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Rosiglitazone For Lipoatrophy: mixed results
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Colleen Hadigan, Steve Grinspoon and colleagues (Massachusetts General Hospital, Boston) reported on a double-blind, randomized, controlled study examining the effect of rosiglitazone on insulin sensitivity, subcutaneous fat, and metabolic measures in HIV+ individuals with lipoatrophy and insulin resistance. This differed from the Finnish study presented at the most recent Retrovirus Conference in that the Finnish study include patients without insulin resistance. And the Finnish study did not find a benefit to lipoatrophy from using 8 mg per day of rosiglitazone, but there study method and analysis was not great in trying to find an improvement.
Gelato et al (Jnl AIDS 2002) reported on a study in 8 HIV+ individuals with fat redistribution that they followed for up to 12 weeks that subcutaneous fat increased 23% (p=.05), visceral (belly) fat decreased 21% (p=.04) and glucose disposal improved. Yki-Jarvinen et al (Art Throm Vasc Biol, 2003) reported rosiglitazone trial of 24 weeks in 30 HIV+ with fat redistribution. They saw decreased insulin, liver fat and LFTs. There was no improvement in visceral or subcutaneous fat (lipoatrophy); and rosiglitazone increased triglycerides.
For evaluation Hadigan's study utilized hyperinsulemia-euglycemic clamps, CT scan, DEXA, bioelectrical Impedance Analysis (BIA), and lipoatrophy self-rating be patient. Also evaluated were fasting lipids, adiponectin, free fatty acids.
Patients were included if they had fasting insulin >15uU/mL and/or 2 hour insulin >75uU/mL after OGTT (glucose tolerance test). Patients were excluded if they were diabetic, had hemoglobin <9 g/dL (concern regarding heart disease), LFTs >2.5 x ULN, or a history of kidney or heart failure.
Eleven patients were randomized to receive placebo and 16 to rosiglitazone. Patients had HIV for 8-10 yrs, received ART for 7 to 9 yrs, CD4 count 480, HIV-RNA 75% undectable, and BMI was 25-26 kg/m2 in each study group. Patients had comparable characteristics in both arms of study.
In this study patients were randomized for 3 months to rosiglitazone (4 mg/day) vs placebo. This was followed by a 3 month open label trial where all patients, including placebo patients from first 3 months, received 8 mg/day.
RESULTS
Rosiglitazone resulted in improved insulin sensitivity, with increased glucose utilization. Glucose disposal improved during the first 3 months for patients on rosiglitazone vs placebo (p=0.01).
Regarding body fat or lipoatrophy, the study results were a bit mixed but encouraging. Body fat by BIA at 3 months was significantly improved by 15% for patients receiving rosiglitazone vs placebo (-5%). Using Cat Scans, subcutaneous fat showed trends towards improvement at months 3 and 6, and this is referring to improved subcutaneous fat in belly. At month 3 by DEXA, leg fat improved by 5% above baseline in rosiglitazone arm ve placebo (p=0.06). There was no difference in visceral fat at 3 months between the two study arms.
The subjects receiving rosiglitazone reported a mean reduction in lipoatrophy severity of 25% compared to their baseline and this was statistically significant compared to placebo (p=0.03) where there was little or no improvement.
Total cholesterol increased by about 10% for patients on rosiglitazone, although they did not see increase in triglycerides in this study. The potential increase in lipids is a concern.
At the 6 month assessment (after all patients had been taking rosiglitazone), insulin sensitivity increased 20%, total cholesterol increased 12%, hemoglobin decreased by almost 10%, ALT decreased, and 25% of patients reported improved lipoatrophy.
In sum, the study authors reported improved insulin sensitivity which most researchers at the meeting concurred with in terms of seeing a positive finding from the study. However, most researchers at the meeting felt the study showed mixed results in terms of improved lipoatrophy. Although the CT Scans showed improvement the DEXA did not show a significant improvement in leg fat. The study was powered to examine insulin resistance but not to examine improved lipoatrophy, so the feeling by observers was that the study was too small to feel excited about improved lipoatrophy. Because DEXA of leg fat was not significant this detracted from reported improvement of subcutaneous fat in the belly. The study was small and considering mixed results from other studies researchers here felt as David Cooper said at the microphone "the jury is still out" on whether rosiglitazone can improve lipoatrophy.
However, doctors at the meeting are impressed that insulin resistance was improved, so if an HIV+ patient has diabetes and lipoatrophy, using rosiglitazone has potential benefits regarding the insulin resistance and it might improve lipoatrophy. Several studies are ongoing examining rosiglitazone in HIV-infected patients with lipoatrophy. The Australian research group has a randomized study in about 100 patients and the results are about to be analyzed. Results are expected to be presented at the 2004 Retrovrus Conference. So until we see further results which are more definitively positive rosiglitazone use to treat lipoatrophy is not recommended. Observers felt these study results are encouraging regarding lipoatrophy but we need to see further data from larger ongoing studies.
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