News — January 2009

Recommendations for Cardiovascular Risk Evaluation in Diabetes Drugs: FDA
The US Food and Drug Administration (FDA) has recommended that manufacturers developing new drugs and biologics for type 2 diabetes provide evidence that the therapy will not increase the risk of such cardiovascular events as a myocardial infarction (MI). The recommendation is part of a new guidance for industry that applies to all diabetes drugs currently under development, according to an FDA news release.

"We need to better understand the safety of new antidiabetic drugs. Therefore, companies should conduct a more thorough examination of their drugs' cardiovascular risks during the product's development stage," said Mary Parks, MD, FDA's Director, Division of Metabolism and Endocrinology Products, Center for Drug Evaluation and Research (CDER). "The FDA's guidance outlines the agency's recommendations for doing such an assessment."

More than 23 million people in the United States have been diagnosed with type 2 diabetes, and patients with diabetes have a two to four times greater risk of heart disease than their nondiabetic counterparts. None of the currently approved antidiabetic therapies has been convincingly proven to reduce that risk. Because diabetes often requires life-long treatment, prescribers and patients need to know more about whether antidiabetic therapies increase the risk of MI, the FDA said.

The guidance, effective immediately, defines more robust and adequate design and data collection approaches for phase 2 and phase 3 clinical trials than previously required. Specifically, the guidance recommends that these studies demonstrate that new antidiabetic therapies do not increase cardiovascular risk in comparison with existing therapies—especially when the drugs are used by patients of advanced age or by those with advanced diabetes or renal impairment.

The FDA also recommends that manufacturers have any cardiovascular events in their clinical trials analyzed by committees of outside cardiologists who are blinded to treatment groups. The FDA can then better ensure that product labeling includes comprehensive information on safety and effectiveness.

The FDA said it remains confident that currently marketed antidiabetic therapies are safe and effective when used according to approved labeling and advises patients to work with their health care professionals to select the most appropriate therapy to achieve adequate blood glucose control. The FDA is continuing to evaluate how the new recommendations will be applied to already-approved antidiabetic drugs and expects to release further guidance on this issue in the future.

FDA Approves Fenofibric Acid in Combination With Statins for Cholesterol Management
The FDA has approved fenofibric acid (TriLipix, Abbott) delayed-release capsules for use along with diet to help lower triglycerides and low-density lipoprotein (LDL) cholesterol and to raise high-density lipoprotein (HDL) cholesterol in patients with lipid abnormalities. Fenofibric acid can be used alone or in combination with a statin.

"Only 35% of patients with lipid problems are currently being treated with lipid therapies, and many are not reaching treatment targets for all three key lipids," said Michael Davidson, MD, from the University of Chicago Pritzker School of Medicine in an Abbott news release. "The approval of [fenofibric acid] is good news for patients because now there is a new treatment option that can be used alone or in combination with a statin to help address lipid problems."

The approval is based on the results from a trial evaluating the efficacy and safety of a fibrate in combination with various statins. The efficacy and safety of fenofibric acid in combination with rosuvastatin, atorvastatin (Lipitor, Pfizer), and simvastatin was evaluated in three randomized, multicenter, double-blind, controlled, 12-week, phase 3 studies, totaling 2,698 patients with mixed dyslipidemia. Patients included in the studies had multiple lipid problems, with an LDL ≥130 mg/dL, triglycerides ≥150 mg/dL, and HDL <40 mg/dL for men and <50 mg/dL for women. A total of 1,911 patients who completed one of the 12-week studies subsequently enrolled in a 52-week long-term, open-label extension study. The phase 3 combination studies all met their primary endpoints. Combination therapy significantly improved HDL and triglycerides compared with statin therapy alone and significantly improved LDL compared with fenofibric acid alone. All of the combinations and the statins were associated with clinically meaningful reductions in LDL. Common side effects included headache, heartburn, nausea, muscle aches, and increases in muscle or liver enzymes.

Associations Revise Glycemic Recommendations for Some
Some individuals with diabetes may require less stringent glycemic control than previously recommended, but most should stick with the target goal of <7% long advised for reducing the risk of diabetes-related complications, according to a position statement issued jointly by the American College of Cardiology (ACC), American Diabetes Association (ADA), and American Heart Association (AHA).

