News — March 2009

Lowering A1C Levels May Reduce Decline in Cognitive Function
Higher average blood glucose levels in people with type 2 diabetes are linked to lower cognitive functioning, according to a study in Diabetes Care.

The ongoing MIND (Memory in Diabetes) study, a substudy of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, found that higher levels of A1C are significantly associated with poorer performance on three cognitive tasks, which require memory, speed, and the ability to manage multiple tasks at the same time. A higher A1C level was also associated with a lower score on a test of global cognitive function.

Previous studies have shown that people with diabetes are 1.5 times more likely to experience cognitive decline and dementia than people without diabetes, according to an American Diabetes Association (ADA) news release. The MIND results suggest diabetes may be associated with mild cognitive impairment.

"Even a mild impairment in cognitive function is of concern for people with type 2 diabetes," said lead researcher Tali Cukierman-Yaffe, MD, MSc, of the Gertner Institute for Epidemiology & Health Policy Research, Endocrinology Institute at Sheba Medical Center & Sackler School of Medicine at Tel-Aviv University. These results, however, are cross-sectional, so it is not yet known whether higher levels of blood sugar increase the risk for cognitive impairment or whether impairment decreases the ability to control blood sugar levels. This will be answered in the ongoing ACCORD-MIND study, in which patients are followed over time and are tested three times during the trial. One aim of the ACCORD-MIND follow-up is to test the hypothesis that lowering A1C levels could result in improved cognitive function, according to the researchers.

Diabetes Significantly Increases Risk for Alzheimer's Disease
Patients with diabetes have a significantly greater risk of dementia, both Alzheimer's disease—the most common form of dementia—and other dementia, reveals important new data from an ongoing study of twins. The risk of dementia is especially strong if the onset of diabetes occurs in middle age, according to the study.

"Our results … highlighted the need to maintain a healthy lifestyle during adulthood in order to reduce the risk of dementia late in life," said Margaret Gatz, PhD, who directs the Study of Dementia in Swedish Twins.

In a study that appeared in Diabetes, Dr. Gatz and researchers from Sweden showed that getting diabetes before the age of 65 years corresponds to a 125% increased risk for Alzheimer's disease. This risk of Alzheimer's disease or other dementia was significant for middle-aged individuals with diabetes as opposed to those who develop diabetes after age 65 years even when controlling for family factors. In other studies, genetic factors and childhood poverty have been shown to independently contribute to the risk of both diabetes and dementia, according to a University of Southern California (USC) news release.

"Twins provide naturally matched pairs, in which confounding factors such as genetics and childhood environment may be removed when comparisons are made between twins," said Dr. Gatz, Professor of Psychology, Gerontology and Preventive Medicine at USC and Foreign Adjunct Professor of Medical Epidemiology and Biostatistics at the Karolinska Institute in Sweden.

The chances of a patient with diabetes developing Alzheimer's disease may be even greater in the population than in the controlled environment of the study, the researchers said. They identify several factors that might have led them to underestimate the risk of dementia and Alzheimer's among those who develop diabetes before the age of 65 years.

The results of the study implicate adult choices such as exercise, diet and smoking, as well as glycemic control in patients with diabetes, in affecting risk for Alzheimer's disease and diabetes, according to the researchers.

Insulin Is a Possible Treatment for Alzheimer's Disease
Researchers from Northwestern University reported that insulin, by shielding memory-forming synapses from harm, may slow or prevent the damage and memory loss caused by toxic proteins found in patients with Alzheimer's disease.

The findings, which provide additional new evidence that Alzheimer's could be due to a novel third form of diabetes, was published in the Proceedings of the National Academy of Sciences.

In a study of neurons taken from the hippocampus, scientists treated cells with insulin and rosiglitazone (Avandia, GlaxoSmithKline). According to a news release, the researchers discovered that damage to neurons exposed to amyloid beta-derived diffusible ligands (ADDLs) was blocked by insulin, which kept ADDLs from attaching to the cells. They also found that protection by low levels of insulin was enhanced by rosiglitazone.

