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Update From the Medical Journals: January 2008
January 31, 2008  By Mary Pickett, M.D.
Harvard Medical School What's the latest news in the medical journals this month? Find out what your doctor is reading. Vytorin and Zetia Lower LDL Cholesterol But May Not Lower Heart Disease Risk The drug manufacturers of ezetimibe (Zetia) and the combination drug ezetimibe/simvastatin (Vytorin) issued a news release on January 14 that raises doubts about the value and safety of these drugs with respect to heart disease. The news release describes some of the major findings from a 2-year study, called the ENHANCE trial, that ended in 2006. (Full details of the study are not yet available but it is likely that they will be presented at the American College of Cardiology meeting in March.) The 720 people in the study had unusually high cholesterol due to a hereditary condition called "heterozygous familial hypercholesterolemia." They were randomly divided into two groups. One group took Vytorin (ezetimibe/simvastatin), and the other group received Zetia (simvastatin). The trial was designed to determine whether the addition of ezetimibe reduces the thickness of artery plaques (atherosclerosis) in the carotid artery. The researchers also wanted to know how well ezetimibe/simvastatin lowers cholesterol compared with simvastatin alone. They examined the participants' carotid arteries at the beginning and end of the study using ultrasound. Ezetimibe/simvastatin (Vytorin) lowered LDL (the bad cholesterol) by 58% during two years of treatment. The group that received simvastatin alone (Zetia) had a much smaller drop in LDL — 41%. However, on average the plaques were slightly thicker in the people who took ezetimibe/simvastatin compared with people who took just simvastatin. The measurements were too close to say that the difference was statistically significant. Since the purpose of cholesterol control is to reduce heart attack risk, a study that hints at plaque growth in the arteries is a large disappointment. Until now, ezetimibe has been viewed as a helpful new tool for lowering cholesterol. This study raises concerns that ezetimibe may either be a danger, or it may be a "win some, lose some" drug with no benefit in the end. This study didn't look at actual cardiac events, such as heart attacks, chest pain emergencies that require hospitalization, or the need for angioplasty or bypass surgery. There are three large studies underway that will, however, watch for ezetimibe's effect on the rate of heart attacks and strokes in the drug-treated groups. One of them includes near to 10,000 patients. Unfortunately, we won't know the results from those trials until at least 2011. In the meantime, doctors and patients will probably cut back on using this drug because at this time there is no clear proof it is beneficial. Do not stop this medicine before speaking to your doctor. Back to top Low Vitamin D Levels Are Linked To Heart Events and Stroke An eye-opening study released on January 7 suggests a connection between vitamin D deficiency and heart disease. The study — published online by Circulation, the Journal of the American Heart Association — measured vitamin D levels in 1,739 healthy people. Researchers followed the participants for five years to see who had a heart attack, heart failure or a stroke. The results were dramatic. People who had vitamin D levels below 15 ng/mL (nanograms per milliliter) had twice the risk of having a heart or stroke event, compared with people who had higher levels. The researchers took into account other cardiac risk factors, such as diabetes and smoking before calculating the risk that was associated with vitamin D deficiency. People with hypertension who also had vitamin D deficiency appeared to have the highest risk. Vitamin D deficiency is common. In this study, 28% of people had a level of vitamin D that was below 15 ng/mL. This study does not prove that vitamin D supplements lower heart disease risk. Only a randomized study in which some people get a vitamin D pill and others get a placebo pill can do that. Still, at standard doses, vitamin D is a safe and helpful treatment for many people with muscle pain. Adequate vitamin D also keeps bones in good health. We can expect follow-up studies to see if supplementing vitamin D can protect against heart disease. Back to top Meat-Eating Leads to Metabolic Syndrome Risk factors for heart disease tend to cluster together. For example, there's a good chance that a person with hypertension or someone who is obese will develop high glucose levels (prediabetes or type 2 diabetes), high triglycerides or low HDL cholesterol even if they are careful to seek appropriate medical care for their first health issue. (These problems are probably linked by a common problem in metabolism, although experts still aren't sure what the true trigger might be.) Together, these problems increase heart and stroke risk to very high levels. When a person has three or more of these risk factors, they have "metabolic syndrome." Circulation: Journal of the American Heart Association published a study online on January 22 that looked at the eating habits of 9,514 Americans. The men and women in the study were 45 to 64 years old when they entered the study. During the study, they filled out questionnaires about the foods they typically ate. Over the nine-year study period, 3,782 or nearly 