The ACC, ADA, and AHA reexamined the glycemic control guidelines in light of three recent clinical trials in patients with long-standing type 2 diabetes and high cardiovascular risk that suggested no significant benefit and/or risks related to intensive glycemic control and heart disease prevention. The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial was halted early because of an increased death rate in the intensive control group, while the ADVANCE (Action in Diabetes and Vascular Disease) study and VADT (Veterans Affairs Diabetes Trial) found no apparent increase in deaths, but no significant cardiovascular benefit.

Previous observational studies found an association between higher A1C levels and cardiovascular events. Long-term follow-up of the DCCT (Diabetes Control and Complications Trial) and UKPDS (UK Prospective Diabetes Study) cohorts found cardiovascular benefit for people with type 1 and type 2 diabetes who underwent intensive glycemic control soon after the diagnosis of diabetes.

"Given the confusion created by these conflicting results, we thought it imperative to review our recommendations for all people with diabetes," said Jay Skyler, MD, Professor of Medicine, Pediatrics and Psychology at the University of Miami Miller School of Medicine, who headed the writing group. "What we conclude is that for most people with diabetes, there's no need to change treatment goals in light of these findings and many reasons to continue to strive for good glycemic control. But for some people with type 2 diabetes, depending upon their history and current medical condition, it may be wise to make adjustments," he said in an AHA news release. The recommendations are consistent with prior suggestions that glycemic goals should be individualized depending on the medical history of the patient.

"The lack of significant reduction in [cardiovascular disease] events with intensive glycemic control should not lead clinicians to abandon the general target of A1C levels of <7% and thereby discount the benefit of good control on what are serious and debilitating microvascular complications," the joint statement concluded.

For those who have a "history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and those with long-standing diabetes in whom the general goal is difficult to attain despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin," less stringent A1C goals should be considered, according to the statement.

The ADA's Standards of Medical Care and the AHA's prevention guidelines call for reducing cardiovascular risk factors through blood pressure control, lipid lowering with statins, aspirin therapy, and lifestyle modifications such as weight loss, proper nutrition, and increased physical activity.

Low-Glycemic Diet Beats High-Fiber Diet for Glycemic Control
Individuals with type 2 diabetes who adhered to a diet high in low-glycemic-index foods such as nuts, beans, and lentils had greater improvement in glycemic control and risk factors for coronary heart disease (CHD) than individuals on a diet with an emphasis on high-cereal fiber, according to a study in the Journal of the American Medical Association (JAMA).

One dietary strategy aimed at improving both diabetes control and cardiovascular risk factors is the use of low-glycemic-index diets, but there is disagreement over their effectiveness, according to background information in the article.

David J. A. Jenkins, MD, of St. Michael's Hospital and the University of Toronto, and colleagues assessed the effects of a low-glycemic-index diet versus a high-cereal-fiber diet on glycemic control and cardiovascular risk factors for 210 patients with type 2 diabetes, according to a JAMA news release. The participants, who were treated with antihyperglycemic medications, were randomized to one of the two dietary interventions for 6 months.

In the low-glycemic-index diet, the following foods were emphasized: beans, peas, lentils, nuts, pasta, rice boiled briefly, and low-glycemic-index breads (including pumpernickel, rye pita, as well as quinoa and flaxseed) and breakfast cereals (including large-flake oatmeal and oat bran). In the high-cereal-fiber diet, participants were advised to take the "brown" option (whole-grain breads; whole-grain breakfast cereals; brown rice; potatoes with skins; and whole-wheat bread, crackers, and breakfast cereals). Three servings of fruit and five servings of vegetables were encouraged on both treatments.

The researchers found that A1C decreased by -0.50% absolute A1C units in the low-glycemic-index diet group versus -0.18% absolute A1C units in the high-cereal-fiber diet group. Significant treatment effects were observed for HDL and the LDL:HDL ratio. HDL increased in the low-glycemic-index diet group by 1.7 mg/dL and decreased by -0.2 mg/dL in the high-cereal-fiber diet group. The LDL:HDL ratio showed a greater reduction in the low-glycemic-index diet group compared with the high-cereal-fiber diet group.

