Diabetes Drug Rosiglitazone (Avandia) Improves Limb Fat Loss in HIV Patients on Antiretroviral Therapy

By Liz Highleyman

Peripheral lipoatrophy -- or fat loss in the limbs, buttocks, and face -- is a concern for many people with HIV, especially those who have used the thymidine nucleoside reverse transcriptase inhibitors (NRTIs), stavudine (d4T, Zerit) or zidovudine (AZT or Retrovir, also in the Combivir coformulation).

In a presentation at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last week in Montreal, Marisa Tungsiripat of the Cleveland Clinic Foundation described a study evaluating the diabetes drug rosiglitazone (Avandia) as a treatment for limb lipoatrophy in HIV patients on antiretroviral therapy.

Rosiglitazone belongs to the class of thiazolidinediones, drugs that increase the activity of the PPAR-gamma cell receptor protein, which plays a role in fat metabolism. Since thymidine NRTIs strongly inhibit PPAR-gamma, the investigators assessed whether rosiglitazone could counteract this effect.

The 71 HIV positive participants in this double-blind, placebo-controlled study had lipoatrophy at baseline. All had used thymidine NRTIs for at least 12 months in the past (median 4 years), but had not done so for at least 6 months.

Overall, baseline characteristics were similar in the 2 groups, except that placebo recipients had a higher mean total cholesterol level. Most participants (85%) were men, half were white, and the average age was about 50 years. Patients had well-controlled HIV disease, with a mean CD4 count of about 650 cells/mm3 and 90% with HIV RNA < 400 copies/mL. While individuals with had full-blown diabetes were excluded, 37% had pre-existing insulin resistance.

Study participants were randomly assigned to receive 4 mg twice-daily rosiglitazone or placebo for 48 weeks, along with their antiretroviral therapy.

Laboratory tests and DEXA scans were used to assess metabolic and limb fat changes. Unfortunately, the investigators did not look at changes in facial fat, which patients often find most distressing because it can change their appearance and is an obvious sign of HIV/AIDS. Visceral fat also was not assessed.

Insulin resistance was measured using the HOMA-IR method. Since rosiglitazone has been associated with increased risk of cardiovascular disease and bone loss in studies of the HIV negative general population, the researchers will also conduct further assessments including carotid artery intima-media thickness and biomarkers of inflammation and bone metabolism (not reported at CROI).

Results

Limb fat increased in both groups by 48 weeks, consistent with discontinuation of thymidine NRTIs.

The mean limb fat gain was significantly greater in the rosiglitazone arm compared with the placebo arm (about 900 gram vs about 300 grams, respectively).

This corresponded to limb fat percentage increases of 15% and 5%, respectively.

Insulin resistance and insulin levels decreased in the rosiglitazone arm, compared with a small increase in the placebo arm.

Mean increases in total cholesterol and non-HDL ("bad") cholesterol at 48 weeks were significantly larger in the rosiglitazone group.

Triglyceride levels showed a trend in the same direction, but the difference did not reach statistical significance.

HDL ("good") cholesterol did not change significantly in either group.

There were no significant changes in body mass index or bone mineral density in either arm.

Rosiglitazone was generally well tolerated.

9 participants (half in each arm) discontinued the study prematurely, but only 1 patient in the rosiglitazone arm did so due to a possible drug-related adverse event (worsening of pre-existing coronary artery disease).

These findings led the investigators to conclude that among patients not taking thymidine NRTIs, rosiglitazone "significantly improves peripheral lipoatrophy even in subjects without insulin resistance."

About half of the past studies of rosiglitazone and pioglitazone (Actos) in HIV positive people have not demonstrated similar improvements, but these often included patients who remained on stavudine or zidovudine, which may overcome any benefits.

Due to lipoatrophy and other side effects, these drugs are no longer listed as preferred agents in current U.S. treatment guidelines, though they are still widely used in developing countries due to their low cost and wide availability. Newer NRTIs, including abacavir (Ziagen, also in the Epzicom coformulation) and tenofovir (Viread, also in the Truvada and Atripla pills) do not have the same association with fat loss.

2/17/09

Reference
D El Bejjani, M Tungsiripat, N Rizk, and others. Rosiglitazone improves lipoatrophy in patients receiving thymidine-sparing regimens. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 42LB.