News — February 2009

11 Million Older Americans Could Be Newly Eligible for Statin Therapy
Researchers estimate that more than 11 million older Americans may be newly eligible for statin therapy if findings from a recently published large clinical trial are adopted into clinical practice guidelines, according to a new analysis of the trial data. The analysis is published in Circulation: Cardiovascular Quality and Outcomes.

Using data from the 1999 to 2004 NHANES (National Health and Nutrition Examination Survey), researchers found that 33.5 million older Americans (men aged ≥50 years and women aged ≥60 years) are currently taking a statin (24.4%) or have risks that would indicate a need for statin therapy based on current guidelines but do not take a statin (33.5%). They estimated that an additional 19.2% of older adults could be considered eligible for statin therapy based on their matching the inclusion criteria used in a recently published clinical trial, JUPITER (Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin), presented in November at the American Heart Association's (AHA) Scientific Sessions in New Orleans.

"Based on our analysis, more than 44.7 million older Americans might have an indication for statin therapy when you consider those who already meet current guidelines for statin therapy and those who might be eligible based on the criteria proposed in JUPITER," said lead author of the analysis Erica S. Spatz, MD, an internist and fellow in the Robert Wood Johnson Clinical Scholars Program at Yale University, in an AHA news release. "That's nearly 80% of this segment of the population who could potentially be recommended a statin therapy if those criteria were adopted into guidelines." (Dr. Spatz was not involved in the JUPITER trial.)

The study is a numerical analysis rather than an endorsement of using statins to aggressively lower cholesterol and high-sensitivity C-reactive protein in people not currently considered candidates for that therapy, as was done in JUPITER. Additionally, the exclusion criteria for study participants in the JUPITER trial may make it difficult to generalize those findings.

Dr. Spatz hopes her study will help provide important information for the development of future guidelines about using statin medications to reduce cardiovascular disease (CVD) by providing some of the information necessary to determine whether the number of people who would receive statin therapy under JUPITER criteria would be cost-effective from a public health standpoint.

CHD Not Accurately Predicted by Traditional Risk Assessment Tools
The Framingham and NCEP (National Cholesterol Education Program) tools do not accurately predict coronary heart disease (CHD), according to a study performed at the Yale University School of Medicine.

The study included 1,653 patients who had no history of CHD; although 738 patients were taking statins because of increased risk of developing CHD. All 1,653 patients underwent a coronary computed tomography angiogram, and doctors compared their risk of CHD, determined by the Framingham and NCEP risk assessment tools, to the amount of plaque actually found in their arteries as a result of the scan. Results showed that 21% of the patients who were thought to need statins before the scan (because of the Framingham and NCEP assessment tools) did not require them; "26% of the patients who were already taking statins (because of the risk factor assessment tools) had no detectable plaque at all," said Kevin M. Johnson, MD, lead author of the study, in a news release from the American Roentgen Ray Society.

"Risk assessment tools are used by physicians implicitly. Physicians use them as a way to separate and treat patients accordingly. Ultimately, the Framingham influences what every physician does, but I feel it is not good enough to show what is happening with each individual patient," said Dr. Johnson.

"The average person tends to put a lot of weight on family history, but the association between that and [CHD] is only modest," said Dr. Johnson. "We are living in an era where genetic research is in the headlines, but reality is a lot more complicated than that," he said. "There are still 400,000 people a year who die from [myocardial infarctions {MI}] and have no warning signs at all; doctors want to be able to find those people before that happens, and I hope this study gets people interested in finding out better predictors for CHD," said Dr. Johnson.

This study appeared in the American Journal of Roentgenology.

A New Weapon to Fight Dyslipidemia: Synthetic HDL
Northwestern University scientists may have found a promising new weapon for improving cholesterol—synthetic high-density lipoprotein (HDL) cholesterol—that could help fight chronically high cholesterol levels.

The researchers successfully designed synthetic HDL and show that their nanoparticle version is capable of irreversibly binding cholesterol. The synthetic HDL, based on gold nanoparticles, is similar in size to HDL and mimics HDL's general surface composition. The study is published in the Journal of the American Chemical Society.

"We have designed and built a cholesterol sponge. The synthetic HDL features the basics of what a great cholesterol drug should be," said Chad A. Mirkin, PhD, George B. Rathmann Professor of Chemistry in the Weinberg College of Arts and Sciences, Professor of Medicine and Professor of Materials Science and Engineering, in a university news release.

"Drugs that lower … [low-density lipoprotein cholesterol] LDL are available, and you can lower LDL through your diet, but it is difficult to raise … HDL," said Dr. Mirkin. "We are hopeful that our synthetic HDL will one day help fill this gap in useful therapeutics."

