News — April 2009

ADA, AACE Comment on Intensive vs Conventional Glucose Control in Critically Ill Patients: NICE-SUGAR
A study published in the New England Journal of Medicine (NEJM) suggests that intensive blood glucose control for critical care patients with hyperglycemia does not improve outcomes and is associated with an increase in deaths.

The American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) maintain that the findings of the NICE-SUGAR (Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation) study should not lead to an abandonment of the concept of good glucose management in the hospital setting. Uncontrolled high blood glucose can lead to serious problems for hospitalized patients, such as dehydration and increased propensity to infection.

According to the joint news release, it is important to consider that the severely ill patients in this trial were treated intensively with intravenous insulin to very tight targets (average 115 mg/dL). The participants were compared with a control group whose glucose control was good (average 144 mg/dL).

In the news release, ADA and AACE caution against letting this study swing the pendulum of glucose control too far in the other direction where providers in hospitals are complacent about uncontrolled hyperglycemia. The two organizations maintain that strategies must be identified to help hospitals establish structured protocols for safe and effective management of blood glucose in both intensive care units and other hospital settings.

"Since 2003, AACE and the ADA have worked together to provide recommendations for treatment of inpatient hyperglycemia, and these efforts have contributed to a growing national movement viewing the management of hyperglycemia in hospitals as a quality care measure," said Etie S. Moghissi, MD, AACE Chair of the Inpatient Glycemic Control Task Force.

Recognizing the critical importance of controlling hyperglycemic states in conjunction with the results of recent randomized trials such as NICE-SUGAR, the two organizations recently convened a consensus panel. The panel will extensively review the most current literature and up-to-date recommendations for treatment of hyperglycemia in the hospital, the statement said.

"The central goal of the ADA/AACE inpatient task force is to identify reasonable, achievable, and safe glucose targets, and to describe the protocols, procedures, and system improvements needed to achieve inpatient optimal glucose control efficiently and safely," said Mary Korytkowski, MD, ADA Chair of the Inpatient Glycemic Control Task Force.

Complete recommendations from the panel will be published in Endocrine Practice and Diabetes Care later in the spring.

Statins May Falsely Indicate Thyroid Problems
Statins may falsely indicate thyroid problems, according to researchers at Texas Health Presbyterian Hospital Dallas.

"These findings could help physicians make quicker, more accurate diagnoses of suspected thyroid problems," said William Harvey, MD, a nuclear medicine physician and author of the study in Thyroid. "It also has very provocative scientific implications as we learn more about how statins affect different systems in the body."

Researchers re-examined 307 patients whose initial thyroid-stimulating hormone (TSH) blood tests showed overactive thyroids. Symptoms of hyperthyroidism can include a fast heart rate and palpitations, tremors, anxiety, weak muscles, and difficulty sleeping, according to a news release from Texas Health Resources.

For their study, the researchers administered more specialized diagnostics. These new tests showed that the majority of patients on statins who appeared to be hyperthyroid by TSH tests actually had normal thyroid function. The tests also confirmed that the majority of patients not taking statins did indeed have thyroid problems, as the initial TSH tests suggested.

"These findings are fascinating because there's a possibility that statins may improve thyroid function in patients with overactive thyroids," said Mark Feldman, MD, Chairman of Internal Medicine at Texas Health Dallas and the study's senior author. "It could be an unexpected but delightful consequence of this research one day."

New Recommendations on Aspirin in CVD Prevention
Physicians should consider risk factors including age, gender, diabetes, blood pressure, cholesterol levels, smoking, and risk of gastrointestinal bleeding (GI) before deciding whether to use aspirin to prevent myocardial infarctions (MI) or strokes.

The new recommendations from the US Preventive Services Task Force are published in the Annals of Internal Medicine. According to a news release from the Agency for Healthcare Research and Quality, the task force reviewed new evidence from the National Institutes of Health's (NIH) Women's Health Study, including a recent meta-analysis of the risks and benefits of aspirin and found aspirin may have different benefits and harms in men and women.

