The purpose is to examine the safety and efficacy of 16wks of pioglitazone (Actos; 30mg/d)
with and without aerobic and strength exercise training for reducing glucose intolerance and
central adiposity in HIV-infected people. We anticipate that pioglitazone + exercise
training will improve glucose metabolism and insulin sensitivity, and reduce central
adiposity more than pioglitazone alone. These improvements should translate into reduced
cardiovascular disease risk in HIV-infected people.
Our prior research has examined the pathogenesis and potential treatments for metabolic
complications in people living with HIV. We have adopted the "lipotoxicity" hypothesis for
Metabolic Syndrome X to explain the pathogenesis of impaired glucose tolerance (IGT) and fat
redistribution in HIV: increased lipolysis and mobilization of lipids and free fatty acids
from subcutaneous adipose depots leads to their excessive deposition in muscle and liver
which contributes to dyslipidemia, insulin resistance, increased hepatic glucose output, and
possibly visceral fat accumulation. Effective treatments have not been identified. Consensus
groups recommend regular exercise and dietary modifications as primary and pharmacologic
interventions as secondary treatments for the syndromes. We propose to test the efficacy of
aerobic and weight lifting exercise training and an oral insulin-sensitizing agent
(pioglitazone) as treatments for HIV-associated IGT and fat redistribution. We propose a
4-month, 2-group randomized study to evaluate the efficacy of pioglitazone and exercise +
pioglitazone in 40 men and 40 women living with HIV and IGT and fat redistribution. We will
measure: insulin sensitivity, glucose disposal rate, hepatic glucose production rate
(5hr-hyperinsulinemic euglycemic clamp with 6,6-[2H2]-glucose); whole-body and regional fat
and muscle content (1H-MRI of the abdomen and thigh & DEXA), soleus muscle and liver lipid
content (1H-MRS), muscle and fat PPARgamma/alpha mRNA and protein expression, serum lipid
profiles, and serum adiponectin levels before and at the end of 4 months of treatment. We
hypothesize that exercise training + pioglitazone will be more effective than pioglitazone
alone at improving insulin sensitivity, reducing visceral fat, liver and muscle lipid
content, and increasing peripheral subcutaneous fat content in HIV-infected people. We
hypothesize that combined treatment will be more effective because exercise training will
activate PPARalpha expression in muscle and pioglitazone will activate PPARy expression in
fat and muscle. We anticipate that this project will provide direct evidence that supports
the combined use of exercise training and pioglitazone in people living with HIV and
experiencing metabolic and anthropomorphic disorders that increase cardiovascular disease
1. 18-65 yr old HIV-infected men (n=40) and women (n=40).
2. Source documentation of HIV status.
3. Stable on highly active antiretroviral therapy (HAART) that may or may not include
HIV-protease inhibitors for at least 3 months prior to enrollment. As of Jan 2005,
HIV-infected long-term non-progressors will be included, even though they are not
receiving HAART because it is likely that their disease status will not advance
during the study period.
4. Impaired glucose tolerance (IGT) or type 2 diabetes and fat redistribution. IGT is
defined as: fasting (8hr) plasma glucose 100-126mg/dL or plasma glucose >140 mg/dL
2-hours after a 75g-oral glucose load. This definition (proposed/revised May 2006)
includes volunteers with adult onset type 2 diabetes (non-insulin dependent
diabetes), because we believe that these volunteers may benefit from the potential
glucose-lowering actions of pioglitazone with or without exercise training. Fat
redistribution is defined as any 2 of the following: waist-to-hip ratio >0.85 women
or >0.95 men, or trunk/appendicular adipose ratio using whole-body DEXA >0.85 women
or >1.3 men, or <15% leg fat (DEXA; (leg fat/total body fat) x100), or visceral
adiposity VAT >120 cm2 women or >140 cm2 men, or a VAT/TAT ratio >0.30 women or >0.40
men. Overall, the eligibility criteria are designed to include subjects with
metabolic syndromes that increase CVD risk, and the potential to gain the greatest
benefit from pioglitazone and exercise training. These inclusion criteria will help
select/maintain homogeneous groups of study participants.
