RxPG News : Anticholesterol

Lap-band weight-loss surgery can reverse metabolic syndrome in obese teens

Wed, 01 Jul 2009 03:59:36 PST

( from http://www.rxpgnews.com ) NEW YORK (June 30, 2009) -- A new study of obese adolescents has shown that laparoscopic gastric banding surgery -- the Lap-Band procedure -- not only helps them achieve significant weight loss but can also improve and even reverse metabolic syndrome, reducing their risk for cardiovascular disease and diabetes.

Metabolic syndrome is defined as a cluster of risk factors -- high blood pressure; low levels of HDL or good cholesterol; excessive abdominal fat; and elevated levels of blood sugar, C-reactive protein and triglycerides -- that increase a person's chances of developing cardiovascular disease or diabetes later in life. The single biggest risk factor is obesity, and metabolic syndrome usually improves when a person loses weight.

The study was led by Drs. Ilene Fennoy, Jeffrey Zitsman and colleagues at NewYork-Presbyterian Morgan Stanley Children's Hospital and Columbia University Medical Center and presented at the annual Endocrine Society meeting in Washington, D.C.

An estimated 17 percent of all American adolescents are obese, and increasing numbers of them also have metabolic syndrome, says Dr. Fennoy, a pediatric endocrinologist at NewYork-Presbyterian Morgan Stanley Children's Hospital, clinical professor of pediatrics at the Columbia University College of Physicians and Surgeons and co-author of the study. Until recently, there have been few treatments capable of helping these young patients lose weight, much less improving their lifelong health prospects. The Lap-Band may well be a useful intervention for tackling teen obesity -- which is why it is so important to investigate the procedure's safety and efficacy in this growing population.

In the new study, Dr. Fennoy and her colleagues followed 24 morbidly obese adolescents between the ages of 14 and 17 who underwent the Lap-Band procedure. The study participants either had a BMI of greater than 40 or greater than 35 if already suffering from diabetes or obesity-related illnesses.

Six months after surgery, they noted a significant drop in participants' BMI, waist circumference, and blood levels of C-reactive protein. These indicators continued to improve among the 12 patients being followed up at the one-year point.

Other measures of metabolic syndrome such as blood lipid and sugar levels, the authors reported, came down quickly in the first six months, with less dramatic changes seen one year after surgery.

Of all the bariatric procedures, she says, the Lap-Band is the most benign, with complication rates of less than 1 percent. The device, inserted via minimally invasive laparoscopic surgery, consists of a simple band to make the stomach smaller and a balloon that can be decompressed when necessary, she explains.

Although it is technically reversible, the procedure should be considered a long-term solution for extreme and intractable obesity.

The Lap-Band is the favored bariatric procedure in Europe, while in the U.S., gastric bypass has been the preferred approach. At present, NewYork-Presbyterian Morgan Stanley Children's Hospital/Columbia University Medical Center is one of a few medical centers offering the Lap-Band option in this country.

The Lap-Band procedure, an approved treatment for adults with extreme obesity, has not yet been thoroughly studied in adolescents. Larger, multicenter studies with longer follow-up periods will be needed, Dr. Fennoy says, to validate the findings of the current study.

Increased food intake alone explains the increase in body weight in the United States

Fri, 08 May 2009 03:59:36 PST

( from http://www.rxpgnews.com ) Amsterdam, the Netherlands: New research that uses an innovative approach to study, for the first time, the relative contributions of food and exercise habits to the development of the obesity epidemic has concluded that the rise in obesity in the United States since the 1970s was virtually all due to increased energy intake.

How much of the obesity epidemic has been caused by excess calorie intake and how much by reductions in physical activity has been long debated and while experts agree that making it easier for people to eat less and exercise more are both important for combating it, they debate where the public health focus should be.

A study presented on Friday at the European Congress on Obesity is the first to examine the question of the proportional contributions to the obesity epidemic by combining metabolic relationships, the laws of thermodynamics, epidemiological data and agricultural data.

There have been a lot of assumptions that both reduced physical activity and increased energy intake have been major drivers of the obesity epidemic. Until now, nobody has proposed how to quantify their relative contributions to the rise in obesity since the 1970s. This study demonstrates that the weight gain in the American population seems to be virtually all explained by eating more calories. It appears that changes in physical activity played a minimal role, said the study's leader, Professor Boyd Swinburn, chair of population health and director of the World Health Organization Collaborating Centre for Obesity Prevention at Deakin University in Australia.

The scientists started by testing 1,399 adults and 963 children to determine how many calories their bodies burn in total under free-living conditions. The test is the most accurate measure of total calorie burning in real-life situations.

Once they had determined each person's calorie burning rate, Swinburn and his colleagues were able to calculate how much adults needed to eat in order to maintain a stable weight and how much children needed to eat in order to maintain a normal growth curve.

They then worked out how much Americans were actually eating, using national food supply data (the amount of food produced and imported, minus the amount exported, thrown away and used for animals or other non-human uses) from the 1970s and the early 2000s.

The researchers used their findings to predict how much weight they would expect Americans to have gained over the 30-year period studied if food intake were the only influence. They used data from a nationally representative survey (NHANES) that recorded the weight of Americans in the 1970s and early 2000s to determine the actual weight gain over that period.

If the actual weight increase was the same as what we predicted, that meant that food intake was virtually entirely responsible. If it wasn't, that meant changes in physical activity also played a role, Swinburn said. If the actual weight gain was higher than predicted, that would suggest that a decrease in physical activity played a role.

The researchers found that in children, the predicted and actual weight increase matched exactly, indicating that the increases in energy intake alone over the 30 years studied could explain the weight increase.

For adults, we predicted that they would be 10.8 kg heavier, but in fact they were 8.6 kg heavier. That suggests that excess food intake still explains the weight gain, but that there may have been increases in physical activity over the 30 years that have blunted what would otherwise have been a higher weight gain, Swinburn said.

To return to the average weights of the 1970s, we would need to reverse the increased food intake of about 350 calories a day for children (about one can of fizzy drink and a small portion of French fries) and 500 calories a day for adults (about one large hamburger), Swinburn said. Alternatively, we could achieve similar results by increasing physical activity by about 150 minutes a day of extra walking for children and 110 minutes for adults, but realistically, although a combination of both is needed, the focus would have to be on reducing calorie intake.

He emphasized that physical activity should not be ignored as a contributor to reducing obesity and should continue to be promoted because of its many other benefits, but that expectations regarding what can be achieved with exercise need to be lowered and public health policy shifted more toward encouraging people to eat less.

Study: Vibration plate machines may aid weight loss and trim abdominal fat

Fri, 08 May 2009 03:59:36 PST

( from http://www.rxpgnews.com ) Amsterdam, the Netherlands: New research suggests that, if used properly, vibration plate exercise machines may help you lose weight and trim the particularly harmful belly fat between the organs.

In a study presented on Friday at the European Congress on Obesity, scientists found that overweight or obese people who regularly used the equipment in combination with a calorie restricted diet were more successful at long-term weight loss and shedding the fat around their abdominal organs than those who combined dieting with a more conventional fitness routine.

These machines are increasingly found in gyms across the industrialized world and have gathered a devoted following in some places, but there has not been any evidence that they help people lose weight. Our study, the first to investigate the effects of vibration in obese people, indicates it's a promising approach. It looks like these machines could be a useful addition to a weight control package, said the study's leader, Dirk Vissers, a physiotherapist at the Artesis University College and the University of Antwerp in Belgium.

Vissers and his colleagues studied the effects of the Power Plate in 61 overweight or obese people - mostly women - for a year. The intervention lasted six months, after which the scientists advised all the volunteers to do the best they could with a healthy diet and exercise regime on their own for another six months. Body measurements, including CT scans of abdominal fat, were taken at the beginning of the study and after three, six and 12 months.

The researchers divided the volunteers into four groups. One group was prescribed an individually calculated calorie restricted diet. Dietician visits were scheduled every fortnight for the first three months and every month for the second three months. The dieters were asked not to engage in any exercise for the duration of the six-month intervention.

A second group received the same diet intervention, with the addition of a conventional fitness regime. They attended supervised exercise classes twice a week for an hour and were urged to exercise on their own a third time each week. The sessions included group cycling, swimming, running, step aerobics and some general muscle strengthening exercises.

A third group got the diet intervention plus supervised vibration plate training instead of conventional exercise. They were asked not to do any aerobic exercise during the six-month intervention phase. The physiotherapists gradually increased the speed and intensity of the machine each week, as well as the variety and duration of the exercises from 30 seconds for each of 10 exercises to 60 seconds for each of 22 exercises, such as squats, lunges, calf raises, push-ups and abdominal crunches. The average time spent on the machine was 11.9 minutes per session in the first three months and 14.2 minutes in the second three months.

A fourth group got no intervention. There were no significant differences between the groups in obesity and abdominal, or visceral, fat at the start of the study.

Over the year, only the conventional fitness and vibration groups managed to maintain a 5% weight loss, which is what is considered enough to improve health, Vissers said.

During the first six months, the diet only group lost about 6% of their initial body weight, but could not maintain a 5% weight loss in the subsequent six months. The group that got diet plus conventional fitness lost about 7% of their initial body weight in the first six months, but they didn't put much of it back on and by the end of the study, they had managed to keep off a 6.9% loss. The vibration group lost 11% of their body weight during the intervention phase and by the end of the follow-up period they had maintained a 10.5% loss. The control group gained about 1.5% of their original body weight.

The vibration group lost 47.8 square centimetres of visceral fat during the first six months and still had a loss of 47.7 square centimetres at 12 months. Visceral fat shrank by 17.6 square centimetres in the conventional fitness group in the first six months, but by the end of the year, it was only 1.6 square centimetres less than at the beginning. The diet group had a visceral fat loss of 24.3 square centimetres after six months and 7.5 square centimetres after a year.

These are very encouraging results, but it doesn't mean people trying to lose weight can ditch aerobic exercise and jump on the vibration plate instead. They still need a healthy diet and aerobic exercise, but this could be a viable alternative to weight lifting, Vissers said, explaining that the plate works by making muscles rapidly contract, which builds lean muscle mass.

People say vibration machines are fitness for lazy people. It may feel like a short cut, but if it's easy, you are not doing it properly, he added. Supervision in the beginning is imperative and the longer the better. What we see in gyms very often - people just standing on the machine holding the handles - is not going to do anything.

Vissers said further research on a larger group of obese patients is needed to confirm how beneficial the machines are. His team is also planning to study why vibration seems to be more effective than aerobic exercise in trimming visceral fat, including whether increased blood flow to the abdomen and hormonal response to vibration might play a role in more efficient fat breakdown. His study was funded by the Artesis University College of Antwerp.

Genes for 9 health indicators

Sun, 07 Dec 2008 04:59:37 PST

( from http://www.rxpgnews.com ) A new genome-wide study examines genetic variants associated with nine metabolic traits and is the first to draw out novel variants from a population unselected for current disease. The traits are indicators for common disease such as cardiovascular disease, type 2 diabetes, blood pressure, inflammation and lipid levels.

Cohorts are followed throughout their lives, gathering lifelong information about their health: these data will help researchers to dissect the complex causes of common disease, whether genetic or environmental. The current study might indicate genetic variants that influence early development of disease, informing public health measures.

Unlike case-control studies, which make genomic comparisons of apparently healthy people with patients with a specific condition, cohort studies provide long-term information across a population.

The power of studies such as ours lies in their ability to examine these traits for early life events, to reflect the genetic make-up of the wider population and to investigate the relationship between genetic variation and environment over time, says Professor Leena Peltonen, Head of Human Genetics at the Wellcome Trust Sanger Institute and a senior author of the paper. Our study indicates that the environment accounts for around 30% or less of the consequences of the traits. Clearly we have to increase our efforts to understand the genetic factors involved.

The population study looked at a cohort of people born in northern Finland in 1966: the environmental exposure and genetic background of this population is relatively homogeneous and, because the sample includes almost all people born in that year, it reflects the overall composition of the population.

The team looked at more than 360,000 genetic variants in almost 5000 people. These samples were typed to uncover variants associated with levels of triglycerides, high density lipoprotein, low density lipoprotein, glucose, insulin, C-reactive protein, as well as body mass index and blood pressure. Eight 'environmental' factors, including alcohol use, smoking and birth weight, were also included in the analysis.

We found 23 regions of the genome associated with these traits, says Professor Nelson Freimer, University of California, Los Angeles, the other senior author. We were delighted that our study identified 14 that had been described before: it is essential that a study such as this picks up the known variants.

More important, we found nine novel variants: in five of these cases, our knowledge of the role of the gene suggests they are good candidates for important variants.

The research differs from prior investigations in power and study design, which might explain its ability to identify nine previously unknown loci. Five of these associations - HDL with NR1H3 (LXRA), LDL with AR and FADS1/FADS2, glucose with MTNR1B, and insulin with PANK1 - implicate genes with known or postulated roles in metabolism, and are good candidates for further study of the biological role they might play in these conditions.

The comprehensive cohort study also allowed the team adjust for the additional data such as environmental influences and body mass index. Three regions were associated with LDL or insulin when the population was divided into normal or elevated body mass index.

Our population sample allows us to look at gene-environment interactions, explains Professor Chiara Sabatti, University of California, Los Angeles, a co-author of the paper, but we need to examine larger populations in order to validate these. We are only starting to have a glimpse of how the power of modern genetics can work with population data to uncover genes that will be able to help clinical and public health work in the future. We still have many challenges ahead.

Although genetic influences are thought to account for at least half of the variation in each of the traits, the current results explain perhaps one-tenth of that. There remains much more to be discovered.

Work underway, such as The 1000 Genomes Project and wider population studies, will help to determine whether the additional genetic effects lie in many common variants with relatively small effect or in rare variants with a larger effect.

Statins can provide some protection against dementia

Thu, 03 Jul 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Cholesterol-lowering drugs known as statins have a profound effect on an elite group of cells important to brain health as we age, scientists at the University of Rochester Medical Center have found. The new findings shed light on a long-debated potential role for statins in the area of dementia.

Neuroscientists found that statins, one of the most widely prescribed classes of medication ever used, have an unexpected effect on brain cells. Researchers looked at the effects of statins on glial progenitor cells, which help the brain stay healthy by serving as a crucial reservoir of cells that the brain can customize depending on its needs. The team found that the compounds spur the cells, which are very similar to stem cells, to shed their flexibility and become one particular type of cell.

The new findings come at a time of increasing awareness among neurologists and cardiologists of the possible effects of statins on the brain. Several studies have set out to show that statins provide some protection against dementia, but the evidence has been inconclusive at best. Meanwhile, there is some debate among physicians about whether statins might actually boost the risk of dementia. The new research published in the July issue of the journal

Study: highly involved patients don't always see better health outcomes

Fri, 22 Feb 2008 04:59:37 PST

( from http://www.rxpgnews.com ) Patients who prefer to be highly involved in their treatment don't necessarily have better luck managing chronic health conditions, a new study suggests.

A research team based at the Veterans Affairs (VA) Iowa City Health Care System and the University of Iowa surveyed 189 veterans with high blood pressure to determine the patients' preferences for involvement in their health care. They discovered those who wanted an active role in their treatment had higher blood pressure and cholesterol over a 12-month span than those who wanted a less active role.

The study, published this week in the Annals of Behavioral Medicine, was led by Austin Baldwin, a post-doctoral fellow in the Center for Research in the Implementation of Innovative Strategies in Practice (CRIISP) at the VA Iowa City Health Care System and an adjunct assistant professor of psychology in the UI College of Liberal Arts and Sciences.

The intuitive assumption is that the more involved people are with their health, the better they'll be at managing chronic conditions. We found evidence to the contrary, Baldwin said. Those who preferred a more 'patient-centered' or active role actually had higher blood pressure and lipid levels. Those who preferred a 'provider-centered' approach, in which the doctor is more authoritative, did better at managing their blood pressure and lipid levels.

Patients who preferred the most active role averaged a blood pressure of 141 over 79 and a low-density lipoprotein (LDL) cholesterol level of 112, while those who preferred the least active role averaged a blood pressure of 137 over 72 and an LDL of 92. Doctors tell most patients with high blood pressure to aim for a blood pressure less than 140 over 90 and keep LDL cholesterol under 130.

The average participant was 65.8 years old, and 97 percent were men. Participants were recruited from the Iowa City and Minneapolis VA health care systems and four affiliated community-based outpatient clinics as part of a larger hypertension trial. The data were collected in 2004.

The research team offered a couple potential explanations for the results.

One possibility is that patients who wanted an active role were dissatisfied with the relatively passive treatment of taking medication to control their conditions, and therefore may not have followed doctors' orders as well.

They were presumably provided advice and guidance about modifying their lifestyle, but all of these patients were on hypertension medication, and many were on lipid-lowering medications, Baldwin said. For those who want more control over their treatment, a relatively passive treatment like taking medication may not be a good match.

One aspect of the study gave traction to this explanation. Some patients were diabetic. While those who preferred an active role did worse at managing blood pressure and cholesterol, they did slightly better at managing blood sugar (although the effect on managing blood sugar was not statistically significant). Researchers believe that's because managing blood sugar is a more hands-on treatment involving blood sugar tests, diet regulation and sometimes medication.

Another potential explanation is that the patients' role preferences didn't match their doctors' role preferences. While this study did not assess providers' preferences, previous research suggests that a mismatch between patients' and providers' role preferences impacts adherence to treatment recommendations. (See related UI study at

Intensive blood sugar treatment in trial of diabetes and cardiovascular disease changed

Wed, 06 Feb 2008 23:39:37 PST

( from http://www.rxpgnews.com ) The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health has stopped one treatment within a large, ongoing North American clinical trial of diabetes and cardiovascular disease 18 months early due to safety concerns after review of available data, although the study will continue.

In this trial of adults with type 2 diabetes at especially high risk for heart attack and stroke, the medical strategy to intensively lower blood glucose (sugar) below current recommendations increased the risk of death compared with a less-intensive standard treatment strategy. Study participants receiving intensive blood glucose lowering treatment will now receive the less-intensive standard treatment.

The ACCORD (Action to Control Cardiovascular Risk in Diabetes) study enrolled 10,251 participants. Of these, 257 in the intensive treatment group have died, compared with 203 within the standard treatment group. This is a difference of 54 deaths, or 3 per 1,000 participants each year, over an average of almost four years of treatment. The death rates in both groups were lower than seen in similar populations in other studies.

Role of a key enzyme in reducing heart disease identified

Wed, 24 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Virginia Commonwealth University researchers have identified the role of a key enzyme called CEH in reducing heart disease, paving the way for new target therapies to reduce plaques in the arteries and perhaps in the future, help predict a patient�s susceptibility to heart disease.

Furthermore, unlike currently available therapies, which prevent or reduce the formation of new plaques, increasing CEH may also reduce existing plaques.

Heart disease results from the formation of plaques in the coronary artery, which supplies blood to the heart. Plaques form when monocytes, which are cells from the blood, enter the wall of the artery and consume large amounts of the �bad� cholesterol, or LDL. The monocytes then become artery-clogging foam cells. The only way for foam cells to get rid of their cholesterol is to make it available to HDL, or �good� cholesterol, for removal. A key enzyme present in the foam cells called cholesteryl ester hydrolase (CEH) regulates the amount of cholesterol that can be removed by HDL.

