News — May 2009

Rosiglitazone Discontinuation Left Many Patients Without Good Control
When concerns were raised about the safety of the diabetes medication rosiglitazone (Avandia, GlaxoSmithKline) in May 2007, many patients and their doctors made the decision to discontinue use of the drug. A study published in Endocrine Practice reported that many patients who discontinued rosiglitazone received less therapy and had higher blood glucose levels as a result.

A meta-analysis published in 2007 showed an increased risk of cardiovascular disease (CVD) and myocardial infarctions for patients using rosiglitazone. After that data was published, the US Food and Drug Administration (FDA) called for a black box warning on both available thiazolidinediones (TZDs), rosiglitazone, and pioglitazone (Actos, Takeda).

The current study by Etta L. Fanning, MD, PhD, MPH, from the University of Texas Health Science Center, showed that 89% of patients in the study group were using combination therapy before discontinuing use of rosiglitazone. After discontinuation, only 33% of patients were on combination therapy. Another 13% of the group were not prescribed any diabetes medication at all, according to a news release from the American Association of Clinical Endocrinologists.

The glycemic control of the group was also diminished after discontinuing rosiglitazone. In patients who received combination therapy and who had laboratory values in both pre- and postdiscontinuation periods, significant increases were observed in both fasting blood glucose and and A1C.

In an accompanying editorial, cardiologists Stuart Zarich, MD, and Richard Nesto, MD, from Yale Medical School and Lahey Clinic, respectively, emphasized that patients who discontinue TZDs are at risk for higher fasting blood glucose and A1C levels (as reported by Fanning et al), which might further increase their cardiovascular risk. They point out that five large prospective studies have not found that rosiglitazone has any more cardiovascular risk than placebo or other hypoglycemic drugs and that a recent meta-analysis has also shown that TZDs do not increase cardiovascular mortality.

Endocrine Society Releases New Guideline on Adult Hypoglycemic Disorders
The Endocrine Society released a new clinical practice guideline for the evaluation and management of adult hypoglycemic disorders. The guideline appears in the Journal of Clinical Endocrinology & Metabolism (JCEM).

"Prevention and treatment of hypoglycemia can be complex as symptoms and causes of the condition can vary from patient to patient," said Philip Cryer, MD, Washington University School of Medicine, St. Louis, a codeveloper of the guideline. "This new clinical guideline offers recommendations to doctors about how best to confirm that an adult patient has a hypoglycemic disorder, determine its cause, and prevent its recurrence."

Experts say that a hypoglycemic disorder can't be diagnosed with confidence simply on the basis of low blood sugar, therefore the clinical guideline recommends that doctors use three criteria often referred to as Whipple's triad to diagnose a hypoglycemic disorder. The three components of Whipple's triad are signs and symptoms of hypoglycemia, low blood sugar measured by a reliable chemical test, and disappearance of signs and symptoms after the blood sugar level is raised, according to a news release from the Endocrine Society.

Saxagliptin Cardiovascular Profile Acceptable According to FDA Advisory Committee
Bristol-Myers Squibb Company and AstraZeneca announced that the FDA Endocrinologic and Metabolic Drugs Advisory Committee determined that the data supporting the new drug application (NDA) for saxagliptin (Onglyza) for the treatment of adults with type 2 diabetes were sufficient to rule out unacceptable cardiovascular risk relative to comparators in the program. Saxagliptin is an investigational, selective, reversible inhibitor of the dipeptidyl peptidase-4 enzyme.

According to the company news release, the committee unanimously recommended that the sponsors perform a postmarketing trial to confirm the cardiovascular profile of saxagliptin. Bristol-Myers Squibb and AstraZeneca are working on a series of phase 3b and 4 studies, including a large, controlled, randomized, postmarketing trial, to further characterize the long-term clinical effectiveness as well as the cardiovascular profile of saxagliptin. The companies will now work with the FDA to finalize the postmarketing trial design.

"Bristol-Myers Squibb and AstraZeneca are encouraged by the committee's recommendation. We will work closely with the FDA to support the review of [saxagliptin]," said Brian Daniels, senior vice president, Global Development and Medical Affairs, Bristol-Myers Squibb.

