News — August 2008

Committee Says Diabetes Drugs Should Undergo Cardiovascular Safety Studies
Manufacturers of new diabetes drugs should submit long-term cardiovascular trial results or provide other evidence to rule out an unacceptable level of cardiovascular risk, a US Food and Drug Administration (FDA) advisory committee has recommended.

The Center for Drug Evaluation and Research's Endocrinologic and Metabolic Drugs Advisory Committee voted 14–2 in favor of the requirement, according to the FDA. Panel members said such a long-term study would need to last 5 years and could be under way at the time the drug is approved. The vote followed discussions of the adverse cardiovascular events associated with rosiglitazone (Avandia, GlaxoSmithKline), sales of which have plummeted amid safety concerns and charges that the company did not disclose postmarketing data pointing to the problem.

A 5-year trial may not catch all long-term benefits or risks of diabetes drugs, but it "seems like a reasonable, practical duration for the trial," said Saul Genuth, MD, Professor of Medicine at Case Western Reserve University, Cleveland, and a nonvoting member of the advisory committee. "I would want a new drug to be better than any current drug at lowering glucose. I still believe there is an independent cardiovascular benefit from lowering glucose, even though there may not be evidence yet from previous trials that may have been flawed in their design," he said.

Dr. Genuth is referring to recent results from at least three major clinical trials that have thus far been able to show a reduction in macrovascular events associated with lowering glucose to near-normal levels among patients with diabetes.

Other members disagreed. A new cardiovascular study requirement for diabetes drugs could result in an unacceptable delay in the approval of new drugs, said Eric Felner, MD, Assistant Professor of Pediatrics in the Department of Pediatrics, Division of Endocrinology at Emory University School of Medicine, Atlanta. He voted against the requirement.

AAP Recommends Screening Lipids in Special-Risk Children
The American Academy of Pediatrics (AAP) has released a clinical report that recommends cholesterol screening for overweight children, regardless of family history or risk factors. The report reemphasizes the need for prevention of cardiovascular disease (CVD) by following the US Department of Health and Human Services' Dietary Guidelines for Americans (www.health.gov/Dietary Guidelines) and increasing physical activity and also includes a review of the pharmacologic agents and indications for treating dyslipidemia in children, according to the AAP.

In summary, the report recommends (1) a population approach to diet for children aged ³2 years, (2) an individual approach for children and adolescents at higher risk for CVD and elevated LDL cholesterol, including changes in diet and increased physical activity, (3) screening children and adolescents with a positive family history of dyslipidemia or premature CVD or dyslipidemia, (4) the first screening should take place after 2 years of age but no later than 10 years of age, (5) a fasting lipid profile, (6) weight management is the primary treatment for pediatric patients who are overweight or obese and have high triglycerides or low HDL, and (7) for patients aged ³8 years and LDL of 190 mg/dL (or 160 mg/dL with a family history of early heart disease or two additional risk factors present or 130 mg/dL if diabetes is present), pharmacologic intervention should be considered.

"These guidelines are an important update from the preexisting guidelines published in 1998," Sarah Armstrong, MD, told Review of Endocrinology. "Much evidence regarding development of atherosclerosis and childhood factors that increase risk of CVD, as well as pharmacotherapeutic options for childhood dyslipidemia has evolved since then." Dr. Armstrong is Director, Healthy Lifestyles Program, Duke Division of Primary Care Pediatrics.

She said that the three most striking changes/developments are:

• Evidence that cardiovascular risk factors, especially elevated LDL and low HDL, obesity, smoking, diabetes (type 1 or 2), and hypertension are associated with the development of adult CVD regardless of adult risk factors, meaning that some of the cardiovascular consequences of the underlying pathologies are likely progressive.
• New recommendation that overweight toddlers or those who have familial risk of CVD can transition to low-fat milk at age 1 year, as opposed to the prior universal recommendation they transition from whole milk to low-fat milk at age 2 years.
• Initiation of pharmacotherapy at age 8 to 10 years if specified lipid levels and risk factor criteria are met.

This is a much more specific guideline than the previous one, and includes more specific cutoffs for lipid values based on age and gender, Dr. Armstrong added.

Prevention Activities Could Increase US Adults' Life Span
Aggressive use of nationally recommended clinical prevention activities, such as smoking cessation programs, controlling prediabetes, or lowering cholesterol, could increase life expectancy for US adults by reducing CVD, according to a joint report of three major national health care organizations.

The report was published online in Circulation and Diabetes Care. The study was conducted by researchers from the American Heart Association (AHA), the American Diabetes Association (ADA), and the American Cancer Society (ACS). Using the sophisticated mathematical model Archimedes, investigators evaluated the impact of 11 widely recognized, tailored clinical preventive services for reducing CVD, such as smoking cessation, preventive aspirin therapy, cholesterol-lowering medications, and weight reduction. A similar analysis is being conducted that includes preventive measures for cancer. Scientists found that using these CVD clinical preventive measures to their fullest potential could add about 220 million life-years over the next 30 years or an average of 1.3 years of life expectancy for each adult in the United States.

