The diabetes drug rosiglitazone (Avandia) produces a significant improvement in body fat redistribution and insulin resistance in HIV-positive patients with HAART-related lipodystrophy, according to a randomised controlled trial published in the May 18th edition of the Annals of Internal Medicine.
The relationship between body fat changes, insulin resistance and increased levels of circulating fatty acids associated with HAART is not well understood. However, this study suggests that rosiglitazone, a member of the thiazolidinedione family, can improve the prognosis of patients with lipodystrophy by increasing insulin sensitivity and stimulating the deposition of subcutaneous fat.
“The metabolic complications of this syndrome are becoming more significant as patients spend more time on HAART,” says the report’s lead author. “We know that 14% of men on this therapy may develop type two diabetes, which is four times the usual risk; and concerns are also increasing about the related risk of heart disease.”
The authors, from Massachusetts General Hospital in Boston, USA, recruited 27 patients with some degree of lipoatrophy for their double-blind placebo-controlled trial. Previous studies examining the effects of rosiglitazone and related drugs on HAART-related metabolic changes have been inconclusive. However, the participants in this study were restricted to those with resistance to insulin and high levels of insulin in their blood.
The patients were randomised to receive either oral rosiglitazone (4mg daily) or placebo for three months. At the end of the study, the patients who had received the drug showed a 26% improvement in their sensitivity to insulin, measured by a standard test called an insulin clamp. This is compared to a 7% decrease in patients assigned to the placebo group (p = 0.02).
The patients taking rosiglitazone also showed significant increases in peripheral fat, measured by computerised tomography. Fat measurements in the leg increased by 24% in the treatment group but only 2% in the placebo group (p = 0.02). However, the drug did not cause any significant changes in the volume of subcutaneous or visceral fat tissue in the abdomen, or in body mass index.
Patients treated with rosiglitazone reported a significant improvement in lipoatrophy compared to the control group (p = 0.02), although the report does not distinguish between body regions. It is not possible, therefore, to determine whether the drug may improve fat loss from the face or from the limbs.
Rosiglitazone caused a 19% decrease in the levels of circulating fatty acids, compared with a 2% increase in patients receiving placebo (p = 0.02), which, the authors argue, may reflect the reduced breakdown of fat tissue in the treatment group. It caused no significant alterations in CD4 counts or HIV viral loads.
Despite these promising findings, patients taking rosiglitazone showed a 12% increase in levels of total cholesterol and a 14% increase in ‘bad’ LDL cholesterol. Both of these decreased in the placebo group (7%; p = 0.01, and 13%; p
Side-effects of rosiglitazone treatment were mild at the low dose used. No patients withdrew from the trial on account of adverse effects of the drug, and none showed signs of fluid retention or congestive heart failure, although one patient did develop anaemia during the trial.
Although these findings are promising for people affected by lipodystrophy, longer studies with more patients are needed to establish whether the drug can be used to treat the condition in the long term. “There are still a lot of questions to be answered about safety before these results can be widely applied,” state the authors. “Larger and longer trials of this drug are needed to determine the best therapeutic approaches for individual patients.”
The results also contradict findings from an Australian-led study published in February, which concluded that rosiglitazone treatment at the same dose used in this study did not result in significant improvements in body fat distribution after 48 weeks of follow-up. However that study did report a significant improvement in insulin sensitivity.
Colleen Hadigan and colleagues note that the population studied in this trial all had insulin resistance at baseline. Insulin resistance has not been a consistent feature of all trial populations previously reported, suggesting that the effects on fat loss of rosiglitazone might be limited to individuals with insulin resistance and lipoatrophy rather than more generalised fat distribution.
Further information on this website
Tarnished glitazones fail to reverse fat wasting - news story, February 2004.
Reference:
Hadigan C et al. Effects of rosiglitazone on metabolic indices and fat in HIV lipodystrophy: a randomized controlled trial. Ann Intern Med 140: 786-794, 2004.