The task force found good evidence that aspirin decreases first MIs in men and first strokes in women. The more risk factors individuals have, the more likely they are to benefit from aspirin, according to the findings. The task force recommended that men aged 45 to 79 years should use aspirin to reduce their risk for MI when the benefits outweigh the harms for potential GI bleeding. Women aged

55 to 79 years should use aspirin to reduce their risk for ischemic stroke when the benefits outweigh the harms for potential GI bleeding.

The task force recommended against using aspirin to prevent either strokes or heart disease in men aged <45 years or women aged <55 years because MIs and strokes are less likely to occur in men and women in this age group and because limited evidence exists in these age groups. People aged ≥80 years could benefit more than younger people from aspirin because of their higher risk of CVD, but the harms are also greater because the risk of GI bleeding increases with age.

Reduced-Calorie Diets Promote Long-Term Weight Loss, Regardless of Diet Type
Heart-healthy diets that reduce calorie intake—regardless of differing proportions of fat, protein, or carbohydrate—can help overweight and obese adults achieve and maintain weight loss, according to a study published in the NEJM.

Researchers from the POUNDS LOST (Preventing Overweight Using Novel Dietary Strategies) study found similar weight loss after 6 months and 2 years among participants assigned to four diets that differed in their proportion of fat, protein, or carbohydrate, according to a news release from the NIH.

"This new information should focus weight-loss approaches on reducing calorie intake rather than any particular proportions of fat, protein, or carbohydrate," said principal investigator Frank M. Sacks, MD, Department of Nutrition, Harvard School of Public Health. "This is important information for health professionals who prescribe weight loss for their patients, and for adults who are seeking ways to sustain a healthful eating pattern."

For the study, 811 overweight and obese adults aged 30 to 70 years (38% male) were assigned to one of four diets and asked to record their food intake in a diary or an online tool that showed how intake compared with goals. Group diet counseling sessions were held at least twice per month throughout the 2 years of the study, and individual sessions were held every 8 weeks.

The target nutrient compositions of the four diets were: (1) 20% fat, 15% protein, 65% carbohydrate; (2) 20% fat, 25% protein, 55% carbohydrate; (3) 40% fat, 15% protein, 45% carbohydrate; or (4) 40% fat, 25% protein, 35% carbohydrate. The diets all used the same calorie reduction goals and were low in saturated fat and cholesterol and high in dietary fiber.

Participants were given personalized calorie goals (1,200–2,400 calories per day), which reduced their overall caloric intake as compared with their daily energy requirement, according to the study. All participants were asked to participate in moderate-intensity activity for at least 90 minutes per week.

On average, individuals lost 6.5 kg (13 lbs) at 6 months and maintained a 4.5 kg (9 lbs) loss at 2 years. Participants also reduced their waistlines by 1 to 3 inches by the end of the study. Craving, fullness, hunger, and diet satisfaction were all similar across the four diets, and all diets improved risk factors for CVD both 6 months and 2 years in ways consistent with previous studies.

Red Flag For CVD: Daytime Sleepiness
Clinicians should be alert to patients reporting excessive daytime sleepiness, according to the European Society of Cardiology (ESC), after a French study found healthy elderly people who regularly report feeling sleepy during the day have a significantly higher risk of dying from CVD.

The Three City study, published in Stroke, found that elderly people who reported excessive daytime sleepiness have a 49% relative risk increase of cardiovascular death (from cerebrovascular disease, MI, and heart failure), compared with those who do not report sleepiness.

"Based on this study, asking patients the simple question of whether they feel sleepy during the day is a useful way of identifying a subgroup of elderly patients at higher risk of CVD who require a more thorough follow-up," said Guy DeBacker, MD, from the Division of Cardiology at the University of Ghent, Belgium, and former chair of the ESC Joint Prevention Committee, in an ESC news release.

Torben Jorgensen, MD, from the Research Centre for Prevention and Health, Glostrup, Denmark, commented: "The study offers the opportunity to practice prevention by investigating the underlying causes of patient's sleep problems, and then introducing lifestyle changes with the intention of preventing later cardiovascular complications."

According to the ESC, the Three City study represents the largest investigation to date exploring the prospective association between excessive daytime sleepiness and mortality in the community dwelling elderly, and the only study yet to have been conducted in Europe.

