A Toronto-based study has concluded that "glitazones," an effective class of medications for diabetes and a longtime contender in the study of treatments for lipoatrophy, don't offer any significant benefit compared to placebo in terms of reversing fat loss in the arms, legs, face, and buttocks in people with HIV.
While the precise mechanism by which HIV medications cause lipoatrophy has not been completely mapped out, there is enough evidence to conclude that certain nucleoside reverse transcriptase inhibitors (NRTIs) – Zerit® (stavudine) and less commonly Retrovir® (zidovudine) – are most likely to blame.
Avoiding these medications may limit the risk of fat loss, and switching off of them may halt or slow the progression of lipoatrophy among people showing signs of the complication. Unfortunately, these strategies may not reverse lipoatrophy once it has occurred. In turn, researchers have been looking into the use of other compounds to help correct and restore the stigmatizing loss of fat in the face, arms, legs, and buttocks.
Thiazolidinediones (TZDs) – better known as "glitazones" – are a small group of medications used to treat diabetes. Avandia® (rosiglitazone) and Actos® (pioglitazone) are the two glitazones approved for use in the United States.
They act on a transcription factor – a protein that controls gene expression – called PPAR-γ. The glitazones are agonists of this protein, meaning that they stimulate its ability to activate genes responsible for regulating the formation of fat cells (adipogenesis), glucose levels, and the metabolism of lipids in the blood.
Studies, involving patients with diabetes and non-HIV forms of lipodystrophy, have repeatedly shown that glitazones can increase fat in the extremities, decrease visceral fat (fat deep within the body), and improve glucose abnormalities.
While there have been case reports suggesting that glitazone therapy was helpful in terms of improving body fat in HIV-positive people with diabetes and lipodystrophy, more rigorous studies to date have produced conflicting results.
The most recent results come from a study conducted by Rodrigo Cavalcanti, MD, of the University of Toronto and his colleagues, published ahead of press on the Journal of Infectious Diseases website. The study enrolled HIV-positive patients taking a protease inhibitor-based regimen, all of whom had lipoatrophy. The patients were randomized to receive Avandia (4 mg a day) or placebo for 24 weeks.
It is worth noting that the study was originally designed to enroll 252 patients. Unfortunately, because of circumstances beyond the control of the investigators, including the severe acute respiratory syndrome virus epidemic in Toronto, the study enrolled only 96 subjects, 78 of whom completed all six months of follow up.
The primary goal of the study was to compare increases in arm fat between the two groups after 24 weeks of treatment. Upon study entry, DEXA scanning found arm fat concentrations to be 1.3 kg in the Avandia group and 1.0 kg in the placebo group. After 24 weeks, arm fat increased by 7.1% in the Avandia group and 5.1% in the placebo group. However, the difference between the two groups was not statistically significant, meaning that it could have been due to chance.
There were also no significant differences between groups in the absolute or percentage changes in leg fat, limb fat, trunk fat, and total body fat. What's more, compared to placebo, Avandia did not have any significant impact on glucose metabolism or blood lipid levels.
Dr. Cavalcanti's group noted that, among patients with lipoatrophy who were not taking either Zerit or Retrovir in the study – or switched off of these meds while participating in the clinical trial – fat gains in the arms and other extremities were more pronounced among those in the Avandia group. In turn, the researchers argue, "it is possible that concomitant [Retrovir or Zerit] therapy might negate any positive effects of rosiglitazone on PPAR-γ." However, the overall conclusion of the study was that Avandia did not show a benefit in slowing or reversing HIV-associated lipoatrophy.
An accompanying editorial by Steven Grinspoon of the Massachusetts General Hospital Program in Nutritional Metabolism and Harvard University School of Medicine suggests that glitazones may still be useful in terms of reversing lipoatrophy, but should probably be reserved for those who also have bona fide problems with glucose metabolism.
Dr. Grinspoon writes: "How should we put all of this into perspective? Taken together, the data suggest that TZDs modestly improve subcutaneous fat in at least some HIV-infected subjects, an effect greater in those not receiving [Zerit]. However, use of TZDs as a specific strategy to improve subcutaneous fat may not be justified, given the magnitude of this response. In contrast, among HIV-infected patients with type 2 diabetes mellitus who have concomitant lipoatrophy, these drugs may be very useful to improve insulin resistance and modestly increase subcutaneous fat."
Sources:
Cavalcanti RB, Raboud J, Shen S, et al. A randomized, placebo-controlled trial of rosiglitazone for HIV-related lipoatrophy. J Infect Dis. Published online, ahead of print (May 2, 2007).
Grinspoon S. Use of thiazolidinediones in HIV-infected patients: what have we learned? J Infect Dis. Published online, ahead of print (May 2, 2007).