In this study, led by Shobha Ghosh, Ph.D., an associate professor of internal medicine, pulmonary division in the VCU School of Medicine, the team examined, for the first time, how cells in the artery wall make cholesterol available for removal by HDL. Using transgenic mice, which were fed a high fat and cholesterol-rich diet, the team was able to show that by increasing the removal of cholesterol from the artery clogging foam cells, the mice with the human gene for CEH developed significantly less heart disease.

�Currently the emphasis for managing heart disease is on reducing the �bad� cholesterol or LDL in the circulation. Our study demonstrates that if you can increase the removal of cholesterol from the plaques, even without changing the LDL levels, there is still a significant reduction in the plaques,� said Ghosh.

�These findings not only change the current thinking of managing heart disease but also clearly open avenues for the development of new therapies. By identifying CEH as a new therapeutic target, we expect that in the future patients with heart disease will have more options to aggressively treat heart disease. In addition, by determining the levels of CEH in human blood cells, we hope to be able to predict susceptibility to heart disease in the future,� she said.

According to Ghosh, the team focused their efforts on the examination of macrophage foam cells, which are responsible for storing large amounts of cholesterol and lead to the clogging of the arteries by forming plaques. The findings appear in the October print issue of the Journal of Clinical Investigation.

The team is actively exploring the mechanisms underlying CEH regulation and to determine how its activity can be increased in order to reduce heart disease.

Cholesterol metabolism links early- and late-onset Alzheimer's disease

Thu, 04 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Oct. 4, 2007 -- Although the causes of Alzheimer's disease are not completely understood, amyloid-beta (A-beta) is widely considered a likely culprit � the sticky protein clumps into plaques thought to harm brain cells.

But now researchers at Washington University School of Medicine in St. Louis have uncovered evidence strengthening the case for another potential cause of Alzheimer's. The finding also represents the first time scientists have found a connection between early- and late-onset Alzheimer's.

In a study published in the Oct. 4, 2007 issue of the journal Neuron, the scientists report that when A-beta is made, a small bit of protein is also released that can regulate cholesterol levels in the brain. The discovery adds weight to the less prominent theory that abnormal brain cholesterol metabolism plays a role in the mental decline seen in Alzheimer's patients.

Our research links two major determinants for early- and late-onset Alzheimer's disease, says senior author Guojun Bu, Ph.D., professor of pediatrics and of cell biology and physiology. And we've shown that the process that links them is implicated in brain cholesterol metabolism.

The report follows closely on another study reporting that statins, widely prescribed cholesterol-lowering drugs, could prevent certain neural changes that signal the progression of Alzheimer's disease. Additional earlier studies support the idea that statins could benefit Alzheimer's patients; however, other studies have found no such protective effect from statins.

The studies of statins and Alzheimer's have generated quite a bit of controversy, Bu says. Those that show positive effects from statins seem to suggest that high cholesterol could increase the risk of Alzheimer's disease. But other evidence contradicts this idea.

In fact, the brain needs a high level of cholesterol, according to Bu. The brain represents only about 2 percent of your body weight, but actually has about 20 percent of your body's cholesterol, Bu says. There is strong evidence that cholesterol is important for synaptic function and is an essential component of cell membranes in the brain, and I believe partial defects in the regulation of cholesterol metabolism in the brain likely contribute to the development of Alzheimer's.

In the current study, Bu and colleagues found an aspect of cholesterol transport and metabolism in the brain was a link between early- and late-onset Alzheimer's disease. Both forms of the disease result in similar brain lesions and have the same symptoms, including difficulties communicating, learning, thinking and reasoning, which suggests they share underlying mechanisms. But until now, no one has been able to identify such a mechanism.

Early-onset Alzheimer's can be traced to mutations in one of three genes, and the gene coding for A-beta's precursor, APP, is one of these. People with mutations in APP nearly always develop Alzheimer's disease, usually at a relatively young age.

The genetic origins of late-onset Alzheimer's, which accounts for 95 percent of cases, have proven harder to pin down. However, studies have shown that people who have a particular mutation in the gene for a cholesterol carrier called apolipoprotein E are far more likely to develop Alzheimer's in old age than those who don't have the mutation.

Bu and colleagues demonstrated that APP and apolipoprotein E have a molecular connection. When APP is cleaved by a specific enzyme in the brain, it releases A-beta plus a small protein fragment. The fragment then can regulate apolipoprotein E, which moves cholesterol in the brain from support cells to neurons.

Past research by others implies that neural synapses, the junctions that nerves use to send impulses and communicate, are particularly sensitive to cholesterol levels and that interfering with cholesterol transport and metabolism could cause loss of synapses and degeneration of nerves.

Cholesterol metabolism in the brain is an understudied area, and our findings could inspire Alzheimer's researchers to look further into the role of the cholesterol pathway, Bu says. Right now, research on Alzheimer's treatment focuses largely on reducing A-beta production or increasing its clearance from the brain. Our study suggests that there could be an alternate way to treat the disease, perhaps by modulating the function of apolipoprotein E and cholesterol in the brain.

Bu and his colleagues plan to screen for compounds that regulate the molecular components that they found to be involved in cholesterol metabolism. They hypothesize that such compounds could work to enhance the brain's cholesterol metabolism and alleviate Alzheimer's symptoms.

Low maternal cholesterol tied to premature birth

Mon, 01 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Pregnant women who have very low cholesterol may face a greater risk of delivering their babies prematurely than women with more moderate cholesterol levels, a team led by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), reported today.

In a study published in the October issue of the journal Pediatrics, NHGRI�s Max Muenke, M.D.; Robin J. Edison, M.D., M.P.H.; Kate Berg, Ph.D.; and colleagues from the NIH Clinical Center; Kennedy Krieger Institute, Baltimore; Howard University, Washington; and Greenwood Genetic Center, Greenwood, S.C., confirm previous findings by other groups that very high levels of maternal cholesterol can increase the risk of premature birth. However, in a surprising new twist, the researchers found that low maternal cholesterol levels, which may be related to a woman's genetic makeup, diet or other health factors, also may lead to adverse birth outcomes, including premature birth and low birth weight.

�Based on our initial findings, it appears that too little cholesterol may be as bad as too much cholesterol during pregnancy, but it is too early to extrapolate these results to the general population. More research is needed to replicate this outcome and to extend it to other groups,� said Dr. Muenke, the study�s senior author and chief of the Medical Genetics Branch in NHGRI�s Division of Intramural Research. �For now, the best advice for pregnant women is to follow the guidance of their health care providers when it comes to diet and exercise.�

Premature birth is a major cause of infant death and raises the risk of many potentially disabling conditions, including cerebral palsy, cognitive impairment, blindness, deafness and respiratory illness. Factors contributing to premature birth include maternal genetics, fetal genetics and environmental components, such as nutrition, stress, and infection.

In their study of 1,058 South Carolina women and their newborns, researchers found about 5 percent of the women with cholesterol levels in the moderate range of 159-261 milligrams per deciliter (mg/dl) gave birth prematurely. In contrast, white women with the lowest cholesterol levels � less than 159 mg/dl � had a 21 percent incidence of premature births. Interestingly, no increase in premature births was observed among African American women in the low-cholesterol category. However, full-term babies born to both white and African Americans with low cholesterol weighed 5 ounces less on average than full-term babies born to women with moderate cholesterol.

�The right amount of cholesterol is fundamental for good health, both before and after birth,� explained Dr. Muenke. �During pregnancy, cholesterol is critical for both the placenta and the developing baby, including the brain.�

As in past studies, the new research showed very high cholesterol levels (more than 261 mg/dl) to be a major risk factor for premature birth. About 12 percent of white and African American women with very high cholesterol levels gave birth prematurely.

The study involved pregnant women between the ages of 21 and 34 who were referred to South Carolina clinics for routine prenatal care between 1996 and 2001. According to their medical records, they were all nonsmokers without diabetes who were carrying just one child. It looked at cholesterol levels from their second trimester of pregnancy. Premature birth was defined as delivery before 37 weeks of gestation.

Taking into account the natural rise in maternal cholesterol during pregnancy, researchers examined the effects of maternal cholesterol levels on rates of premature delivery, impaired fetal growth and birth defects. In addition, they analyzed measurements of newborn weight, length and head circumference. No differences were seen in the rate of birth defects, but researchers did detect a trend towards smaller head sizes among babies born to women with very low cholesterol.

�This study sheds important light on the intricate biological mechanisms at work during human gestation,� said NHGRI Scientific Director Eric Green, M.D., Ph.D. �In light of these findings, researchers have a renewed impetus to establish the genetic and environmental causes of low cholesterol levels because of its relevance to pregnancy.�

In the Pediatrics paper, the NHGRI-led research team called for more studies to refine our understanding of cholesterol levels in pregnant women, and to explore the genetic, nutritional and other factors that influence maternal cholesterol. They also pointed out the need for further investigation into the differing impact of low cholesterol levels on the rates of premature delivery in white and African American mothers.

Besides the South Carolina study, Dr. Muenke and his colleagues have undertaken a number of other investigations aiming to determine the role of cholesterol in embryonic development. They have identified genes that impact congenital brain defects and established the role that cholesterol plays in modulating the actions of such genes.

Treating obstructive sleep apnea, preventing heart attacks and strokes

Fri, 28 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Researchers in Brazil have found that treating patients who suffer from obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) dramatically reduces early indications of atherosclerosis in just months, linking OSA directly to the hardening or narrowing of the arteries. Until now, no study has demonstrated such a direct relationship between the two.

�OSA is independently associated with increased risk of fatal cardiovascular events that can be reversed by treatment with CPAP,� wrote Luciano Drager, M.D., of the University of S�o Paulo Medical School in Brazil.

The research was published in the first issue of the American Journal of Respiratory and Critical Care Medicine for October of 2007, published by the American Thoracic Society.

The researchers selected 24 men with severe OSA and no other comorbidities and randomly assigned them to receive either CPAP therapy or no treatment. After establishing the baseline data for each subject, they then tracked several indicators of pre-clinical atherosclerosis, including carotid intima-media thickness (a measure of arterial plaque), pulse-wave velocity (a measure of arterial stiffness), carotid diameter, C-reactive protein (a marker of inflammation), and catecholamine level (a marker of physical stress) over the course of four months.

�[All markers] were similar across the study period in the control group,� wrote Dr. Drager. �In contrast, the group treated with CPAP had a significant decrease in carotid intima-media thickness, pulse-wave velocity, C-reactive protein, and catecholamines.�

While there is a known association between OSA and risk of myocardial infarctions and strokes, the causal connection between OSA and atherosclerosis as the principle mechanism behind those cardiovascular events has proven difficult to establish.

�The majority of patients with OSA share several risk factors for atherosclerosis, including obesity, hypertension, hypercholesterolemia, insulin resistance, and hyperglycemia,� explained T. Douglas Bradley, M.D., and Dai Yumino, M.D., both of the Sleep Research Laboratory at the Toronto Rehabilitation Institute at the Centre for Sleep Medicine and Circadian Biology at the University of Toronto, in an editorial in the same issue of the journal.

Furthermore, while non-randomized observational trials have suggested that the risk of adverse cardiovascular events is lower among patients who accept treatment by CPAP than in patients who do not accept CPAP therapy, it is possible that this difference may be due to better overall adherence to all prescribed treatments in patients who accept CPAP than in those who do not, as opposed to any direct benefit of CPAP itself.

�Whereas physiological studies suggest that OSA provides a substrate for the development of atherosclerosis, and epidemiological and observational studies suggest an association between OSA and odds of having atherosclerosis, there remains a gap between cause and effect yet to be filled,� wrote Drs. Yumino and Bradley. �Drager and colleagues provide evidence that begins to fill that gap.�

Indeed, after four months of CPAP therapy, carotid intima-media thickness declined by nine percent, which is remarkable in light of the fact that in a large-scale study, patients undergoing cholesterol-lowering pravastatin therapy saw carotid intima-media thickness decline by twelve percent after a full year. Other indicators showed similar magnitudes of improvement.

The researchers put forth a number of potential pathways whereby OSA could contribute to atherosclerosis progression, including inflammation, oxidative stress, lymphocyte activation, and high-density lipoprotein dysfunction. �CPAP treatment could reverse several of these pathways,� they wrote.

Still, the investigators caution that, while they are confident in the biological validity of their results, the rigid inclusion criteria makes it difficult to extrapolate their results to different populations, including women, patients with other co-morbidities and patients with mild to moderate OSA.

'Bad carbs' not the enemy, University of Virginia professor finds

Fri, 28 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) The latest common wisdom on carbohydrates claims that eating so-called �bad� carbohydrates will make you fat, but University of Virginia professor Glenn Gaesser says, �that�s just nonsense.� Eating sandwiches with white bread, or an occasional doughnut, isn't going to kill you, or necessarily even lead to obesity, he said.

In an article in the October issue of the Journal of the American Dietetic Association, Gaesser analyzes peer-reviewed, scientific research on carbohydrate consumption, glycemic index and body weight and gives the first detailed review of the literature on the correlation between them. His findings run counter to the current consensus on the effects of �good� and �bad� carbohydrates.

Gaesser, author of �It�s the Calories, Not the Carbs� and other books, found that diets high in carbohydrates are almost universally associated with slimmer bodies. More importantly, Gaesser found that consuming lots of high-glycemic foods is not associated with higher body weights. In fact, several large studies in the United States revealed that high-glycemic diets were linked to better weight control.

�There is no reason to be eating fewer carbs � they�re not the enemy,� says Gaesser, a professor of exercise physiology and director of the kinesiology program in the Curry School of Education.

The description of carbohydrates as �good� or �bad� is based on glycemic index, a measure of the quality of the carbohydrate in terms of how much it raises blood sugar. Foods having a high GI are generally thought to be �bad� because they raise blood sugar more than �good� carbs do. Proponents of the glycemic index claim that this leads to excessive insulin secretion, which can cause weight gain and health problems. Foods such as whole-grain breads are said to offer �good� carbs, because they have a lower GI than white bread, for example. Likewise, a glass of pineapple juice has a high GI compared to apple juice.

Several popular low-carb diets use glycemic index as a key feature for optimum weight control, but it is not a reliable description of carbohydrate quality, Gaesser says. Digestion is a complicated process. It�s very difficult to determine the GI of a whole meal, for instance, so it doesn�t really make sense to use GI or �glycemic load� � the glycemic index multiplied by the quantity ingested � as a guide to eating.

After looking at hundreds of articles on large-scale studies using surveys or randomized, controlled trials, Gaesser says they show that �people who consume high-carb diets tend to be slimmer, and often healthier, than people who consume low-carb diets.� Even high-glycemic foods have a place in the diet, he said, attributing that to the overall higher quality of a high-carb diet, which includes more fiber-rich and other nutritional foods.

Gaesser also looked for a clear association between carbohydrate consumption and illnesses, such as type 2 diabetes, heart disease and cancer. He found no compelling evidence that avoiding carbohydrates with a high GI helps prevent these diseases and others. People with diabetes, as well as very sedentary women who are obese, may benefit from lowering their consumption of foods with a high GI, Gaesser says.

Reducing any part of the diet � carbs or proteins or fats � will result in modest weight loss in the short term, if calorie consumption is reduced, he points out. But for long-term weight maintenance, a high-carb, low-fat diet is still the best bet, he said.

Metabolic study in mice could lead to 'good cholesterol' boosters

Tue, 07 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Researchers have identified a new player in the control of so-called good cholesterol that circulates in the bloodstream and reduces heart attack risk, according to a report in the August issue of Cell Metabolism, a publication of Cell Press. Should the metabolic pathway uncovered in mice operate similarly in humans, the new discovery could point the way to therapies that protect against heart disease by boosting concentrations of the beneficial high-density lipoprotein cholesterol (HDL-C).

By and large, the medicines now available lower levels of the bad low-density lipoprotein cholesterol [LDL-C], said Weijun Jin of the University of Pennsylvania School of Medicine. There is a great need for methods to raise good cholesterol levels. Our findings suggest there may be multiple places to interrupt the metabolism of HDL-C.

LDL-C can build up in blood vessel walls, increasing the risk of heart disease or stroke. By contrast, HDL-C tends to carry cholesterol away from the arteries to the livera process known as reverse cholesterol transportwhere it is broken down and then eliminated from the body.

Existing LDL-C-lowering drugs such as statins can reduce the risk of heart attack by 20 to 35 percent, Jin said. However, treatment methods that would simultaneously lower bad cholesterol and increase good cholesterol have the potential to work even better. Indeed, researchers believe that increasing HDL-C while lowering LDL-C might cut heart attack risk by as much as 70 percent, he explained.

In the current study, the researchers found that treatments that partially block the activity of liver enzymes called proprotein convertases decreased plasma HDL-C levels in mice. They showed that the metabolic effect of the proprotein convertases depended on yet another factor, an enzyme called endothelial lipase (EL), which breaks down HDL-C. Proprotein convertases normally reduce EL function, they reported. Thus, the loss of proprotein convertase activity leads to an increase in EL and a decline in HDL-C.

Likewise, they showed that increased activity of proprotein convertases in the liver gives a significant boost to the protective HDL-C.

Proprotein convertases are an unexpected new player in HDL-C metabolism, Jin said. By manipulating levels of the enzyme in both directions, we were able to reduce HDL-C to almost nothing or double it. That wide range of effects suggests that it may be theoretically possible to manipulate good cholesterol levels to whatever point you like.

He emphasized, however, that the new findings represent basic research in animals. Further investigation will examine to what extent the pathway is preserved in humans, Jin said. The authors will also look for chemicals capable of modifying the pathway, which could hold promise as new good-cholesterol-boosting drugs.

Older is better -- Top-10 comparison of diabetes drugs give metformin top grade

Tue, 24 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A type 2 diabetes drug taken orally and in widespread use for more than a decade has been found to have distinct advantages over nine other, mostly newer medications used to control the chronic disease, according to a study by researchers at Johns Hopkins.

In their report, published online July 16 in the journal Annals of Internal Medicine, the Hopkins team found that metformin, first approved by the U.S. Food and Drug Administration in 1995 (and sold as Glucophage, Riomet and Fortamet), not only controlled blood sugar levels but also was less likely to cause weight gain and more likely than others to lower bad cholesterol levels in the blood.

Researchers say these health benefits are important because they can potentially ward off heart disease and other life-threatening consequence from diabetes. More than 15 million Americans have type 2 diabetes.

Sometimes newer is not necessarily better, says lead study author Shari Bolen, M.D., an internist at Hopkins. Issues like blood sugar levels, weight gain and cost could be significant factors to many patients struggling to stay in good health, says Bolen, an instructor at The Johns Hopkins University School of Medicine.

In what is believed to be the largest drug comparison of its kind, the scientists showed that all of the commonly used oral medications worked much the same at lowering and controlling blood sugar levels, and were equally safe. But metformin stood out because it offered the same level of effectiveness without lowering glucose measurements too much, and it did so for a lower price.

Metformin was found to lower LDL or bad cholesterol by about 10 milligrams per deciliter of blood, while newer medications studied, such as pioglitazone (Actos) and rosiglitazone (Avandia), or so-called thiazolidinediones, were found to have the opposite effect, increasing levels of the artery-clogging fat by the same amount.