Shortly after the above report, the companies announced that the FDA has determined that it needs additional time to complete the NDA review for saxagliptin. Accordingly, the FDA has extended the date from April 30 to July 30. The companies said they will continue to work closely with the FDA to support the review.

FDA: Liraglutide Update
Novo Nordisk announced that the Endocrinologic and Metabolic Drugs Advisory Committee of the FDA has finalized its discussions of questions related to liraglutide, a once-daily human glucagon-like peptide 1 analog.

The Advisory Committee voted on questions related to the risk profile of liraglutide.

A majority of Advisory Committee members supported that appropriate evidence of cardiovascular safety had been provided to rule out excess cardiovascular risk of liraglutide relative to comparators.

Although a majority of Advisory Committee members did not find that Novo Nordisk, based on the available data, had ruled out that the finding of C-cell tumors in rodents was not relevant to humans, the Advisory Committee was split on the FDA question related to whether the available data on C-cell tumors permitted approvability.

The Advisory Committee unanimously supported approvability of liraglutide with regard to risk of papillary thyroid cancer.

"We remain convinced that liraglutide has a positive benefit:risk profile and represents an important advance for people with type 2 diabetes. We will work closely with the FDA as it completes its review of our application to address the concerns expressed by members of the Advisory Committee," said Mads Krogsgaard Thomsen, Executive Vice President and Chief Science Officer of Novo Nordisk.

Severe Hypoglycemia Increases Dementia Risk for Elderly Patients With Type 2 Diabetes
Having hypoglycemic episodes that are severe enough to require hospitalization are associated with a greater risk of dementia for older adults with type 2 diabetes, according to a study published in the Journal of the American Medical Assocation (JAMA).

Rachel A. Whitmer, PhD, of Kaiser Permanente, Oakland, Calif., presented the findings at a National Press Club media briefing. Dr. Whitmer and colleagues conducted a study to determine whether prior episodes of hypoglycemia that required hospitalization or emergency department (ED) visits are associated with an increased risk of dementia. The study included 22 years of follow-up (1980–2002) for hypoglycemic episodes and more than 4 years (starting in 2003) of follow-up for diagnosis of dementia, and included 16,667 patients with type 2 diabetes (mean age, 65 years). The researchers found that a total of 11% had a diagnosis of dementia and 8.8% had at least one episode of hypoglycemia; 16.95% of patients had both dementia and at least one episode of hypoglycemia, according to a JAMA news release.

Age-adjusted incidence rates of dementia by frequency of hypoglycemic episodes were significantly elevated for patients with at least one episode compared with patients with no episodes. "Specifically, we observed a 2.39% increase in absolute risk of dementia per year of follow-up for patients with history of hypoglycemia, compared with patients without a history. Although this 1-year absolute risk difference is modest, the cumulative effects would be sizeable," the authors wrote.

Compared with patients who had no hypoglycemia, patients with single or multiple episodes had a graded increase in risk of dementia. Patients with one hypoglycemic episode had a 26% increased risk; two episodes, an 80% increased risk; and three or more hypoglycemic episodes were associated with nearly double the risk for dementia.

"Our results suggest that hypoglycemic episodes severe enough to require hospitalization or an ED visit are associated with increased risk of dementia, particularly for patients who have a history of multiple episodes," the authors wrote. "A large body of evidence suggests that individuals with diabetes are at an increased risk of dementia, yet exact mechanisms are not known; our study suggests a potentially modifiable mechanism. Pharmacologically induced severe hypoglycemia may be associated with neurological consequences in an older population already susceptible to dementia. More scientific studies examining hypoglycemia and cognitive performance and brain-imaging sequelae in populations of older patients with type 2 diabetes are needed."

Low Birth Weight Tied to Heart Disease, Diabetes in Adulthood
Lower weight at birth may increase inflammatory processes in adulthood, which are associated with chronic diseases such as heart disease and diabetes, according to a study that appeared in JCEM.

Previous studies have suggested babies with lower weight at birth are at a higher risk for developing chronic diseases, but until now, there has been little understanding of why. This study suggests that the association between lower weight at birth and inflammation in adulthood may be an explanation.

Earlier studies have found that babies born small for gestational age have weak immune systems, but at age 6 years have more white blood cells than normal-weight babies. These findings suggest that age might amplify the association between early growth and inflammatory processes.

