Diabetes, Insulin Resistance
Conditions
Brief summary
We will test the safety of a new class of anti-diabetes compounds (DPPIV-inhibitors) in people living with HIV. Future trials will examine efficacy for treating diabetes and reducing cardiovascular disease risk in people living with HIV.
Detailed description
Human immunodeficiency virus (HIV)-infection and treatment with antiretroviral therapies are associated with several cardiometabolic risk factors; insulin resistance, diabetes, dyslipidemia, central adiposity, that increase risk for MI and stroke. A new class of drugs used to treat type 2 diabetes has been introduced; Dipeptidyl peptidase-IV (DPPIV)-inhibitors (Januvia®, Onglyza®, alogliptin). Dipeptidyl peptidase-IV (DPPIV)-inhibition could be a safe and effective therapy for HIV-associated insulin resistance and diabetes. However, no safety data exist. The research question is: If HIV+ adults with stable immunologic (CD4+ T-cell count \>350 cells/μL) and virologic (plasma HIV RNA \<50 copies/mL) function are given a DPPIV-inhibitor would their CD4+ T-cell count and plasma HIV RNA level increase, decrease, or stay the same? Theoretically, DPPIV-inhibition could enhance their immune system by increasing SDF-1α levels; a potent inhibitor of HIV-entry into T-cells, or harm the HIV+ immune system by inactivating CD26 on immune cells. We hypothesize that DPPIV-inhibition will not harm the immune system in HIV+ people. We propose a blinded randomized controlled pilot safety trial of an FDA-approved DPPIV-inhibitor in virologically- and immunologically-stable HIV+ men and women. We will monitor CD4+ T-cell count, plasma HIV RNA levels, immune activation markers, and safety outcomes (lipid/lipoprotein profiles, blood pressure, kidney and liver function) during 4-6 months of DPPIV-inhibitor exposure vs placebo in 20 HIV+ adults. If safety is confirmed, the efficacy of DPPIV-inhibition in HIV+ with insulin resistance will be tested in future trials that examine potential glucoregulatory and cardiovascular benefits.
Interventions
DRUGSitagliptin
100 mg sitagliptin daily for 4-6 months
DRUGPlacebo
Daily placebo for 4-6 months
Sponsors
The Campbell Foundation
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Thirty 18-65 yr old HIV-infected men and women (with source documentation of HIV status) who are stable on any antiretroviral therapy (cART) regimen 2. Have stable (at least the past 12-months) immunologic (\>350 CD4+ T-cells/µL) and virologic (\<50 copies HIV RNA/mL) status. 3. BMI 18-42kg/m2; 4. Normal blood chemistry for at least 1 month prior to enrollment; 5. Platelet count \> 30,000/mm3, absolute neutrophil count \>750/mm3, transaminases \< 2.5x the upper limit of normal (ULN). 6. Long-term non-progressors (not on ART) are not eligible.
Exclusion criteria
1. CD4+ T-cell count \<350 cells/µL or detectable plasma HIV RNA (\>50 copies HIV RNA/mL) within the past 12-months. During the study, if CD4+ T-cell count declines by \>100 cells/µL, or if plasma HIV RNA becomes detectable (\>50 copies HIV RNA/mL after repeat analysis 2wks apart), and the participant denies any lapse in their anti-HIV medication regimen, the study medication will be stopped and an adverse event documented. If at any time during the study, two participants experience a reduction in T-cell count \>100 cells/µL, or their plasma HIV RNA levels become detectable (\>50 copies HIV RNA/mL after repeat analysis 2wks apart), and they are confirmed (by unblinding) to have received sitagliptin, the study will be stopped for serious safety concerns. 2. Systemic, secondary or opportunistic infection within past 12-months. 3. Fasting glucose intolerance (FBG \>100mg/dL), fasting hyperinsulinemia (\>15µU/mL), or fasting insulin resistance (Homeostasis model for insulin resistance (HOMA) \>3.0). Any agents that might alter glucose metabolism (insulin, TZDs, metformin, glucocorticoids, sulfonylurea, corticosteroids, megace, rhGH, GH-secretagogue) during the 3 months prior to enrollment or at any time during enrollment. Volunteers with T2DM, IDDM or diabetic ketoacidosis will not be enrolled. 