"The [individuals] with excessive daytime sleepiness were less educated and had a lower income so there were differences between the two groups in socioeconomic status, which was not accounted for in the multivariate analysis. Socioeconomic status is a strong independent predictive factor for total and for cause specific mortality, and it might be that the difference between the two groups is just the effect of socioeconomic differences," said Prof. DeBacker.

Both Prof. DeBacker and Dr. Jorgensen said the results are "hypothesis generating," and that the data needs to be confirmed in other large-scale studies in different populations before any changes should be made to existing guidelines.

Simplified OSA Treatment as Effective as Traditional Therapy
Treating obstructive sleep apnea (OSA) using experienced nurses, home ambulatory diagnosis, and autotitrating continuous positive airway pressure (CPAP) machines is not inferior to the traditional model which relies on specialist physicians and sleep studies, according to a study published in the American Journal of Respiratory and Critical Care Medicine.

The randomized, multicenter study directly compared the results of two OSA diagnosis and treatment protocols—simplified and traditional—as well as their respective costs. "The main finding of the study was that the simplified model of care was not inferior to the usual physician-led, hospital-based model," said Nick A. Antic, PhD, Adelaide Institute for Sleep Health, Adelaide, Australia, in a news release from the American Thoracic Society.

To determine whether diagnosis and subsequent treatment could be simplified without health costs to the patient, Dr. Antic and colleagues developed a nurse-led diagnosis and treatment model that featured ambulatory overnight oximetry and autotitrating CPAP machines to set fixed CPAP under nurse supervision. They compared the results of patients thus diagnosed and treated with those who underwent standard sleep medicine pathways, including laboratory-based polysomnography, CPAP titration, and physician management of the patient.

They assessed the patients' sleepiness on the validated Epworth Sleepiness Scale (ESS) and set the minimal clinically significant change at ±2 points. They also assessed other outcomes of sleep, including quality of life measures, executive neurocognitive function on maze tasks and maintenance of wakefulness tests, and CPAP adherence. In all, the study assessed about 200 patients with moderate-to-severe OSA who were randomly assigned to the simplified or traditional model.

The patients in the nurse-led group spent about 50 minutes longer with the nurse than the patients in the physician-led groups, but were seen by physicians 12% of the time. Patients in the physician-led group, meanwhile, had an average of 2.36 consultations with physicians, as opposed to 0.18 for patients in the nurse-led group.

Despite these obvious differences, none of the secondary outcomes measured showed significant differences between the groups, and differences in ESS scores between groups were lower than the predetermined minimum for clinical significance. Notably, the patients in the nurse-led group were diagnosed and treated for $722 US dollars less per patient than those in the physician-led group, but did not receive inferior care or experience worse outcomes, according to the news release.

FIELD: Diabetes Patients With High Triglycerides, Low HDL Benefit Most From Fenofibrate
Fenofibrate treatment reduced CVD risk in patients with type 2 diabetes and atherogenic dyslipidemia (triglycerides ≥2.3 mmol/L and HDL <1.03 mmol/L in men and <1.3 mmol/L in women), according to new data from the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study published in Diabetes Care.

In these patients, fenofibrate treatment was associated with a significant 27% relative reduction in the risk of cardiovascular events, compared with 11% in FIELD patients overall, according to a news release from Solvay.

Russell Scott, MD, investigator and executive member of the FIELD Study Management Committee, Director of the Lipid and Diabetes Research Group, and Professor of Medicine, Christchurch Hospital, New Zealand, said: "This 27% relative reduction in total CVD events with fenofibrate in type 2 diabetes patients with marked atherogenic dyslipidemia is of a similar order to that observed with statin treatment. Physicians can prevent one fatal or nonfatal cardiovascular event by treating only 23 of these patients over 5 years with fenofibrate."

More than 80% of patients in FIELD met the NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III) criteria for metabolic syndrome. This latest study investigated whether cardiovascular risk and the effects of fenofibrate treatment differed in type 2 diabetes patients with and without the metabolic syndrome. The study also examined the effect of more marked atherogenic dyslipidaemia. One in five FIELD patients had marked atherogenic dyslipidemia and one in four had markedly high triglycerides.