5. Plasma HIV RNA (Roche Amplicor® assay) <5000 copies/ml OR a CD4 T-cell count >100
cells/µL and stable for previous 3 months.
6. BMI 20-40kg/m2.
7. "Normal" blood chemistries for at least 1 month prior to enrollment; platelet count
>30,000/mm3, absolute neutrophil count <750/mm3, transaminases <2.5x the upper limit
of normal (ULN), creatinine <3x ULN, fasting triglycerides <500 mg/dL.
1. Medications or agents that might alter/impair glucose metabolism (insulin,
glucocorticoids, corticosteroids, megace) during the 3 months prior to enrollment or
at any time during enrollment. Volunteers who developed type 2 diabetes after
HIV-infection or after starting anti-HIV medications, who are receiving insulin
sensitizers (metformin, meglitinides, alpha-glucosidase inhibitors) or insulin
secretagogues (sulfonylureas), but still do not have their blood sugars in control
(defined as IGT above) are eligible.
2. Abnormal or unstable (for 3 months prior to enrollment) endocrine blood chemistries
that might otherwise explain insulin resistance. TSH <0.2 or >12µIU/mL, morning
cortisol >22µg/dL, IGF-1 <115ng/mL, total testosterone <200ng/dL (men) <15ng/dL
(women). Use of testosterone, ACTH, thyroid hormone, or rhGH replacement to normalize
low levels is permitted, but must be stable on hormone replacement for 3 months prior
to enrollment and will not discontinue this replacement during enrollment. Hormone
replacement cannot be started during treatment.
3. Allergy or hypersensitivity to thiazolidinediones. Currently taking a
4. Anti-obesity or anorectic medications during the 3 months prior to enrollment or at
any time during enrollment. Lipid-lowering medications are permitted (fibrate or
statin), but the subject must be stable on that agent for at least 3 months prior to
enrollment. Lipid-lowering agents cannot be started during the treatment period.
5. 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. This was revised in May 2006 to better clarify some uncertainties about
hepatitis and eligibility.
6. History of serious cardiovascular conditions or NY Heart Association (NYHA) cardiac
status Class III or IV, (e.g., recent MI, unstable angina, edema, CHF, CAD, CABG,
valve disease (murmur), stroke, uncontrolled high blood pressure (resting >140/90
mmHg on 3 occasions), irregular heart rhythm, bundle-branch block, aortic stenosis,
resting ST-segment depression >1mm) that would preclude exercise testing/training, or
substantially increase risk of a CV-event during exercise, or would limit the
subjects ability to participate in exercise training. Treatment with medications for
a cardiovascular condition (cardiac glycosides, alpha- or beta-blockers). Some
antihypertensive medications (Ca++-channel blocker, diuretic, or ACE inhibitor) will
7. Insulin-dependent diabetes mellitus (IDDM) or a history of ketoacidosis, symptomatic
diabetic neuropathy or retinopathy, or renal disease (creatinine >3x ULN).
8. Hematocrit <34% in men or <25% in women with symptoms (fatigue, "tired-legs",
shortness of breath). Hemoglobin <10 gm/100ml with symptoms.
9. History of eating disorder, significant GI-disease
10. Nausea, vomiting, diarrhea (>4 loose stools/day) that are unresponsive to treatment
during 2wks prior to enrollment or that persists for >2wks during enrollment.
11. Active secondary infection. Any significant change in chronic suppressive therapy for
an opportunistic infection during the 1-month prior to enrollment.