For the current study, researchers followed 5,619 children—born in 1966—until they reached adulthood. As compared with children who were normal weight in the first year of life, researchers observed that babies born relatively smaller who gained the least weight during infancy had a higher number of white blood cells.

"Our findings suggest that the link between poorer growth early in life and adult chronic diseases may involve inflammation as a common underlying factor," said lead researcher Dexter Canoy, MD, of the University of Manchester, Manchester, UK. "Ensuring appropriate growth during this narrow window in early development may confer lifelong benefits to health."

Heart Screening Unnecessary in Asyptomatic Diabetes Patients
Routine screening for coronary artery disease in type 2 diabetes patients with no symptoms of angina or a history of coronary disease is unnecessary and may lead initially to more invasive and costly heart procedures, according to researchers at Yale School of Medicine.

"Patients with type 2 diabetes with no symptoms who are feeling well can generally be managed effectively with preventive therapies such as lipid-lowering drugs, blood pressure medication, aspirin, and diabetes treatment," said Lawrence Young, MD, Professor of Medicine at Yale School of Medicine, in a Yale University news release.

In this study, published in JAMA, Dr. Young and colleagues sought to determine whether routinely screening diabetic patients without a history of heart problems helped identify those at higher cardiac risk.

The team spearheaded the DIAD (Detection of Ischemia in Asymptomatic Diabetics) study in which 1,123 participants were randomized to either a screening stress test that looks at the blood flow to the heart, or to a group that received no screening. Participants enrolled at 14 centers in the United States and Canada and were evaluated over the next 5 years.

The team found that routine screening of patients with type 2 diabetes identifies a small group of patients at higher risk, but does not significantly affect overall outcome. With each test costing about $1,000 and with 200 million patients with diabetes worldwide, Dr. Young said, "Routine screening would have tremendous economic implications and our findings did not indicate that routine stress testing had additional benefit in this population." The study also found that routine screening leads initially to more invasive procedures such as cardiac catheterization, stents, or bypass surgery.

"On the other hand," he cautioned, "stress testing has an important role in evaluating patients with type 2 diabetes who have symptoms suggesting heart disease, [as] these individuals are at very high risk.

"This is a bit of good news in the field of diabetes where patients and their physicians have real concern for heart disease. In patients getting modern medical therapy in our study, serious heart problems were infrequent," Dr. Young said.

Patient-Tailored Treatment Regimens Superior to Strict Glycemic Control
Physicians routinely emphasize tight glycemic control for patients with type 2 diabetes. Tight glycemic control, however, may require highly complex treatment regimens that can result in frustration, nonadherence, and financial stress for some patients, according to a report in the Archives of Internal Medicine.

Victor M. Montori, MD, MSc, of the Mayo Clinic, and colleagues reviewed large trials in which type 2 diabetic patients were randomly assigned to either tight or loose targets for glycemic control. Based on the evidence, the researchers developed practical suggestions for managing these patients. According to the authors, physicians should support healthy lifestyles, preventive care, and cardiovascular risk reduction in patients with type 2 diabetes.

Physicians should individualize drug treatment approaches so that patients can aim for a blood glucose level that best balances the burden of medication with the benefit in reducing symptoms and complications of diabetes. The authors advocate for tools and tactics that encourage patient involvement in treatment decisions, as these may lead to treatment programs that are both evidence-based and consistent with patients' lifestyles and informed values.

Psoriasis Linked to Diabetes and Hypertension in Women
Women with psoriasis appear to have an increased risk for developing diabetes and hypertension, according to a report in Archives of Dermatology.

Psoriasis, a chronic inflammatory skin disease, affects between 1% and 3% of the population, according to background information in the article. Recent studies indicate that psoriasis is associated with an increased risk of other illnesses and death. "Systemic inflammation in psoriasis and an increased prevalence of unhealthy lifestyle factors have been independently associated with obesity, insulin resistance, and an unfavorable cardiovascular risk profile," the authors wrote.

