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Metabolic Effects of Rosiglitazone in HIV Lipodystrophy: A Randomized, Controlled Trial

Colleen Hadigan, MD, MPH; Sigal Yawetz, MD; Abraham Thomas, MD; Fiona Havers, MA; Paul E. Sax, MD; and Steven Grinspoon, MD
[+] Article and Author Information

From Massachusetts General Hospital and Brigham and Women's Hospital, Boston, Massachusetts.


Ann Intern Med. 2004;140(10):786-794. doi:10.7326/0003-4819-140-10-200405180-00008
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Twenty-seven of the 28 randomly assigned patients completed the study. One patient randomly assigned to placebo was discontinued from the study after 2 weeks for increased liver aminotransferase level based on predetermined safety criteria. Table 1 presents the demographic characteristics of the study patients. Overall, waist-to-hip ratio (1.00 ± 0.04 for women and 0.98 ± 0.08 for men) was increased and percentage of leg fat (14.1% ± 8.4%, as measured by dual-energy x-ray absorptiometry) was reduced, consistent with the presence of fat redistribution. Metabolic and body composition variables were similar between the treatment groups at baseline (Table 2). One patient assigned to placebo switched from one non-nucleoside reverse transcriptase inhibitor to another; no patient switched nucleoside reverse transcriptase inhibitor or protease inhibitor medications during the study.

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Figure.
Insulin sensitivity and body fat response to rosiglitazone.

Top. and Middle. Insulin-stimulated glucose disposal rate determined by hyperinsulinemic euglycemic clamp testing and the ratio of insulin-stimulated glucose disposal rate to mean serum insulin level at steady state are presented. Circles indicate placebo (n = 11), and squares indicate rosiglitazone (n = 15). Clamp testing data were not available for 2 patients because of limited intravenous access, and the ratio was not available for 1 patient because of a sample processing error. Bottom. Mean percentage change from baseline in total body fat and subcutaneous leg fat area in patients treated with placebo (n = 12) or rosiglitazone (n = 16). Error bars represent SEs, and P values represent treatment effect between groups by analysis of covariance, controlling for baseline values.

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In Response:
Posted on June 28, 2004
Colleen Hadigan
Massachusetts General Hospital
Conflict of Interest: None Declared

In Response:

We acknowledge that rosiglitazone was associated with modest but statistically significant increases in total cholesterol and LDL cholesterol, similar to findings seen in the non-HIV diabetes literature regarding the use of this agent. It is important to recognize, however, that insulin resistance, elevated free fatty acids and hypoadiponectinemia are also significant independent predictors of cardiovascular disease, all of which improved with rosiglitazone in this population. Furthermore, there is evidence that PPAR-gamma agonists increase LDL particle size and increase small HDL particles, thereby creating a less atherogenic lipid profile(1). In addition, PPAR-gamma agonists such as pioglitazone may have more favorable effects on lipid levels while improving insulin sensitivity and adipogenesis. We agree that the long-term cardiovascular effects of thiazolidinediones are not known for this population and warrants further investigation.

In contrast to our study, a report by Carr et al. (2), failed to demonstrate significant increases in subcutaneous fat after 48 weeks of rosiglitazone compared to placebo in HIV infected patients with lipoatrophy. There are several important differences between our study and Carr et al.(2). Hyperinsulinemia, a surrogate marker for insulin resistance, was required in the current study as in the study of Gelato et al. (3) which also showed increased subcutaneous fat in response to rosiglitazone. The observed increase in subcutaneous fat in our study is consistent with known biological effects of PPAR-gamma agonists to stimulate adipogenesis. Carr et al. (2) showed a mean increase in limb fat of 5% with rosiglitazone but a 7% increase with placebo. In contrast, in our study subcutaneous fat decreased overtime in the placebo group, but increased in response to rosiglitazone. The spontaneous improvement in limb fat in the placebo arm of the Carr study may have contributed to the negative finding with respect to limb fat in that study. Further, stavudine use, a medication associated with progression of lipoatrophy (4) was disproportionate in the rosiglitazone vs. placebo arms (53% vs 26%, respectively) in Carr et al. In addition to having less severe lipoatrophy, 25% of subjects in Hadigan et al. were women, compared to only 2% in the study by Carr et al. (2) which may also contribute to differences in study results. While further study is needed, our data indicate a net potential benefit in metabolic parameters and body composition in this population of HIV infected patients with insulin resistance.