Researchers say the main drawbacks to metformin are digestive problems and diarrhea. Previous reports have found evidence that the medication leads to the buildup of lactic acid in the blood in people with moderate kidney or heart disease, and they note that it should not be prescribed to anyone with either of these conditions. The main advantages to both newer thiazolidinediones were a small increase in HDL or good cholesterol, and less too-low blood sugar levels than three other older, cheaper drugs studied -- glimepiride (Amaryl), glipizide (Glucotrol), glyburide (Micronase, DiabBeta, Glynase PresTab) -- known as second-generation sulfonylureas.

Annual treatment with metformin or the sulfonylureas, they note, costs on average $100, roughly one-fourth the cost of oral diabetes medications FDA-approved since then, including the two newer thiazolidinediones, both approved in 1999. (Their price is expected to drop once generic versions become available.)

When you are dealing with an epidemic like diabetes, it is important for people to weigh their treatment options with their physician and to make informed decisions about which medication best suits their needs, says Bolen.

In the study, Bolen and her colleagues reviewed the scientific evidence from 216 previous studies and compared each drug for its clinical effectiveness, risks and costs. In addition to metformin, the thiazolidinediones and sulfonylureas, drugs included in their analysis were repaglinide (Prandin), miglitol (Glyset), acarbose (Precose), and nateglinide (Starlix).

Among the teams other findings were that glimepiride, glipizide, and glyburide led more frequently to too-low blood sugar levels than the other drugs. The sulfonylureas and acarbose appeared to have no effect on bad cholesterol. And except for metformin and acarbose, drug treatment led to an increase in weight from 2 to 11 pounds.

Researchers also noted the increased risk of heart failure, albeit small (less than three people in a hundred), in people taking thiazolidinediones who did not have a history of heart disease. They also caution that despite recent reports about the potential for increased risk of heart attack from rosiglitazone, there is not yet sufficient information to verify the finding.

Researchers say further studies are needed to compare the long-term effectiveness of one treatment to another and to compare drug effects on quality of life and life expectancy. Additional research will also be needed to compare these findings with results for injectible medications for diabetes, most notably insulin, which was not included in the latest report.

Bak protein sets stressed cells on suicide path, researchers show

Thu, 12 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) When a cell is seriously stressed, say by a heart attack, stroke or cancer, a protein called Bak just may set it up for suicide, researchers have found.

In a deadly double whammy, Bak helps chop the finger-like filament shape of the cells powerhouse, or mitochondrion, into vulnerable little spheres. Another protein Bax then pokes countless holes in those spheres, spilling their pro-death contents into the cell.

We found out Bak has a distinct function in regulation of the mitochondrial morphology, says Dr. Zheng Dong, cell biologist at the Medical College of Georgia and the Veterans Affairs Medical Center in Augusta and corresponding author on a paper published this week in Proceedings of the National Academy of Sciences. Bax, on the other hand, is not involved in morphological regulation but needs to be there to puncture holes.

One has to break up, kind of soften, the mitochondria for injury, and the other one actually punches the holes to kill it, says Craig Brooks, MCG graduate student and the papers first author.

Bak and Bax have similar structures and scientists have long suspected they play major, similar roles in programmed cell death, or apoptosis. These two proteins are very important for mitochondrial injury and subsequent apoptosis, says Dr. Dong.

To stress cells, they blocked oxygen supplies and used the common chemotherapeutic agent cisplatin, then documented that filamentous mitochondria became fragmented very early and quickly in apoptosis. Ironically they also found the deadly fragmentation results from Baks interaction with mitochondria-shaping proteins called mitofusins, which help mitochondria keep their filamentous shape in non-stressed cells. Dr. Dong suspects Bak may also play a role in mitofusin regulation in normal, non-stressful conditions.

In fact, the researchers suspect Bak, Bax and the contents they spill into the cell all have roles in keeping a cell functioning until a stressor kicks in.

They probably are both kept in check normally in the cell by other proteins, and when something happens that overwhelms the cell, it activates Bak and Bax to start cell death, says Mr. Brooks. Some of the same proteins, cytochrome c is the big one, are needed for daily mitochondrial function like making energy, but if they are released from the mitochondria, they activate a cell killing or apoptotic pathway, says Dr. Dhong, referencing the contents that spill from punctured mitochondria.

Looking at kidney cells and neurons in a Bak deficient mouse, they also showed that Bak and Bax need each other to successfully spawn cell suicide. If you have Bak but not Bax, the mitochondria still fragment but they dont die; if you have Bax but not Bak, you still have punctures in the mitochondria but with low efficiency, says Mr. Brooks.

Now they want to know exactly how Bak interacts with mitofusins, how the interaction is regulated and how it affects mitochondrial morphology, physiology and pathology. Their long-term goal for better understanding the cell suicide mechanism is developing drugs to block it in the case of a stroke, for example, or induce it to kill cancer.

Insulin sensitizer also serves as energy-conserving signal to the brain

Tue, 10 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A fat-derived protein known for its effects on the liver and skeletal muscle might also serve as an energy-conserving signal to the brain during periods of starvation, suggests a new study in the July issue of Cell Metabolism, a publication of Cell Press. The substance, known as adiponectin, acts on the brain to boost appetite and slow energy expenditure in an effort to maintain adequate fat stores during lean times, the researchers report.

Energy homeostasis may be mediated by both short-term regulators, such as gut hormones, and long-term regulators, said Takashi Kadowaki of the University of Tokyo. In this study, we identified, for the first time, a potential long-term regulator that allows energy to be stored efficiently, namely, adiponectin. The findings offer critical insight into adiponectins influence over the central nervous system and suggest that selective inhibition of the chemical in the brain may represent a novel therapeutic strategy for obesity and obesity-linked diseases, he added.

White adipose tissue (WAT) is a major site of energy storage and plays an important role in energy balance, the researchers said. It is also recognized as an important endocrine organ that secretes a number of biologically active signaling proteins, called adipokines. Adiponectin, an adipokine secreted exclusively by WAT, is present at relatively high concentrations in the circulation and has been shown to increase the bodys response to insulin. Studies have also suggested that decreased circulating levels of adiponectin in obesity and type 2 diabetes may contribute to the insulin resistance that characterizes both conditions.

In addition to its peripheral actions on the liver and skeletal muscle, adiponectin has also been reported to have central actions, Kadowaki said. Recently, however, it was reported that adiponectin is undetectable in human cerebrospinal fluid and does not cross the blood-brain barrier, leaving some doubt about its physiological role in the central nervous system, he added.

The researchers now report evidence in mice that adiponectin receptors are present in the hypothalamic region of the brain and that some forms of the chemical enter the cerebrospinal fluid from the blood. Once in the brain, adiponectin enhances the activity of a metabolic enzyme called AMP-activated protein kinase (AMPK) to stimulate greater food consumption. Moreover, the researchers found that adiponectin decreased energy expenditure. They also showed that blood and spinal fluid adiponectin levels in the brain normally increase during fasting and decrease after refeeding, suggesting that adiponectin acts mainly during food shortages.

In adiponectin-deficient mice, AMPK activity in the brain slowed, causing the animals to eat less and expend more energy. That action, in turn, made the animals resistant to becoming obese even on a high-fat diet. Moreover, animals lacking adiponectin lost more fat after 12 hours of fasting than normal mice did.

Blood levels of another fat hormone, leptin, are regulated inversely in relation to serum adiponectin levels, the researchers noted.

Thus, central adiponectin/leptin signals may represent the physiological pathway by which hypothalamic AMPK activity and food intake are stimulated during fasting and suppressed after refeeding, they said. In addition to this short-term regulation of food intake and energy expenditure by adiponectin and leptin, these two adipokines may also participate in the long-term regulation of energy homeostasis. The fundamental roles of leptin and adiponectin seem to be to preserve an adequate fat reserve: leptin acts as a satiety signal, and adiponectin acts as a starvation signal.

New heart disease risk score will help minimize health inequalities

Fri, 06 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A new score for predicting the risk of heart disease gives a more accurate measure of how many UK adults are at risk of developing the disease and which adults are most likely to benefit from treatment.

The study, published on bmj.com on July 6, estimates that in the general population without pre-existing cardiovascular disease or diabetes, there are 3.2 million adults under the age of 75 in Britain at high risk of developing heart disease. This is lower than previous scores have suggested, but the researchers believe that it is a more appropriate estimate for the UK and will help minimise health inequalities.

The study comes as the governments drugs watchdog, the National Institute for Health and Clinical Excellence, recommends that people with a 20 per cent chance of developing heart disease over the next 10 years should be offered statins.

A persons chance of developing heart disease is estimated using standard risk factors such as age, sex, smoking, blood pressure and cholesterol. This risk score is typically based on equations derived from the US Framingham cohort study.

But the Framingham equations tend to over-predict heart disease risk in the UK population and fail to include measures of deprivation, family history of heart disease, body mass index, and treatment with blood pressure lowering drugs, despite known links between these factors and poor health.

So a team of researchers from The University of Nottingham, Bristol Primary Care Trust, and the Universities of Bristol and Queen Mary, set out to derive a new cardiovascular risk score (QRISK) for the UK and test its performance against the established Framingham score and a new a score used in Scotland called ASSIGN, which includes a measure of social deprivation.

The research has been conducted using data from a general practice research database called QRESEARCH, which is a joint partnership between the University of Nottingham and EMIS, a leading provider of IT systems to GPs.

The researchers tracked the progress of 1.28 million healthy men and women, registered at 318 general practices over a period of 12 years up to April 2007, recording first diagnosis of cardiovascular disease. All the participants were aged between 35 and 74 at the start of the study.

They found that the QRISK score was more accurate than either Framingham or ASSIGN. In patients aged 35-74, Framingham over-predicted cardiovascular disease risk at 10 years by 35%, ASSIGN by 36% and QRISK by 0.4%. QRISK predicted 9% of patients aged 35-74 years to be at high risk compared with 13% for the Framingham equation and 14% for ASSIGN.

Using this more focused tool for risk estimation, the research team estimate that 34% of women and 73% of men aged 64-75 would be at high risk compared with 24% and 86% according to the Framingham equation.

QRISK would also identify a different group of patients than the Framingham equation, with one in ten patients being reclassified into high or low risk, they say. QRISK is likely to provide more appropriate risk estimates of cardiovascular disease risk based on age, sex and social deprivation, write the authors. It is therefore likely to be a more equitable tool to inform management decisions and help ensure treatments are directed towards those most likely to benefit.

In people under 75 years without pre-existing cardiovascular disease or diabetes, QRISK identifies 3.2 million patients at high risk in 2005, compared with 4.7 million from Framingham and 5.1 million from ASSIGN.

They suggest that QRISK should be further tested in other populations, but point out that this is the largest such study to have ever been undertaken, and the first time routine data in a UK general practice population have been used in this way.

Study leader, Professor Julia Hippisley-Cox, of The University of Nottingham, said: QRISK is derived from primary care data for use in primary care, and takes account of social deprivation to better identify patients most at most risk of heart disease and stroke who are most likely to benefit from treatment.

We thank the many thousands of doctors who have enabled this research by freely contributing anonymised data to QRESEARCH, without which this work would not have been possible.

Protein's role in lipid absorption may be important to future weight-loss strategies

Thu, 05 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) July 5, 2007 -- Researchers at Washington University School of Medicine in St. Louis have found that a protein absorbs lipids in the upper part of the intestine, and they believe its key role in this process may provide a novel approach for obesity treatment in the future.

Principal investigator Nada A. Abumrad, Ph.D., the Dr. Robert C. Atkins Professor of Medicine and Obesity Research at Washington University School of Medicine, first identified the protein, CD36, that facilitates the uptake of fatty acids. The protein is located on the surface of cells and distributed in many tissues, including fat cells, the digestive tract, heart tissue and skeletal muscle tissue.

Her studies have shown that the intestine makes large amounts of CD36, and that it is important to the absorption of fatty acids. Initially when she compared normal mice that made the protein to genetically altered mice lacking CD36, she couldn't find any net difference in their fat absorption.

But the new study, reported in the July 6 issue of the Journal of Biological Chemistry, reveals the reason it was not possible to identify a difference. Apparently, the intestine has some built-in redundancy.

Normally, CD36 absorbs fatty acids in the upper, or proximal part of the intestine, but when it is absent, lower, more distal, sections of the intestine compensate and absorb the fat.

We think of the intestine as a single organ, but it's really made up of distinct areas that are so specialized it's almost like several organs, Abumrad says. The fat that is not absorbed in the proximal areas ends up being bumped into the distal intestine where different systems absorb it,

Abumrad and her colleagues, including first author Fatiha Nassir, Ph.D., research assistant professor in the Division of Gerontology and Nutritional Science, believe that targeting the upper part of the intestine and interfering with normal CD36 function might be a useful tool in weight loss. The team found that animals that could not make CD36 absorbed fat less efficiently, and as a result they tended to eat less of it.

And the most exciting part for us right now is the fact that these things may apply to humans, Abumrad says. Humans with mutations in the gene that makes CD36 don't seem to process fat normally either.

She learned from the mice that when fatty acids and cholesterol are not absorbed in the proximal part of the intestine, as normally occurs, the distal intestine packages those fats very differently.

The proximal intestine makes molecular packages called chylomicrons, she says. These bundles that contain lipids and proteins transport these molecules from the intestine to other parts of the body. CD36, which is abundant in the proximal intestine, turns out to play a role both in absorbing fatty acids and cholesterol and in packaging these lipids into chylomicron bundles that facilitate their use throughout the body.

When no CD36 was present in the genetically altered mice in Abumrad's study, the lipids were absorbed more slowly since they had to travel to lower, more distal parts of the intestine. And they also were packaged differently. Rather than being bundled into chylomicrons, the lipids were released as parts of smaller particles that are not as easily absorbed by other tissues as the chylomicrons.

For years, Abumrad has studied how CD36 modulates the acute and chronic responses of muscle and fat cells to energy fluctuations and other stresses. Her goal is to translate her findings from rodents into humans, where variations in the CD36 gene are common.

There is evidence that people have different amounts of CD36 and that mutations in the gene are quite common, she says. Those variations are associated with abnormalities of blood lipids, with high levels of fatty acids in the blood, abnormal blood triglycerides and increased risk of diabetes-associated heart disease. It's clear that some of us have different amounts of this protein in different tissues, and some individuals don't have any of it.

Although scientists in Abumrad's laboratory think it may be possible eventually to help people lose weight by interfering with the CD36 protein, they first want to learn more from the mouse. Currently, they work with mice that cannot make CD36 anywhere in their bodies. But because the protein also operates in heart tissue and skeletal muscle, disabling CD36 everywhere can have detrimental effects. So the team is working to develop a new kind of mutant mouse, one that can make CD36 everywhere except in the intestine.

If we find that such a mouse still has delayed absorption of fatty acids and cholesterol and ends up eating less fat, we'll have more evidence that this might be a good approach to use in humans, she says. Block the function of the protein in the intestine, absorb fewer lipids, and since your absorption is delayed, you don't feel as hungry and you eat less.

But until such a mouse is developed, Abumrad's team cannot be certain that blocking the effects of CD36 in the intestine might not also have harmful effects. Interfering with CD36 function to absorb less fat is not necessarily a good thing if it causes problems in the heart, the liver or elsewhere in the body.

Weight management program cuts diabetes risk, improves BMI in overweight children

Tue, 26 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A family-based weight management program developed by researchers at Yale School of Medicine was more effective at reducing weight, body fat, body mass index (BMI) and insulin sensitivity than traditional clinic-based weight counseling.

Mary Savoye-Desanti, research associate in Yales Department of Pediatrics, will present the findings at a JAMA media briefing in New York on June 26 at 10 a.m. The study will be published in JAMAs June 27 theme issue on chronic diseases of children.

Savoye-Desanti, a registered dietician and certified diabetes educator, and her team conducted the one-year clinical trial of 209 overweight children between the ages of 8 and16 to address the increasing prevalence of childhood obesity, especially in the African American and Hispanic population. The childhood obesity epidemic has also sparked an increase of type 2 diabetes among adolescents.

Savoye-Desanti and colleagues measured the effectiveness of the weight management program Bright Bodies, in comparison to care provided at a pediatric obesity clinic. Bright Bodies was created 10 years ago by Savoye-Desanti and combines nutrition education, behavior modification and exercise tailored to the needs of inner-city children. The study sought to compare changes in BMI, body composition, insulin sensitivity, blood pressure and lipid profiles.

The 105 children randomly assigned to the Bright Bodies program participated in 50 minutes of exercise for two nights per week. The eight to 10-year-old group participated in several games such as relay races, obstacle courses and several other games including Swim Fish Swim. The older group (11- to 16-year-olds) played flag football, basketball and other activities. Both groups played Dance, Dance Revolution by Konami.

The study revealed great differences in BMI, body weight, body fat and percent body fat between the control group and the weight management group. While the average body weight was essentially unchanged among the weight management group, BMI was reduced by 1.7 units and there was an improvement in overall cholesterol. The control group gained an average of 17 pounds and increased their BMI by 1.6 units. Percent and total body fat was reduced in the weight management group and increased in the control group.

Insulin sensitivity, which measures the risk of developing type 2 diabetes, was increased in the weight management group and decreased in the control group. Increased insulin sensitivity is linked to a reduced risk of developing type 2 diabetes.

We have shown that a family-based program that uses nutrition education, behavior modification and supervised exercise can lower BMI, improve body composition and increase insulin sensitivity, said Savoye-Desanti, who stresses that the success of the Bright Bodies program relates to frequent contact between the families and staff members. This is a family problem. The child cant do it alone.

Savoye-Desanti said that while the program was very successful in treating overweight children, the expense incurred in operating such a program is substantial. We will focus future studies on cost-benefit analyses, as this would be helpful for pediatric clinicians or health management organizations that are considering offering similar services to overweight children and adolescents, said Savoye-Desanti.

Diachrome improves blood sugar control in people with type 2 diabetes

Tue, 05 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Nutrition 21, Inc. today announced new published results from a 447 subject, randomized, double-blind, placebo-controlled clinical study that showed Diachrome, a patented combination of chromium picolinate and biotin, significantly improved glycemic control in patients with poorly controlled blood sugar levels who were being treated with oral anti-diabetic medication (OADs). Patients in the treatment group showed significant improvements in glycemic control (A1C) compared with placebo (an absolute decrease of 0.54%). The greatest improvement was seen in those patients with the poorest glycemic control (baseline A1C levels equal to or greater than 10%). These patients saw an additional absolute A1C decrease of 1.76% despite the fact that they were taking one or more OAD medications.The American Diabetes Association's (ADA) recommended goal for type 2 diabetes patients is an A1C level below 7.0%. Lowering A1C by just 1%, especially in patients with poor blood sugar control, can delay or prevent serious complications, reduce diabetes-related deaths and reduce healthcare costs. Uncontrolled, obese and overweight type 2 diabetes patients present an ongoing clinical challenge to health professionals. Prescribing another anti-diabetic medication can increase the risk of unwanted side effects, including weight gain or hypoglycemic events, and could place an added financial burden on the patient, said Cesar Albarracin, MD, lead investigator and a leader in the field of nutritional management of type 2 diabetes. This study shows that adding Diachrome to anti-diabetic medications can help patients reach their blood sugar goal simply, effectively and safely.

