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  9th Intl Workshop on Adverse Drug Reactions and Lipodystrophy in HIV
Sydney, Australia
July 19-21 2007
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Pioglitazone ± exercise training reduces liver lipid content and improves insulin sensitivity in HIV with impaired glucose tolerance; pioglitazone increased limb fat, exercise reduced limb fat
  Reported by Jules Levin
9th Intl Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, July, Sydney, Australia
Dominic Reeds, W.Todd Cade, Kristin Mondy, Corinne Bopp, Sherry Lassa-Claxton, Kevin E. Yarasheski
Washington University School of Medicine
St. Louis, MO USA
See tables/graphs below
In HIV, is pioglitazone + exercise training more effective than pioglitazone alone:
--Both improve peripheral insulin sensitivity, but Pio+Exer does better than Pio alone.
--Pio+Exer appears to reduce visceral adiposity, Pio does not (pio had small increase in VAT fat).
--Pio appears to modestly increase subq adiposity, but Pio+Exer reduces it.
--Overall reduction in liver lipid content. Correlated with enhanced ability to suppress endogenous glucose production.
--Except for 1 participant, unremarkable alterations in serum lipid/lipoprotein profiles.
--Safety: Good, so far....
--This is a Preliminary report from small intensive study
--Don't know mechanisms of action yet but they are working on it. Adiponectin; Intracellular signaling pathways in fat and muscle samples.
--they are working also on the Impact of these findings on CVD/CHD risk in HIV+
We are looking for safe and effective treatments for HIV-related metabolic/ anthropomorphic/CVD complications?
Exercise training: in HIV-negatives exercise improves insulin sensitivity, reduce adiposity, reduce total- and LDL-chol, triglycerides, and increase HDL-chol, reduce HTN, reduce CVD risk. A few studies in HIV+ have been done
Pioglitazone (PPARg agonist): improves insulin sensitivity, may reduce visceral adiposity, and modestly increase limb fat (Capeau et al. ADR Lipo 2006), may reduce triglycerides and increase HDL-chol (Gavrila et al. CID 2005), reduce liver lipid content (Belfort et al. NEJM 2006), improve CVD risk factors/surrogates (Staniloe et al. Cardiol 2007), and anti-inflammatory properties (PIOSTAT Circ 2007).
In HIV, is pioglitazone + exercise training more effective than pioglitazone alone:
--Improve insulin sensitivity
--Reduce visceral adiposity
--Increase subq adiposity
--Reduce liver lipid content
--Less pro-atherogenic serum lipid/lipoprotein profiles
They thought that pioglitazone would improve insulin sensitivity but both exercise+pio would improve it more. They hoped pio would reduce trunk fat and exercise+pio would reduce it more. They hoped pio would improve limb fat and perhaps exercise might override this benefit with an flatening out of effect. They hoped exercise and pio would both reduce liver lipids, and pio+exercise would improve serum lipids.


They screened HIV+ with impaired glucose tolerance determined by a 2-hour glucose tolerance test, patients had redistribution. Patients were randomized to just pioglitazone 30mg/day along with nutrition counseling, or they received pioglitazone 30mg/day + exercise in their exercise/gym facility, 1.5-2 hr/day (one-third of time aerobic exercise, one-third weight building), plus nutrition intake counseling. Study testing was performed prior to and after 4 weeks of the randomized interventions.


-- 2-hr oGTT
-- Body composition; DEXA, Abdominal MRI
-- 1H-MRS; Liver lipid content
-- Resting EKG & Echocardiogram
-- 5-hr hyperinsulin-glucose clamp
-- Fasting Lipid/Lipoprotein/LDL-particle size
-- Safety Labs (CD4, VL, H&H, ALT/AST)
Statistical Analyses:
--Within group comparisons: Paired t-test --Between group comparisons: ANOVA
Hyperinsulinemic-euglycemic clamp protocol


8 men and 1 woman were on pioglitazone, and 6 men on pio+exercise. 3 African-Americans in pio group, and 2 in pio+exercise. 75% of patients were on boostedPI HAART and 25% on non-boosted PI HAART. Age 47-51 yrs. Weight 83 kg. % fat: 22-24. Years with HIV: 10 in pio group, 17 in pio+exercise group.


Peripheral insulin sensitivity (peripheral glucose disposal rate) improved more in the Pio+Exer than Pio group
In both groups , pio and pio+exercise, there is a significant increase or improvement in disposal rate of glucose in the periphery. The change was greater in the pio+exercise group compared to the pio group (92% vs 67%) although disposal rate was better at baseline in the pio+exercise group.


Endogenous glucose production rate is suppressed equivalently following Pio±Exer
At baseline patients in both groups the first bar in the graph shows they produce glucose at too high a rate which is why they have hyperglycemia. The second bar at wk0 shows if you give them insulin endogenous glucose production is reduced. Four months after interventions endogenous glucose production was improved by 25% in pio group and 31% in pio+exercise group. These results are not different between groups.


Adipose tissue distribution is modestly, but differentially altered by Pio vs Pio+Exer
Pio increased weight, some of it is lean tissue or might be fluid as pio can cause edema or fluid retention; they gained a little whole body fat which was distributed to the trunk and limb (which is 400-500 grams, the same amount reported by Jacqueline Capeau last year in her study of pioglitazone that found increased limb fat. The effect of adding exercise shows some trends, not significant chamges: reduces weight, reduced wholr body fat, reduced trunk fat, and reduced limb fat. Pio+exercise did improve whole body lean tissue. So the addition of exercise had the exact opposite effect on some changes seen with only pioglitazone, adding exercise reduced improved limb fat, reduced trunk fat, and reduced weight.


Abdominal adipose tissue volumes are modestly, but differentially altered by Pio vs Pio+Exer
This is MRI results. Taking pioglitazone resulted in small increases in fat in SAT and VAT, but pio+exercise resulted in decreases in fat in SAT and VAT equaling at least the amount of fat gains from pio in SAT and VAT. Yarasheski said the effect of adding exercise to pioglitazone "exacerbates lipoatrophy but reduces fat in VAT that has bad cardiovascular implications".


Lipid and lipoprotein levels are only modestly affected by Pio, but tend to be reduced by Pio+Exer.
Pioglitazone did not change lipids over the 16 week study. Pio+exercise showed a trend towards reduced triglycerides (from 250 to 100 in grapg below) but no changes in other lipid values. However, one patient had bad experience, Triglycerides were 300 at baseline and went up to 700 on pio so they stopped the patient from the study and his triglycerides went down. So they concluded that pioglitazone does not appear to have any problems related to lipids, except for the one patient.


Liver lipid content appears to be reduced similarly in both groups
Baseline liver lipid fat was "pretty high", about 13% in both groups. Pioglitazone for 4 months reduced liver fat by 3% and pio+exercise reduced liver fat by 6%. These changes are not statistically significant.


There were no changes in CD4, viral load, ALT (normal at baseline), creatinine, or hemoglobin.