Fibrates and Statins and Glitazones (Oh My!)
It's hard to say what's more frustrating -- the fact that we still don't know what causes lipodystrophy, or the fact that we still don't know how best to treat it. Even if researchers eventually conclude that specific antiretrovirals are responsible for the more dangerous manifestations of this syndrome -- most notably increases in lipid levels and insulin resistance -- it's not clear what this pronouncement will actually mean for people with HIV. For example, it's not as if any of us can afford to avoid the protease inhibitors. They remain one of the most powerful virus-clobbering tools we have, and many of us wouldn't get very far without them.
If ongoing research determines if -- and how -- certain anti-HIV drugs cause lipodystrophy, pharmaceutical companies might be able to cash in on these discoveries and begin turning out less toxic versions of their more powerful compounds. But writing and rewriting drug recipes will require a whole lot of testing and a great deal of time. Thus, it would likely be several years before "sugar- and fat-free" formulations hit the pharmacy shelves.
Given this frustrating predicament, there has been a rush to find some outside help in the form of treatments to manage the side effects themselves. On one level, this is total madness -- having to treat the side effects of one drug with the use of other drugs, many of which have their own long list of toxicities. Then again, the alternative is even more troublesome -- an increased risk of heart attacks and strokes, for example.
As this issue of ACRIA Update focuses on some of the more important nutritional and dietary considerations for HIV-positive people, including those with lipodystrophy, this review of drugs in development is dedicated to pharmaceutical agents being studied for the potential ability to improve two nutritional parameters that are of central concern to patients with lipodystrophy: lipid levels and insulin levels. Other drugs being studied for their ability to improve the more physical symptoms of lipodystrophy, chiefly fat loss in the limbs and face and fat increases around the gut, continue to make headway in clinical trials. These agents -- including recombinant human growth hormone (Serostim) and cosmetic devices (e.g., New Fill injections) -- will be reviewed by this author in a future issue of the Update.
Lipid-lowering drugs have had a profound effect on the lives of millions of Americans living with elevated cholesterol and triglyceride levels. Elevated cholesterol levels can lead to clogging of the arteries and, with it, an increased risk of heart attacks and stroke. Elevated triglyceride levels are associated with their own set of problems, including life-endangering damage to the pancreas (pancreatitis). However, much of what we know about increased lipid levels and the drugs used to bring them under control come from studies involving HIV-negative people in their late 50s to 70s, many of whom have long histories of smoking, high blood pressure, and fat-soaked diets. It still isn't clear to what extent elevated cholesterol and triglyceride levels raise the risk of problems in otherwise healthy and younger HIV-positive people. But there aren't too many healthcare providers who will sit by idly, waiting to see what may or may not happen to their HIV-positive patients who have cholesterol levels well above 200 and triglyceride levels in the thousands. (A healthy cholesterol level is below 200 mg/dL, and a healthy triglyceride level is below 150 mg/dL.) For these people, lipid-lowering drugs are definitely an option to consider.
Beyond the rather unattractive name for this class of drugs, bile-acid resins such as cholestyramine (Questran) and colestipol (Colestid) have been shown to reduce LDL "bad" cholesterol by 10% to 30% in HIV-negative people. These drugs bind with cholesterol in the intestines and prevent it from being absorbed into the bloodstream. The cholesterol is then removed from the body with each bowel movement.
Bile-acid resins are often used in combination with other lipid-lowering drugs. This is because bile-acid resins can actually cause triglyceride levels to increase. Side effects of these drugs include stomachaches, bloating, flatulence (farting), heartburn, and constipation. Another problem with bile-acid resins is that they should be taken two hours before or after other medications, including antiretrovirals. This can be a major headache for HIV-positive people who are already overwhelmed by a two- or three-times-daily medication schedule.
Bile-acid resins have not yet been studied in HIV-positive patients with increased lipid levels associated with lipodystrophy.
Nicotinic Acid (Niacin)
Niacin, a derivative of vitamin B, lowers both cholesterol and triglyceride levels. It has been shown to reduce total cholesterol by approximately 20% to 30%, lower triglycerides by 35% to 55%, and increase HDL "good" cholesterol by 20% to 35%. Like bile-acid resins, niacin has not been studied in HIV-positive individuals with lipodystrophy.