"Lowering the glycemic index of the diet improved glycemic control and risk factors for [CHD]. These data have important implications for the treatment of diabetes in which the goal has been tight glycemic control to avoid complications. The reduction in A1C was modest, but we think it has clinical relevance," the investigators said. "Low-glycemic-index diets may be useful as part of the strategy to improve glycemic control in patients with type 2 diabetes taking antihyperglycemic medications.

"Pharmacological interventions to improve glycemic control in type 2 diabetes have often failed to show a significant reduction in cardiovascular events. In view of the two- to fourfold increase in CHD risk in participants with type 2 diabetes, the ability of a low-glycemic-index diet to address both glycemic control and CHD risk factors increases the clinical relevance of this approach for patients with type 2 diabetes, such as those in this study, who are overweight and also taking statins for CHD risk reduction."

Screening Tool May Identify Patients With Prediabetes
Researchers have created a clinical tool to identify those at highest risk for having undetected hyperglycemia, impaired fasting glucose (IFG), and undiagnosed diabetes. The study was published in the Annals of Family Medicine. If these conditions are identified early, patients may benefit from preventive strategies that can minimize progression to diabetes, other diseases, and mortality.

"Diabetic risk factors are not equal, and assessing a combination of risk factors can be confusing," said Richelle J. Koopman, MS, MS, from the University of Missouri School of Medicine, Columbia, Mo., in a university news release. "A tool that weighs the relative contributions of multiple risk factors and creates an overall risk score will help clinicians decide which patients to screen for diabetes. The tool we have developed is easy to use, and the screening can be done with pencil and paper. Patients can do it at a health fair or a physician's office."

The Tool to Assess Likelihood of Fasting Glucose Impairment (TAG-IT) is designed to use factors that are self-reported or easily measured. The six factors include: age, gender, body mass index (BMI), family history, resting heart rate, and measured high blood pressure. According to Dr. Koopman, as type 2 diabetes becomes an increasing burden in younger populations, it is important to have a screening tool that can assess undiagnosed diabetes and IFG in people aged as young as 20 years.

"There has been increasing evidence that prediabetic states are associated with diseases and other complications, and strategies that prevent diabetes in those with prediabetes are effective," said Dr. Koopman. "The TAG-IT tool will help physicians assess patients' risk levels. Hopefully, knowing their TAG-IT scores will encourage high-risk patients to use preventive strategies and make positive changes in their behaviors. The tool has potential as a Web-based screening [component] that could improve awareness and encourage compliance with lifestyle changes."

Bariatric Surgery May Resolve Liver Disease Complications
Complications of nonalcoholic fatty liver disease (NAFLD), including steatosis, steatohepatitis, and fibrosis appeared to improve or completely resolve in a majority of patients after bariatric surgery-induced weight loss, according to a study published in Clinical Gastroenterology and Hepatology.

"Even today, the effect of weight loss after bariatric surgery on the liver, particularly NAFLD, remains unclear. There is a lack of well-defined trials exploring this relationship," said lead author Gagan K. Sood, MD, University of Texas Medical Branch, Galveston. "Our team assessed and quantified this effect and found encouraging news: a majority of patients experience complete resolution of NAFLD after bariatric surgery, and the risk of progression of inflammatory changes and fibrosis seems to be minimal," Dr. Sood said in a news release from the American Gastroenterological Association.

For the meta-analysis, 15 studies were selected for final data extraction. The mean age of the participants at the time of weight loss surgery ranged from 35.6 to 49 years. Mean BMI at the time of weight loss surgery ranged from 43.9 to 56 kg/m2, and the mean BMI at follow-up liver biopsies ranged from 28.6 to 39 kg/m2. Percentage reduction in mean BMI values ranged from 19.11 to 41.76. The pooled proportion of patients with improvement or resolution in steatosis was 91.6%, steatohepatitis was 81.3%, fibrosis was 65.5%, and complete resolution of nonalcoholic steatohepatitis was 69.5%.