4. History of serious CV disease or NYHA Functional Class III or IV, (e.g., recent MI, unstable angina, edema, CHF, CAD, CABG, valve disease (murmur), stroke, uncontrolled high blood pressure (resting \>160/95 mmHg), irregular heart rhythm, resting ST-segment depression \>1mm). Treatment with medications for a CV condition (cardiac glycosides α- or ß-blockers). Some antihypertensive medications (calcium-channel blocker, diuretic, angiotensin II receptor blockers (ARB), angiotensin converting enzyme inhibitors (ACE)) will be permitted. 5. Moderate to severe renal insufficiency. Serum creatinine \>1.7 mg/dL (men) \>1.5 mg/dL (women). 6. Known allergy or hypersensitivity to DPPIV-inhibitors. 7. Plan to change anti-HIV medication regimen or prophylaxis for opportunistic infection within 6-months of starting study.Transitions among efavirenz-based regimens will be allowed (e.g., Efavirenz + lamivudine + zidovudine (combivir) to Efavirenz + emtricitabine + tenofovir (Atripla)). 8. Lipid-lowering medications are permitted (fibrate or statin or niacin), but must be stable on that agent for at least 3 months prior to enrollment. Lipid-lowering agents cannot be started during the treatment period. 9. Chronic hepatitis B infection (HB surface antigen positive). Active hepatitis C infection (detectable Hep C RNA). Those who have cleared hepatitis B or C infection are eligible. 10. Hematocrit \<34% in men or \<25% in women with symptoms (fatigue, tired-legs, shortness of breath). Hemoglobin \<10 gm/100ml with symptoms. 11. Nausea, vomiting, diarrhea (\>4 loose stools/day) that are unresponsive to treatment. History of eating disorder or significant GI-disease. 12. Pregnant or nursing mothers. Women must agree to use an acceptable form of birth control during the study. If birth control pills are used, the woman must be stable on these medications for at least 6 months prior to enrollment. 13. Active malignancy or treatment with chemotherapeutic agents or radiation therapy (within past 12 months). 14. \>10% unintentional body weight loss during the 12 months prior to enrollment. 15. Blinded investigational drugs/medications during the 3 months prior to enrollment that will not be unblinded before enrollment. Open-label investigational drugs are permitted (within past 3 months, no plan to stop during enrollment and not known to affect glucose, lipid, adipose tissue or liver metabolism). 16. Over the counter agents that might alter glucose, lipid, or adipose tissue metabolism (e.g., creatine monohydrate, chromium picolinate, amino acid/protein supplements, medium- or long-chain fatty acids) within 1 month of enrollment. These supplements are not permitted during the treatment period. 17. Reduced cognitive function/unable to provide voluntary informed consent. Prisoners are excluded. 18. Active substance abuse that the physician-scientist believes may compromise safety, compliance, or interfere with study drug or data interpretation. 19. Any cytokine or anti-cytokine therapy during 3 months prior to enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CD4+ T-cell Count | Monthly for 4 months | — |
| Plasma HIV Viremia (Viral Load) | Monthly for 6 months | Percentage of participants with plasma HIV RNA copy number less than 48 copies/mL |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| RANTES; Serum Biomarkers of Immune Activation | Baseline, week 8, week 16 | serum Regulated on Activation, Normal T cell Expressed and Secreted concentration |
| Soluble TNFR2; Serum Biomarkers of Immune Activation | Baseline, week 8, week 16 | serum soluble tumor necrosis factor receptor-2 concentration |
| Self-reported Symptoms | Monthly for 4 months | Cumulative number of self-reported symptoms based on the Division of AIDS Grading Scale for the Severity of Adult Adverse Events (0-4 scale where 0 is no new symptoms, 4 is serious adverse event or toxicity) |
| Oral Glucose Tolerance | Baseline, week 8, week 16 | Area under the 75-gr oral glucose tolerance curve (AUCg) based on plasma glucose values measured at 0, 30, 60, 90, and 120 mins post-glucose challenge. |
| SDF1α; Serum Biomarkers of Immune Activation | Baseline, week 8, week 16 | serum stromal cell-derived factor-1α concentration |
Countries
United States
Participant flow
Recruitment details
HIV-infected adults (18 - 65 years old) were recruited from the AIDS Clinical Trials Unit and the Infectious Diseases Clinic at Washington University School of Medicine. Thirty-one candidates were screened and 20 were enrolled; all participants were HIV positive but were otherwise healthy with stable immunologic and virologic status on HAART.