Side effects of niacin include nausea, diarrhea, increased liver enzymes, and vasodilatory symptoms (e.g., flushing). There are two types (and many different brands) of niacin available: an immediate-release formula and an extended-release formula. According to one study, the immediate-release formula is much more likely to cause flushing than the extended-release formula, whereas the extended-release formula is much more likely to cause liver problems than the immediate-release formula. While it is not believed that niacin has any negative drug interactions if combined with any of the antiretrovirals, HIV-positive people with elevated liver enzymes due to their antiretrovirals or coinfection with either hepatitis B or hepatitis C should be cautious if using the extended-release formulation of niacin. Niacin can also increase sugar (glucose) levels in the blood, which may not be a good idea for HIV-positive people with insulin resistance (see below).
Niacin can be purchased with a prescription through a pharmacy or without a prescription at grocery stores and health-food markets. However, it should be used with caution and always under the supervision of a healthcare provider.
Fibric Acid Derivatives
Fibric acid derivatives (fibrates) include fenofibrate (TriCor) and gemfibrozil (Lopid). These drugs work by speeding up the chemical breakdown (catabolism) of triglyceride-rich lipoproteins that circulate in the body. Fibrates are best known for their ability to lower triglyceride levels -- by 30% to 55% in HIV-negative clinical trial participants -- but don't offer much in the way of cholesterol-lowering effects. In turn, fibrates are usually taken with other lipid-lowering agents, typically a statin. However, some experts believe that a fibrate/statin combination might increase the risk of rhabdomyolysis. This is a rare condition where damage to muscles results in the release of muscle cell contents into the bloodstream, which can lead to serious damage to the kidneys and other organs. If your doctor recommends these two types of lipid-lowering drugs, he or she will need to keep an eye on your kidney, liver, and muscle functions through regular blood tests.
Gemfibrozil is the most commonly used fibrate in the United States. However, some experts suggest that HIV-positive people stick to fenofibrate, because it is not metabolized by the same enzyme system (cytochrome P450 3A4) used by many of the protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). In other words, fenofibrate is less likely to have a negative interaction with anti-HIV drugs -- at least in theory.
Not much is known about the effectiveness of fibrates in HIV-positive folks with lipodystrophy. In one small study, researchers evaluated the medical charts of 14 HIV-positive patients who combined their antiretroviral therapy with gemfibrozil. Eight of these patients took gemfibrozil for at least four weeks. Before starting fibrate treatment, the average triglcyceride level was 1,800 mg/dL. After three months of gemfibrozil therapy, triglcyceride levels were down to 300 in most patients. Cholesterol levels did not change in this study.
As for side effects associated with the fibrates, the most common are stomach pain, bloating, and nausea. Liver enzymes can also become elevated, and there is an increased risk of developing gallstones. Decreased libido and impotence can also occur.
Statins (HMG-CoA Reductase Inhibitors)
By far the most popular lipid-lowering drugs, the statins block the activity of the HMG-CoA reductase enzyme, which controls the rate of cholesterol production in the body. In HIV-negative study participants, the statins have been shown to reduce total and LDL cholesterol and to actually keep people with elevated cholesterol levels alive longer and healthier.
For HIV-positive people, there is a caveat to consider with these drugs -- many of the statins are broken down in the body by the same enzyme used to metabolize the PIs and NNRTIs. This can cause blood levels of either the PIs/NNRTIs or the statins to fluctuate, which can increase the risk of side effects and reduce the potential benefits of either treatment. [A quick sketch of the possible interactions between each of the PIs, NNRTIs, and the statins, as well as other lipid-lowering drugs, is available at www.hiv-druginteractions.org, courtesy of the Liverpool HIV Pharmacology Group.]
One AIDS Clinical Trials Group study completed a few years ago enrolled 43 HIV-negative individuals to take the protease inhibitors ritonavir (Norvir) and saquinavir (Fortovase) in combination with one of three statins: atorvastatin (Lipitor), simvastatin (Zocor), or pravastatin (Pravachol). Because this study was a brief "pharmacokinetics" study -- an evaluation of drug levels during a short period of time -- it was not necessary to enroll HIV-positive patients. According to the results, first presented at the 7th Conference on Retroviruses and Opportunistic Infections in February 2000, blood levels of pravastatin declined by approximately 47% when it was combined with ritonavir/saquinavir. Atorvastatin levels increased by 79% and simvastatin levels increased by a whopping 3,059%.