About 78% of US adults aged 20 to 80 years are candidates for at least one of these clinical prevention activities, and the report notes a number of ways prevention could bring benefits. There are large gaps in the application of prevention, thus large opportunities to reduce morbidity and mortality from CVD.

"The ACS, ADA, and the AHA have joined forces to look at clinical prevention and its impact because, although we represent different health conditions, the same prevention strategies that can significantly reduce the risk of CVD É could reduce the risk of diabetes and cancer," said Rose Marie Robertson, MD, AHA Chief Science Officer and coauthor of the report.

"However, our current health care system is not optimally designed to promote health or prevent illness," Dr. Robertson said. "The lesson from these findings is that we need a system in which we can apply these interventions in a way that is efficient and cost effective. The benefits are too important to be ignored. A healthier, more productive society is good for us all."

Elevated Liver Protein Linked to Increased Diabetes Risk
Having a higher-than-normal level of fetuin-A is associated with an increased risk of the development of diabetes, according to a study in the Journal of the American Medical Association.

Previous studies have found an association between higher fetuin-A levels and insulin resistance, but the association with incident type 2 diabetes is unknown. Joachim H. Ix, MD, from the University of California, San Diego, and San Diego Veterans Affairs Healthcare System and colleagues, conducted a study to examine whether higher fetuin-A levels are associated with the occurrence of diabetes in older individuals. The study included 406 people, aged 70 to 79 years, without diabetes at baseline. All patients had fetuin-A levels measured at the beginning of the study and had 6 years of follow-up. Diabetes developed in 135 participants (10.1 cases/1,000 person-years).

Analysis indicated a graded increase in the incidence of diabetes with increased fetuin-A levels. The third of the group with the highest levels had more than twice the incidence rate compared with the lowest third (13.3 vs 6.5 cases/1,000 person-years). The association was independent of physical activity, inflammatory biomarkers, and other commonly available measures of insulin resistance and was regardless of gender, race, and obesity status. The association was moderately weakened by adjustment for visceral adiposity.

Fatty Liver Disease May Raise Heart Risk in Obese Children
Nonalcoholic fatty liver disease (NAFLD) in overweight and obese children may be a precursor of CVD, researchers reported in Circulation.

Researchers performed a case-controlled study of 150 overweight children with biopsy-proven NAFLD and 150 overweight children without NAFLD. Participants were well matched in age, gender, and severity of obesity. More than half of the children in each group were in the 99th percentile for body mass index. The overweight children with NAFLD had significant cardiovascular risk including higher levels of fasting glucose, insulin, total cholesterol, LDL, triglycerides, and higher systolic and diastolic blood pressure than the control group. The children with NAFLD also had significantly lower levels of HDL than the control group.

Researchers found the distribution of the disease by race and ethnicity was also significantly different, with more Hispanic and Asian children in the NAFLD group and more white and black children in the control group. They also found that children with metabolic syndrome were five times more likely to have NAFLD as overweight and obese children without metabolic syndrome.

Rosiglitazone May Delay PDR
Rosiglitazone may delay the onset of proliferative diabetic retinopathy (PDR), possibly because of antiangiogenic properties associated with the agent. According to investigators reporting in the Archives of Ophthalmology, future clinical investigations should consider this potential benefit.

Lucy Q. Shen, MD, of Harvard Medical School, and colleagues performed a longitudinal medical record review of all patients treated with rosiglitazone receiving both medical and ophthalmic care at Joslin Diabetes Caneter (n = 124) and matched control patients not taking the drug ( n = 158).

In eyes with severe nonproliferative DR at baseline, progression to PDR over 3 years occurred in 19.2% of those taking rosiglitazone versus 47.4% in the control group (59% relative risk reduction). Additionally, fewer eyes in the rosiglitazone group experienced 3 or more lines of visual acuity loss.

Hearing Loss Common Diabetes Complication
Hearing impairment is common among adults with diabetes, and it appears to be an independent risk factor for the condition, according to a report in the Annals of Internal Medicine. "Diabetes might affect the vasculature and neural system of the inner ear," wrote Kathleen E. Bainbridge, PhD, MPH, of Social & Scientific Systems, Silver Spring, Md., and colleagues.