Exercise may slightly boost 'good' cholesterol levels

Mon, 28 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Regular exercise appears to modestly increase levels of high-density lipoprotein, or good, cholesterol, according to a meta-analysis study in the May 28 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

A low level of high-density lipoprotein cholesterol (HDL-C) is an independent risk factor for cardiovascular disease, the leading cause of death worldwide, according to background information in the article. There is strong evidence that individuals who are more physically active have higher HDL-C levels. Thus, the value of regular aerobic exercise in increasing serum [blood] HDL-C level and in reducing the risk of cardiovascular disease has received widespread acceptance, the authors write. In contrast, results of aerobic exercise studies vary considerably, depending on the exercise program (e.g., duration, intensity or frequency) and characteristics of subjects at baseline.

Satoru Kodama, M.D., of Ochanomizu University, Tokyo, and colleagues performed a meta-analysis of 25 articles reporting the results of randomized controlled trials that were published between 1966 and 2005 and assessed the effects of exercise on HDL-C. To be included in the analysis, the studies had to evaluate aerobic exercise in adults with an average age of 20 or older, specify HDL-C measurements at the beginning and end of the study, have a length of at least eight weeks, and randomly assign some participants to a group of exercisers and others to a control group of non-exercisers.

The 25 articles analyzed included a total of 1,404 participants with an average age range of 23 to 75 years and an average study period of 27.4 weeks. The exercise groups were told to exercise for an average of 3.7 sessions per week at an average of 40.5 minutes each, burning an average of 1,019 calories per week.

In all the studies combined, HDL-C increased by an average of 2.53 milligrams per deciliter in the exercise groups. The minimum amount of weekly exercise that appeared necessary to change HDL-C levels was 120 minutes or 900 calories burned. The effect of exercise was greater in those who had a higher total cholesterol level (220 milligrams per deciliter or greater) and in those with a body mass index of less than 28.

In a previous observational study, every 1-milligram per deciliter increment in HDL-C level was reported to be associated with a 2 percent and 3 percent decreased risk of cardiovascular disease in men and women, respectively, the authors write. If this observation were applied to our results, the increase in HDL-C level by exercise determined by this analysis would, by a rough estimate, result in a cardiovascular disease risk reduced by approximately 5.1 percent in men and 7.6 percent in women. This is potentially of substantial importance in public health, although the effect of reducing cardiovascular risk by increasing HDL-C level might be smaller than that by use of medications such as fibrates or niacin.

Only exercise duration, and not frequency or intensity, was associated with a change in HDL-C levels in the analysis. When the participants exercised for 23 to 74 minutes per session, each 10-minute increase in exercise duration corresponded to a 1.4-milligram per deciliter increase in HDL-C level. This suggests that in improving blood HDL-C values, increasing time per session is better than performing multiple brief exercise sessions when total time for exercise is limited, as is the case for many people, the authors write.

Reducing cardiovascular disease risk factors when discontinuing hormone replacement therapy

Tue, 15 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Hormone replacement therapy (HRT) has been shown to reduce many cardiovascular disease (CVD) risk factors, but many women have stopped using HRT due to reports from the Womens Health Initiative that HRT may increase the risk of breast cancer and heart disease. In a study published in the June issue of the American Journal of Preventive Medicine, researchers from the University of Pittsburgh Graduate School of Public Health examined whether the increased CVD risk from stopping HRT could be minimized by lifestyle change intervention.

Participants were part of the five-year Women On the Move through Activity and Nutrition (WOMAN) study, a randomized clinical trial of CVD prevention. The focus of this investigation was 240 women who were taking HRT at baseline; 134 of these women were randomized to the lifestyle intervention and the remaining 106 were randomized to the health education group.

Participants were followed for 18 months. At 18 months, 110 (46%) of the women had continued HRT and the remaining 130 had discontinued HRT.

The lifestyle change group significantly decreased weight, Body Mass Index, waist circumference, total cholesterol and LDL-C, had improved fat intake and increased leisure physical activity, when compared to the health education group. In general, HRT discontinuation resulted in an increase in total cholesterol and LDL-C.

In the health education group, HRT discontinuers averaged over 22 mg/dL increase in total cholesterol and LDL-C while HRT continuers averaged less than 4 mg/dL increases. No such differences were observed in the lifestyle change group.

The lead author, Kelley K Pettee, Ph.D. currently a post-doctoral research associate at Arizona State University, states, Considering the controversies regarding HRT, the findings from the present report are timely. These results have important public health implications and suggest that a non-pharmacological lifestyle approach is both safe and effective for CVD risk factor reduction in postmenopausal women, especially those who discontinued HRT use.

She continues, CVD continues to be the leading cause of morbidity and mortality among women in westernized countriesConcern about the possible risks associated with HRT has left women and their heath care providers searching for safe and effective means to reduce CVD risk factors. One potential consequence of diminished HRT use is increased use of pharmacological agents, such as statins and aspirin; however, both are associated with side effects. Based on the findings of the current investigation, special attention should be paid to encouraging lifestyle strategies that are likely to impart more benefit and less risk than drug therapies.

Employee health program improves blood pressure, diabetes control

Thu, 10 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) WASHINGTON, May 10 Employees who participated in a worksite health program improved blood pressure control by 9 percent and diabetes control by 15 percent, researchers reported at the American Heart Association's 8th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke.

During three years (200406) of follow-up on 2,100 workers, researchers also found that absenteeism declined significantly at JEA, a municipal utility in Jacksonville, Fla. The number of employees who missed work due to hypertension dropped from 25.8 percent to 15.6 percent, while those who missed work because of diabetes dropped by 66.2 percent (from 50 percent to 16.9 percent).

Workplace accidents also dropped by nearly 70 percent from 83 incidents in 2003 to 25 incidents in 2006. In all, 20 of the 83 incidents in 2003 resulted in lost time away from work, compared to only seven incidents in 2006.

The rising cost of medical care and the utility's predominantly male workforce (median age, 47) contributed to the need for a program that focused on preventing heart and blood vessel disease, said Sharon A. Clark, D.H.Sc., lead author of the study and JEA's health promotion specialist.

With an aging workforce, we were concerned with making a change to the modifiable risk factors for cardiovascular disease for our employees, Clark said.

While safety has long been a priority at the utility, about a dozen employees started the worksite health program in 1989. The workers had been walking along the bridges in Jacksonville's downtown river area during their lunch hours and decided they wanted a more formal exercise facility, Clark said.

They approached the company to create a fitness center, she said. Being a public utility, JEA has to be mindful of where its resources are spent.

The company agreed to provide the space, custodial help and security services, and the employees took out a loan for the equipment. The employees also chose the exercise classes and took over most of the day-to-day administration of what has expanded into seven fitness centers at various company facilities.

Over the years, the company began to notice benefits to helping workers stay fit, Clark said. The program has grown to where it is now part of the company's strategic plan.

For the study, JEA teamed up with its healthcare provider, Blue Cross/Blue Shield of Florida and with Pfizer Global Pharmaceuticals in Jacksonville.

With their help, the company expanded its safety and health program into a comprehensive wellness system that includes live and written health education information, health screenings, coaching and an incentive program to encourage participation.

Researchers, collecting mounds of data during the three years of follow-up, attempted to quantify the effects of lifestyle-changing activities aimed at reducing cardiovascular disease risks such as smoking, excess weight, high blood pressure and diabetes.

The backbone of the program is the Health Risk Assessment (HRA), a screening tool that includes measures of employees' health through blood pressure, blood sugar and cholesterol testing. It also includes a 60-question survey that asks about current health status, family history, daily nutrition, physical activity, the use of alcohol and tobacco, safe habits (such as seat belt usage), stress and depression, use of available medical screening tests and gender-related health questions.

The survey ends by asking questions that measure how willing an employee is to make lifestyle changes related to health and safety, and providing coaching to accomplish that change.

Just knowing about something doesn't make you change, Clark said. So the last part of the HRA is one-on-one coaching.

Employees are asked what they want to change first, such as weight, blood pressure or diabetes control. The coaching, set up through the health insurance company, is structured so that patients can call the same coach repeatedly to build a dialogue.

The researchers also used a Wellness Inventory Survey (WIS) to gather data and provided incentives such as time off or the chance to win prizes for participating in the survey and other aspects of the health and safety program.

The survey includes questions about absenteeism (time away from work due to illness) and presenteeism (unproductive time spent at work due to health or personal situations that make it hard to concentrate).During the study, the percentage of employees with normal blood pressure increased from 28 percent to 37 percent and the percentage with normal blood glucose (sugar) increased from 43 percent to 58 percent. The percentage of non-smokers increased from 86 percent to 89 percent.

Employees also reported feeling better about themselves, with a significant increase in the percentage describing their health status as excellent or very good, jumping 22 percent from 41.7 percent to nearly 51 percent.

We are planning to continue to work with modifiable risk factors because we think it benefits both the employees and the employer, Clark said.

MU researchers find statin drugs also may help reduce risk of heart failure, sudden cardiac death

Tue, 01 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) COLUMBIA, Mo. -- Statin drugs, known primarily for their ability to lower cholesterol, also may reduce the overactive sympathetic nervous system response that contributes to the worsening of heart failure and increases the risk of sudden cardiac death, two University of Missouri-Columbia researchers have found. Heart failure is the leading cause of morbidity and mortality in the United States.

James Fisher, a postdoctoral fellow at MU, and Paul Fadel, an assistant professor of medical pharmacology and physiology in the MU School of Medicine, reported their findings of the effect of the popular statin drugs at Experimental Biology 2007 in Washington, D.C., part of the scientific program of The American Physiological Society.

Heart failure, sometimes called congestive heart failure, is a chronic condition in which the heart can no longer pump enough blood to the rest of the body, causing damage and negatively impacting the quality and duration of life.

In several large clinical trials, cholesterol-lowering statin medications improved survival and other health outcomes in patients with heart failure, an effect that appeared not to be solely due to lowering these patients cholesterol levels. In the search for a possible mechanism to explain this observation, scientists have turned to measures of sympathetic nervous system activity.

The sympathetic nervous system controls blood pressure and heart rate. When a heart begins to fail, the sympathetic nervous system works harder to compensate by helping to maintain heart function, blood pressure and the delivery of needed blood to vital organs and peripheral muscles. While this increased activity is beneficial in the early stages of heart failure, prolonged full-tilt sympathetic nervous system overactivity soon becomes harmful, causing damage to the heart and kidneys.

The largest difference in sympathetic nervous system activity between individuals with and without heart failure can be seen when they are resting, when the body is placing no unusual demands on the heart. An earlier University of Nebraska study found that animals with heart failure characteristics experience a return to normal sympathetic nervous system activity after being treated with statin drugs.

Fisher and Fadel continued the study with humans, treating those with longstanding mild-to-moderate heart failure. The researchers measured sympathetic nervous system activity by placing an electrode in a nerve of the lower leg.

After one month of treatment, all patients had reduced sympathetic nerve activity while resting. Although none of the patients had experienced cholesterol or blood pressure levels elevated enough to require treatment, significant decreases in cholesterol and diastolic blood pressure also were absorbed and considered beneficial for the patients overall health.

Fadel said that the preliminary results are promising and exciting. The findings indicate that short-term treatment with a low level of statin medication significantly lowered resting sympathetic nerve activity, thus lowering a factor known to be associated with increased mortality in heart failure patients, Fadel said.

Higher trans fat levels in blood associated with elevated risk of heart disease

Tue, 27 Mar 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Boston, MA -- High consumption of trans fat, found mainly in partially hydrogenated vegetable oils and widely used by the food industry, has been linked to an increased risk of coronary heart disease (CHD). New York and Philadelphia have passed measures eliminating its use in restaurants, and other cities are considering similar bans. A new study from the Harvard School of Public Health (HSPH) provides the strongest association to date between trans fat and heart disease. It found that women in the U.S. with the highest levels of trans fat in their blood had three times the risk of CHD as those with the lowest levels. The study was published online on March 26, 2007, and will appear in the April 10, 2007 print issue of Circulation: Journal of the American Heart Association.

The strength of this study is that the amount of trans fatty acid levels was measured in blood samples from the study population. Because humans cannot synthesize trans fatty acids, the amount of trans fat in red blood cells is an excellent biomarker of trans fat intake, said senior author Frank Hu, associate professor of nutrition and epidemiology at HSPH.

Clinical trials have shown that trans fatty acids increase LDL cholesterol and lower HDL cholesterol, making them the only class of fatty acids, which includes saturated fat, to have this dual effect. HDL (high-density lipoprotein) is considered a good cholesterol; LDL (low-density lipoprotein) a bad cholesterol.

The researchers, led by Hu and lead author Qi Sun, a graduate research assistant at HSPH, set out to test the assumption that higher trans fatty acid levels in erythrocytesred blood cellswere associated with a higher risk of heart disease among U.S. women. Blood samples collected in 1989 and 1990 from 32,826 participants in the Brigham and Womens Hospital-based Nurses Health Study were examined. During six years of follow-up, 166 cases of CHD were diagnosed and matched with 327 controls for age, smoking status, fasting status and date of blood drawing.

After adjusting for age, smoking status and other dietary and lifestyle cardiovascular risk factors, the researchers found that a higher level of trans fatty acids in red blood cells was associated with an elevated risk of CHD. The risk among women in the top quartile of trans fat levels was triple that of the lowest quartile. Positive associations have been shown in earlier studies based on dietary data provided by the participants, but the use of biomarkers of trans fatty acids is believed to be more reliable than self-reports. This is probably the reason why we see an even stronger association between blood levels of trans fat and risk of CHD in this study, said Sun.

These data provide further justifications for current efforts to remove trans fat from foods and restaurant meals, said Hu. Trans fat intake in the U.S. is still high. Reducing trans fat intake should remain an important public health priority.

Infusion with reconstituted HDL may have some benefit for atherosclerosis

Mon, 26 Mar 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Preliminary research suggests that use of reconstituted HDL may have some benefit in coronary atherosclerosis, according to a JAMA study published online March 26. The study is being released early to coincide with its presentation at the American College of Cardiology's annual conference.

There is a strong inverse association between high-density lipoprotein (HDL) cholesterol (the good cholesterol) and risk of coronary atherosclerotic disease, according to background information in the article. Preliminary data have suggested that HDL infusions can reverse atherosclerosis (the progressive thickening and hardening of the arterial walls as a result of fat deposits on their inner lining).

Jean-Claude Tardif, M.D., of the Montreal Heart Institute, University of Montreal, and colleagues with the Effect of rHDL on Atherosclerosis-Safety and Efficacy (ERASE) study assessed the effects of infusion with a reconstituted HDL, CSL-111, on coronary atherosclerosis. CSL-111 consists of apolipoprotein A-I from human plasma combined with soybean phosphatidylcholine (a type of lipid molecule; the combination product) that chemically and biologically resembles HDL. Between July 2005 and October 2006, intravascular ultrasound (IVUS) and quantitative coronary angiography were performed on 183 patients to assess coronary atheroma (plaque deposit) at baseline and 2 to 3 weeks after the last study infusion. Sixty patients were randomly assigned to receive four weekly infusions of placebo (saline), 111 to receive 40 mg/kg of reconstituted HDL (CSL-111); and 12 to receive 80 mg/kg of CSL-111. This highest dosage was discontinued early because of indications it caused a certain elevation in liver function tests, suggesting possible harmful liver effects.

This study showed differences in coronary atheroma volume after 4 weekly infusions of CSL-111 or placebo (-3.4 percent vs. -1.6 percent, -5.3 mm³ vs. -2.3 mm³, respectively), but the differences between these groups were not statistically significant. However, CSL-111 may nevertheless potentially induce some favorable vascular effects as seen in the significant reductions of atheroma volume of 3.4 percent or 5.3 mm³ with active infusions in the analysis comparing follow-up to baseline values. Although the latter finding is not significantly different when compared with placebo and is only suggestive of a possible favorable treatment effect, both the plaque characterization indexes on IVUS and coronary score on quantitative coronary angiography revealed statistically significant differences between CSL-111 and placebo groups that support this analysis, the authors write.

Whether these findings will translate into clinical benefits to patients is not known. Elevation of HDL remains a valid target in vascular disease and further clinical evaluation of HDL infusions with CSL-111 with longer follow-up appears warranted, the researchers conclude.

JAMA. 2007;297:(doi:10.1001/jama.297.15.jpc70004). Available pre-embargo to the media at

Single genetic defect causes early heart disease

Thu, 01 Mar 2007 04:59:37 PST

( from http://www.rxpgnews.com ) A team of researchers from the United States and Iran has identified a genetic mutation that causes early onset coronary artery disease in members of a large Iranian family. The genetic mutation leads to heart disease by causing high blood pressure, high blood levels of bad cholesterol and diabetes, all risk factors for heart disease. Coronary artery disease is the leading cause of death worldwide.

Unfortunately, most of the individuals in this family who carried the mutation died in their early fifties from coronary artery disease that resulted in heart attacks and heart failure, said the research team leader, Richard P. Lifton, a Howard Hughes Medical Institute investigator at Yale University School of Medicine. Our studies identify a single mutation that has quite a large effect on many of the metabolic risk factors for coronary artery disease.

Lifton and his colleagues published their research article in the March 2, 2007, issue of the journal Science. Arya Mani, a cardiologist and member of Liftons laboratory at Yale, was first author of the article. The Yale group collaborated on the studies with researchers at Amir Kabir University of Technology, Azad University and The Social Welfare and Rehabilitation Sciences University, all of which are in Tehran, Iran.

The genetic defect is rare, so the discovery by itself will not provide an explanation for the more common forms of coronary artery disease, which are caused by a constellation of factors, said Lifton. However, he said, understanding the molecular nature of this single genetic defect, which is at the root of a familial form of such a complex disease, offers invaluable clues. Researchers may be able to apply that knowledge to improve understanding of what causes the bodys metabolic machinery to malfunction in the more garden variety forms of heart disease.

According to Lifton, physicians in Tehran had long been aware of the familys tragic struggle with early coronary artery disease. In fact, 23 of 28 blood relatives of the first patient identified with this genetic mutation died from coronary artery disease by an average age of 52. The research team obtained medical records and blood samples from all surviving members of the family. The medical records showed that the family members had a characteristic cluster of symptoms called metabolic syndrome. People with this syndrome have hypertension, high blood lipid levels and diabetes, and they are at much higher risk of developing heart disease.

Dr. Mani identified this family as an example of an extreme outlier of a common disease, said Lifton. Studying extreme forms of common disease has been a longtime theme in our laboratory. Liftons strategy is to pinpoint and analyze the rare genetic traits that cause complex disorders. By understanding the causes of those familial forms of complex diseases such as hypertension, Lifton and others have laid the foundation for identifying the mechanisms that underlie more common forms of the disease.

One of the important features of the Iranian family, Lifton noted, was that affected family members exhibited metabolic syndrome and early coronary artery disease, but unaffected family members were normal. So this told us that the coronary disease was traveling with this cluster of metabolic risk factors, he said. Those risk factors were behaving as though they were being transmitted through the family as a single factor.

When the researchers performed a detailed genetic comparison of affected and disease-free family members, they found that a specific segment of chromosome 12 was the most likely genomic hiding place for this unknown factor. In mapping the six genes present on this small chunk of chromosome 12, they found that the gene for LDL receptor-related protein 6 (LRP6) was present in that region of the chromosome.