Based on these findings, the United States Public Health Service (USPHS) has pretty much ruled out the use of simvastatin in combination with any of the PIs or NNRTIs given the potential risk of serious side effects. Atorvastatin is an option, but if it is used, the dose should be reduced -- by half, say some doctors -- and then gradually increased (if necessary) with careful monitoring. Pravastatin is the only HMG-CoA to pass muster with the USPHS, although it might be necessary to increase the dose of this drug somewhat if the desired reduction in cholesterol is not achieved.
Other cholesterol-lowering statins that are approved but not yet formally studied in combination with any of the antiretrovirals include lovastatin (Mevacor) and fluvastatin (Lescol); the drug cervastatin (Baycol) was recently taken off pharmacy shelves by the FDA because of toxicity concerns. Lovastatin is metabolized very much like simvastatin and is best avoided if you are taking either a PI or NNRTI. Fluvastatin levels may drop if it is combined with either a PI or NNRTI, thus there may not be much of a lipid-lowering benefit at the usual recommended dose.
Do the statins actually work for people with lipodystrophy? Unfortunately, there have only been a few small, short-term studies looking at the safety and effectiveness of statins in HIV-positive people. Frustratingly, the pharmaceutical companies that produce statins are reluctant to get involved in the crowded and often messy HIV drug-development game. According to one pharmaceutical spokesperson who agreed to speak with ACRIA Update on the condition of anonymity: "Nobody understands why lipid increases are occurring [in HIV-positive people] and companies producing [statins] see this as a huge liability issue. The possibility of drug interactions, an increased risk of side effects, and limited effectiveness in HIV-positive patients could make the statins look bad."
Fortunately, there have been a few research reports to go on. In one study conducted in Spain, 15 HIV-positive people with elevated cholesterol and triglyceride levels took atorvastatin in combination with their antiretroviral drugs. After 12 weeks, cholesterol levels dropped by approximately 25% and triglyceride levels fell by roughly 35%. After another three months, these improvements held, although some of the patients still had cholesterol levels above 200. Similar data were reported at the 3rd International Workshop on Lipodystrophy and Adverse Drug Reactions, held in Athens, Greece in October. In this study, researchers at Baylor College of Medicine in Houston reviewed the medical files of patients with lipodystrophy who took either fibrates or statins to lower their cholesterol and triglyceride levels to see how effective these drugs were. Numerous patients had been taking the drugs in combination with their antiretrovirals for at least a year. Although many saw their cholesterol and triglyceride levels decrease dramatically while using the lipid-lowering treatments, only a few people were able to reduce their lipids to the healthy ranges.
In a nutshell, not much research has taken place with respect to the safety and effectiveness of lipid-lowering drugs in people with HIV-associated lipodystrophy. In the handful of studies that have been completed so far, it appears that lipid levels do improve with the use of fibrates and statins. Unfortunately, these same studies -- along with numerous doctors who prescribe these drugs -- indicate that these therapies are a ripple in the ocean for many HIV-positive patients. While it is safe to say that any improvements in cholesterol or triglyceride levels may help reduce the risk of life-threatening complications, more needs to be done to help those with lipid levels in the red to get their numbers back in the black.
Treatments for Insulin Resistance
A handful of studies have looked at the possibility of using two common types of diabetes treatments to treat lipodystrophy, particularly for HIV-positive people who have insulin resistance. Insulin resistance means that cells in the body are less sensitive to insulin, a hormone produced by the pancreas that helps cells absorb sugar (glucose), which they need to function properly. Insulin resistance can lead to diabetes, which can go on to cause blindness, heart disease, and a slew of other problems.
Metformin (Glucophage) helps to reduce the amount of glucose produced by the liver, which generally leads to reduced amounts of insulin and glucose in the bloodstream. At least one clinical trial, conducted by researchers at Massachusetts General Hospital in Boston, suggests that metformin holds a great deal of promise for HIV-positive people with insulin resistance.
At the 3rd International Workshop on Lipodystrophy and Adverse Drug Reactions, Dr. Steven Grinspoon presented data from a clinical trial that compared metformin to placebo in 26 HIV-infected people (20 men, 6 women) with elevated insulin and glucose levels. After three months, all of the patients were allowed to take metformin for an additional nine months. At the time of Dr. Grinspoon's presentation, 19 patients had been enrolled in the study for at least a year.