40% of the participants developed metabolic syndrome. (They reached a total of three or more risk factors.) When the researchers took into account the people who already had three risk factors at the start of the study, slightly more than 60% of this fairly representative group of Americans had metabolic syndrome after nine years when as a group they ranged in age from 54 to 73 years. Considering the huge numbers of people affected and the dramatic way metabolic syndrome increases heart risk, information about what leads to metabolic syndrome is extremely valuable. A closer look at the questionnaires showed that the people who usually ate meat twice a day, compared with the people who ate meat twice a week or less often had a 25% increased risk for developing metabolic syndrome. Fried foods and diet soda also increased the risk. Dairy products seemed to lower the risk. The authors don't fully understand why meats, frying oils or diet soda have this strong effect. The first two foods increase fatty acids in the bloodstream. This may play a role. This study should encourage us to eat less meat and fried foods, and ideally, to eliminate diet sodas. Back to top More News in Brief - Metformin Prevents Weight Gain from Antipsychotic Drugs. The January 9/16 issue of the Journal of the American Medical Association reports findings from a study that will be helpful for people who take antipsychotic medicines. Drugs for psychosis can relieve hallucinations and disordered thinking. Many of them, however, frequently cause weight gain and can trigger diabetes. Antipsychotic drugs with these side effects include clozapine (Clozaril), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ziprasidone (Geodon), aripiprazole (Abilify), and, in some countries, sulpiride. This study included 128 people with schizophrenia who had each gained more than 10% of their pre-treatment body weight in their first year of taking an antipsychotic medicine. The participants were randomly assigned to receive either the drug metformin (Glucophage), a diet and exercise program, both the drug and the program, or neither the drug nor the program. After 12 weeks, those who were treated with one of the first three plans lost weight, reduced their body mass index, decreased their waist measurement and had better insulin sensitivity. The group that received no treatment had increases in weight and the other measurements. For many people, treating psychosis with medication is not optional. Metformin provides an important strategy to avoid drug-induced weight gain. Diet and exercise are also necessary tools.
- Published Studies May Exaggerate The Benefit of Antidepressants. Not all research studies make it into print. Depending on which studies are published, readers may or may not have the most accurate information that's available. A study considering this problem — called publication bias — appeared in the January 17th issue of The New England Journal of Medicine. Publication bias usually happens because studies are more likely to be published if a treatment shows a large benefit and less likely to be published if a treatment's benefit is small or unapparent. It is a major barrier to consumers and doctors alike getting accurate scientific information. Researchers expect that the performance of drugs, for example, will vary somewhat from one study to another. But publication bias distorts the view of a drug's benefit and can make its effectiveness look more consistent and more impressive than it really is. The researchers who conducted the study focused specifically on studies about antidepressants. They knew that all researchers need permission before doing drug studies using people as subjects. So they made a list of every trial that resulted in a drug's approval from the U.S. Food and Drug Administration (FDA) between 1987 and 2004. They found that only two-thirds of the studies subsequently appeared in medical journals. The researchers noticed that 37 of the published studies showed promising results from drug treatment, while 14 studies that were published had unimpressive or worrisome findings. Then the researchers identified unpublished studies of antidepressants. They contacted the experts who had been involved in these studies and asked for the data. They also requested unpublished research from drug companies using the Freedom of Information Act and sorted through unpublished data from an FDA online reporting system. All in all, they were able to get data from 22 trials. Only one trial found the effectiveness of antidepressant treatment to be close to the usually quoted success rates. In the end, 94% of the "positive" studies had been published, and only 14% of the disappointing studies had been published. Whether this bias is the result of pharmaceutical companies, the result of special interest groups withholding information, or whether it occurs because journal editors give priority to studies with exciting findings, it is a good reason for us to view all research with a dose of skepticism and to approach new drugs with appropriate caution.
Back to top Mary Pickett, M.D. is a lecturer for Harvard Medical School and an assistant professor of medicine at Oregon Health & Science University. At OHSU, she is a director of student programs and she oversees teaching of students and medical residents. She practices general internal medicine in Portland, Ore.
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