Placing the new findings in clinical context, Prof. Scott said: "Atherogenic dyslipidemia, characterized by high triglycerides É and low HDL, as defined by ATP III, is a strong contributor to residual vascular risk in millions of patients with diabetes treated with the best standard of care, including statin therapy. These new findings, together with the microvascular benefits associated with fenofibrate, argue for consideration of fenofibrate in the clinical management of patients with type 2 diabetes and marked atherogenic dyslipidemia."

High Triglycerides Common, Often Untreated
High concentrations of triglycerides are common in the United States, according to a report in Archives of Internal Medicine. Lifestyle changes are the preferred initial treatment for hypertriglyceridemia, but physical inactivity, obesity, and other modifiable risk factors remain prevalent.

"Increasing evidence supports triglyceride concentration as a risk factor for [CVD]," the authors wrote. "If triglyceride concentrations are indeed a risk factor for [CVD], then it becomes important to establish the prevalence of hypertriglyceridemia in the US population and to learn about the degree of pharmacologic management of this risk factor."

According to a news release from the journal's publisher, Earl S. Ford, MD, MPH, and colleagues at the Centers for Disease Control and Prevention, examined data for 5,610 participants aged ≥20 years who participated in NHANES (National Health and Nutrition Education Survey) between 1999 and 2004. A total of 33.1% of participants had a triglyceride concentration of ≥150 mg/dL (150–199 mg/dL = borderline-high according to the 2001 NCEP), 17.9% had levels ≥200 mg/dL (high), 1.7% had levels ≥500 mg/dL, and 0.4% had levels of ≥1,000 mg/dL.

Compared with those who did not have hypertriglyceridemia, those who did were more likely to be older, be white, have not pursued an education beyond high school, smoke, be overweight or obese, or have diabetes.

"An important approach to the patient with hypertriglyceridemia is the implementation of nonpharmacological interventions," according to Dr. Ford and colleagues. "The high percentages of participants with a triglyceride concentration of ≥200 mg/dL who were overweight or obese, who failed to engage in physical activity for approximately 150 minutes per week, or who smoked, attest to the challenge confronting health care providers in working with their patients to implement therapeutic lifestyle changes."

A total of 1.3% of participants used either fenofibrate, gemfibrozil, or niacin to treat hypertriglyceridemia, including 2.6% of those with a concentration of ≥150 mg/dL and 3.6% of those with a concentration of ≥200 mg/dL. This may reflect uncertainty about the need to treat this abnormality, the authors noted. The benefits of pharmacotherapy are clear for patients with levels of ≥500 mg/dL who are at risk for pancreatitis, but therapeutic lifestyle changes remain the initial therapy of choice for those with levels between 200 and 500 mg/dL.

"As research clarifies uncertainties in the relation between triglyceride concentration and [CVD], guidelines to treat hypertriglyceridemia will likely be modified," they concluded.

Bariatric Surgery Shows Potential to Resolve Diabetes
As the incidence of obesity-induced type 2 diabetes continues to increase worldwide, medical research indicates that surgery to reduce obesity can eliminate all manifestations of diabetes. In a study from the American Journal of Medicine, investigators analyzed 621 studies from 1990 to April of 2006, which showed that 78.1% of patients with diabetes had complete resolution and diabetes was improved or resolved in 86.6% of patients as the result of bariatric surgery. The primary risk factor for type 2 diabetes is obesity, and 90% of all patients with type 2 diabetes are overweight or obese.

The dataset included 135,246 patients where 3,188 patients reported resolution of the clinical and laboratory manifestations of type 2 diabetes, according to a news release from the journal's publisher. Nineteen studies with 11,175 patients reported both weight loss and diabetes resolution outcomes separately for the 4,070 diabetic patients in those studies. Clinical findings were substantiated by the laboratory parameters of serum insulin, A1C, and glucose.