Generally speaking, metformin treatment resulted in marked reductions in the "two-hour postprandial" insulin levels. This means that the drug was most effective two hours after eating a meal, the time when insulin levels are highest in the body. Metformin was less effective on glucose levels, both "fasted" (before the first meal of the day) and two hours after eating. Because higher-than-normal two-hour postprandial insulin levels are considered to be an early sign of insulin resistance, these findings suggest that metformin might slow the progression of insulin resistance, rather than being a curative therapy once it occurs.
Also of interest was the effect of therapy on body weight and changes in body shape. Patients treated with metformin experienced significant decreases in body weight and saw improvements in their waist size (decreased fat around the gut). The drug was also well tolerated: No patients discontinued the study because of side effects, and there were no reports of lactic acidosis, a dreaded side effect of metformin that has been seen in some HIV-negative patients with diabetes.
Unfortunately, metformin failed to pan out as a therapy for either HIV-associated insulin resistance or lipodystrophy in a second study conducted in Barcelona. In this clinical trial, 51 individuals with lipodystrophy received metformin, the lipid-lowering agent gemfibrozil, or placebo for one year. Only slight decreases in body weight and improvements in body shape were reported. Whatever improvements were seen, were similar in all three groups, including those receiving the placebo. Lackluster improvements in LDL cholesterol, triglycerides, and insulin levels were also reported -- again, in all three groups.
Also being studied for the treatment of lipodystrophy are the glitazones. Glitazones belong to a class of drugs called the thiazolidinediones and are best known for their ability to make cells more sensitive to insulin. Glitazones have also been shown to help correct the function of adipocytes (fat cells). In one clinical trial of HIV-negative diabetic patients, glitazone therapy was associated with increases in subcutaneous fat (i.e., fat in the face, arms, and legs) and decreases in visceral fat (i.e., fat that accumulates deep in the belly) -- benefits many researchers have been hoping to duplicate in patients with HIV-associated insulin resistance and lipodystrophy.
Unfortunately, the results of several small studies suggest there is little to be excited about. In one study evaluating pioglitazone (Actos) in nine HIV-positive patients with lipodystrophy, there were no significant improvements in body weight or body shape. However, in a questionnaire, four of the nine patients reported improvements in their physical appearance. A review of nine patients with lipodystrophy who took rosiglitazone (Avandia) every day for six months showed only mild improvements in triglycerides, cholesterol levels, body weight, and fat distribution.
The largest, most "scientific" study of a glitazone for the treatment of lipodystrophy was reported in February at the 9th Conference on Retroviruses and Opportunistic Infections in Seattle. The study, conducted in Helsinki, randomized 30 HIV-positive individuals with lipodystrophy to take either rosiglitazone or placebo for six months. Before entering the study, the patients had mildly elevated triglyceride and cholesterol levels, increased insulin levels, and noticeable fat loss in their limbs.
After three months of treatment with either rosiglitazone or placebo, insulin levels decreased in the patients who received rosiglitazone. In patients who received the placebo, insulin levels continued to increase. But that's where the good news ends. Triglyceride levels increased in those who took rosiglitazone -- even more than they did in patients who took the placebo -- and cholesterol levels continued to rise at the same rate in both groups. The Helsinki team also observed no noticeable improvements in fat size in the limbs.
Sadly, these findings suggest that glitazones will be of limited benefit to patients as a broad-spectrum treatment for the various signs and symptoms of lipodystrophy. Perhaps more encouraging results will come out of ACTG 5082, a randomized, controlled study being conducted by the AIDS Clinical Trials Group, comparing a combination of rosiglitazone and metformin to metformin alone and rosiglitazone alone in HIV-infected patients with insulin resistance and lipodystrophy. Early results are anticipated sometime this year.
It's safe to say that the experience of lipid-lowering and insulin-sensitizing drugs so far has been less than stellar. Then again, it is important to consider what researchers have been looking for -- a magic bullet that will effectively reverse any and all signs of lipodystrophy. The fact is there are clear-cut benefits to these treatments. First there are the fibrates and statins, which have been shown to reduce triglyceride and cholesterol levels. Then there is the encouraging data involving metformin and the glitazones, two classes of drugs that can effectively improve insulin sensitivity and, as a result, potentially ward off the threat of diabetes. Short of a magic bullet, there are clearly individual weapons available to, once again, keep HIV-positive people alive longer and healthier.
Tim Horn is executive editor of the PRN Notebook, published by Physicians' Research Network in New York.
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.