They immediately focused on LRP6, tipped off in part by an earlier discovery by HHMI investigator Matthew Warman at Childrens Hospital Boston. In 2001, Warman had shown that members of the LRP gene family were important in bone development. What caught our attention was that multiple people in the Iranian family we were studying had coronary artery disease and unexplained hip fractures at young ages. We had not made much of the hip fractures at the outset, but once we knew that LRP6 was in this small genomic interval that contained the coronary-artery-disease-causing gene, we immediately thought of LRP6 as the likely culprit, said Lifton.

By sequencing the LRP6 gene in affected family members, the scientists found that the mutation caused the substitution of a single amino acid in the protein the gene produced. In contrast, the researchers did not find the mutation when they analyzed large comparison populations of Iranians and Americans. However, the researchers statistical analysis of the family members revealed a high correlation between the presence of the mutation, metabolic syndrome, and osteoporosis.In cell culture studies, Dan Wu, a Yale biochemist, found that the mutation compromised how the LRP6 protein functions in the Wnt signaling pathway. Wnt is at the heart of a key metabolic signaling pathway that is important in embryonic development and contributes to an array of normal physiological processes in adults. Lifton emphasized that the compromised Wnt pathway is intriguing and the pathway will likely become an important research target for understanding coronary artery disease.

For example, now that we know that altered Wnt signaling can lead to multiple components of the metabolic syndrome, this raises the question of whether other mutations in the Wnt signaling pathwayor acquired defects that cause alteration of Wnt pathway activitymight commonly contribute to metabolic syndrome and coronary artery disease, he said.

Basic understanding of how the Wnt pathway malfunctions could lead to new treatments for coronary artery disease. Although its a long way off, we might ultimately develop ways to either disrupt or increase the activity of particular components of the pathway, to prevent development of metabolic syndrome and coronary artery disease, he said.

The discovery that the LRP6 mutation also causes osteoporosis raises the possibility of a linkage with coronary artery disease, said Lifton. There is emerging recognition that osteoporosis and coronary artery disease occur together more often than expected by chance, he said. We have now implicated altered activity of the Wnt pathway in development of both coronary artery disease and osteoporosis. So, one can imagine identifying patients with osteoporosis and coronary artery disease as a way of selecting those who might be particularly interesting to investigate for altered Wnt signaling.

Pharmacist-driven outreach lowers metabolic syndrome rates

Wed, 28 Feb 2007 04:59:37 PST

( from http://www.rxpgnews.com ) ORLANDO, Fla., Feb. 28 -- Adults who met with pharmacists or pharmacy students during a community outreach and screening project about metabolic syndrome, returned four months later with lower risk factors for heart disease, researchers reported today at the American Heart Associations 47th Annual Conference on Cardiovascular Disease Epidemiology and Prevention.

Metabolic syndrome is a cluster of cardiovascular disease and diabetes risk factors including excess waist circumference, high blood pressure, elevated triglycerides, low levels of high-density lipoprotein (HDL) and high fasting glucose levels. The presence of three or more of the factors increases a persons risk of developing diabetes and cardiovascular disease.

The purpose of our study was to educate people about the metabolic syndrome, because it is not a term used often in the lay public, said Amy M. Franks, Pharm.D., lead author of the study and assistant professor in the College of Pharmacy at the University of Arkansas for Medical Sciences in Little Rock. Our hope was that if we educated people about their individual risks for metabolic syndrome and suggested ways to reduce those risks, we would make a positive impact on heart disease risk in the community.

A group of pharmacists and pharmacy students held individual educational sessions on the metabolic syndrome with 112 people (average age 45 years) employed by a public school in a town near Little Rock.

We did a clinical screening that measured each one of the five risk factors for metabolic syndrome, then sat with each person to talk about their risk and what they could do to lower their overall risk for heart disease, Franks said. When it was necessary, we referred them to their regular healthcare provider to talk about drug therapy or other things they could implement.

Seventy-three of the participants returned four months later to determine if the pharmacists made an impact in health status.

Initially, the researchers found that about 30 percent of study participants had the metabolic syndrome.

When we went back four months later, only 18 percent of them met the criteria for metabolic syndrome, Franks said.

The participants significantly reduced their total cholesterol during the four months, from an average of 197 milligrams per deciliter (mg/dL) to 189 mg/dL. Average systolic (top number) blood pressure dropped from 123 millimeters of mercury (mmHg) to 117 mmHg and diastolic (bottom number) dropped from 79 mmHg to 72 mmHg.

Researchers didnt find significant changes in the amount of exercise or positive dietary changes reported by participants at the four-month assessment; however, at the follow-up, an additional 7 percent of participants reported initiating drug therapy to combat high blood pressure and 12 percent started taking medication to lower triglycerides, Franks said.

The researchers noted particularly significant changes among those at the highest risk for heart disease. While 50 percent of participants had total cholesterol greater than 200 mg/dL at the start of the study, only 41 percent met that high-risk criterion at the four-month mark.

The more striking numbers were in blood pressure, Franks said. When we looked at systolic blood pressure greater than 140 mmHg, 23 percent of the participants met this high-risk criterion at the start and only 14 percent later. And while 26 percent of the participants had a diastolic reading of higher than 90 mmHg at the studys start, only 7 percent had such high diastolic pressures by four months.

The researchers concluded that healthcare providers, including pharmacists, can help combat the components that make up the metabolic syndrome by educating patients and making lifestyle recommendations, Franks said.

Garlic does not appear to lower cholesterol levels

Mon, 26 Feb 2007 04:59:37 PST

( from http://www.rxpgnews.com ) Three forms of garlicincluding raw garlic and two types of commercial garlic supplementsdid not significantly reduce low-density lipoprotein (LDL or bad) cholesterol during a six-month trial, according to results published in the February 26 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

Garlic supplements, many of which seek to package the benefits of raw garlic in more palatable forms, are promoted as cholesterol-lowering agents and are among the top-selling herbal supplements, the authors write as background information in the article. Crushing garlic triggers the formation of a compound known as allicin, which has been shown to prevent the formation of cholesterol in the laboratory. However, clinical trials on garlic as a cholesterol-lowering agent in humans have been inconsistent.

Christopher D. Gardner, Ph.D., Stanford University Medical School, Calif., and colleagues enrolled 192 adults age 30 to 65 who had moderately high LDL levels (130 to 190 milligrams per deciliter) beginning in November 2002. Forty-nine participants were randomly assigned to receive raw garlic, 47 to take a powdered garlic supplement, 48 to take an aged garlic supplement and 48 to take placebo. The amount of garlic consumed in the three garlic groups was the equivalent of an average-sized garlic clove each day, six days per week. Fasting blood cholesterol levels were assessed monthly, and the chemical composition of the supplements was checked regularly.

A total of 169 adults completed the study, which continued through June 2005. Retention was 87 percent to 90 percent in all four treatment arms, and the chemical stability of study materials was high throughout the trial, the authors write. There were no statistically significant effects of the three forms of garlic on LDL cholesterol concentrations. Levels of other types of cholesterolincluding high-density lipoprotein (HDL or good cholesterol), triglycerides and total cholesterolhigh density lipoprotein cholesterol ratioalso remained the same. No serious adverse events occurred, although bad body and breath odor were reported to occur often or almost always by 28 participants (57 percent) in the raw garlic group.

The results of this trial should not be generalized to other populations or health effects. Garlic might lower LDL in specific subpopulations, such as those with higher LDL concentrations, or may have other beneficial health effects, the authors write. Based on our results and those of other recent trials, physicians can advice patients with moderately elevated LDL cholesterol concentrations that garlic supplements or dietary garlic in reasonable doses are unlikely to produce lipid benefits.

Statin users risk heart attacks by dropping treatment or taking low doses

Wed, 06 Dec 2006 04:59:37 PST

( from http://www.rxpgnews.com ) Thousands of statin users worldwide are suffering preventable heart attacks, simply because they are not complying with their treatment or are taking too low a dose, according to new research published on-line (Thursday 7 December) in European Heart Journal[1].

These life-saving drugs, used to lower cholesterol levels in people at risk of coronary heart disease (CHD), can only be optimally effective if patients use them properly and many are not.

That is the conclusion by the research team, who followed the prescription records of nearly 60,000 patients in the Netherlands for up to 14 years.

Dr Fernie Penning-van Beest and colleagues from the PHARMO Institute[2], the Utrecht Institute of Pharmaceutical Sciences and the Academic Hospital in Amsterdam, analysed 548,084 prescriptions of statin treatment issued over the first two years of treatment[3] in 59,094 new users in the period January 1991-December 2004, and followed the patients until their first hospital admission for heart attack, death, or the end of the study in December 2004.

The aim was to see how effective robust statin treatment was for primary and secondary CHD in the real world' as opposed to in clinical trials. Their results enabled them to calculate the absolute number of avoidable heart attacks that occurred because patients had stopped taking their drugs or were not taking them consistently. They were also able to compare the preventive effects of different doses and types of statins.

Patients were divided into two groups those at high risk of heart attack and those at intermediate or low risk, with over a fifth of patients (12,762) considered high risk.

They found more than half of all patients (31,557) stopped taking statins within two years and only just over a third (20,883) were persistent users on a high or intermediate dose.

Among persistent users, hospital admission for heart attacks fell by nearly a third (30%) compared to non-persistent users, in both primary and secondary prevention groups. In the primary prevention group, admission was down from 0.52 per 100 patient years among non-persistent users to 0.42 per 100 patient years in persistent users. In the secondary prevention group it was down from 0.86 to 0.62.

Among patients using the high or intermediate doses the risk reduction was as high as 40%, while a low dose reduced the risk by only 20%.

The researchers calculated that, every year, around 300 to 400 statin users in the Netherlands have an avoidable heart attack because of sub-optimal doses or discontinuing treatment. They believe the results are likely to be typical of Europe as a whole and of the USA, which means 7,000 to 9,000 Europeans and 5,000 to 7,000 Americans a year are suffering unnecessary heart attacks.

What this clearly tells us, said lead researcher Dr Penning-van Beest, a research associate at the PHARMO Institute, is that our observational study supports robust cholesterol lowering, as recommended on the basis of clinical trials. But, drugs are only really effective if they are used properly and persistently. Unfortunately, statins are not being used optimally, so thousands of people are having unnecessary heart attacks. Getting users to stay on statins and to use them persistently saves lives, and doctors must get over to patients the message that complying with treatment is essential.

Different types of statins are used in different doses, so the researchers dealt with these differences by grading the five statins they assessed for equipotency (the dose of one type of statin needed to achieve the same effect as another type).

They found that as well as the largest reduction in heart attacks needing hospital admission being among patients consistently taking the drugs over the whole two-year period at persistently high or intermediate equipotent doses, these patients were also relatively more likely to be using second generation statins i.e. atorvastatin or rosuvastatin, rather than the first generation types, pravastatin, fulvastatin or simvastatin. Higher doses of first generation statins were being prescribed, but increasing the dose of these older statins is limited by the maximum safe dose.

Co-author Dr Ron Herings, scientific director of the PHARMO Institute and associate professor of pharmacoepidemiology at Utrecht University, said: It is preferable to achieve a high equipotent dose by using the new, highly potent statins. But, the new statins have considerable economic impact on pharmaceutical budgets and the opposite trend is being encouraged in the Netherlands and Germany, where reimbursement measures promote the use of relatively inexpensive generic older types.

He said: This is fine, as long as guidelines for higher doses of these older statins are implemented, and bearing in mind that there may be limitations to giving the highest doses. But, restricting the use of older generic statins to standard low doses will make the problems worse.

Ideally, to improve the population effectiveness of statin treatment, persistent drug use and the use of new, potent statins, should be encouraged. he concluded.

ILLUMINATE study: Pfizer Stops All Torcetrapib Clinical Trials

Sun, 03 Dec 2006 17:48:03 PST

( from http://www.rxpgnews.com ) FDA was notified that Pfizer will suspend a large, Phase 3 trial evaluating the investigational cardiovascular therapy torceptrapib/atorvastatin (T/A) due to an increased rate of mortality (death) in patients receiving the combination compared to those receiving atorvastatin alone. With the T/A development program, as it does with all such development programs, FDA assured that Pfizer had the appropriate protections in place for patients participating in the drug’s development, including informed consent, a Data Safety Monitoring Board (DSMB) for its outcome study, and that the development program was done in a careful, stepwise manner.

For this trial, the DSMB was conducting a monthly analysis of mortality data and a quarterly analysis of a number of outcomes including stroke, heart attack, and revascularizations (e.g., coronary stents or bypass surgery) to ensure the ongoing safety of patients in this trial. This independent board notified Pfizer of the mortality finding early the morning of December 2, 2006 and FDA was notified at 4:00 PM EST that evening that Pfizer planned to halt this trial and the development program overall.

FDA fully supports Pfizer's decision to suspend this trial. The system of biomedical research monitoring was effective in this case, assuring that once a certain signal was seen, the trial was halted. FDA will continue to work with Pfizer and other sponsors developing molecules in this class of drugs to ensure that appropriate protections are in place to identify any safety signals as early in the development process as possible.

Clinical trials are an integral part of the process for developing new medical innovations and the healthcare system is dependent upon this research, and the patients willing to participate, to advance therapies. Clinical trials often tell us unexpected things, both positive and negative, about new medical products, which is why carefully designed and conducted trials are an essential part of the pre-market process for demonstrating that new drugs are safe and effective before they can be approved for marketing.

Weight cycling associated with increased risk for gallstones among men

Mon, 27 Nov 2006 04:59:37 PST

( from http://www.rxpgnews.com ) Intentionally losing weight and then regaining it may increase mens risk for gallstones later in life, according to a report in the November 27 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

Gallstone diseasewhich occurs when a solid mass of cholesterol, bile and calcium salts forms in the gall bladderis common among adults in Western countries, according to background information in the article. Obesity is a risk factor for gallstone disease, as is rapid weight loss for the treatment of severe obesity. Although approximately 30 percent of adult U.S. men are trying to lose weight, intentional weight loss is rarely sustained and is often associated with unintentional weight regain, leading to weight cycling, the authors write. The long-term health consequences of repeated intentional weight loss and the mechanisms of weight recovery are still not well understood. Studies have suggested that large weight fluctuations at some point earlier in life represent an independent risk factor for chronic diseases, including metabolic syndrome.

To assess whether weight cycling influenced the risk of developing gallstones, Chung-Jyi Tsai, M.D., Sc.D., University of Kentucky Medical Center, Lexington, and colleagues analyzed data from 24,729 men who were part of the Health Professionals Follow-up Study. The men provided information about any weight fluctuations between 1988 and 1992. They were then sent a questionnaire every two years from 1992 to 2002 to monitor whether they had developed gallstone disease.

A total of 7,443 men reported that they were weight maintainersin other words, that they had remained within five pounds of their initial weight between 1988 and 1992. Of those who were weight cyclers, 10,027 were light cyclers (who had a maximum weight loss per attempt of between 5 and 9 pounds); 5,185 were moderate cyclers (weight loss between 10 and 19 pounds); and 2,074 were severe cyclers (weight loss of 20 pounds or more).

Overall, 1,222 cases of symptomatic gallstones developed between 1992 and 2002. Gallstones were more likely in each of the weight cycling groups than in the weight maintaining group. Those who were light cyclers had a 21 percent increased risk, moderate cyclers had a 38 percent increased risk and severe cyclers increased their risk by 76 percent, compared with weight maintainers. Risk for gallstones also increased when the number of weight cycles increased, with severe cyclers who had more than one weight cycle experiencing nearly double the risk of weight maintainers. The associations remained when researchers considered each participants body mass index (BMI), further suggesting that it is the weight cycling, rather than being overweight or obese alone, that increases risk.

The potential mechanisms contributing to the association between weight cycling and gallstone formation observed in our study are likely to be multiple, the authors write. When an individual loses and then regains weight, much of that additional weight is made up of body fat. Studies have shown that large swings of body weight, especially the phase of weight recovery, are particularly sensitive to the accumulation of body fat and to the development of metabolic abnormalities, including insulin resistance, and thereby may facilitate gallstone formation, they write. In addition, levels of the compounds leptin and insulin in the blood have been shown to be higher in weight cyclers than weight maintainers, which could also contribute to gallstone risk.

A little TLC goes a long way toward reducing high cholesterol

Thu, 24 Aug 2006 03:59:37 PST

( from http://www.rxpgnews.com ) If you're one of the nearly 65 million Americans with high blood cholesterol, National Cholesterol Education Month (September) is a perfect time to read a new publication designed to help you make the lifestyle changes needed to reduce cholesterol and, with it, your risk for heart disease.

Your Guide to Lowering Your Cholesterol with TLC (Therapeutic Lifestyle Changes) from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health details a three-part program of diet, physical activity, and weight management designed to bring cholesterol levels down.

Lifestyle is crucial for lowering cholesterol but it's not enough to tell people it's important you have to help them do it. This guide offers a set of tools to help people get started and to embrace a heart-healthier way of living, said the NHLBI's James Cleeman, M.D., coordinator of the National Cholesterol Education Program (NCEP).

The 80-page easy-to-read booklet is based on the NCEP's guidelines on cholesterol management. These guidelines emphasize the importance of therapeutic lifestyle changes (TLC) -- intensive use of heart-healthy eating, physical activity, and weight control for cholesterol management. TLC is the cornerstone of treatment, according to Cleeman, even if someone also has to take a cholesterol-lowering medication.

As the booklet explains, following a TLC diet means reducing saturated fat, trans fat, and cholesterol in order to lower LDL, the bad cholesterol. How do you know how low your LDL cholesterol should be? Your goal LDL level is determined by your risk for developing heart disease or having a heart attack. To help you determine your risk, the new guide includes the NCEP 10-year coronary heart disease risk calculator. Once your LDL goal is determined, you and your doctor can use the new booklet to implement TLC and reach your goal.

To help reduce saturated fat, trans fat, and dietary cholesterol, the guide offers tips on choosing and preparing low fat meals, selecting healthy snacks, reading nutrition labels, and dining out while staying on the TLC diet. The booklet includes sample menus for different types of cuisine (traditional American, Southern, Mexican-American, and Asian).

The LDL-lowering power of the TLC diet can be boosted by adding soluble fiber and plant stanols and sterols, substances derived from plants that help block cholesterol absorption. The guide suggests ways to add fiber to the diet and discusses the value of plant stanols and sterols and which food products have them.

In addition to what you eat, how much you move is also important for heart health. Lack of physical activity is an important risk factor for heart disease. Inactivity contributes to weight gain and raises LDL as well as lowering HDL, the good cholesterol. The booklet offers a step-by-step program to get people moving and includes a chart of calories burned in common activities.

Overweight and obesity increase a person's LDL level and can also raise triglycerides and lower HDL. To help people lose those extra pounds, the guide includes calorie-cutting strategies, ideas for substituting lower calorie foods for high calorie favorites, and a handy chart of portion sizes based on NHLBI's Portion Distortion Interactive Quiz:

Aggressive reduction in cholesterol levels can reduce risk for stroke by 16 percent

Wed, 09 Aug 2006 03:59:37 PST

( from http://www.rxpgnews.com ) NORTH CHICAGO, ILL. (August 10, 2006) According to data from the National Stroke Association, up to 40 percent of patients who have had a stroke will experience a second stroke within five years of the first. An international team of researchers recently completed a study to determine if the cholesterol-lowering drug Lipitor® (atorvastatin calcium) would reduce the occurrence of a second stroke. The Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) team of investigators, led by Dr. K. Michael Welch, neurologist and President and CEO of Rosalind Franklin University of Medicine and Science, published their research in today's issue of the New England Journal of Medicine.