ADDLs are known to attack memory-forming synapses. After ADDL binding, synapses lose their capacity to respond to incoming information, resulting in memory loss. The protective mechanism of insulin works through a series of steps by ultimately reducing the actual number of ADDL binding sites, which in turn results in a marked reduction of ADDL attachment to synapses, the researchers reported.

"Therapeutics designed to increase insulin sensitivity in the brain could provide new avenues for treating Alzheimer's disease," said senior author William L. Klein, PhD, a professor of neurobiology and physiology in the Weinberg College of Arts and Sciences and a researcher in Northwestern's Cognitive Neurology and Alzheimer's Disease Center. "Sensitivity to insulin can decline with aging, which presents a novel risk factor for Alzheimer's disease. Our results demonstrate that bolstering insulin signaling can protect neurons from harm."

Low Vitamin D Linked to Cognitive Problems in Elderly
Researchers from the Peninsula Medical School, the University of Cambridge, and the University of Michigan, have for the first time identified a relationship between vitamin D and cognitive impairment in a large-scale study of older people.

The importance of these findings lies in the connection between cognitive function and dementia: People who have impaired cognitive function are more likely to develop dementia, according to research in the Journal of Geriatric Psychology and Neurology. The study was based on data from approximately 2,000 adults aged ≥65 years who participated in the Health Survey for England and whose levels of cognitive function were assessed. The study found that as levels of vitamin D went down, levels of cognitive impairment went up. Compared with those with optimum levels of vitamin D, those with the lowest levels were more than twice as likely to be cognitively impaired, according to a news release from the Peninsula College of Medicine and Dentistry.

Vitamin D is important in maintaining bone health, in the absorption of calcium and phosphorus, and in helping the immune system. In humans, vitamin D comes from exposure to sunlight, foods such as oily fish, and foods that are fortified with vitamin D. One problem faced by older people is that their capacity to manufacture vitamin D from sunlight decreases as the body ages, so they are more reliant on obtaining vitamin D from other sources.

SDB and Insulin Resistance, Linked, Independent of Obesity
In a study that addressed the issue of insulin sensitivity with respect to sleep-disordered breathing (SDB), Naresh Punjabi, MD, PhD, sought to examine the relationship between SDB and insulin resistance. The results, published in the American Journal of Respiratory and Critical Care Medicine, definitively link SDB to prediabetic changes in insulin production and glucose metabolism.

"In the past, researchers have used body mass index [BMI] … as a proxy measure for body fat, but we know this to be a variable and crude tool to assess the true percentage of body fat," said Dr. Punjabi in a news release from the American Thoracic Society (ATS). "In addition, previous studies have used surrogate measurements to assess the body's response to insulin without investigating the interaction that occurs between reduced insulin sensitivity and increased insulin production in the body."

To address the shortcomings of previous studies, Dr. Punjabi and colleagues used dual-energy x-ray absorptiometry and the frequently sampled intravenous glucose tolerance test (FSIVGTT).

They recruited 118 individuals, 39 who had no SDB, and 79 who were newly diagnosed with SDB but who had not been treated. Each person underwent a sleep study to assess their level of SDB and then underwent a FSIVGGT to determine their glucose metabolism and insulin sensitivity/production the following day.

"Our major finding was that, as we suspected, SDB was strongly associated with a decrease in the three major metabolic pathways that the body uses to metabolize glucose—insulin sensitivity, glucose effectiveness, and pancreatic cell function—independent of adiposity," said Dr. Punjabi. "What our research tells us is that SDB is characterized by multiple physiological deficits that increase the predisposition for type 2 diabetes mellitus."

OSA Linked to the Progression of Liver Disease
In another study published in the same issue of the journal, researchers from Johns Hopkins Bayview Medical Center Bariatric Surgery Clinic found that the chronic intermittent hypoxia that often characterizes obstructive sleep apnea (OSA), a common form of SDB, is also independently linked to the progression of liver disease.