The investigators used NHANES (National Health and Nutrition Examination Survey) data from 5,140 noninstitutionalized adults aged 20 to 69 years who had audiometric testing to determine whether hearing impairment was more prevalent among US adults with diabetes. Age-adjusted prevalence of low- or midfrequency hearing impairment of mild or greater severity in the worse ear was 21.3% (95% confidence interval [CI], 15.0%–27.5%) among 399 adults with diabetes compared with 9.4% (CI, 8.2%–10.5%) among 4,741 adults without diabetes. Similarly, age-adjusted prevalence of high-frequency hearing impairment of mild or greater severity in the worse ear was 54.1% (CI, 45.9%–62.3%) among those with diabetes compared with 32.0% (CI, 30.5%–33.5%) among those without diabetes. The association between diabetes and hearing impairment was independent of known risk factors for hearing impairment, such as noise exposure, ototoxic medication use, and smoking (adjusted odds ratios for low- or mid-frequency and high-frequency hearing impairment were 1.82 [CI, 1.27–2.60] and 2.16 [CI, 1.47–3.18], respectively).

Dietary Adherence Improves Glucose Control in Type 1 Kids
Adherence to prescribed dietary recommendations is associated with better glucose control in children with type 1 diabetes, according to a study published in Diabetes Care.

"In recent years, diabetes management has been focused around new medications and technologies," said senior author Lori Laffel, MD, Pediatric, Adolescent and Young Adult Section, Joslin Diabetes Center. "In this study, we were encouraged to identify the unique importance of diet on blood sugar control in children and teens with type 1 diabetes."

The study surveyed the parents of 119 children and teens aged 9 to 14 years and asked how closely they followed prescribed dietary behaviors, such as estimating carbohydrate intake, matching the child's insulin dose to carbohydrate intake, and the quality of the diet itself. Children who adhered closely, or fairly closely, to the prescribed dietary recommendations showed an A1C level of up to almost a full point lower than those who were least adherent.

Method Can Determine Birth Weight of Babies Born to Obese Women
Researchers have found what they believe to be the most accurate way of predicting the birth weight of babies born to the growing number of obese mothers, according to a study published in Ultrasound in Obstetrics and Gynecology.

Researchers from the University of Rochester Strong Memorial Hospital, Rochester, NY, have recorded accurate results in more than nine out of 10 cases using the gestation-adjusted projection method (GAP). The GAP method uses a range of ultrasound measurements, taken when the mother is 34 to 36 weeks pregnant, and a mathematical formula to determine whether the baby is larger than the average size of babies for its gestational age. These data are then used to predict the final birth weight.

"Obesity is a risk factor for almost all obstetric complications. It is particularly important to identify high birth-weight babies [more than] 4,000 grams, as these are associated with higher complication rates for mothers and babies," said Loralei Thornburg, MD, Division of Maternal Fetal Medicine, University of Rochester Strong Memorial Hospital. "Because a simple visual ultrasound is less accurate in obese women, we need to use any measurements that we can glean from the ultrasound to predict birth weight."

Device Blocking Stomach Nerve Signals Shows Promise
An implantable medical device, developed in collaboration with Mayo Clinic researchers, shows promise as a reversible and less-extreme alternative to existing bariatric surgeries, according to findings published in the journal Surgery.

"For this study, we wanted to get an initial assessment of whether blocking the vagus nerve electrically could cause obese patients to feel full after a normal-sized meal," Michael Camilleri, MD, Mayo Clinic, said. "Patients were not put on any restricted diets or given counseling that typically accompanies gastric banding or bypass. We wanted to determine how much weight loss could be attributed to the device alone."

In a 6-month, open-label trial involving three medical centers in Australia, Mexico, and Norway, the 31 obese participants who received the vagal nerve-blocking device, also called VBLOCTM vagal blocking therapy, lost an average of nearly 15% of their excess weight. A quarter of the participants lost >25%, and three patients lost >30%. A follow-up, double-blinded study, which will involve up to 300 patients at multiple medical centers including a limited number from Mayo Clinic, will be important for gauging the device's effectiveness, according to a news release.

Racial Discrepancies Among CKD Patients Common
Black patients have a higher risk of dying in the early stages of chronic kidney disease (CKD) than whites, according to a study appearing in the Journal of the American Society of Nephrology. The findings may explain why blacks have better survival rates once they reach advanced stages of the disease—in essence, because only the healthiest blacks are surviving long enough to develop later stages of the disease. If white patients are given better care in managing their condition early on, even less healthy patients may live to develop advanced disease. But, their compromised health may put them at increased risk of death in the long term compared with blacks.

The results of this study indicate that racial differences in the death rates of CKD patients depend more on sociological factors than on biological ones. Poverty and lack of education and medical insurance in particular may contribute to the high death rates among black individuals.

Previous research has documented that, in general, mortality rates for black individuals are persistently higher than those for whites. However, among patients with late-stage chronic kidney disease, the trend is reversed, and black individuals have a survival advantage over whites. Hispanic patients also seem to have a survival advantage over whites in these situations.