The SPARCL study included 4,731 patients with no history of heart disease who had experienced a stroke or TIA (mini stroke) within six months of study enrollment. The patients had mildly elevated cholesterol levels, and received either 80 mg of Lipitor® or a placebo; they were then monitored for an average of five years.

Study findings indicate that patients taking Lipitor® experienced a 16-percent reduction in the risk of secondary stroke compared with patients taking a placebo. Lipitor patients also saw a 35-percent reduction in the risk of major coronary events (cardiac death, non-fatal heart attacks, or resuscitated cardiac arrest) compared to the patients taking placebo. These cardiovascular results are remarkable in a population not known to have had heart disease, said principal investigator, Dr. K. Michael Welch.

The SPARCL study researchers conclude that their results support the initiation of statin (i.e., Lipitor®) treatment shortly after a stroke or TIA. We believe that the findings indicate that Lipitor 80 should become an established part of secondary stroke prevention, said Dr. Welch.

An analysis of the SPARCL data was designed and conducted after the study ended to explore the types of strokes -- ischemic or hemorrhagic -- that occurred among patients in the study. Eighty-five percent of the strokes in this trial were ischemic. Patients taking Lipitor® experienced a 22-percent reduction in the risk of ischemic stroke.

Also, the number of patients in the analysis who experienced hemorrhagic stroke was very small. There were more patients in the Lipitor® group who experienced this type of stroke (2.3 percent), compared to patients taking placebo (1.4 percent). However, the overall benefit in terms of reducing the risk of stroke was still significant despite this increase, and there was no difference in the number of deaths from hemorrhagic stroke between the two treatment groups.

Every year, an estimated 15 million people worldwide suffer strokes, and 10 million will either remain disabled or die. Strokes also exact a heavy economic toll, with the lifetime cost of treating one patient with a stroke averaging more than $3 million. Reducing the risk of stroke through the application of new data, such as those revealed by the SPARCL investigation, is a key priority in cardiovascular medicine.

The 16-percent reduction in secondary stroke risk that was achieved through aggressively reducing cholesterol levels of study patients is indeed significant. These data are important information for physicians because patients who have had a stroke are at much greater risk for suffering another one, yet treatment options to reduce their risk are limited, commented Dr. Welch.

SPARCL is an investigator-led trial coordinated by an independent steering committee and funded by Pfizer, Inc. For more information, contact Dr. K. Michael Welch, principal investigator, at

Study indicates widely-used nutritional supplement does not improve cholesterol levels

Tue, 16 May 2006 03:59:37 PST

( from http://www.rxpgnews.com ) Policosanol is a natural substance produced from the waxy coating of sugar cane. Cuban sugar cane policosanol is sold in more than 40 countries mainly because of its supposed lipid-lowering effects, according to background information in the article. Numerous policosanol products from a variety of sources (sugar cane, wheat germ, rice bran, beeswax) are available over-the-counter and on the Internet in several countries. Advertising emphasizes predominantly its reputed lipid-lowering effects, comparable with statins (prescription medications taken to lower cholesterol). Most of the published scientific literature, more than 80 trials, supporting the beneficial effects of policosanol on lipids has been authored by a single research group from Cuba. One clinical trial from the Netherlands showed wheat germderived policosanol ineffective in lowering total cholesterol and low-density lipoprotein cholesterol (LDL-C), sometimes called bad cholesterol.

Heiner K. Berthold, M.D., Ph.D., of the University of Cologne, Germany, and colleagues conducted a study to determine the lipid-lowering effects of policosanol. The multicenter, randomized, double-blind, placebo-controlled, trial included 143 patients with hypercholesterolemia (high cholesterol) or combined hyperlipidemia (excess of fats or lipids in the blood) having baseline LDL-C levels of at least 150 mg/dL and either no or 1 cardiovascular risk factor other than known coronary heart disease, or baseline LDL-C levels of between 150 and 189 mg/dL and 2 or more risk factors. The patients were randomized into 5 groups: 10, 20, 40, or 80 mg/d of policosanol or placebo. The study was conducted from September 2000 to May 2001.

In none of the 5 treatment groups did LDL-C levels decrease more than 10 percent from baseline. No statistically significant difference between policosanol and placebo was observed. In none of the secondary outcome measures, namely total cholesterol, high-density lipoprotein cholesterol (HDL-C; known as good cholesterol), very low-density lipoprotein cholesterol, triglycerides, lipoprotein(a) (a family of lipoprotein particles varying in density and size), and ratio of total or LDL-C to HDL-C, were there any significant effects of policosanol. Policosanol was tolerated well and no severe adverse events occurred.

Our results suggest that [policosanol] is devoid of clinically relevant lipoprotein-lowering properties in white patients. Still, more independent studies are required to counterbalance the vast body of available positive trials. Although policosanol has been used for more than a decade in clinical trials, there are still no data on patient-related outcomes, such as cardiovascular morbidity and mortality. Moreover, independent information should be given to consumers who might take policosanol to improve their cardiovascular risk profile, the authors conclude.

Markers of PCOS inherited, persist and raise risk for heart disease, diabetes

Mon, 17 Apr 2006 03:59:37 PST

( from http://www.rxpgnews.com ) That finding is reported in a new study published April 17 in the early online edition of the Proceedings of the National Academy of Sciences (

There have been few studies looking at the long-term consequences of PCOS. Results of our study strongly suggest that metabolic problems will continue as women with PCOS age, said senior author Andrea E. Dunaif, M.D., Charles F. Kettering Professor of Endocrinology at Northwestern University Feinberg School of Medicine.

Dunaif is also professor of medicine and chief of endocrinology, metabolism and molecular medicine at Feinberg and president of The Endocrine Society.

PCOS is a common problem affecting about 7 percent young adult women. Women with this disorder have irregular menstrual cycles and elevated levels of male hormones, or androgens, which may result in excessive facial hair growth and acne.

PCOS is frequently also associated with insulin resistance, and the syndrome is a leading cause of type 2 diabetes in adolescent and young adult women. Another negative health feature of PCOS is abnormal lipid levels, but the reasons are controversial. Insulin resistance, type 2 diabetes, increased low-density lipoprotein (LDL) levels and metabolic syndrome all increase risk for heart disease.

Studies of women with PCOS, by definition, have been limited to women in their reproductive years; therefore, little is known about their health as they age. The long-term health consequences of PCOS are of considerable importance because many of these women have risk factors that confer substantially increased risk for developing cardiovascular disease and other problems.

It is well documented that PCOS runs in families. Though limited, past studies of mothers of women with PCOS have shown increased androgen levels, insulin resistance, and glucose intolerance, suggesting that these traits are inherited.

Dunaif and colleagues Susan Sam, M.D., of Feinberg, and Richard S. Legro, M.D., of Pennsylvania State University College of Medicine, Hershey, tested their hypothesis that abnormal lipid levels are inherited in families of women with PCOS, and assessed the impact of age on reproductive and metabolic characteristics.

The researchers studied 215 non-Hispanic white mothers of women with PCOS and a control group of 62 women of comparable age, weight and ethnicity, drawn from the National Health and Nutrition Examination Survey III (NHANES III).

The study group was limited to non-Hispanic white women because of the potential confounding effects of ethnicity on insulin sensitivity and lipid levels. All participants were asked to complete a questionnaire on their reproductive history, exercise habits, tobacco use, and alcohol intake.

In investigating lipid levels, the researchers found that mothers of women with PCOS had elevated total and LDL cholesterol, but triglycerides and high-density lipoprotein (HDL) cholesterol levels did not differ between the groups. The mothers had markers of insulin resistance. They also had an increased prevalence of the metabolic syndrome, compared with nationwide prevalence in normal women of similar age.

The strongest predictor of LDL levels in mothers was their daughters' LDL levels. The researchers had previously found that elevated LDL levels are the predominant lipid abnormality in women with PCOS, a finding that was mirrored in the mothers' group.

Over 30 percent of mothers reported a history of irregular menstrual periods. There were no differences in age or body mass index between these mothers and those with a history of regular menses. Mothers with menstrual problems also had higher levels of androgens, glucose and LDL compared with mothers with a history of regular menses, suggesting that these mothers may have had PCOS.

Total testosterone and unbound testosterone levels were higher in mothers with a history of irregular menses than in controls. Prevalence of elevated androgen levels was likely underestimated in this study because of a general decline in ovarian function with age, which leads to lower circulating androgen levels.

Menstrual history is an accurate marker for PCOS in both epidemiologic and genetic studies, Legro said.

Almost 50 percent of mothers had metabolic syndrome compared with 32 percent of the control group. There was a significant increase in the prevalence of metabolic syndrome in obese mothers compared with the general population represented by the women in NHANES III.

Moreover, the researchers believe that the prevalence of metabolic syndrome in mothers is underestimated because mothers receiving medications for hypertension, diabetes or elevated lipid levels were excluded. Overall, these findings suggest that mothers of women with PCOS should be screened for cardiovascular disease risk factors.

New research finds direct link between high cholesterol and prostate cancer

Tue, 11 Apr 2006 03:59:37 PST

( from http://www.rxpgnews.com ) A possible association has been suggested before but evidence has been limited. This new study, published on-line (Wednesday 12 April) in Annals of Oncology[1] shows a statistically significant direct relationship between the two conditions.

Lead author Dr Francesca Bravi, an epidemiologist from the Istituto di Ricerche Farmacologiche Mario Negri in Milan, said: Although the study relied on participants' self-reported medical conditions, the absence of an association between prostate cancer and about 10 other medical conditions we investigated indicates that the relationship we found between prostate cancer and high cholesterol appears to be a real one.

The research team worked on data from a case-control study carried out in four Italian areas between 1991 and 2002, involving 1,294 men under age 75 with prostate cancer and 1,451 matched controls admitted to the same hospitals with acute non-cancerous conditions.

All cases and controls were interviewed in hospital by trained interviewers using wide-ranging structured questionnaires. These included a problem-oriented section on patients' medical history covering about 10 non-cancerous conditions, including hypercholesterolaemia (high cholesterol) and gallstones.

Dr Bravi said: We found that, after allowing for any potential confounding factors, men with prostate cancer were around 50% more likely to have had high cholesterol levels[2] than our non-prostate cancer controls. The association was somewhat stronger for men whose high cholesterol levels had been diagnosed before they were 50 and for men over 65, where there was an 80% greater likelihood of high cholesterol levels. We also found that prostate cancer patients were 26% more likely to have suffered from gallstones than our controls, with an apparently higher relationship in thinner men. Although that figure was not statistically significant, gallstones are often related to high cholesterol levels. To our knowledge there have been no previous studies reporting any relationship between gallstones and prostate cancer.

Co-author Dr Cristina Bosetti, a senior epidemiologist and biostatistician at the same institute, explained: Androgens hormones that have a role in prostate tissue and cancer are synthesised from cholesterol, suggesting a possible biological relationship between high cholesterol and prostate cancer. Gallstones are related to high cholesterol levels as well and are often composed of cholesterol. So, the direct relationship we found between gallstones and prostate cancer, while it was not statistically significant, suggests a similar biological mechanism may explain the link.

This study had relied on participant's self-reporting medical conditions: the researchers believe that their results should be confirmed by further studies, including prospective investigations with reliable measured cholesterol levels.

Dr Bosetti concluded: There are some laboratory data suggesting statins may have preventive potential against prostate cancer and our results do give an indirect suggestion that statins may help in lowering prostate cancer risk. However, studies to date on cholesterol-lowering statins and prostate cancer have been limited and inconclusive.

Einstein researchers identify genetic variants that lend clues to living longer

Mon, 03 Apr 2006 03:59:37 PST

( from http://www.rxpgnews.com ) The researchers looked for genetic clues to longevity in a group of 214 Ashkenazi Jews who have passed or nearly reached 100 years of age. In the April 4 issue of PLoS Biology, they report that a specific genetic profile, or genotype, was associated with longevity as well as cardiovascular health, lower incidence of hypertension and healthy insulin metabolism.

Since centenarians typically escape cardiovascular disease, diabetes, and other age-related disorders, we suspected these most senior of senior citizens might possess gene variations that help them reach a ripe old age, said Dr. Nir Barzilai, director of the Institute for Aging Research at Einstein and senior author on the paper. If so, then these genotypes should occur with higher frequency in centenarians than in the rest of us.

Dr. Barzilai and his colleagues recruited Ashkenazi Jews for the study, because this population--descended from a founder group of just 30,000 or so people--is more genetically uniform than other groups, simplifying the challenge of associating a genotype with its physical manifestation (phenotype).

When studying centenarians, finding an age-matched control group is obviously difficult. But since longevity runs in families, the researchers were able to get around this problem by recruiting children of the centenarians and matching them against a control group consisting of other Ashkenazi Jews the same age.

Each participant had blood drawn--to determine their genotype and to measure levels of several cardiovascular disease markers including insulin, cholesterol, triglycerides, high-density lipoproteins (HDL, the good cholesterol), low-density lipoproteins (LDL, the bad cholesterol), and concentrations of two lipoprotein components called apolipoproteins (APO). In a previous study, the researchers had found that centenarians' LDL and HDL particle sizes are larger than normal, so these were also measured.

To identify genes associated with long life, they looked for single nucleotide polymorphisms (SNPs) in 36 genes involved in lipoprotein metabolism and other pathways linked to cardiovascular disease. (DNA contains four possible nucleotides--adenine, thymine, guanine and cytosine--and SNPs are variations of a single nucleotide in the DNA sequence.)

This analysis revealed a SNP in a gene with a clear pattern of age-dependent frequency: apolipoprotein C3 (APOC3). This polymorphism substitutes cytosine for adenine in the gene's promoter region, where gene transcription is initiated. The frequency of finding the APOC3 polymorphism in both copies of the gene was 25% among centenarians, 20% in their offspring, and only 10% in controls.

APOC3 codes for a protein that is a major component of very low density lipoproteins (VLDL, another type of bad cholesterol) and also occurs in HDL. The researchers expected that people carrying the APOC3 SNP would have a favorable lipoprotein profile. And indeed, all participants carrying the APOC3 polymorphism had better triglyceride and cholesterol levels, as well as the beneficial larger LDL and HDL particle sizes. In addition, they had a much lower prevalence of hypertension.

Altogether, the statistical links between APOC3 and longevity and the significant associations between favorable lipoprotein-related traits and longevity strongly suggest that the genotype contributes in several ways to cardiovascular health and longevity.

While the genetic pathways driving longevity remain unknown, it seems clear that lipoprotein metabolism plays an important role. The favorable lipoprotein profiles reported by the Einstein researchers correlate with studies of Japanese and Italian centenarians as well. The Einstein researchers hope to uncover more clues regarding the genetic influences on aging--and begin to develop strategies to ease the inevitable slide into our twilight years.

New Torcetrapib/Atorvastatin Research Further Supports Raising "Good" HDL Cholesterol

Wed, 15 Mar 2006 17:58:22 PST

( from http://www.rxpgnews.com ) Pfizer said today that new data, involving its medicine in development torcetrapib/atorvastatin, provides important information on the benefit of raising HDL, or "good" cholesterol, while simultaneously lowering LDL, or "bad" cholesterol. These new findings may play a critical role in reducing the burden of cardiovascular disease and potentially improving quality of life for patients. Data from three separate studies were presented this week at the American College of Cardiology meeting.

"As the first potential treatment to offer substantial HDL cholesterol elevations and significant LDL cholesterol lowering, torcetrapib/atorvastatin could well change how physicians manage their patients with cardiovascular disease," said Dr. John LaMattina, president of Pfizer Global Research and Development. "This comprehensive clinical trial program will help determine if this hypothesis can offer patients the benefit of slowing atherosclerosis and ultimately preventing cardiovascular events beyond what can be achieved with Lipitor alone."

It is estimated that 71 million Americans suffer from cardiovascular disease, a leading cause of death in the United States. Most people with elevated cholesterol, a leading risk factor for heart attacks and strokes, are either not diagnosed or have not reached their target LDL levels with medication. In addition, research has shown that raising HDL-cholesterol may provide further benefits in the management of cardiovascular disease, which may have the potential to further reduce cardiovascular risk for patients.

Discovered and developed by Pfizer, torcetrapib works by blocking CETP (cholesterol ester transfer protein) which is a protein that regulates cholesterol and is responsible for transferring cholesterol from its "good" HDL carrier to LDL, the "bad" carrier of cholesterol that results in plaque buildup in the arteries. Scientists believe that CETP inhibition raises HDL levels which results in cholesterol removal from the artery walls. Torcetrapib also lowers LDL cholesterol and LDL is known to cause heart attacks and stroke.

Presentation 1—HDL and LDL as Predictors for CV Disease/Sub- Analysis of Lipitor TNT Study

The primary objective of the Treating to New Targets (TNT) study was to demonstrate the clinical benefits of intensive LDL cholesterol lowering. This sub-analysis of TNT found that patients treated to LDL cholesterol levels that were below current medical guidelines showed a direct relationship between HDL cholesterol levels and the frequency of cardiovascular events—1 mg/dL increase in HDL cholesterol levels was estimated to have an associated 2 percent reduction in the risk of a heart attack or stroke.

"This study further supports the potential benefits of managing HDL levels as an additional target for patients who are already receiving statin therapy," said Dr. Philip Barter, lead author, TNT sub-analysis, The Heart Institute in Sydney, Australia. "While lowering LDL cholesterol remains a critical focus in cardiovascular disease prevention, the TNT sub-analysis suggests that HDL cholesterol may also provide important therapeutic benefits that may result in further reductions in cardiovascular risk."

Presentation 2—Torcetrapib/Atorvastatin: AM vs PM: Examining the Optimal Time of Dosing

Patients received either torcetrapib (100 mg) alone or torcetrapib (60 mg) and atorvastatin (20 mg) together, taken in the mornings or evenings, to determine if greater increases in HDL would be achieved based on the time of dosing. Torcetrapib, a CETP inhibitor is believed to be most effective when taken in the morning. Unlike most statins—which are taken in the evening for maximum reduction in LDL cholesterol—atorvastatin can be dosed anytime of the day and obtain equal LDL lowering effects.

Patients who took torcetrapib (60 mg) and atorvastatin (20 mg) in the morning experienced the most significant increase of 54.4 percent in HDL-cholesterol which was 12 percent higher than patients who took both torcetrapib and atorvastatin in the evening. Additionally, patients achieved a reduction in LDL cholesterol levels regardless of the time of day that therapy was taken.

"This is the first data to show that there are important differences in raising HDL cholesterol levels with torcetrapib depending on whether it is dosed in the morning or evening, and also highlights the flexibility and efficacy of atorvastatin," said Dr. Megan Gibbs, associate director of clinical research of Pfizer Global Research and Development.

Presentation 3—Torcetrapib/Atorvastatin: Exploring Benefits of Lipid-Modifying Effects

Pfizer researchers also presented data from another study involving 493 patients to determine the effectiveness of torcetrapib (30, 60, 90 mg) either alone or in combination with atorvastatin (10, 20, 40, 80 mg).