Pre-assignment details
Twenty participants were randomized to n=10 placebo or n=10 sitagliptin (Januvia(R)). Eleven volunteers were screened and found ineligible (see eligibility criteria), or did not choose to participate in the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Four months of placebo to people living with HIV-1 who have well-controlled immunologic (CD4+ T-cell count \>350 cells/µL) and virologic (plasma HIV RNA \<50 copies/mL) status.
Placebo : Daily placebo for 4 months | 10 |
| DPPIV Inhibition Four months of sitagliptin administration (100mg/d) to people living with HIV-1 who have well-controlled immunologic (CD4+ T-cell count \>350 cells/µL) and virologic (plasma HIV RNA \<50 copies/mL) status.
Sitagliptin : 100 mg sitagliptin daily for 4 months | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | DPPIV Inhibition | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 10 Participants | 20 Participants |
| Age, Continuous | 36 years STANDARD_DEVIATION 9 | 40 years STANDARD_DEVIATION 15 | 38 years STANDARD_DEVIATION 12 |
| Region of Enrollment United States | 10 participants | 10 participants | 20 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 9 Participants | 8 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 10 | 6 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
CD4+ T-cell Count
Time frame: Monthly for 4 months
Population: CD4+ T-cell count
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | CD4+ T-cell Count | Week 4 | 689 cells/µL | Standard Deviation 153 |
| Placebo | CD4+ T-cell Count | Week 12 | 686 cells/µL | Standard Deviation 167 |
| Placebo | CD4+ T-cell Count | Week 8 | 696 cells/µL | Standard Deviation 194 |
| Placebo | CD4+ T-cell Count | Week 16 | 681 cells/µL | Standard Deviation 151 |
| Placebo | CD4+ T-cell Count | Baseline | 602 cells/µL | Standard Deviation 91 |
| DPPIV Inhibition | CD4+ T-cell Count | Week 16 | 636 cells/µL | Standard Deviation 173 |
| DPPIV Inhibition | CD4+ T-cell Count | Baseline | 648 cells/µL | Standard Deviation 185 |
| DPPIV Inhibition | CD4+ T-cell Count | Week 4 | 750 cells/µL | Standard Deviation 225 |
| DPPIV Inhibition | CD4+ T-cell Count | Week 8 | 656 cells/µL | Standard Deviation 207 |
| DPPIV Inhibition | CD4+ T-cell Count | Week 12 | 706 cells/µL | Standard Deviation 168 |
Comparison: The main effect analysis was applied to both rows (timepoint) and categories (groups). It used linear mixed models to simultaneously assess differences in CD4+ T-cell count between the DPP4 inhibitor and placebo groups (categories) over time (rows). Pairwise post-hoc contrasts were performed to assess the between and within group differences in outcome measures at each time point.p-value: >0.05Mixed Models Analysis
Primary
Plasma HIV Viremia (Viral Load)
Percentage of participants with plasma HIV RNA copy number less than 48 copies/mL
Time frame: Monthly for 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Plasma HIV Viremia (Viral Load) | Baseline | 100 percentage of participants below 48 c/mL |
| Placebo | Plasma HIV Viremia (Viral Load) | Week 4 | 100 percentage of participants below 48 c/mL |
| Placebo | Plasma HIV Viremia (Viral Load) | Week 8 | 100 percentage of participants below 48 c/mL |
| Placebo | Plasma HIV Viremia (Viral Load) | Week 12 | 100 percentage of participants below 48 c/mL |
| Placebo | Plasma HIV Viremia (Viral Load) | Week 16 | 100 percentage of participants below 48 c/mL |
| Placebo | Plasma HIV Viremia (Viral Load) | Week 24 | 100 percentage of participants below 48 c/mL |
| DPPIV Inhibition | Plasma HIV Viremia (Viral Load) | Week 16 | 100 percentage of participants below 48 c/mL |
| DPPIV Inhibition | Plasma HIV Viremia (Viral Load) | Baseline | 100 percentage of participants below 48 c/mL |
| DPPIV Inhibition | Plasma HIV Viremia (Viral Load) | Week 12 | 100 percentage of participants below 48 c/mL |
| DPPIV Inhibition | Plasma HIV Viremia (Viral Load) | Week 4 | 100 percentage of participants below 48 c/mL |
| DPPIV Inhibition | Plasma HIV Viremia (Viral Load) | Week 24 | 100 percentage of participants below 48 c/mL |
| DPPIV Inhibition | Plasma HIV Viremia (Viral Load) | Week 8 | 100 percentage of participants below 48 c/mL |
Comparison: The main effect analysis was applied to both rows (timepoint) and categories (groups). It used linear mixed models to simultaneously assess differences in plasma HIV RNA copy number/mL between the DPP4 inhibitor and placebo groups (categories) over time (rows). Pairwise post-hoc contrasts were performed to assess the between and within group differences in outcome measures at each time point.p-value: >0.05Mixed Models Analysis
Secondary
Oral Glucose Tolerance
Area under the 75-gr oral glucose tolerance curve (AUCg) based on plasma glucose values measured at 0, 30, 60, 90, and 120 mins post-glucose challenge.