Researchers observed a progressive relationship of diabetes resolution and weight loss as a function of the operation performed: laparoscopic adjustable gastric banding, gastroplasty, gastric bypass, and biliopancreatic diversion/duodenal switch (BPD/DS). Gastric banding yielded 56.7% resolution, gastroplasty 79.7%, gastric bypass 80.3%, and BPD/DS 95.1%. After more than 2 years postoperatively, the corresponding resolutions were 58.3%, 77.5%, 70.9%, and 95.9%. In addition, the percent excess weight loss was 46.2%, 55.5%, 59.7%, and 63.6%, for the type of surgery performed, respectively.

Henry Buchwald, MD, PhD, of the Department of Surgery, University of Minnesota, wrote: "This systematic review and meta-analysis demonstrate that bariatric surgery has a powerful treatment effect in morbidly obese persons with type 2 diabetes; 82% of patients had resolution of the clinical and laboratory manifestations of diabetes in the first 2 years after surgery, and 62% remained free of diabetes more than 2 years after surgery (80% and 75% for the total group). Randomized clinical trials comparing surgery and medical therapies for type 2 diabetes are urgently needed. Considering the potential benefits for millions of people, such trials should assess the risk/benefit ratio of surgery in less obese (body mass index [BMI] 30–35 kg/m2) populations, as well as in the morbidly obese (BMI >35 kg/m2) population."

Testosterone Deficiency Syndrome Risk in 50% of Men With Type 2 Diabetes
Data presented at the Diabetes UK Annual Conference reveal that Testosterone Deficiency Syndrome (TDS) is found in more than 50% of men with type 2 diabetes, more than double the rate in the nondiabetic population. TDS is associated with a 42% additional risk of developing type 2 diabetes, and up to 60% additional risk of all-cause and coronary heart disease (CHD) mortality, according to a news release from Bayer HealthCare.

TDS, or hypogonadism, describes symptomatic patients with low serum testosterone levels (generally <12 nmol/L). TDS is estimated to affect one in 10 men aged >50 years. The data reveal that TDS is associated with insulin resistance, raised A1C, visceral adiposity, increased BMI, and erectile dysfunction (ED), all of which are significant CHD risk factors.

Geoff Hackett, MD, Consultant in Sexual Medicine at Good Hope Hospital, Sutton Coldfield, UK, said: "[TDS] is more common than [general practitioners] realize, particularly amongst men with type 2 diabetes. [ED] has been shown to be a robust predictor of CHD risk in men with type 2 diabetes and yet neither testing for low testosterone nor ED assessment are part of the [UK's Quality Outcome Framework]. Assessment of testosterone is regarded as mandatory by all published authoritative guidelines on ED management."

TDS can be treated with testosterone therapy. Data presented reveal that testosterone therapy in hypogonadal diabetic men reduces insulin resistance and has beneficial effects on glycemic control, waist circumference, leptin, and cholesterol.

Recently published recommendations on the identification, monitoring, and treatment of hypogonadism have been formulated by major international scientific organizations, including the European Association of Urology, the European Society of Endocrinology, and the European Academy of Andrology. These state that all patients presenting with type 2 diabetes or with ED should have their serum testosterone levels measured.

Increasing Number of Americans Have Insufficient Vitamin D Levels
Average blood levels of vitamin D appear to have decreased in the United States between 1994 and 2004, according to a report in the Archives of Internal Medicine.

Clinicians previously believed the major health problems associated with vitamin D deficiency were rickets in children and reduced bone mineral content in adults, conditions reduced by fortifying foods with vitamin D, according to background information in the article. More recently, insufficient vitamin D levels have been associated with cancer, heart disease, infection, and suboptimal health overall. Evidence suggests that levels of 30 ng/mL to 40 ng/mL may be needed for optimum health, according to a news release from the journal's publisher.

"Vitamin D supplementation appears to mitigate the incidence and adverse outcomes of these diseases and may reduce all-cause mortality," the authors wrote.

Currently recommended levels of supplementation—200 IU/day from birth to age 50 years, 400 IU/day from age 51 to 70 years, and 600 IU/day for adults aged ≥71 years—focus primarily on improving bone health. In addition, decreases in outdoor physical activities and successful campaigns to reduce sun exposure may have contributed to vitamin D insufficiency, as sunlight exposure is a main determinant of vitamin D status in humans, the authors reported.