In this study, researchers recruited 90 severely obese patients presenting for bariatric surgery without known diagnoses of OSA. Each patient underwent a sleep study and blood tests for markers of liver function, insulin resistance and systemic inflammation. And, because standard practice for patients undergoing bariatric surgery is to biopsy the liver, the researchers were able to analyze liver tissue for signs of disease and link it to the severity and type of SDB they observed during the sleep study.

The results validated the link between OSA and insulin resistance, and further linked it to the level of hypoxemia experienced during the night versus simply the number of apneic events. Strikingly, of the patients whose liver tissue was analyzed, those who were observed to have severe nocturnal hypoxemia also exhibited "ballooning" of their hepatocytes and a pericellular fibrosis of the liver, indicating liver injury, according to the ATS news release.

"We demonstrated that the severity of nocturnal oxyhemoglobin desaturation predicted the severity of insulin resistance and might be implicated in the development of liver disease. In contrast, severe obesity was associated with high levels of serum C-reactive protein [CRP], indicating systemic inflammation," said lead researcher, Vsevolod Y. Polotsky, MD, PhD, of Johns Hopkins' Asthma and Allergy Center. "Interestingly, there was no relationship between the severity of nocturnal hypoxemia and serum CRP. This suggests that that obesity and OSA have distinct metabolic, inflammatory, and hepatic profiles, which act in different detrimental ways on the liver.

"We hypothesize that severe obesity per se acts as a Ôfirst hit' in the progression of liver disease, inducing hepatic steatosis, whereas the presence of the chronic intermittent hypoxemia that often characterizes OSA acts as a Ôsecond hit.' The hypoxic stress of OSA may induce oxidative stress in the livers of patients with severe obesity, leading to further inflammation."

The clinical implications of the findings are clear: obesity and OSA exert separate and perhaps additive negative effects on insulin resistance and the liver, and each disorder must be treated concomitantly in order to address the secondary complications.

"Our data suggest that patients with OSA and severe nocturnal hypoxemia should be screened for liver disease and, conversely, patients with liver disease should be screened for OSA," said Dr. Polotsky.

Severity of OSA Linked to Sedentary Lifestyle
Not only is OSA linked to insulin resistance and liver disease independent of obesity, but at least one risk factor is also common to obesity and OSA: prolonged daytime sitting or standing. Even when the sedentary lifestyle does not lead to obesity, it may still lead to OSA and its concomitant health risks, according to an article in the journal.

"Overnight fluid displacement from legs, related to prolonged sitting, may play a previously unrecognized role in the pathogenesis of OSA," wrote principle investigator, T. Douglass Bradley, MD, Professor of Medicine and Director of the Centre for Sleep Medicine and Circadian Biology at the University of Toronto.

The research also found that the volume of fluid shift was directly linked to the hours in a day that the patient reported sitting or standing and was independent of the excess weight that often accompanies sedentary lifestyles, according to the news release.

"An important implication of our observations is that sedentary living may predispose to OSA not only by promoting obesity but also by causing dependent fluid accumulation in the legs, which can shift rostrally to the neck overnight," said Dr. Bradley.

This finding may also help explain why 40% of patients with OSA are not obese and why a reduction in OSA has been described when subjects begin exercise programs, even in the absence of weight loss.

Medicare Announces Final Coverage Policy for Bariatric Surgery as Diabetes Treatment
The Centers for Medicare & Medicaid Services (CMS) announced a clarification in its policy for Medicare coverage of bariatric surgery as a treatment for certain individuals with type 2 diabetes.

The decision specifies type 2 diabetes as one of the comorbidities CMS would consider in determining whether bariatric surgery would be covered for a Medicare beneficiary who is morbidly obese, as long as the surgery is performed at a CMS-approved facility, according to the CMS news release. An individual with a BMI of ≥35 kg/m² is considered morbidly obese.

"Medicare beneficiaries who are morbidly obese may face tremendous health complications," said CMS Acting Administrator Charlene Frizzera. "Today's coverage decision assures that beneficiaries who are morbidly obese can access safe, effective weight loss options to help prevent these complications."