The authors noted that the results may require confirmation from large, multicenter trials using uniform histopathological criteria for liver biopsy specimens.

Radiotherapy Plus Hormone Halves Prostate Cancer Death
In patients with locally advanced or high-risk prostate cancer, combining prostate radiotherapy with the conventional endocrine treatment halves mortality. Thus, endocrine treatment plus radiotherapy should be the new standard, according to a study online and in The Lancet.

Anders Widmark, MD, PhD, from the Department of Radiation Sciences, Oncology, Umeå University, Sweden, and colleagues conducted a phase 3 randomized trial in 875 men with locally advanced prostate cancer, according to a news release from The Lancet. Patients were assigned to endocrine treatment alone (n = 439), consisting of 3 months androgen blockage followed by continuous endocrine treatment with flutamide or to the same treatment combined with radiotherapy (n = 436).

Researchers found that after a median follow-up of 7.6 years, 79 men in the endocrine-only group and 37 men in the endocrine-plus-radiotherapy group had died of prostate cancer. The 10-year prostate cancer-specific mortality rate in the endocrine-only group (23.9%) was double that of the endocrine-plus-radiotherapy group (11.9%). Death from any cause was also higher in the endocrine-only group (39.4%) than in the endocrine-plus-radiotherapy group (29.6%). Cumulative incidence of recurrence of prostate cancer at 10 years, as determined by a positive test for prostate-specific antigen, was nearly three times higher in the endocrine-only group (75%) than in the endocrine-plus-radiotherapy group (26%). After 5 years, urinary, rectal, and sexual problems were slightly more frequent in the combined-treatment group than in the endocrine-only group.

"The present study indicates a significant superiority of the endocrine-plus-radiotherapy treatment compared with endocrine-treatment alone in patients with locally advanced prostate cancer," the investigators wrote. "The endocrine plus radiotherapy resulted in a substantial reduction of prostate cancer mortality. This significant difference, which at 10 years reached 12%, also translated into improved difference in overall survival (9.8%). The quality of life and adverse effect profile [of radiotherapy] is acceptable. We therefore suggest that endocrine treatment plus radiotherapy should be the new standard of care for these patients."

High-Dose Thiamine May Improve Diabetic Nephropathy
High doses of thiamine can dramatically decrease the excretion of albumin and reverse early-stage kidney disease in patients with type 2 diabetes, according to a pilot study published online in Diabetologia.

Naila Rabbani, MD, from the Warwick Medical School, University of Warwick, Coventry, UK, and colleagues from the Sheikh Zayed Hospital, Lahore, Pakistan, conducted a randomized, double-blind study to assess whether oral supplements of thiamine could reverse microalbuminuria in patients with type 2 diabetes. A total of 40 patients, aged 35 to 65 years, with type 2 diabetes were recruited from the Diabetes Clinic in Sheikh Zayed Hospital. Patients were randomized to receive thiamine 300 mg daily for 3 months or a placebo.

According to a news release from Warwick University, the primary endpoint was change in urinary albumin excretion (UAE). Results showed that patients taking 300 mg of thiamine had a reduced rate of albumin excretion by 41% from baseline (P<.001). In addition 35% of patients with microalbuminuria saw a return to normal UAE after being treated with thiamine. There was no effect of thiamine treatment on glycemic control, dyslipidemia, or blood pressure. There were no adverse effects of therapy.

Rosiglitazone, Pioglitazone Double Fracture Risk in Women
Rosiglitazone (Avandia, GlaxoSmithKline) and pioglitazone (Actos, Takeda) may increase the risk of fractures in women, according to a meta-analysis published in the Canadian Medical Association Journal (CMAJ).

Yoon K. Loke, MD, from the School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, UK, and colleagues looked at 10 randomized controlled trials of at least 1 year's duration involving 13,715 patients with diabetes taking thiazolidinediones and two observational studies, according to a news release from CMAJ.