12. During the 3 months prior to enrollment, regular aerobic or weight lifting exercise
training that exceeds the minimum (45min/d, 3d/wk, >75% exercise capacity) required
for the metabolic, biochemical, and anthropomorphic benefits of exercise to be
attained as described in the American College of Sports Medicine Guidelines. In Apr
2006, this exclusion criterion was modified in order to facilitate enrollment of
volunteers who are moderately-highly active during the 3months prior to screening for
this study. We will randomize volunteers who exercise regularly into the two
treatment groups. This will reduce the potential confounding effects of regular
exercise on the metabolic, biochemical, and anthropomorphic benefits of exercise
training that is prescribed during the treatment phase. We have excluded several
volunteers who are regular exercisers, and we believe we may be unnecessarily
excluding them. They can be included, enrollment will be facilitated, and the study
design will not be adversely affected, as long as we randomize them into pioglitazone
or exercise+pioglitazone (1:1).
13. Unwilling or unable to do supervised exercise 3 sessions/wk at the Medical School
exercise facility. Any condition that might be contraindicated for exercise training
(disabling joint, cartilage or muscle injury/disorder that prohibits or severely
limits participation in regular exercise, disabling arthritis, severe physical
disabilities, claudication, pulmonary disease, sinus tachycardia, arrhythmias,
premature atrial or ventricular contractions).
14. Pregnancy or nursing mothers. Women cannot be pregnant and must agree to use an
acceptable form of birth control during the treatment period. If birth control pills
are used, the woman must be stable on these medications for at least 6 months prior
to enrollment. All metabolic testing will be done in the early follicular phase.
Urine pregnancy tests (hCG) will be done at baseline and every month the woman is
enrolled in the study.
15. Pancreatitis within prior 1 year. Serum triglycerides >500mg/dL esp. with history of
pancreatitis, or otherwise at high risk for pancreatitis.
16. Medications that inhibit or slow blood coagulation (ie., blood thinners). Prothrombin
(clotting) time exceeds 2 sec > control (only in subjects who agree to muscle/fat
17. Active malignancy or treatment with chemotherapeutic agents or radiation therapy
during the 3 months prior to enrollment.
18. Excessive weight loss (>10% body weight) during the 3 months prior to enrollment.
History of hyperlactatemia or lactic acidosis, esp. with rapid weight loss.
19. "Blinded" investigational drugs/medications during the 3 months prior to enrollment
that will not be unblinded before enrollment. Open-label investigational drugs are
permitted. Must be stable on these for 3 months prior to enrollment, must remain
stable on them during the treatment period, and they must be known not to affect
glucose, lipid, adipose tissue or liver metabolism.
20. Non-prescription over the counter drugs/supplements that might alter glucose, lipid,
or adipose tissue metabolism (eg., creatine monohydrate, chromium picolinate, amino
acid/protein supplements, beta-hydroxy-beta-methyl-butyrate, anabolic-androgenic
steroids, medium- or long-chain fatty acids, branched chain amino acid supplements,
amino acids that potentially increase insulin or GH secretion (eg., arginine)) within
1 month of enrollment. These supplements will not be permitted during the treatment
21. Dementia or reduced cognitive function or unable to provide voluntary informed
consent. Prisoners will not be enrolled.
22. Active substance abuse (e.g., alcoholism, cocaine, heroin, crack, methamphetamine,
phencyclidine). Upon evaluation, if the physician-investigator considers that this
substance abuse does not put the volunteer at risk for an adverse (ie.
cardiovascular) event, or if the physician-investigator feels that the volunteer will
be reliable and compliant with the treatment regimens, and that this substance abuse
will not interfere with the study medications, exercise regimens, or data
interpretation, then at the physician-investigators discretion the volunteer may be
23. Any cytokine or anti-cytokine therapy during the 3 months prior to enrollment.
24. Patients felt by the Physician Investigator to have uncontrolled hypertension or
other diseases (i.e. vasculitis, pulmonary HTN) that otherwise may be a cause of
significant underlying or variable endothelial dysfunction
25. Receiving vasoactive substances (i.e. nitrates, viagra) other than antihypertensives
that cannot be discontinued at least 12 hours before endothelial function testing