In creating synthetic HDL, the researchers started with a gold nanoparticle as the core. They then layered on a lipid that attaches to the gold surface, then another lipid and last apolipoprotein A-I, the main protein component of naturally occurring HDL. The final HDL nanoparticles are each about 18 nanometers in diameter, a size similar to natural HDL.

"HDL is a natural nanoparticle, and we've successfully mimicked it," said Dr. Mirkin, director of Northwestern's International Institute for Nanotechnology. "Gold is an ideal scaffolding material—its size and shape can be tailored, and it can be easily functionalized. Using gold nanoparticles, which are nontoxic, for synthetic HDL bodes well for the development of a new therapeutic."

Cardiac Risk Not Indicated by Cholesterol Levels in Most MI Patients
A new national study has shown that nearly 75% of patients hospitalized for an MI had cholesterol levels that would indicate they were not at high risk for a cardiovascular event, according to current national cholesterol guidelines. Patients had LDL levels that met current guidelines, and close to half had LDL levels classified as optimal (<100 mg/dL).

"Almost 75% of [MI] patients fell within recommended targets for LDL, demonstrating that the current guidelines may not be low enough to cut MI risk in most who could benefit," said Gregg C. Fonarow, MD, Eliot Corday Professor of Cardiovascular Medicine and Science at the David Geffen School of Medicine at UCLA and the study's principal investigator.

Although the risk of cardiovascular events increases substantially with LDL levels >40 mg/dL, current national cholesterol guidelines consider LDL levels <100 mg/dL acceptable for many individuals. The guidelines are thus not effectively identifying the majority of individuals who will develop fatal and nonfatal cardiovascular events, according to the study's authors.

Researchers also found that more than half of patients hospitalized for a heart attack had poor HDL levels, according to national guidelines.

Published in the American Heart Journal, the study suggests that lowering guideline targets for LDL for those at risk for CVD, as well as developing better treatments to raise HDL, may help reduce the number of patients hospitalized for MI in the future, according to a UCLA news release.

"The study gives us new insight and intervention ideas to help reduce the number of [MIs]," said Dr. Fonarow, who is also Director of the Ahmanson-UCLA Cardiomyopathy Center. "This is one of the first studies to address lipid levels in patients hospitalized for a[n] [MI] at hospitals across the entire country."

The research team used a national database sponsored by the AHA's Get with the Guidelines program. The database includes information on patients hospitalized for CVD at 541 hospitals across the country. Researchers analyzed data from 136,905 patients hospitalized for an MI nationwide between 2000 and 2006 whose lipid levels were documented upon hospital admission. This accounted for 59% of total hospital admissions for MI at participating hospitals during the study period.

FDA Issues Update to Safety Review of ENHANCE Trial
The US Food and Drug Administration (FDA) has completed its review of the final clinical study report of the ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin versus Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia) trial.

Preliminary results from this trial had indicated that there was no significant difference between patients treated with ezetimibe plus simvastatin (Vytorin, Merck/Scher-ing-Plough) and patients treated with simvastatin alone in carotid intima-media thickness, despite greater lowering of LDL with ezetimibe/simvastatin compared with simvastatin alone, according to an FDA news release.

The final results of the trial show that after 2 years of treatment, carotid artery thickness increased by 0.011 mm in the ezetimibe/simvastatin group and by 0.006 mm in the simvastatin group. The difference in the changes in carotid artery thickness between the two groups was not statistically significant.

The levels of LDL, however, decreased by 56% in the ezetimibe/simvastatin group and decreased by 39% in the simvastatin group. The difference in the reductions in LDL between the two groups was statistically significant. The results from ENHANCE do not change the FDA's position that elevated LDL is a risk factor for CVD and that lowering LDL reduces the risk for CVD. Based on currently available data, patients should not stop taking ezetimibe/simvastatin or other cholesterol-lowering medications.

Study Examines Burden of Diabetes on US Hospitals
A study in Value in Health estimated the extent of hospital admissions for individuals with diabetes and its economic burden in the United States. The results show that, during 2005, Americans with diabetes had 3.5 times more hospital admissions than those without diabetes. Although 7% of the US population has diabetes, in a study of data from 2005, nearly 22% ($171 billion) of hospital charges resulted from treating individuals with the condition.

"The baby boomer generation is getting older, and more Americans are becoming overweight or obese, and diabetes is also likely to continue to increase," said Sunny Kim, PhD, of Florida International University, coauthor of the study, in a news release from the journal's publisher. "Therefore, an increase in demand for hospital care and increasing financial burdens is anticipated."

