Bay Area Reporter - October 19, 2000
Matt Sharp, Survive AIDS Writers Pool

Side effects were few in this study, leading to larger trials in the future. Metformin has been used for years to treat diabetics.

Researching and discovering treatments for lipodystrophy has been troublesome. Most treatments for the complications are being used without much clinical data to back them up. And there is a conundrum in the research community over exactly what is happening with lipodystrophy in HIV, causing delays in the research.

A few years ago, when strange metabolic complications were being seen in AIDS, resulting in elevations in triglycerides and cholesterol, raised glucose levels, and strange body shape changes, people with AIDS wanted treatments. The complications were creating a setback for those fortunate to have any benefit from lowered viral loads, which were slowing progression to AIDS and reducing the death rate. It became frustrating to deal with the confounding problem in light of all the progress that had been made in slowing HIV.

Unfortunately, figuring out what is happening to the complex endocrine and immune systems in people with HIV is problematic. Scientists and researchers can't agree on the definition of the syndrome(s) therefore, it is difficult to design studies and discover treatments. Today, it is mostly understood that these metabolic complications are a result of many factors, but despite new clinical trials, the treatments remain few and far between. Kathy Mulligan, AIDS wasting expert at the University of California, San Francisco, agreed, saying, "After three years, we still don't know what is fundamentally going on. We don't understand if it is one syndrome or two, what's causing it, or how to manage it.

Interestingly, after studying type II diabetes for decades, researchers don't understand the complexity of insulin resistance and glucose intolerance, and the best ways to measure them. So understanding and sorting out the fundamental issues is the biggest problem we face in HIV lipodystrophy research today."

That being said, older studies have shown that metformin, human growth hormone, and a few lipid-lowering agents can be useful in treatment of metabolic complications in HIV, but the studies have been small. More data needs to be collected to prove their worth. Obvious problems with drug interactions and side effects hamper the development of new treatments for lipodystrophy because of the growing number of drugs people with AIDS have to take. Furthermore, the pharmaceutical industry has not been very supportive of lipodystrophy research because they do not want any negative toxicity data that may cause people to steer clear of their drugs.

The metformin paper published in the July 26 issue of JAMA is an encouraging study because it is one of the first randomized, controlled trials of an agent to treat lipodystrophy that shows real promise.

Although the number of participants in the study was low, we have more evidence in treating insulin resistance and abdominal fat in HIV. And by reducing abdominal fat, the risk of cardiovascular disease is less, so the implications of this study may be life saving.

A small study with 26 patients - six women and 20 men - who were non-diabetic and had lipodystrophy was enrolled at Massachusetts General and Brigham and Women's Hospital in Boston, and from community-based practices. Doses of metformin were at 500 milligrams twice a day. The dose chosen was lower than what was used in past studies. Participants were randomized to receive either metformin or placebo for a three-month period. Results after three months showed a lowering of glucose levels, a lowering of blood pressure, and decrease in both subcutaneous and visceral abdominal fat, (subcutaneous = upper layer of fat; visceral = internal fat surrounding the organs and therefore a risk for cardiovascular disease) in those randomized to receive metformin. The study drug also did not appear to effect triglyceride levels.

The trial is also heartening because previously it was thought that metformin promoted weight loss which might not be the right outcome in people who need to gain weight in their arms, legs, buttocks, and the face or the periphery. This study showed no significant loss of peripheral fat.

Lactic acidosis was seen in previous studies of metformin in HIV-negatives. But in the Massachusetts study, lactate levels, a measure of lactic acidosis, remained stable in those receiving the drug, compared to those on a placebo. However, the authors of the paper caution that most patients in the study were taking nucleoside analog therapies, thus they were healthier and may not be representative of the general HIV population. On the other hand, lactic acidosis is most often seen in people taking nucleosides. Clearly, larger studies need to look at this issue before we know definitively that metformin does or does not cause lactic acidosis.

Mulligan reported that the AIDS Clinical Trials Group will open a very interesting, larger study looking at two anti-diabetic drugs in 160 people early next year. She stated that, "ACTG 5092 in its current form will enroll men and women on stable HIV regimens. We want to recruit as many women as possible first, at least 32, and the rest men. The study will be a randomized, double blind, placebo control study looking at metformin and rosiglitazone alone and in combination using a placebo arm for 16 weeks.

Then, everyone will be rolled over to receive the active drug." In other words, this will be a large study that will use two drugs that work by different mechanisms alone and in combination. It is a promising bigger step in looking at effective control of metabolic complications in HIV.

Even though the ACTG has been known to be a bureaucratic trial network, at least we now can be assured that larger, controlled studies will be initiated to validate the positive findings of metformin. It is good news that finally there is aggressive movement in research for lipodystrophy on the national front.

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