Adit A. Ginde, MD, MPH, of the University of Colorado Denver School of Medicine, Aurora, and colleagues compared levels of serum 25-hydroxyvitamin D (25[OH]D) from NHANES III, collected between 1988 and 1994, with those collected during NHANES 2001–2004. Complete data were available for 18,883 participants in the first survey and 13,369 participants in the second survey.

"Overall, the mean serum 25(OH)D level in the US population was 30 ng/mL during the 1988 to 1994 collection and decreased to 24 ng/mL during the 2001 to 2004 collection," the authors wrote. The prevalence of levels <10 ng/mL increased from 2% to 6% between the two time periods, and fewer individuals had levels ≥30 ng/mL (45% vs 23%).

Racial and ethnic differences persisted throughout the surveys; among non-Hispanic blacks, the prevalence of 25(OH)D levels of <10 ng/mL increased from 9% to 29% and levels of ≥30 ng/mL decreased from 12% to 3%.

"These findings have important implications for health disparities and public health," according to Dr. Ginde and colleagues. "We found that the mean serum 25(OH)D level in the US population dropped by 6 ng/mL from the 1988 to 1994 to the 2001 to 2004 data collections. This drop was associated with an overall increase in vitamin D insufficiency to nearly three of every four adolescent and adult Americans.

"Current recommendations for dosage of vitamin D supplements are inadequate to address this growing epidemic of vitamin D insufficiency," they concluded. "Increased intake of vitamin D (≥1,000 IU/day)—particularly during the winter months and at higher latitudes—and judicious sun exposure would improve vitamin D status and likely improve the overall health of the US population. Large, randomized, controlled trials of these higher doses of vitamin D supplementation are needed to evaluate their effect on general health and mortality."

Vitamin D Supplements Associated With Reduced Fracture Risk in Older Adults
Oral vitamin D supplements at a dose of at least 400 IU/day are associated with a reduced risk of bone fractures in older adults, according to results of a meta-analysis published in the Archives of Internal Medicine.

"The antifracture benefits of vitamin D have been questioned by several recent trials, leading to uncertainty among patients and physicians regarding recommendations for vitamin D supplementation," the authors wrote. "Factors that may obscure a benefit of vitamin D are low adherence to treatment, low dose of vitamin D, or the use of less potent ergocalciferol (vitamin D2)."

Heike A. Bischoff-Ferrari, DrPH, of the University of Zurich, University Hospital, Switzerland, and colleagues performed a meta-analysis on 12 previously published clinical trials of oral vitamin D supplements among adults age ≥65 years. These double-blind randomized controlled trials involved 42,279 participants (average age 78 years) and looked at nonvertebral fractures, including eight trials of 40,886 participants specifically studying hip fractures, according to a news release from the journal's publisher.

When the results of the trials were pooled, vitamin D supplements decreased the risk of nonvertebral fractures by 14% and of hip fractures by 9%. The authors then pooled the results of only the nine trials in which participants received doses of >400 IU/day. At this dosage, vitamin D supplements reduced nonvertebral fractures by 20% and hip fractures by 18%. Doses of ≤400 IU/day did not reduce the risk of either fracture type. A greater reduction in risk was also seen among trial participants whose blood levels of 25(OH)D achieved a greater increase.

Among individuals taking high doses of vitamin D, additional calcium did not appear to have any further protective effect against fractures. "Physiologically, the calcium-sparing effect of vitamin D may explain why we did not see an additional benefit of calcium supplementation at a higher dose of vitamin D," according to the authors.

"The greater fracture reduction with a higher received dose or higher achieved 25(OH)D levels for both any nonvertebral fractures and hip fractures suggests that higher doses of vitamin D should be explored in future research to optimize anti-fracture efficacy. Also, it is possible that greater benefits may be achieved with earlier initiation of vitamin D supplementation and longer duration of use. Our results do not support use of low-dose vitamin D with or without calcium in the prevention of fractures among older individuals."