Diabetes is rapidly on the rise and is projected to increase 165% by 2050 in the United States. Additionally, there are currently an estimated more than 6 million undiagnosed patients with diabetes in the United States. Therefore, understanding and preparing for the upcoming demand of medical care is critical.

Due to the disproportionate number of hospitalizations associated with individuals with diabetes, a small rise in the number of patients will greatly increase the demand for inpatient care. Public health education is important to reduce the prevalence of diabetes and to achieve and maintain diabetes control. Even so, health care communities should anticipate an increase in demand for hospital care as well as increasing financial burdens as a result of the requirements for diabetes care.

Walking Program for Diabetes Patients With Foot Ulcers
Doctors and scientists previously recommended that individuals with diabetic peripheral neuropathy (DPN) stay off their feet. Now, a University of Missouri researcher has concluded that individuals with DPN might be able to engage in a graduated walking program under close supervision of a medical professional and thus prevent other life-threatening illnesses, according to a university news release.

"Physical activity is recommended for people with diabetes because it is proven to reduce the risk of mortality and development of [CVD]," said Joseph LeMaster, MD, MPH, an Associate Professor of Family and Community Medicine at the University of Missouri. "Individuals with type 2 diabetes can increase their risk of CVD by 34% and their risk of mortality by 39% if they do not participate regularly in some type of moderately intense exercise. People who have diabetes are already less active than most of the population, and those with [DPN] tend to be even less active."

In the study, Dr. LeMaster examined the effects of lower extremity exercise and walking intervention programs on foot ulcer occurrence in people with DPN. Participants with DPN were assigned to one of two groups: an intervention group (frequently monitored and assisted through leg strengthening exercises, a graduated walking program, and motivational telephone calls every 2 weeks) and a control group. Both groups received diabetic and regular foot care education and eight sessions with a physical therapist.

During the first 6 months, Dr. LeMaster noted an increase in the total number of minor foot lesions and ulcers. At the end of the year, however, the number of lesions and ulcers in the intervention group had started to decrease compared with the control group, indicating a reduced risk.

Orlistat Does Not Appear to Benefit FLD Patients
Orlistat does not help patients with fatty liver disease (FLD) lose weight, nor does it improve their liver enzymes or insulin resistance, according to a study published in Hepatology.

Stephen A. Harrison, MD, Brooke Army Medical Center, Houston, and colleagues conducted a randomized, controlled trial of overweight patients with FLD to determine the effect of orlistat in conjunction with caloric restriction. They included 50 people who had been diagnosed with FLD after clinical evaluation and liver biopsy. For 36 weeks, all patients followed a diet of 1,400 calories per day, a multivitamin and vitamin E regimen, and were randomized to orlistat 120 mg three times per day with meals or a placebo, according to a news release from the journal's publisher.

After 36 weeks, patients underwent a liver biopsy, and the researchers looked for improvement in fat levels and fibrosis score. They also monitored changes in biochemical data such as fasting insulin, glucose, liver enzymes, lipid panel, vitamin E, and free fatty acid levels.

"Comparing the orlistat group to the nonorlistat group at study completion, no significant differences were identified between the two groups for mean weight loss, serum, insulin resistance or cholesterol," the authors wrote. There were also no significant differences in the liver biopsy findings. Because there were no notable differences between the two groups, the researchers reanalyzed the data to compare patients who lost differing amounts of body weight. They noted a linear relationship between weight loss and liver improvement. In fact, body weight loss of 9% or more resulted in the greatest amount of liver improvement.

"In conclusion, while this preliminary study does not demonstrate a weight-loss advantage with the use of orlistat," the authors said, "it does demonstrate that moderate weight loss is associated with significant improvements in the symptoms of FLD."

Obesity May Play a Role in Erectile Dysfunction
Obese men with erectile dysfunction (ED) have been shown to have low levels of certain hormones, such as testosterone. A correlation between certain conditions associated with obesity, particularly hypertension, are the most important determinants of obesity-related ED, according to a study published in The Journal of Sexual Medicine. Excess abdominal fat, CVD, high blood lipids, and type 2 diabetes characterize metabolic syndrome, which has recently been associated with ED.

The study included 2,435 male patients who sought treatment at an outpatient clinic for sexual dysfunction between 2001 and 2007. The results showed that obesity was significantly associated with a higher physical contribution to ED, while there was no difference seen with relational or psychological determinants. As the severity level of obesity increased, levels of testosterone decreased (two out of three patients with extreme obesity had low testosterone). Obese patients were also more likely to have abnormalities in penile blood flow. Psychological disturbances related to obesity did not seem to play a major role in developing obesity-related ED.