Abrar A. Qureshi, MD, MPH, of Brigham and Women's Hospital and Harvard Medical School, and colleagues studied 78,061 women involved in the Nurses' Health Study II, a group of female nurses age 27 to 44 years in 1991, according to a news release from the journal's publisher. Participants—all of whom were free of diabetes and hypertension at the beginning of the study—responded to a survey, which included a question about lifetime history of psoriasis in 2005 and were assessed for the development of diabetes or hypertension during the 14-year follow-up. Of the women, 1,813 (2.3%) reported a diagnosis of psoriasis. A total of 1,560 (2%) developed diabetes and 15,724 (20%) developed hypertension. Women with psoriasis were 63% more likely to develop diabetes and 17% more likely to develop hypertension than women without psoriasis. These associations remained strong even after the researchers considered age, body mass index, and smoking status.

Inflammation could be a biologically plausible explanation for the association between psoriasis and hypertension, as well as that between psoriasis and diabetes, the authors noted. Inflammation is a risk factor for high blood pressure and may also contribute to insulin resistance. Alternatively, systemic steroid therapy or other treatments for psoriasis may promote development of diabetes or hypertension.

"These data illustrate the importance of considering psoriasis a systemic disorder rather than simply a skin disease," the authors concluded. "Further research is needed to better understand the mechanisms underlying these associations and to find out whether psoriasis therapy can reduce the risk for diabetes and hypertension."

Rapid Weight Gain in Infants Linked to Childhood Obesity
Rapid weight gain during the first 6 months of life may place a child at risk for obesity by age 3 years, according to a study published in Pediatrics.

The study suggests that changes in weight status in infancy, rather than weight status at birth, may determine risk of obesity later in childhood. "There is increasing evidence that rapid changes in weight during infancy increase children's risk of later obesity," said coauthor Elsie Taveras, MD, Department of Ambulatory Care and Prevention and One Step Ahead Clinic, Children's Hospital Boston. "The mounting evidence suggests that infancy may be a critical period during which to prevent childhood obesity and its related consequences."

According to a news release from Harvard Medical School, most prior studies examining the relationship between infant weight gain and later childhood obesity focus primarily on body weight. Measures of length, in addition to weight, together reflect body fatness better than weight alone, however. Dr. Taveras and colleagues examined how weight and body length, or weight-for-length, in infancy can influence later obesity by using data from Project Viva, an ongoing study of more than 2,000 pregnant women and their children.

Researchers isolated a subgroup of 559 mother/child pairs and studied patterns of weight gain in infancy and their subsequent 3-year effect. In addition to looking at static weight and length measures, the team also looked at weight gain as a dynamic process, measuring not only how much but how quickly an infant gained weight. The connection between rapid infant weight gain and later obesity was striking, even after adjusting for factors such as premature babies or those underweight at birth.

"There is still a lot more we need to understand about the mechanisms of how this all fits together," said Dr. Taveras. "But this data clearly shows how the earliest interventions might actually have very long-term benefits."

Stem Cell Transplantation Can Help Patients Achieve Long-Term Insulin Independence
The majority of patients with type 1 diabetes who underwent a certain type of stem cell transplantation became insulin free, several for more than 3 years, with good glycemic control, and also increased C-peptide levels, according to a study published in the JAMA.

Richard K. Burt, MD, Northwestern University Feinberg School of Medicine, presented the findings at a JAMA media briefing at the National Press Club in Washington, DC. According to a JAMA news release, Dr. Burt and colleagues conducted a study to determine if posttransplant insulin independence was due to improved beta-cell function by monitoring the C-peptide levels of 23 patients with diabetes, aged 13 to 31 years, who underwent autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT).

Of the 23 patients, 20 experienced time free from insulin (12 continuously and eight transiently). Patients remained continuously insulin free for an average time of 31 months (range, 14–52 months). One patient had >4 years with no exogenous insulin use; four patients had ≥3 years; three patients for ≥2 years; and four patients for ≥1 year. Eight patients relapsed and resumed insulin use at low doses. The majority of patients achieved good glycemic control.

In the continuously insulin-free group, average area under the curve (AUC) of C-peptide levels before transplantation (225.0 ng/mL per 2 hours) showed a significant increase at 24 months after transplantation (785.4 ng/mL per 2 hours) and at 36 months after transplantation (728.1 ng/mL per

2 hours). In the transient insulin-independent group, average AUC of C-peptide levels also increased from 148.9 ng/mL per 2 hours pretransplantation to 546.8 ng/mL per 2 hours at

36 months, which was sustained at 48 months. In this group, two patients regained insulin independence after treatment with sitagliptin (Januvia, Merck & Co., Inc), which was associated with an increase in C-peptide levels.