Time frame: Baseline, week 8, week 16
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Oral Glucose Tolerance | Baseline AUCg | 142.5 mg*min/mL | Standard Deviation 26.6 |
| Placebo | Oral Glucose Tolerance | Week 8 AUCg | 158.0 mg*min/mL | Standard Deviation 26.7 |
| Placebo | Oral Glucose Tolerance | Week 16 AUCg | 157.5 mg*min/mL | Standard Deviation 23.2 |
| DPPIV Inhibition | Oral Glucose Tolerance | Baseline AUCg | 145.6 mg*min/mL | Standard Deviation 32.5 |
| DPPIV Inhibition | Oral Glucose Tolerance | Week 8 AUCg | 133.6 mg*min/mL | Standard Deviation 24.6 |
| DPPIV Inhibition | Oral Glucose Tolerance | Week 16 AUCg | 142.5 mg*min/mL | Standard Deviation 21.5 |
Comparison: The main effect analysis was applied to both rows (timepoint) and categories (groups). It used linear mixed models to simultaneously assess differences in area under the glucose tolerance curves between the DPP4 inhibitor and placebo groups (categories) over time (rows). Pairwise post-hoc contrasts were performed to assess the between and within group differences in outcome measures at each time point.p-value: <0.04Mixed Models Analysis
Secondary
RANTES; Serum Biomarkers of Immune Activation
serum Regulated on Activation, Normal T cell Expressed and Secreted concentration
Time frame: Baseline, week 8, week 16
Population: RANTES
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | RANTES; Serum Biomarkers of Immune Activation | Baseline | 80.8 ng/mL | Standard Deviation 23.2 |
| Placebo | RANTES; Serum Biomarkers of Immune Activation | week 8 | 85.3 ng/mL | Standard Deviation 27.7 |
| Placebo | RANTES; Serum Biomarkers of Immune Activation | week 16 | 74.9 ng/mL | Standard Deviation 27.8 |
| DPPIV Inhibition | RANTES; Serum Biomarkers of Immune Activation | Baseline | 64.4 ng/mL | Standard Deviation 37.2 |
| DPPIV Inhibition | RANTES; Serum Biomarkers of Immune Activation | week 8 | 68.5 ng/mL | Standard Deviation 43 |
| DPPIV Inhibition | RANTES; Serum Biomarkers of Immune Activation | week 16 | 62.8 ng/mL | Standard Deviation 32.3 |
Comparison: The main effect analysis was applied to both rows (timepoint) and categories (groups). It used linear mixed models to simultaneously assess differences in serum RANTES levels between the DPP4 inhibitor and placebo groups (categories) over time (rows). Pairwise post-hoc contrasts were performed to assess the between and within group differences in outcome measures at each time point.p-value: >0.05Mixed Models Analysis
Secondary
SDF1α; Serum Biomarkers of Immune Activation
serum stromal cell-derived factor-1α concentration
Time frame: Baseline, week 8, week 16
Population: SDF1α
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | SDF1α; Serum Biomarkers of Immune Activation | Baseline | 2327 pg/mL | Standard Deviation 304 |
| Placebo | SDF1α; Serum Biomarkers of Immune Activation | week 8 | 2313 pg/mL | Standard Deviation 364 |
| Placebo | SDF1α; Serum Biomarkers of Immune Activation | week 16 | 2309 pg/mL | Standard Deviation 400 |
| DPPIV Inhibition | SDF1α; Serum Biomarkers of Immune Activation | week 16 | 1277 pg/mL | Standard Deviation 490 |
| DPPIV Inhibition | SDF1α; Serum Biomarkers of Immune Activation | Baseline | 2378 pg/mL | Standard Deviation 441 |
| DPPIV Inhibition | SDF1α; Serum Biomarkers of Immune Activation | week 8 | 1208 pg/mL | Standard Deviation 605 |