In particular, the study addressed the HDL and LDL particle size and number using new technology—nuclear magnetic resonance (NMR). Leading researchers believe both larger HDL and LDL particles, and lower numbers of LDL particles are less likely to contribute to the development of atherosclerosis, or plaque build-up in the arteries, which is important in cardiovascular health. In this study, patients taking torcetrapib and atorvastatin together experienced a decrease in LDL cholesterol, and an increase in HDL cholesterol levels, as well as increases in the particle size of both HDL and LDL.

"These data provide important information on how CETP inhibition with torcetrapib affects the number and nature of lipid particles," said Dr. Tom Thuren, director of clinical development, Pfizer Global Research and Development. "While the impact of these changes on cardiovascular risk is not currently known, we are diligently examining this and other areas in a large-scale clinical trial program."

In this study, side effects of torcetrapib and Lipitor were similar to those most commonly associated with statin therapy. Patients taking 60 mg of torcetrapib with Lipitor also experienced an increase in systolic blood pressure of approximately 2 mm Hg, which will be further defined in ongoing phase 3 studies.

Pfizer's torcetrapib/atorvastatin development program is the largest and most comprehensive clinical trial program the company has ever undertaken and is studying some 25,000 patients at hundreds of medical centers worldwide at a cost of about $800 million.

Medication reduces risk of adverse events for patients with acute coronary syndromes undergoing PCI

Mon, 13 Mar 2006 04:59:37 PST

( from http://www.rxpgnews.com ) NonST-segment elevation (a certain pattern on an electrocardiogram) acute coronary syndromes (ACS - a spectrum of conditions involving chest discomfort or other symptoms) are associated with an increased risk of death and are a major reason for hospital admissions. Although percutaneous coronary interventions (PCIs - procedures such as angioplasty or stent placement used to open narrowed coronary arteries) are an established therapeutic approach in high-risk patients presenting with ACS, it is still unclear what the best adjunctive antithrombotic therapies are, according to background information in the article. There is increasing evidence that treatment with clopidogrel prior to PCI prevents postprocedural ischemic complications. It is not known whether the antiplatelet effect provided by 600 mg of clopidogrel eliminates the need for more potent antiplatelet therapies in patients with ACS undergoing PCI.

Adnan Kastrati, M.D., of the Deutsches Herzzentrum, Munich, Germany and colleagues with the ISAR-REACT 2 Trial assessed whether abciximab is a useful therapy in patients with nonST-segment elevation ACS undergoing PCI, even after pretreatment with a 600-mg loading dose of clopidogrel. The randomized, double-blind, placebo-controlled trial included 2,022 patients and was conducted from March 2003 through December 2005. The patients, with nonST-segment elevation ACS undergoing PCI, were assigned to receive either abciximab or placebo. All patients received clopidogrel, 600 mg, at least 2 hours prior to the procedure, as well as 500 mg of oral or intravenous aspirin.

The primary end point of death, heart attack, or urgent target vessel revascularization occurring within 30 days after randomization was reached in 90 patients (8.9 percent) assigned to abciximab vs. 120 (11.9 percent) assigned to placebo. Thus, there was a significant 25 percent relative reduction of the risk with abciximab. Most of the risk reduction caused by abciximab resulted from a reduction in the occurrence of death and heart attack.

There was no difference in the incidence of ischemic events between the abciximab group and the placebo group among patients without an elevated troponin (muscle protein that is elevated in patients with cardiac ischemia) level. However, among patients with an elevated troponin level, the incidence of ischemic events was significantly lower (29 percent reduced risk) in the abciximab group (13.1 percent) compared with the placebo group (18.3 percent). There were no significant differences between the 2 groups regarding the risk of major and minor bleeding as well as need for transfusion.

The benefits of abciximab appear to be confined to patients with an elevated troponin level, the authors conclude.

Use of statins can improve erectile performance in some

Wed, 22 Feb 2006 01:09:37 PST

( from http://www.rxpgnews.com ) Researchers at the University of Pennsylvania School of Medicine say preliminary results of a small study show promise in improving erectile dysfunction (ED) in men who had shown minimal reaction to Viagra. The study results are published in the March issue of the "Journal of Sexual Medicine."

Erectile dysfunction is often a sign of a more severe vascular problem that involves abnormalities in the lining of the blood vessels. And often, endothelial dysfunction is an underlying problem for ED - it can be one of the first signs of atherosclerosis, a build-up of plaque and blockages in the arteries.

"It's already known that there is a connection between erectile dysfunction and coronary disease. The risk factors are the same for both, and thus, ED can be a marker for coronary disease," explains lead author Howard Herrmann, MD, Professor of Medicine and Director of the Interventional Cardiology and Cardiac Catheterization Laboratories at the Hospital of the University of Pennsylvania. "Normal erections are caused when nitric oxide is made, but with endothelial dysfunction, the body doesn't make enough of it, causing the erectile dysfunction. Normally, Viagra prevents the breakdown of the little nitric oxide that is there, so that there is enough of it for an erection to occur."

However, about 10-30 % of men are classified as "Viagra non-responders" - in these men, Viagra did not significantly help their erectile dysfunction. So in a small, double blind, randomized, placebo-controlled study at Penn, Herrmann looked at a dozen patients with ED who had not responded well to Viagra. He gave them either a high-dose Lipitor or a placebo. He then rechallenged them with Viagra and asked if the ED had improved.

"There did seem to be some improvement for those who received Lipitor versus the placebo," said Herrmann. "We theorized that if you could make the edothelium healthier through the use of statins -- so that there is more nitric oxide available -- you would improve the endothelial dysfunction and Viagra would work better for the patient."

And there are other potential benefits too. Stan Schwartz, MD, Director of the Diabetes Disease Management program at Penn and co-author, states, "Patients with Diabetes, both Type 1 and Type 2, are plagued with complications of the diabetic state that involve endothelial dysfunction. This research points us in a direction that says any drug class that improves endothelial dysfunction may also be beneficial to patients with diabetes."

Additionally, Emile Mohler, MD, Director of Vascular Medicine at Penn and co-author, cautions, "ED is a sign that cholesterol plaque may be present in the heart, neck or leg arteries. Men with ED should be evaluated for vascular disease."

"These preliminary results show promise," adds Herrmann. "They support the hypothesis that erectile dysfunction may be one sign of a generalized vascular disorder characterized by endothelial dysfunction and that statin drugs may improve the endothelial dysfunction, even before altering the lipid profile. But the results are preliminary and warrant further testing in a larger clinical trial," he cautions.

It should be noted that beyond endothelial dysfunction, there are other reasons Viagra may not work well for someone.

Gap widens between optimal versus actual cholesterol levels

Fri, 03 Feb 2006 04:59:37 PST

( from http://www.rxpgnews.com ) Of that group, 38 million are people with health conditions that put them at increased risk for cardiovascular disease.

These findings, by Stephen D. Persell and co-researchers at Northwestern University Feinberg School of Medicine, are reported in the February issue of the Journal of General Internal Medicine. Persell, who led the study, is assistant professor of medicine at the Feinberg School.

The study, which compared 2001 NIH cholesterol level targets with revised, more stringent, optimal targets issued in 2004, found that 10 million more adults had LDL-C (bad cholesterol) levels above the new targets.

The new guidelines recommend that physicians strive to get patients' LDL-C levels lower, particularly for those at moderately high and high risk for heart disease.

Nationally, we are far from achieving the 2001 goals, and as new evidence leads the NIH to push optional goals down further, the gap between what we believe to be ideal goals and what has been achieved gets even wider, Persell said.

Too much LDL-C can build up on the inner lining of arteries that feed the brain and heart, and in conjunction with other substances form plaques (deposits) that can clog vessels and cause a stroke or heart attack.

In combination with cardiovascular disease risk factors, such as high blood pressure, diabetes, tobacco smoking and/or family history of heart disease, high levels of LDL-C put individuals at increased risk for heart disease.

The goal for high-risk (heart disease or diabetes) patients is an LDL-C level was less than 100. However, a level of 70, rather than 100, is suggested in updated recommendations for those who are at very high risk for cardiovascular disease.

The new optional goal for those at moderately high risk is 100, compared to the 2001 goal of 130.

The study notes that despite the fact that nearly all persons in the high-risk group have LDL-C levels that are too high, 25 percent of them already use cholesterol-lowering medications, such as statins.

The study shows that many more people would need drug therapy to reach the recommended LDL-C levels, but it notes that a substantial number are unlikely to achieve these goals with standard-dose statins.

Current costs may also place those drugs out of reach for many patients. At current retail prices, a year's supply of 40 milligrams daily of generic lovastatin can cost $450 to $700.Costs per patient would be even higher if name-brand statins or high-dose statins and combination drug therapy are used.

The updated guidelines, published in July 2004, were based on a review of five major clinical studies of statin therapy conducted after the 2001 guidelines were released.

Persell's co-investigators on this study were Donald M. Lloyd-Jones, M.D., assistant professor of preventive medicine and of medicine; and David W. Baker, M.D., associate professor of medicine and chief of general internal medicine at the Feinberg School.

Key heart and Alzheimer's disease protein imaged for first time in native state

Thu, 12 Jan 2006 04:59:37 PST

( from http://www.rxpgnews.com ) Using the technique known as x-ray crystallography, scientists at the Gladstone Institute of Cardiovascular Disease (GICD) have created the highest-resolution x-ray structure of a lipoprotein particle to date.

The work focuses apoE4, one of three specific forms of apolipoprotein E, commonly known as apoE. The breakthrough has already answered long-standing questions about the configuration of apoE4 in its active, or native, state. A complete understanding of the protein's functioning will be a key factor for development of future therapeutic interventions, according to the researchers.

Details of the works are reported in the January 13 edition of the Journal of Biological Chemistry.

This is the first successful use of x-ray crystallography to reveal the structure of a protein bound to lipids, explains senior author Karl Weisgraber, PhD, a senior investigator at both GICD and the Gladstone Institute of Neurological Disease (GIND). It's crucial to understand this molecule, since it plays such a pivotal role in both cardiovascular and neurological disease.

X-ray crystallography is a technique for determining the three-dimensional structure of a molecule by analyzing the x-ray diffraction patterns of crystals that make up the molecule.

The next step is higher resolution, going from the current 10 angstroms to 3.5 or better, adds Weisgraber, who is also a professor of pathology at the University of California, San Francisco.

Lipid-bound proteins change their shape once they've bound to a lipid and have begun their key functions. Until now, we've only been able to model the lipid-free structures of these proteins, and now we can begin learning about their lipid-bound forms, says lead author Clare Peters-Libeu, a GICD and GIND research scientist. It's a huge step forward for those of us involved in the field.

ApoE, and particularly apoE4, has long been studied for its role as a lipid transport protein and its involvement in cardiovascular disease. Much of the pioneering work on this molecule has been done at Gladstone since the institutes' founding in 1979, led by researchers, including Weisgraber, who had been studying the protein at the National Institutes of Health before transitioning to Gladstone.

In the late 1980s, apoE emerged as a major player in neurological disease, based in part on observations made at Gladstone. Next to one's age, the greatest known risk factor for Alzheimer's disease is the gene for apoE4. ApoE4 is associated with 40-60 percent of cases of sporadic and familial Alzheimer's.

Everyone inherits two copies, or alleles, of every gene, one from each parent, Weisgraber explains. As the number of apoE4 alleles increases from 0 to 2, the risk of AD increases from 20 to 90 percent, and the typical age of onset decreases from 84 years to 68 years. The presence of one apoE4 allele results in an estimated 45 percent chance of developing Alzheimer's by 85 years of age. With two apoE4 alleles, the risk increases to 5090 percent.

Insights into the basic biology of apoE--and particularly apoE4--gained by Gladstone scientists have been invaluable in the study of Alzheimer's disease, says Peters-Libeu. Gaining a complete, three-dimensional understanding of its configuration in its native, lipid-bound state will inevitably lead to even more insights into its role in cardiovascular and neurological disease in the years to come.

Why some cholesterol-lowering drugs cause hot flashes

Fri, 30 Dec 2005 16:03:38 PST

( from http://www.rxpgnews.com ) In a study appearing in the December 1 issue of the Journal of Clinical Investigation, Stefan Offermanns and colleagues from the University of Heidelberg use various mouse models to show why the cholesterol-lowering agent nicotinic acid also commonly causes flushing or "hot flashes" that, although harmless, often prompts patients to discontinue therapy. The authors found that activation of the nicotinic acid receptor GPR109A by nicotinic acid can produce different responses dependent on the location of this receptor in the body.

The authors found that when nicotinic acid activates GPR109A expressed on the surface of fat cells it induces a lowering of lipid levels. However nicotinic acidinduced activation of GPR109A expressed on immune cells in the skin prompts the conversion of arachidonic acid to prostaglandins that cause blood vessels near the skin surface to dilate, resulting in the characteristic flushing response. In an accompanying commentary Nicholas Pike writes, "this elegant studysupports the hypothesis that immune cells in the skin are the most likely source of arachidonic acid and prostaglandins." Furthermore, this study should help researchers develop therapeutics that can achieve the same beneficial cholesterol-lowering effects of nicotinic acid, but without the marked flushing response.

Poor fitness common in teens and adults, with associated rise in cardiovascular disease risk factors

Tue, 20 Dec 2005 04:59:38 PST

( from http://www.rxpgnews.com ) There is strong and consistent evidence from observational studies that physical inactivity and poor cardiorespiratory fitness (i.e., fitness) are associated with higher illness and death from all causes, including cardiovascular disease (CVD) and cancer, according to background information in the article. United States population reports describe an increasingly less physically active society, with marked downturns in reported physical activity during adolescence and young adulthood. Prior to the current National Health and Nutrition Examination Survey (NHANES), data were not available to quantify objectively determined cardiorespiratory fitness in the U.S. population. The extent to which physical inactivity affects the risk of heart disease through its negative impact on cardiorespiratory fitness, which is associated with a high prevalence of other CVD risk factors, is not known at the population level.

Mercedes R. Carnethon, Ph.D., and colleagues from the Feinberg School of Medicine, Northwestern University, Chicago, examined the prevalence of low fitness in the U.S. population of adolescents and adults younger than 50 years and determined the relation between low fitness and CVD risk factors in this population. Using data from NHANES 1999-2002, the researchers analyzed data for adolescents (aged 12-19 years; n = 3,110) and adults (aged 20-49 years; n = 2,205) who were free from previously diagnosed CVD. The participants underwent submaximal graded exercise treadmill testing to achieve at least 75 percent to 90 percent of their age-predicted maximum heart rate. Maximal oxygen consumption (Vo2max) was estimated by measuring the heart rate response to reference levels of submaximal work.

The researchers found that 19.2 percent of the surveyed population--an estimated 16 million U.S. adolescents and adults younger than 50 years--were in the low fitness category, and 33.6 percent of adolescents (approximately 7.5 million) and 13.9 percent of adults (approximately 8.5 million) had low fitness. Among adolescents, the prevalence of low fitness was similar between females (34.4 percent) and males (32.9 percent), but among adults the prevalence of low fitness was significantly higher in females (16.2 percent) compared with males (11.8 percent). Non-Hispanic blacks and Mexican Americans were less fit than non-Hispanic whites. Body mass index and waist circumference demonstrated the most consistent inverse associations with fitness. Total cholesterol levels and systolic blood pressure were higher and levels of high-density lipoprotein cholesterol were lower among participants with low vs. high fitness.

The researchers add that because older adults and individuals with existing risk factors for CVD were not tested on the treadmill because of possible health risks, the results of this study likely underestimate the true prevalence of low fitness in the population.

this report indicates that low fitness is a prevalent and important public health problem in the U.S. population. The consequences of declines in physical activity over time are now evident by the large proportion of society with low levels of fitness. The correlations we report between low fitness and CVD risk factors suggest a potential trend of increasing morbidity and mortality from chronic diseases--the first sign of which is the burgeoning obesity epidemic. Historical evidence from the campaign to educate about the dangers of cigarette smoking indicates that education efforts, particularly among youth, can retard and reverse these negative health behaviors. Thus, it is plausible that a similar education campaign about the health benefits of physical activity to improve cardiorespiratory fitness, in combination with changes in health care policy to make environments more conducive to physical activity, could begin to reverse this serious public health problem, the authors conclude.

Cholesterol levels and use of statins are not associated with breast cancer risk

Tue, 25 Oct 2005 05:13:38 PST

( from http://www.rxpgnews.com ) Cholesterol levels and use of statins or other lipid-lowering drugs are not associated with breast cancer risk, according to a study in the October 24 issue of the Archives of Internal Medicine, one of the JAMA/Archives journals.

Although some evidence suggests that statins (the most commonly used type of lipid-lowering drugs) may inhibit tumor development and may work in combination with chemotherapy drugs against cancer, studies on the association between the use of statins and breast cancer have had conflicting results, according to background information in the article.

A. Heather Eliassen, Sc.D., of the Brigham and Women's Hospital, Boston, Mass., and colleagues analyzed data from the Nurses' Health Study to evaluate the associations of statins, lipid-lowering drugs and serum cholesterol levels (blood levels of cholesterol) with breast cancer. Serum cholesterol levels and use of statins and lipid-lowering drugs were determined for 79,994 women through questionnaires completed in 1988, 1994, 1996, 1998 and 2000. Cases of breast cancer, diagnosed from the start of follow-up (1988) through May 31, 2000, were identified on biennial questionnaires. Medical records were used to confirm cancer reports.

There were 3,177 incident cases of invasive breast cancer, including 1,727 in the analysis among statin users. Neither current nor long-term use of statins nor other lipid-lowering drugs were associated with breast cancer risk, the researchers report. There was no association between reported total serum cholesterol levels and breast cancer risk in either pre-menopausal or post-menopausal women.

"In summary, the results of this study suggest that the beneficial effect of statins on breast cancer observed in experimental studies may not be applicable to humans," the authors conclude. "We also found no associations of general lipid-lowering drugs and serum cholesterol levels with breast cancer risk. Further study is warranted to evaluate the associations of longer durations of statin use and specific types of statins with breast cancer risk."

Statins can prevent heart attacks and strokes even in those with low cholesterol

Wed, 28 Sep 2005 07:32:38 PST

( from http://www.rxpgnews.com ) A class of drugs known as the statins that is already widely used to treat high cholesterol levels would benefit more people if targeted at all people with diseased arteries, regardless of their cholesterol level, according to findings published online in The Lancet on 27 September.

A study jointly coordinated by scientists from the Clinical Trial Service Unit (CTSU) at Oxford and the National Health Medical Research Council Clinical Trials Centre at the University of Sydney combined detailed results from more than 90,000 participants in 14 previously completed trials involving statin treatments. It shows that many people with lower cholesterol levels could benefit from statin treatment.

Statins are known to be effective in preventing the number of heart attacks and strokes in a wide range of patients who are at high risk of such disease. However, most doctors consider statin treatment only when the blood cholesterol level is above a certain threshold. As a consequence, patients with narrowed blood vessels are generally not treated with a statin if their blood cholesterol is below this threshold level.

The trial found that not only did people with lower cholesterol levels benefit from statins, but the biggest benefits occur in those patients with the largest absolute reductions in cholesterol after treatment, largely irrespective of their original cholesterol level.

