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Rosiglitazone Improves Lipoatrophy in Patients Receiving
Thymidine-sparing Regimens
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Reported by Jules Levin
CROI 2009 Feb 8-12 Montreal
D El Bejjani1,2, M Tungsiripat3, N Rizk2, M O'Riordan2,4, A Ross2,4, C Hileman2,4, N Storer2,4, D Harrill2,4, and Grace McComsey*2,4
1Metrohealth Med Ctr, Cleveland, OH, US; 2Case Western Reserve Univ, Cleveland, OH, US; 3Cleveland Clinic Fndn, OH, US; and 4Univ Hosps of Cleveland, OH, US
from Jules: This study reported increased limb fat after 48 weeks of rosiglitazone. This study did not select patients by their insulin resistance status, and patients with diabetes or use of metformin were excluded. Rosiglitazone dose was 4 mg daily for 4 weeks then dose escalated to 4 mg twice daily. This study selected patients who have been off tNRTIs for an average of 44 months or for at least 24 weeks, since it has been shown that concomitant use of tNRTIs can blunt benefit of rosiglitazone. Previous studies of a glitazone (rosiglitazone, pioglitazone) for lipoatrophy have shown mixed results (see slide below). The presenter said none of the previously conducted studies listed in the slide, specifically excluded tNRTIs, and she also said 3 of the 4 studies showing improved fat required patients to be insulin resistant, and the studies have been at different doses and durations. In the current study, total cholesterol increased significantly in patients receiving rosi, after 48 weeks. The study looked at whole body dexa for BMD and did not detect any significant change either from baseline or between groups (placebo vs rosi) in bone mineral density. Todd Brown in his CROI NATAP Bone Report said: "While this is somewhat reassuring, only total BMD was measured as an outcome. It is unclear if rosiglitazone would have an effect on BMD, if sites with more trabecular bone, which is more metabolically active (eg spine), were measured in addition to total body BMD". There was a trend for an increase in non-HDL cholesterol in patients receiving rosi. At baseline 37% of patients had insulin levels greater than 15 and the presenter said I think 37% or 30% had HOMA-IR greater than 3.6. Average triglycerides were 220 at baseline. Insulin resistance indices, insulin & HOMA-IR, improved significantly from baseline in patients receiving rosi compared to the placebo arm and compared to the baseline levels in patients receiving rosi.
Mean limb fat increased by 16% in the rosi group (p<0.001 compared to baseline; p=0.01 compared to placeo), limb fat increased 4% in the placebo group (p=0.04 from baseline). The actual change in limb fat was an increase of 900 grams from mean baseline level of 6500 grams for patients receiving rosi (p<0.001 compared to baseline; p=0.018 compared to placebo group). The placebo group had mean baseline level of 6400 grams and experienced increase in limb fat of 300 grams and this increase from baseline was significant (p=0.03).
Studies in HIV-negative diabetics receiving a glitazone, either pio or rosi - glitazone, have reported bone loss. Heart/CVD adverse events in patients receiving rosiglitazone have been reported, but the findings of CVD adverse events has been controversial, the patients in the studies are diabetics who are at greater risk for CVD events. Studies of pioglitazone have found improved lipids and reduced CVD events. I am unaware of any study in HIV+ individuals where these complications have been reported. The baseline limb fat reported in the Table below of about 6500 grams is I have been told by the study investigators the mean but the median was lower, 4.6 kg, which they say does signal severe lipoatrophy, which they also say is similar to the baseline limb fat reported by the investigators for MITOX, TARHEEL and RAVE. The mean was driven by a few people with high limb fat, so median gives a better idea about the baseline of the patients in this study. The investigators reminded me that prior switch studies (MITOX, RAVE, TARHEEL) have reported increased limb fat of 350-450 grams after 48 weeks. The presenter said none of the previously conducted studies have required patients to be off tNRTIs. The French pioglitazome study also reported an increase of 450 grams after 48 weeks for patients off d4T without a significant increase in limb fat for patients on d4T. Perhaps I was too critical of the results if this study in my prior report. To explain the bone loss seen in HIV-negative diabetics It has been suggested that glitazones may turn precursor bone cells into fat cells, perhaps this should be investigated in HIV+ individuals. When considering the use of rosi or pio -glitazone in HIV the pros and cons should be weighed, perhaps a bone dexa should be considered as well as patient risk factors regarding potential bone loss.
Link to CROI Bone Report:
Bone/Osteoporosis CROI 2009 Update - written by Todd Brown, MD, PhD (03/04/09)
Background: Thymidine NRTI (tNRTI) are strong inhibitors of PPAR-g. Conflicting data exist on the efficacy of the PPAR-g agonists glitazones on lipoatrophy in the setting of tNRTI. We report the first study of a glitazone in lipoatrophy in HIV-infected subjects treated with tNRTI-sparing regimens.
Methods: This randomized, double-blind, placebo-controlled study evaluated the effect of rosiglitazone (ROSI) on limb fat in HIV-infected subjects with lipoatrophy who discontinued their tNTRI at least 24 weeks prior to enrollment. They were randomized to ROSI (4 mg twice daily) vs placebo for 48 weeks. Dual energy X-ray absortiometry (DEXA)-scans and fasting metabolic assessments were serially performed. Distributionally appropriate paired tests were used to determine significant changes from baseline within groups, and 2-sample tests were used to determine differences at baseline and for changes from baseline between groups.
Results: We enrolled 71 subjects: 17% were female and 51% white.
At baseline, the mean ±SD limb fat (grams) was 6533±4381 and 6413±3272; p = 0.70, in ROSI and placebo arms, respectively.
At entry, 26 (37%) had insulin levels >15 μU/mL, and 92% of subjects had HIV-1 RNA <400 copies/mL. Baseline characteristics were similar between groups except for higher mean total cholesterol levels (mg/dL) in the placebo arm (180 vs 200; p = 0.045). Overall, 9 subjects were lost to follow-up (4 on ROSI). Of these, only 1 (in ROSI group) had discontinued the study for a possible adverse event (possible exacerbation of pre-diagnosed coronary artery disease). No subjects modified their entry NRTI during the study. At week 48, 98% of subjects had HIV-1 RNA <400 copies/ mL.
Limb fat (grams) increased significantly more in the rosi group than in the placebo group (mean±sd of 911±1215 vs 253±1039; p = 0.018).
The mean HOMA and insulin levels (μU/mL) decreased from baseline only in the ROSI arm -1.9±6.8 vs 0.5±2.6 and -7.4±27.3 vs 2.7±12.2; p = 0.03 and 0.02, respectively). Triglycerides, HDL- and non-HDL cholesterol did not change significantly within or between groups. Six subjects (3 on ROSI) started statin or fibrate during the study. Total bone mineral density, CD4+ cell count and body mass index did not change significantly between groups.
Conclusions: In the absence of thymidine NRTI, ROSI significantly improves lipoatrophy and insulin resistance, without adversely affecting lipids or bone density.
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