Comparison: The main effect analysis was applied to both rows (timepoint) and categories (groups). It used linear mixed models to simultaneously assess differences in serum SDF1α levels between the DPP4 inhibitor and placebo groups (categories) over time (rows). Pairwise post-hoc contrasts were performed to assess the between and within group differences in outcome measures at each time point.p-value: <0.0002Mixed Models Analysis
Secondary
Self-reported Symptoms
Cumulative number of self-reported symptoms based on the Division of AIDS Grading Scale for the Severity of Adult Adverse Events (0-4 scale where 0 is no new symptoms, 4 is serious adverse event or toxicity)
Time frame: Monthly for 4 months
Population: Cumulative frequency over 16 weeks of any self-reported symptoms on the DAIDS scale
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Self-reported Symptoms | Other (e.g., rash, muscle pain, mood change) | 6 total number of self reported symptoms |
| Placebo | Self-reported Symptoms | Hypoglycemia symptoms | 1 total number of self reported symptoms |
| Placebo | Self-reported Symptoms | GI symptoms | 8 total number of self reported symptoms |
| Placebo | Self-reported Symptoms | Upper respiratory symptoms | 10 total number of self reported symptoms |
| Placebo | Self-reported Symptoms | Generalized fatigue | 5 total number of self reported symptoms |
| Placebo | Self-reported Symptoms | Headache | 5 total number of self reported symptoms |
| DPPIV Inhibition | Self-reported Symptoms | Generalized fatigue | 2 total number of self reported symptoms |
| DPPIV Inhibition | Self-reported Symptoms | Other (e.g., rash, muscle pain, mood change) | 5 total number of self reported symptoms |
| DPPIV Inhibition | Self-reported Symptoms | Upper respiratory symptoms | 5 total number of self reported symptoms |
| DPPIV Inhibition | Self-reported Symptoms | Hypoglycemia symptoms | 3 total number of self reported symptoms |
| DPPIV Inhibition | Self-reported Symptoms | Headache | 4 total number of self reported symptoms |
| DPPIV Inhibition | Self-reported Symptoms | GI symptoms | 3 total number of self reported symptoms |
Comparison: Kruskal-Wallis non-parametric test of cell frequenciesp-value: >0.05Kruskal-Wallis
Secondary
Soluble TNFR2; Serum Biomarkers of Immune Activation
serum soluble tumor necrosis factor receptor-2 concentration
Time frame: Baseline, week 8, week 16
Population: sTNFR2
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Soluble TNFR2; Serum Biomarkers of Immune Activation | Baseline | 2220 pg/mL | Standard Deviation 389 |
| Placebo | Soluble TNFR2; Serum Biomarkers of Immune Activation | week 8 | 2218 pg/mL | Standard Deviation 411 |
| Placebo | Soluble TNFR2; Serum Biomarkers of Immune Activation | week 16 | 2279 pg/mL | Standard Deviation 415 |
| DPPIV Inhibition | Soluble TNFR2; Serum Biomarkers of Immune Activation | Baseline | 2436 pg/mL | Standard Deviation 431 |
| DPPIV Inhibition | Soluble TNFR2; Serum Biomarkers of Immune Activation | week 8 | 2617 pg/mL | Standard Deviation 638 |
| DPPIV Inhibition | Soluble TNFR2; Serum Biomarkers of Immune Activation | week 16 | 2388 pg/mL | Standard Deviation 449 |
Comparison: The main effect analysis was applied to both rows (timepoint) and categories (groups). It used linear mixed models to simultaneously assess differences in serum TNFR2 levels between the DPP4 inhibitor and placebo groups (categories) over time (rows). Pairwise post-hoc contrasts were performed to assess the between and within group differences in outcome measures at each time point.p-value: >0.05Mixed Models Analysis