Colleen Hadigan, MD, MPH Steven Grinspoon, MD Massachusetts General Hospital Boston, MA 02114

References 1. Bavirti S, Ghanaat F, Tayek JA. Peroxisome proliferator-activated receptor-gamma agonist increases both low-density lipoprotein cholesterol particle size and small high-density lipoprotein cholesterol in patients with type 2 diabetes independent of diabetic control. Endocrine Practice. 2003;9(6):487-93.

2. Carr A, Workman C, Carey D, et al. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomized, double-blind, placebo- controlled trial. Lancet. 2004;363(9407):429-38.

3. Gelato MC, Mynarcik DC, Quick JL, et al. Improved insulin sensitivity and body fat distribution in HIV-infected patients treated with rosiglitazone: a pilot study. J Acquir Immune Defic Syndr. 2002;31(2):163-70.

4. Dube M, Zackin R, Tebas P, et al. Prospective study of regional body composition in antiretroviral-naive subjects randomized to receive zidovudine+ lamivudine or didanosine+stavudine combined with nelfinavir, efavirenz, or both: A5005s, a study of ACTG 384. Antiviral Therapy. 2002:L18.

Conflict of Interest:

None declared

Rosiglitazone for treatment of HIV lipodystrophy
Posted on August 3, 2004
Nasser Mikhail
Olive-View-UCLA Medical Center
Conflict of Interest: None Declared

I disagree with Hadigan et al (1) in stating that rosiglitazone had positive effects on metabolic indices in HIV lipodystrophy. In fact, there was significant increase in mean plasma levels of total and low-density lipoprotein (LDL) cholesterol of about 13% with rosiglitazone 4 mg daily. Surprisingly, Hadigan et al (1) did not comment on the important study of Carr et al (2) that evaluated rosiglitazone for the same objective. However, compared with the present study (1), the trial of Carr et al (2) was larger (n=108)and longer-term (48 weeks)using maximum doses of rosiglitazone (4 mg twice daily). Carr et al (2) also reported significant rise in total and LDL cholesterol in the rosiglitazone group. Moreover, there was significant increment in plasma triglycerides, which were not increased in the study of Hadigan et al (1) probably because of using submaximal doses of rosiglitazone. Clearly, the deterioration of lipid profile by rosiglitazone therapy can increase the cardiovascular risk of HIV-infected patients, a population that may be already at high risk mainly because of adverse metabolic effects of antiretroviral therapy (3).

Unlike the present study (1), Carr et al (2) failed to find any beneficial effects of rosiglitazone on lipoatrophy. The improvement of lipoatrophy in the study of Hadigan et al(1) could be attributed, at least in part, to the fact that lipoatrophy was significantly milder in the rosiglitazone group compared with the placebo group at baseline. Chance may also be a factor given the small number of patients. Taken together, the previous data indicate that rosiglitazone can worsen lipid parameters in HIV lipodystrophy without clear beneficial effects on fat redistribution. Accordingly, rosiglitazone should be used with caution, if any, in HIV-infected patients receiving antiretroviral therapy with close monitoring of the lipid profile.

Nasser Mikhail MD, MSc

UCLA Medical Center

UCLA School of Medicine

1. Hadigan C, Yawetz S, Thomas A, Havers F, Sax PE, Grinspoon S. Metabolic effects of rosiglitazone in HIV lipodystrophy. A randomized, controlled trial. Ann Intern Med. 2004; 140: 786-794.

2. Carr A, Workman C, Carey D, Rogers G, Martin A, Baker D, Wand H, et al. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial. Lancet. 2004;363: 429- 438.

3. The Data Collection on Adverse Events of Anti-HIV Drugs (DAD). Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003; 349: 1993-2003.

Conflict of Interest:

None declared

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Summary for Patients

Rosiglitazone Treatment for Fat Redistribution and Metabolic Abnormalities Caused by Anti-HIV Therapy

The summary below is from the full report titled “Metabolic Effects of Rosiglitazone in HIV Lipodystrophy. A Randomized, Controlled Trial.” It is in the 18 May 2004 issue of Annals of Internal Medicine (volume 140, pages 786-794). The authors are C. Hadigan, S. Yawetz, A. Thomas, F. Havers, P.E. Sax, and S. Grinspoon.

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