events

Arm/Group Title	Sitagliptin		Placebo
Arm/Group Description	100 mg sitagliptin/day for 2 months Sitagliptin: Oral, 100 mg/day for 2 months		Matching placebo daily for 2 months Placebo: oral, matching placebo daily for 2 months
All Cause Mortality
	Sitagliptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sitagliptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Sitagliptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/18 (44.4%)		8/20 (40%)
Cardiac disorders
Chest pain, shortness of breath, wheezing, cough	3/18 (16.7%)	3	4/20 (20%)	4
Gastrointestinal disorders
Abdominal pain, nausea, vomiting, constipation, diarrhea, hypoglycemia	3/18 (16.7%)	3	6/20 (30%)	6
General disorders
Fatique, Fever, Chills, Loss of appetite, Weight Loss	8/18 (44.4%)	9	7/20 (35%)	7
Infections and infestations
Sinus, respiratoy urinary tract infections	2/18 (11.1%)	2	3/20 (15%)	3
Musculoskeletal and connective tissue disorders
muscle ache, arthritis, swelling, weakness	4/18 (22.2%)	4	5/20 (25%)	5
Nervous system disorders
headaches, dizziness ,numbness, depression, anxiety, confusion	4/18 (22.2%)	8	5/20 (25%)	10
Renal and urinary disorders
Chnages in urinary frequency, painful urination, blood in urine	2/18 (11.1%)	2	3/20 (15%)	3
Skin and subcutaneous tissue disorders
Rash, pruritus, easy bruising	3/18 (16.7%)	3	3/20 (15%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.