"This is a landmark study in that it shows that sexual health is clearly linked to overall health, and that improving one's general health provides a man the opportunity to improve his erectile function," said Irwin Goldstein, MD, Alvarado Hospital's Sexual Medicine Director, in a news release from the hospital.

Benefit of Vitamin D in Diabetes, Other Diseases
Vitamin D is quickly becoming the "it" nutrient with health benefits for diseases, including cancer, osteoporosis, heart disease, and now diabetes.

A recent review by researchers from Loyola University Chicago Marcella Niehoff School of Nursing concluded that adequate intake of vitamin D may prevent or delay the onset of diabetes and reduce complications for those who have already been diagnosed. These findings appeared in The Diabetes Educator.

"Vitamin D has widespread benefits for our health and certain chronic diseases in particular," said Sue Penckofer, PhD, RN, study coauthor and Professor, Loyola University Chicago Marcella Niehoff School of Nursing, in a university news release. "This article further substantiates the role of this nutrient in the prevention and management of glucose intolerance and diabetes."

Many of the 23 million Americans with diabetes have low vitamin D levels. Evidence suggests that vitamin D plays an integral role in insulin sensitivity and secretion. Vitamin D deficiency results in part from poor nutrition, which is one of the most challenging issues for people with diabetes. Another culprit is reduced exposure to sunlight, which is common during cold weather months when days are shorter and more time is spent indoors.

One study examined for this review article evaluated 3,000 people with type 1 diabetes and found a decreased risk in disease for people who took vitamin D supplements. Observational studies of people with type 2 diabetes also revealed that supplementation may be important in the prevention of this disease.

Diet alone may not be sufficient to manage vitamin D levels. A combination of adequate dietary intake of vitamin D, exposure to sunlight, and treatment with vitamin D2 or D3 supplements can decrease the risk of diabetes and related health concerns. The preferred range in the body is 30 to 60 ng/mL of 25-OH vitamin D.

"People at risk for diabetes should be screened for low vitamin D levels," said Mary Ann Emanuele, MD, FACP, study coauthor and Professor of Medicine, Division of Endocrinology and Metabolism, Loyola University Health System. "This will allow health care professionals to identify a nutrient deficiency early on and intervene to improve the long-term health of these individuals."

Oral Bisphosphonate Use Linked to ONJ
A study published in the Journal of the American Dental Association found that even short-term use of common oral bisphosphonates may leave the jaw vulnerable to necrosis.

Parish Sedghizadeh, DDS, University of Southern California (USC), School of Dentistry, and colleagues sought to investigate the relationship between oral bisphosphonate use and osteonecrosis of the jaw (ONJ). The study included 208 healthy patients from the School of Dentistry. After controlling for referral bias, nine of the 208 patients who take or have taken alendronate for any length of time were diagnosed with ONJ. The study's results are in contrast to drug makers' prior assertions that bisphosphonate-related ONJ risk is only noticeable with IV use of the drugs, not oral usage, said Dr. Sedghizadeh in a USC news release.

"We've been told that the risk with oral bisphosphonates is negligible, but 4% is not negligible." The danger is especially pronounced with procedures that directly expose the jaw bone, such as tooth extractions and other oral surgery.

Dr. Sedghizadeh hopes to have other researchers confirm his findings and thus encourage more doctors and dentists to talk with patients about the oral health risks associated with the widely used drugs. The results confirm the suspicions of many in the oral health field," he said.

High Insulin Levels Associated With Breast Cancer Risk
Higher-than-normal levels of insulin place postmenopausal women at increased risk of breast cancer, according to a study published in the Journal of the National Cancer Institute.

The findings suggest that interventions that target insulin and its signaling pathways may decrease breast cancer risk in these women. The multiyear WHI (Women's Health Initiative) followed health outcomes in more than 93,000 postmenopausal women. At enrollment, each participant's blood samples that were stored for later analysis.

In 2004, researchers from Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, selected a subset of more than 1,600 of these participants: 835 who had developed breast cancer during the study and a random sample of 816 women representative of the WHI as a whole, according to a news release from the university. After dividing the women into four groups based on their fasting insulin and controlling for estrogen levels, researchers found that women with the highest insulin levels were about 50% more likely to have developed breast cancer versus women who had the lowest.

Most of this effect was observed in the large subset of women from the WHI study who did not use hormone-replacement therapy (HRT). HRT has a strong effect on insulin and other hormonal factors, so eliminating this variable gives a clearer picture of insulin's effect on breast cancer.

"Among these women, the influence of insulin on breast cancer risk was quite high," said lead author Marc Gunter, PhD, Department of Epidemiology & Population Health, at Albert Einstein. "Women with the highest insulin levels in their blood were more than two times more likely to develop breast cancer than women with the lowest insulin levels."