As part of the decision, CMS announced bariatric surgery will not be covered by Medicare when it is used to treat type 2 diabetes in a beneficiary with a BMI <35 kg/m². Although recent medical reports claimed that bariatric surgery may be helpful for these patients, CMS did not find convincing medical evidence that bariatric surgery improved health outcomes for these nonmorbidly obese individuals.

"Limiting coverage of bariatric surgery in type 2 diabetic patients who are not considered clinically obese is part of Medicare's ongoing commitment to ensure access to the most effective treatment alternatives with good evidence of benefit, while limiting coverage where the current evidence suggests the risks outweigh the benefits," said Barry Straube, MD, CMS Chief Medical Officer and Director of the Agency's Office of Clinical Standards & Quality.

In 2006, CMS expanded coverage of bariatric surgery for Medicare beneficiaries who underwent surgery in high-volume centers from highly qualified surgeons (as certified by the American College of Surgeons or the American Society for Bariatric Surgery, and as reported on the Medicare Coverage Web site).

Under the 2006 decision, to be considered for coverage, Medicare beneficiaries were required to have a BMI of ≥35 kg/m² and to have exhibited a serious health condition in addition to morbid obesity, such as hypertension, coronary artery disease, or osteoarthritis.

In that same decision, CMS covered four types of bariatric surgery procedures: gastric bypass, open and laparoscopic Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, and open and laparoscopic biliopancreatic diversion with duodenal switch. No other bariatric surgery procedure is currently covered.

Liraglutide Lowers Glucose, Weight in Type 2 Diabetes
Liraglutide (Novo-Nordisk) treatment leads to greater reductions in A1C when added to one oral antidiabetic drug (OAD) compared with adding another OAD, according to two studies. Liraglutide is a human glucagon-like peptide-1 (GLP-1) analog currently in US Food and Drug Administration and European Medicines Agency review for the treatment of type 2 diabetes.

In Diabetic Medicine, researchers reported that adding liraglutide to glimepiride was more effective at lowering blood sugar than either glimepiride monotherapy or glimepiride/rosiglitazone combination therapy. Patients on liraglutide also experienced increased weight benefit and improved beta-cell function compared to the active rosiglitazone comparator treatment.

A separate study published in Diabetes Care further supported the efficacy and tolerability profile of liraglutide in the early treatment of type 2 diabetes, this time when added to metformin and compared with glimepiride plus metformin combination, according to a Novo-Nordisk news release.

Zoledronic Acid Beneficial in Breast Cancer
The addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival in premenopausal patients with estrogen-responsive early breast cancer, according to a report in the New England Journal of Medicine.

Ovarian suppression plus tamoxifen is a standard adjuvant treatment in premenopausal women with endocrine-responsive breast cancer, according to investigators from the Austrian Breast Cancer and Colorectal Cancer Study Group-12. "…preclinical data suggest that zoledronic acid has antitumor properties," Michael Gnant, MD, from the Medical University of Vienna, and colleagues wrote.

The team examined the effect of adding zoledronic acid to goserelin plus tamoxifen or goserelin plus anastrozole in premenopausal women with endocrine-responsive early breast cancer. They randomized 1,803 patients to goserelin (3.6 mg given subcutaneously every 28 days) plus tamoxifen (20 mg per day given orally) or anastrozole (1 mg per day given orally) with or without zoledronic acid (4 mg given intravenously every 6 months) for 3 years.

The primary endpoint was disease-free survival; recurrence-free survival and overall survival were secondary endpoints. After a median follow-up of 47.8 months, 137 events had occurred, with disease-free survival rates of 92.8% in the tamoxifen group, 92.0% in the anastrozole group, 90.8% in the group that received endocrine therapy alone, and 94.0% in the group that received endocrine therapy with zoledronic acid. There was no significant difference in disease-free survival between the anastrozole and tamoxifen groups (hazard ratio for disease progression in the anastrozole group, 1.10; 95% confidence interval, 0.78–1.53; P=0.59).

Dr. Gnant and colleagues wrote that the addition of zoledronic acid to endocrine therapy versus endocrine therapy without zoledronic acid, resulted in an absolute reduction of 3.2% and a relative reduction of 36% in the risk of disease progression.