A total of two patients developed pneumonia in the hospital, three patients developed late endocrine dysfunction, and nine patients developed oligospermia. There were no deaths.

"In conclusion, autologous nonmyeloablative HSCT was able to induce prolonged and significant increases of C-peptide levels associated with absence of or reduction of daily insulin doses in a small group of patients with type 1 diabetes," the authors wrote. "At the present time, autologous nonmyeloablative HSCT remains the only treatment capable of reversing type 1 diabetes in humans. Randomized controlled trials and further biological studies are necessary to confirm the role of this treatment in changing the natural history of type 1 diabetes."

Chronic Insomnia With Short Sleep Duration a Significant Risk Factor for Hypertension
A study in the journal Sleep is the first to demonstrate that chronic insomnia with objectively measured short sleep time is an independent and clinically significant risk factor for hypertension.

According to a news release from the American Academy of Sleep Medicine, results indicated that participants with insomnia and an objectively measured, severely short sleep duration of <5 hours had a risk for hypertension that was 500% higher than participants without insomnia who slept >6 hours.

People with insomnia and a moderately short sleep duration of 5 to 6 hours had a risk for hypertension that was 350% higher than normal sleepers. In contrast, neither insomnia with a normal sleep duration of >6 hours nor a short sleep duration without a sleep complaint was associated with a significant risk for hypertension. This suggests that there is an additive or synergistic effect on hypertension risk when insomnia occurs in combination with a short sleep duration.

According to lead author Alexandros N. Vgontzas, MD, Sleep Research and Treatment Center, Penn State College of Medicine, Hershey, Pa., one of the study's strengths is that sleep duration was measured objectively by overnight polysomnography.

"It should be emphasized that, many times, the amount that we feel we slept is different from the actual amount," he said. "Thus self-reported sleep duration cannot replace measured sleep duration."

The study involved a random sample of 1,741 men and women in central Pennsylvania (mean age, 49 years). Of those, 8% were classified as having chronic insomnia with symptoms persisting for at least 1 year; 22% were poor sleepers with a moderate-to-severe complaint of difficulty falling asleep, staying asleep, early final awakening or unrefreshing sleep; and 70% were normal sleepers. Twenty-one percent had a severely short sleep duration of <5 hours; 23% had a moderately short sleep duration of 5 to 6 hours; and 56% had a normal sleep duration of >6 hours.

Exercise Can Prevent Falls in Elderly
Exercise programs that blend strength, flexibility, and balance might be one of the best ways to prevent falls among people aged >65 years, according to a Cochrane review of more than 100 studies.

A variety of other measures from pacemakers to vitamin D supplements might be useful in preventing certain individuals from falling, but exercise appears to be the most widely effective strategy for reducing both the risk of falling and the overall number of falls among older people, according to a news release from the Health Behavior News Service.

"It may not be possible to prevent falls completely, but people who tend to fall frequently may be enabled to fall less often," said Lesley Gillespie, MD, an orthopedic trauma specialist at the University of Otago in New Zealand. The review appears in The Cochrane Library.

Each year, about 30% of people aged >65 years who live outside of assisted care facilities experience a fall. Poor balance, diminished eyesight, the side effects of medications and dementia are among the reasons older people sometimes fall. One in five of these falls could require medical attention, but even without causing serious injury, falling can make individuals fearful of leaving their homes or participating in activities, the Cochrane researchers noted.

Dr. Gillespie and colleagues examined 111 studies of falling prevention measures, which included more than 55,000 people from 15 countries. The studies suggest that group exercise programs, Tai Chi and home exercise programs all reduce the risk of falls and the rate of falling.

"Effective exercise programs for reducing falls focus on balance, strength and flexibility, and challenge the older adults to improve in all of these components," said Bonita Lynn Beattie, a physical therapist and vice president for injury prevention at the Center for Healthy Aging. She suggested that older adults should check in with their primary doctor before beginning an exercise program, especially if they "have significant weakness, balance issues or dizziness."