Rosiglitazone and pioglitazone were associated with a significantly increased risk of fractures overall in the 10 randomized controlled trials (95% confidence interval [CI], 1.18–1.79; P<.001). Of the trials analyzed, two found significantly reduced bone density in the lumbar spine (P=.02) and hip (P<.001) among women taking thiazolidinediones. Five randomized controlled trials showed a significantly increased risk of fractures among women (odds ratio [OR] 2.23; 95% CI, 1.65–3.01; P<.001) but not among men (OR 1.00; 95% CI, 0.73–1.39; P= .98). The researchers estimate that a fracture would occur in one out of 21 women at high risk of fracture who are taking thiazolidinedione for 1 year, and among low-risk women, there would be one fracture in every 55 if these drugs were taken for more than a year.

With more than 4 million users of thiazolidinediones in the United States alone in 2006, "the public health impact may be considerable," the authors wrote. "If one assumes that half of those users were women and that the baseline risk of fractures is similar to that found in ADOPT (A Diabetes Outcome Progression Trial), an estimated 30,000 excess fractures may have occurred if these women had been prescribed thiazolidinediones rather than metformin for more than a year."

Lack of Vitamin D Causes Weight Gain, Stunts Growth
Insufficient vitamin D can stunt growth and foster weight gain during puberty, according to a study published in the Journal of Clinical Endocrinology & Metabolism. Even in California, where researchers conducted their study, vitamin D deficiency was found to cause higher body mass and shorter stature in girls at the peak of their growing spurt, according to a news release from the McGill University Health Centre in Montreal.

"The high prevalence of vitamin D insufficiency in young people living in a sun-rich area was surprising," said lead author Richard Kremer, MD, from the Musculoskeletal Axis of the McGill University Health Centre. "We found young women with vitamin D insufficiency were significantly heavier, with a higher BMI and increased abdominal fat, than young women with normal levels."

The research team measured vitamin D in 90 girls aged 16 to 22 years using a simple blood test (25-hydroxyvitamin D). They also assessed body fat and height to determine how vitamin D deficiency could affect young women's health. They discovered that young women with normal vitamin D levels were on average taller than peers deficient in vitamin D. In contrast to what has been previously reported in older women, their investigation found no association between lack of vitamin D and bone strength.

"Although vitamin D is now frequently measured in older adults, due to a higher level of awareness in this population, it is rarely measured in young people—especially healthy adolescents," said Dr. Kremer.

WHO Risk Assessment Tool Helps Target Bone Treatment
A new method for determining more accurately at which point an individual needs further diagnostic tests, or when immediate treatment is warranted, has been developed, and the findings appear in the journal, Osteoporosis International.

The new method, developed by researchers from the National Osteoporosis Guideline Group and the World Health Organization (WHO) Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Sheffield, UK, already forms the basis of the new clinical guidelines for the management of osteoporosis in the United Kingdom. Rather than relying primarily on bone mineral density (BMD) measurements, as the majority of current guidelines do, their approach takes into account both the risk of someone suffering a fracture using the WHO's fracture risk assessment tool (FRAX), as well as whether or not treatment is likely to be cost-effective.

"The incorporation of the WHO risk assessment tool, FRAX, into practice guidelines in the United Kingdom is a key development that will target treatment more accurately to those in need and avoid unnecessary treatment in men and women at low risk. I hope that this paper will serve as a template for the development of FRAX-based guidance in other countries," said lead author John A. Kanis, PhD, National Osteoporosis Guideline Group.

The FRAX tool predicts the 10-year risk of men and women suffering a fracture. An individual's age, gender, weight, height, and femoral BMD, if available, are entered into the Web-based tool, followed by clinical risk factors for osteoporosis including a prior fracture, parental history of hip fracture, smoking, long-term use of glucocorticoids, rheumatoid arthritis, and alcohol consumption. The tool then calculates the likelihood of the individual suffering a fracture in the next 10 years.

According to the journal's publisher, because this new method for the management of osteoporosis takes into account the likelihood of someone suffering a fracture, rather than relying solely on BMD, or BMD with one or more recognized clinical risk factors, it is an important milestone towards helping health professionals worldwide to identify patients at high risk of fracture more accurately and treat them cost-effectively.