Dr Colin Baigent in CTSU said: This study shows that statin drugs could be beneficial in a much wider range of patients than is currently considered for treatment. What matters most is that doctors identify all patients at risk of a heart attack or stroke, largely ignoring their presenting blood cholesterol level, and then prescribe a statin at a daily dose that reduces their cholesterol substantially. Lowering the bad LDL cholesterol by 1.5 mmol/L units with a statin should reduce the risk of a heart attack or stroke by at least one third.

The study suggests that many patients given a statin would experience greater benefits if doctors aimed to achieve larger reductions in cholesterol levels. Statins are often prescribed in relatively small doses which may only reduce cholesterol modestly, but the results of the study indicate that the benefits of statins are directly proportional to the size of the reduction in cholesterol produced by treatment so bigger cholesterol reductions with more intensive treatment regimens should lead to greater benefits.

These analyses also provide reassuring new information about the safety of statins. Some earlier studies had raised concerns that statin use might be associated with increased risk of certain cancers or of dying from certain diseases. Professor Rory Collins, Co-Director of CTSU and one of the study authors, said: This work shows clearly that statins are very safe. There is no good evidence that statins cause cancer, and nor do they increase the risk of other diseases. And although statins can cause muscle pain or weakness, our study shows that serious cases are extremely rare. The small excess of serious muscle problems is far outweighed by the large benefits on heart attacks and strokes.

The benefits of statin treatment were seen in all of the many different patient groups studied, including women, the elderly, individuals with diabetes and those with and without prior heart attack or stroke. The largest benefits were seen among those at greatest risk of a vascular event.

Statins use associated with 36% reduced risk of fractures

Tue, 27 Sep 2005 06:50:38 PST

( from http://www.rxpgnews.com ) In a large study of elderly, predominately male veterans, statin use was associated with a 36 percent reduction in risk of fracture when compared with no lipid-lowering therapy, according to a study in the September 26 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

Several biological mechanisms have been proposed to explain an association between statins and bone health, including reduced inflammation and promotion of new bone growth through improvements in small blood vessel function, according to background information in the article. Previous studies have shown an association between statin use and fracture reduction. However, most studies have been of populations of women even though many statin users are elderly men with heart disease. The authors suggest that assessing this relationship in a male population would be especially relevant.

Richard E. Scranton, M.D., M.P.H., of the Massachusetts Veterans Epidemiology Research and Information Center, Boston, and colleagues analyzed data from patients who received care in the V.A. health care system between January 1, 1998, and June 30, 2001 to compare the rate of bone fractures in individuals using statins versus those not taking statins. Information on individuals' health status, race, age and body mass index (BMI) as well as other medications that might be associated with bone fracture were included in the analysis. Of the 91,052 individuals included in the study, 28,063 were prescribed only statins, 2,195 were prescribed nonstatin lipid-lowering medications alone, and the remaining 60,794 were not prescribed any lipid-lowering medications during the period of the study.

"More than 28,000 of these individuals were using statins, making this study one of the largest to evaluate the association between statins and fractures," the researchers report. "The use of statins in this study was associated with a 36 percent reduction in fracture risk compared with no lipid-lowering therapy and a 32 percent risk reduction when compared with other lipid-lowering therapy. These findings did not deviate significantly after adjustment for various covariates, including BMI."

"In our large cohort of mostly male veterans, statin therapy was associated with a reduction in fractures," the authors conclude. Our study represents one of the largest studies to date of individuals receiving statins and the evaluation of fracture risk. Although we were limited in adjusting for all known confounders, this study provides additional information that fuels the debate of whether statins protect individuals against fractures. Further research is necessary to confirm or refute our findings."

Cholesterol-lowering statin therapy may improve survival

Sat, 23 Jul 2005 01:06:38 PST

( from http://www.rxpgnews.com ) Cholesterol-lowering statin therapy may improve survival in patients with diastolic heart failure (DHF) according to a paper published in Circulation: Journal of the American Heart Association by cardiologists at Wake Forest University Baptist Medical Center.

Currently, there are no treatments shown to improve survival in these patients, who make up about 40 percent of all heart failure cases. Systolic heart failure patients have hearts that don't pump out enough blood. In DHF, the heart does not fully relax and therefore does not fill properly with blood. The mortality rate is 5 to 8 percent per year.

William C. Little, M.D., head of the cardiology section at Wake Forest Baptist, and his research team found a dramatic difference in the longevity of 137 diastolic heart failure patients followed over a three-year period. The patients were being treated with ACE inhibitors, beta-blockers, calcium blockers or statins all drugs that are commonly used to treat hypertension or heart-related conditions.

"Some patients in the group had been diagnosed with high cholesterol and placed on statin therapy by their doctors. Others in the group whose cholesterol levels were not as high in general, were not placed on statins," said Little. "But when we followed the patients we found that those who had received statins did dramatically better."

Little and his research team found that during the study period, heart failure patients on statin therapy had a risk of death that was 22 percent lower than the patients receiving the other drugs. Even after adjusting for other factors that could have affected the results, such as hypertension or cardiovascular disease, the heart failure patients on statins still fared better.

Little writes that the improved survival rates in the study might be due to the known beneficial effects of statins in patients with coronary artery disease. Whether diagnosed or not, coronary artery disease is quite common in the elderly population. Too, because diabetes and impaired kidney function are also common in patients with diastolic failure, statins may improve the outcome of these conditions, possibly explaining some of the benefits observed by his team with statins in diastolic heart failure.

"Because the patients were not randomized to which therapy they received, this is not a definitive study," said Little. "However, it certainly suggests that it's worth looking into using statins to treat patients with diastolic heart failure."

According to previous reports in Circulation as well as the New England Journal of Medicine, diastolic heart failure is a significant healthcare problem. Once hospitalized, patients with diastolic heart failure have a 50 percent chance of rehospitalization within six months. It's estimated that the cost of treating patients for diastolic heart failure exceeds $3.5 billion a year.

FDA Gives Final Approval to Fenofibrate Tablets

Thu, 19 May 2005 09:23:38 PST

( from http://www.rxpgnews.com ) Teva Pharmaceutical Industries Ltd. (Nasdaq: TEVA) announced today that the U.S. Food and Drug Administration has granted final approval for the Company's ANDA for Fenofibrate Tablets, 54 mg and 160 mg.

Fenofibrate Tablets are the AB-rated generic equivalent of Abbott's Tricor(R) Tablets. This product is indicated for the treatment of hypercholesterolemia and hypertriglyceridemia.

Today's approval follows a ruling at the U.S. District Court for the District of Delaware, which granted summary judgment of non-infringement in favor of Teva on certain patent claims at issue. The Court ruled that Teva's ANDA for Fenofibrate Tablets, which was made under Paragraph IV of the Hatch-Waxman Act, does not infringe U.S. Patent Nos. 6,589,552 and 6,074,670, and one claim of U.S. Patent No. 6,277,405.

The FDA had initially granted tentative approval of Teva's ANDA in March 2004. At that time, Teva was subject to a second 30-month stay with respect to U.S. Patent No. 6,589,552, which Teva has now been found to not infringe. The court has yet to rule on certain claims relating to U.S. Patent Nos. 6,277,405 and 6,652,881. A trial on these two patents is scheduled for June 6, 2005.

Abbott is no longer marketing the 54 mg and 160 mg strength tablets, having converted its Tricor(R) product to 48 mg and 154 mg strength tablets during the pendency of the patent litigation and second 30-month stay. This is the second such market conversion undertaken by Abbott on Fenofibrate. Prior to this conversion, annual brand sales of the product were approximately $800 million.

In late 2001, Abbott began to convert the previous market for Fenofibrate Capsules to the 54 mg and 160 mg Fenofibrate Tablet products. At that time, Teva had an ANDA pending for Fenofibrate Capsules. Teva received FDA approval to market a generic capsule product following summary judgment on all Orange Book patents, but only after Abbott had ceased sales of its capsule products and had taken steps to frustrate Teva's ability to fully commercialize that product as a generic.

Shortly following Abbott's announcement last year that it was planning to switch the market to a different tablet formulation, Teva filed a motion to amend its answer to assert antitrust counterclaims against Abbott, contending that Abbott's actions have frustrated generic competition in Fenofibrate products through a combination of two market conversions and the gaming of the Hatch-Waxman Act, denying consumers access to a generic alternative to Abbott's products. Teva is seeking triple damages, including lost profits and attorneys' fees, as provided for under the antitrust laws.

Cholesterol-Lowering Agents May Reduce Breast Cancer Risk

Tue, 17 May 2005 01:53:38 PST

( from http://www.rxpgnews.com ) A new study shows that statins drugs widely used to lower cholesterol levels may reduce breast cancer risk by more than half.

"This is a significant study for patients with breast cancer and women at high risk for this disease," said Vikas Khurana, MD, Assistant Professor of Medicine at Louisiana State University Health Science Center at Shreveport and senior author of the study. The study was conducted at the Overton Brooks VA Medical Center, Shreveport, Louisiana. "The findings indicate that statins may have a role in breast cancer prevention."

Statins work by inhibiting an enzyme called 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme regulates production of intermediates for several cell-signaling pathways that play an important role in the development of cancer. Laboratory studies have shown that some statins can trigger "apoptosis," or the natural process of cell death.

Researchers compared statin use between 556 women with a history of breast cancer and 39,865 women without the disease who served as controls. All women were female veterans in the South Central United States. Data were gathered between October 1998 and June 2004 from a database containing health information about veterans.
After controlling for age, smoking, alcohol use, and diabetes, the risk of breast cancer was 51% lower for statin users than for non-users. Researchers noted that they plan to analyze their data further to see if the effect on breast cancer risk varies according to the type and dose of statins used.

Dr. Khurana cautioned that more studies are needed to evaluate the possible protective role of statins in breast cancer, including large, randomized, prospective studies. "It would be premature to tell women to take statins to decrease their breast cancer risk," he said. "But if our results are confirmed, I think statins will have a significant chemopreventive role in women at high risk for breast cancer."

Niaspan(R) Approved as a Lipid Metabolism Regulator to Raise the "Good" Cholesterol Levels

Fri, 29 Apr 2005 10:02:38 PST

( from http://www.rxpgnews.com ) Kos Pharmaceuticals, Inc. (Nasdaq:KOSP) announced today that, through its Canadian development and commercialization partner, Oryx Pharmaceuticals, Inc. (Oryx), regulatory clearance from Health Canada was granted to market all three doses of Kos' Niaspan(R) product (niacin extended-release tablets) in Canada.

The approval was granted on March 11, 2005 and the product was launched today. Niaspan, classified in Canada as a lipid metabolism regulator, is a highly differentiated treatment fulfilling an unmet need for addressing low HDL cholesterol (the "good" cholesterol) levels in treating cardiovascular disease, the number one cause of death in Canada. The cholesterol market in Canada was valued at nearly CAN$1.4 billion in 2004, reflecting an annual growth rate of 15%.

Oryx, a Canadian specialty pharmaceutical company that focuses on several therapeutic areas, including cardiovascular disease, will deploy a dedicated cardiovascular sales force to commercialize Niaspan. Pursuant to the agreement with Kos, which was established in August 2003, Oryx has exclusive commercialization rights to Niaspan and Advicor(R) in Canada and is responsible for all promotional investments.

Kos is responsible for manufacturing and supplying Niaspan for sale in Canada. Under the terms of the agreement, Kos will receive a significant share of revenue from the sale of the products in Canada.

Niaspan, internally developed by Kos, is indicated in Canada as an adjunct to diet for reduction of elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B) and triglyceride (TG) levels, and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia and mixed dyslipidemia, when the response to an appropriate diet and other non-pharmacological measures have been inadequate. Niaspan is a safe and effective therapy and increases the mean HDL-C levels nearly 30%. Kos launched Niaspan in the United States in 1997 and recorded revenue of around $321 million in 2004.

"Niaspan is the most potent, patient friendly pharmaceutical therapy available for increasing HDL-C," stated Adrian Adams, President and CEO of Kos. "With the Canadian approval, Niaspan is now available in numerous countries throughout the world, with more approvals to come. This will facilitate broader penetration in the multi-billion worldwide cholesterol market and we are confident that this therapy will make a significant difference in improving the health of patients afflicted with cholesterol disease in Canada and around the world."

"The launch of Niaspan in Canada represents a major milestone for Oryx and we are pleased to be able to make available this significant new therapy to all Canadians who may benefit from increasing their HDL-C," stated Douglas Reynolds, President of Oryx.

About Niaspan:

Available since 1997, Niaspan is the only FDA-approved, once-daily extended-release prescription formulation of niacin for treating abnormal cholesterol levels. Niacin had been known for decades to be an effective cholesterol medication at high doses but was limited by significant side effects. Kos' solid-dose drug delivery technology transformed niacin, the most powerful agent available for increasing HDL-C (High-Density Lipoprotein; "good" cholesterol) into a highly effective, patient friendly therapy used by thousands of patients. In the United States, Niaspan is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate, to reduce elevated total cholesterol, LDL-C (Low-Density Lipoprotein; "bad" cholesterol), Apo B, and triglycerides (TG) levels, and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia. Additionally, Niaspan is also indicated to reduce the risk of recurrent heart attacks in patients who have a history of heart attack and hypercholesterolemia.

Niaspan is contraindicated in patients with allergies to any of its ingredients, active liver or peptic ulcer disease, significant or unexplained persistent liver dysfunction, or arterial bleeding. Niaspan should not be substituted for equivalent doses of immediate-release niacin.

Niaspan should be prescribed with caution in patients who consume substantial amounts of alcohol and/or have a past history of liver disease. Liver function tests should be performed on all patients during therapy with Niaspan. Use of Niaspan with other lipid-altering medications called statins may increase the risk of rhabdomyolysis, a rare condition that causes muscles to breakdown.

The most common side effect with Niaspan is flushing of the skin. Other commonly reported side effects include indigestion, headache, pain, abdominal pain, nausea, itching, diarrhea, running nose, vomiting, and rash. Patients with diabetes should carefully monitor their blood sugar and report changes to their doctor.

Class Effect of Statins in Elderly Patients

Tue, 26 Apr 2005 18:54:38 PST

( from http://www.rxpgnews.com ) Evidence has shown that the use of statins after acute myocardial infarction (AMI) is effective in reducing the incidence of both fatal and nonfatal cardiovascular events. Since they belong to the same drug class, they are generally thought to be therapeutically equivalent.

However, evidence supporting this assumption has been limited, and prescribing practice suggest that some statins are preferred over others. Zhou and colleagues compared the effectiveness of 5 commonly prescribed statins in a head-to-head retrospective analysis of data 18 000 elderly patients who had AMI and who filled a prescription for a statin within 90 days after discharge. They found that the 5 statins were equally effective for secondary prevention after AMI.

However, the costs of statins differ, as Wright points out in a related commentary, which gives physicians an opportunity to reduce costs to patients and the health care system while still achieving optimal health outcomes for their patients.

Statin simvastatin linked to protection against endothelial dysfunction in diabetic rats

Sun, 03 Apr 2005 10:32:38 PST

( from http://www.rxpgnews.com ) Almost two years ago, the diabetes arm of the Heart Protection Study, the largest-ever study using a cholesterol-lowering medication, found that diabetics who took a daily dose of the statin drug simvastatin over five years reduced the risk of a first nonlethal heart attack by 37 percent and risk of a first nonfatal or fatal stroke by 24 percent, regardless of their cholesterol or glucose levels. That is significant, since people with diabetes are two to four times more likely than others to have a coronary event even though their low-density lipid (LDL) cholesterol levels are similar to those in the general population.

Since most patients with diabetes die from some vascular complication, Medical College of Georgia researchers set out to determine the effects of simvastatin on endothelial cell dysfunction, an early pivotal event in atherogenesis and a major cause of the microvascular complications in diabetics. The researchers found that in addition to lowering cholesterol levels, simvastatin also appeared to prevent or reverse vascular injury by vasoprotective means. In a well-established rat model of diabetes, simvastatin protected against the development of diabetes-induced endothelial cell dysfunction in vessels of the heart, kidney, and eye.

Endothelial cells make up the inner lining of blood vessels. The stimulation of intact endothelial cells by neurotransmitters, hormones and other substances causes release of a substance that induces relaxation of the underlying vascular smooth muscle. Endothelial dysfunction is characterized by an imbalance between these vasodilators and vasoconstrictors and appears early in diabetes.

The researchers induced diabetes in rats, then treated half of the diabetic rats with simvastatin. After four weeks the untreated rats had high levels of cholesterol and various indicators of endothelial dysfunction in the vessels of the heart, eye, and kidney. The rats that received 5 mg of simvastatin daily showed no or little such damage. Their plasma levels were normal, compared to a 67 percent rise of total cholesterol and 7.5 fold increase of triglycerides in the untreated rats. Unlike the untreated rats, treated rats had no elevation of nitrotyrosine in the retina or lipid peroxidation in the heart and retina. Relaxation of the aorta was normal, as was vascular permeability in all tissues, whereas the untreated diabetic rats had elevations of 2 to 13 times.

Dr. Ma concludes, "The data indicate that simvastatin protects against diabetes induced dysfunction," and Dr. Caldwell says, "The usefulness of statins in the treatment of diabetic patients is being realized."

Study pinpoints protein inhibitor that raises HDL levels

Fri, 09 Apr 2004 17:54:27 PST

( from http://www.rxpgnews.com ) An important clinical advance in the prevention of heart disease has been identified by researchers at the University of Pennsylvania School of Medicine, in collaboration with researchers at Tufts University and Pfizer. The study led by Daniel Rader, MD, Associate Professor of Medicine and Director of Penn's Preventive Cardiovascular Medicine & Lipid Center, involved a novel pharmacologic approach – inhibition of the cholesteryl ester transfer protein (CETP) – and showed that this approach is highly effective in raising high-density lipoprotein (HDL) levels in patients with low levels. The study will be published in the April 8th issue of The New England Journal of Medicine.

The drug torcetrapib, made by Pfizer, significantly increased levels of HDL in patients with low levels of this "good" cholesterol, whether or not they were also being treated with the cholesterol-lowering drug atorvastatin (Lipitor). The combination therapy used in the trial proved so effective that, among those patients who received the highest dosages of both drugs, HDL cholesterol levels were increased by more than 100%. "These results are striking because it is generally very difficult to raise HDL levels in people with already low-levels of good cholesterol," said Rader.

According to Rader, torcetrapib works by inhibiting the ability of the cholesteryl ester transfer protein to transfer cholesterol from HDL (the "good" cholesterol) into LDL (the "bad" cholesterol). And, although the drug's CETP-inhibitor properties proved effective when administered by itself, its effectiveness was maintained when given in combination with a statin -- which is the most common class of drugs used to lower LDL cholesterol levels.

The implications of this study – which took place at Penn and Tufts/New England Medical Center, Boston -- could have far-reaching effects when it comes to heart disease. A low level of HDL cholesterol is the most common lipid abnormality observed in patients with known coronary heart disease. Torcetrapib is still in clinical development but is designed as chronic long-term therapy to raise HDL levels and reduce heart disease risk, just as statins are used to lower LDL levels. Further studies are being done to determine whether it successfully reduces the risk of heart disease.