Rajnish Mehrotra, MD, of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and colleagues set out to find an explanation. They assessed data from a total of 14,611 patients in NHANES III. The investigators found that 2,892 of the individuals in the survey had CKD, 1,127 of whom died during follow-up. Among those with early-stage disease who were aged ²65 years, blacks had a 78% higher risk of death compared with whites. This elevated risk was significantly related to socioeconomic status and access to care. There was also a nonsignificant trend for higher mortality among Hispanics compared with whites.

Test Requests for Vitamin D Levels Skyrocketing
As studies raise awareness about the adverse effects of vitamin D deficiency, testing vitamin D levels has increased sharply. Quest Diagnostics in Madison, NJ, reports an 80% increase of tests ordered for vitamin D from May 2007 to May 2008, according to a report in USA Today. Two other diagnostic labs, Lab Corp. in Burlington, NC, and the Mayo Clinic report a 90% and 74% increase, respectively.

The jump in testing comes on the heels of emerging research linking vitamin D to infectious disorders, cancers, cardiovascular disease and autoimmune disorders, according to Patsy Brannon, PhD, Professor of Nutritional Sciences at Cornell University. Research also indicates that many Americans are deficient in vitamin D, another factor for the rise in tests, said Catherine Gordone, MD, MSc, Director of the Bone Health Program at Children's Hospital Boston.

Mom's Vitamin D Status During Pregnancy Affects Baby's Teeth
Low maternal vitamin D levels during pregnancy may affect primary tooth calcification, leading to enamel defects, which are a risk factor for early childhood tooth decay.

During the 86th General Session of the International Association for Dental Research in Toronto, Ontario, investigators from the University of Manitoba, Winnipeg, presented the results of a study they conducted to determine the vitamin D status of pregnant women, the incidence of enamel defects and early childhood tooth decay among their infants, and the relationship with prenatal vitamin D levels. Two hundred and six pregnant women in their second trimester participated in the study, according to a news release. Only 21 women were found to have adequate vitamin D levels. Vitamin D concentrations were related to the frequency of milk consumption and prenatal vitamin use. The investigators examined 135 infants aged an average of 16 months and found that 21.6% of them had enamel defects, while 33.6% had early-childhood tooth decay.

Mothers of children with enamel defects had lower, but not significantly different, mean vitamin D levels during pregnancy than those of children without defects. Mothers of children with early childhood tooth decay, however, had significantly lower vitamin D levels versus those whose children were cavity free. Infants with enamel defects were significantly more likely to have early childhood tooth decay.

Long-Term Alendronate Use Ups Risk for Fracture in Some
New evidence suggests a link between the risk for a type of femoral stress fracture and long-term bisphosphonate use.

A preliminary study followed 70 patients, 25 of whom were taking alendronate (Fosamax, Merck) for an average of 5 years. Among those receiving the therapy, 19 patients presented with a femoral stress fracture that resulted from little or no trauma. The fracture type was only evident in one patient not receiving the therapy. The average duration of alendronate use in those patients with the fracture pattern was significantly longer than in those who were not taking the therapy, at 6.9 years versus 2.5 years, respectively.

"While bisphosphonates like [alendronate] have been proven to successfully treat osteoporosis and other metabolic bone disease, we believe long-term use of these drugs may suppress the ability of bones to heal in some patients. As a consequence, patients with routine stress fractures are unable to properly heal, and minor damage can worsen until a serious fracture occurs," said senior author, Dean G. Lorich, MD, in a news release. Dr. Lorich is from the Weill Cornell Medical College, New York-Presbyterian/Weill Cornell Medical Center, and the Hospital for Special Surgery.

"It is not surprising that nearly 12 years after the approval and release of alendronate, we are seeing some side effects of long-term use," Michael Kleerekoper, MD, MACE, from the Department of Internal Medicine, St. Joseph Mercy Reichert Health Center, Ypsilanti, Mich., told Review of Endocrinology. "However, they must be put into perspective as those affected reflect a miniscule portion of those who have been helped by this and other similar drugs."

Dr. Kleerekoper, a member of the Review of Endocrinology Editorial Board, added that the type of side effect is also not surprising since the therapy works by inhibiting bone remodeling, which is an essential component of optimum skeletal health. For the vast majority of treated patients, it seems clear that the inhibition of remodeling does not reach a level that is directly injurious to the skeleton.

"Because we really do not have fail-safe tools for early detection of that small number who are likely to have over-suppression of bone turnover (remodeling), I have long adopted the approach of recommending a drug-free holiday to patients in whom the treatment-induced increase in bone mineral density ([BMD] as measured by DXA) has stabilized. By that I mean two consecutive properly done DXA studies 2 years apart demonstrate no change in BMD. I confirm the effectiveness of the inhibition of remodeling by measurement of biochemical markers of bone remodeling looking for values in the lower half of the normal range (reference interval). I then monitor the markers every 3 to 4 months and restart therapy as the values get into the upper half of the range."