News — July 2009

Expert Committee Recommends A1C Assay to Diagnose Diabetes
An international expert committee assembled by the American Diabetes Association (ADA), the International Diabetes Federation (IDF), and the European Association for the Study of Diabetes (EASD) is recommending the A1C assay as the new test for the diagnosis of diabetes. According to an ADA news release, the recommendations have not yet been officially endorsed by the three diabetes organizations; the report was discussed at the 2009 ADA meeting and published online in Diabetes Care.

Experts said that the recommendation has the potential to usher in a major change in the way diabetes is diagnosed. According to the ADA, currently, fasting plasma glucose (FPG) and less often, oral glucose tolerance tests (OGTT), are used to diagnose diabetes. In making this new recommendation, the committee examined the relationship between long-term glycemic exposure and complications and suggested that a reliable measure of chronic glycemic levels, such as A1C, may serve as a better marker of diabetes and should be used as a diagnostic test.

"A1C values vary less than FPG values, and the assay for A1C has technical advantages compared with the glucose assay," said David M. Nathan, MD, Director of the Diabetes Center at Massachusetts General Hospital, Professor of Medicine at Harvard Medical School, and Chair of the Expert Committee. "Also, testing for diabetes using A1C is more convenient and easier for patients who will no longer be required to perform an FPG or OGTT."

In reviewing data examining A1C levels and long-term complications such as retinopathy, the committee concluded that an A1C value ³6.5% be used for the diagnosis of diabetes. This cut-point should not be construed as an absolute dividing line between normal glycemia and diabetes, Dr. Nathan said. The committee concluded that an A1C level of 6.5% is sufficiently sensitive and specific to identify people who have diabetes.

"Glucose impairment runs on a continuum, therefore making selection of a specific value where diabetes risk begins somewhat arbitrary. Those whose A1C levels are close to the 6.5% diagnostic level are clearly at higher risk," Dr. Nathan said.

The committee hopes that their report will serve as a stimulus to the international community and professional organizations to consider the use of the A1C assay to diagnose diabetes. The ADA responded to the report by endorsing in principle the use of A1C testing to diagnose diabetes and will establish a task force to explore the implications of this report including how best to implement its recommendations.

For more news from the 2009 ADA meeting, see Conference Coverage

Endo Society Statement Identifies Endocrine-Disrupting Chemicals as a Concern
The Endocrine Society presented its first-ever scientific statement on endocrine-disrupting chemicals at its 91st Annual Meeting (ENDO 09). The statement presents evidence on the health effects of endocrine-disrupting chemicals as well as recommendations for increasing understanding and raising awareness of these effects.

According to a news release from the society, endocrine-disrupting chemicals are substances in the environment that interfere with hormone biosynthesis, metabolism, or action resulting in adverse developmental, reproductive, neurological, and immune effects in both humans and wildlife.

"From chemicals in pesticides, food, plastic bottles, and other items that we use every day, the concern is real," said Robert M. Carey, MD, president of The Endocrine Society. "We present evidence that shows endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid disease, metabolism and obesity, and cardiovascular endocrinology.

"Within this statement, we also make a number of recommendations to increase understanding of the effects of endocrine disruptors," said Dr. Carey. "The recommendations include enhancing basic and clinical research and advocating involvement of individual and scientific society stakeholders in communicating and implementing changes in public policy and awareness."

For more news from ENDO 09, see Conference Coverage.

ADA, AACE, ACE Applaud President Obama's Nomination of Sonia Sotomayor
President Obama's nomination of Federal Appeals Court Judge Sonia Sotomayor to the Supreme Court of the United States affirms that people with diabetes should not be discriminated against, and each person with diabetes should be judged based on his or her merits, not on stereotypes or misinformation about diabetes.

"In the days leading up to this nomination, there were several media reports suggesting that Judge Sotomayor should not be considered for this position simply because she has type 1 diabetes," said R. Paul Robertson, MD, President, Medicine & Science, ADA. "The advancements in the management of type 1 diabetes have been just amazing over the last 2 decades, and the ability of people to manage their diabetes successfully has been proven. People with diabetes can function and live a long and healthy life."

As this process moves forward, the diabetes community expects that Judge Sotomayor's nomination will be evaluated based on her qualifications and years of experience—and not her diabetes, the statement said. To evaluate her in any other way would be a disservice to the United States.

A joint news release from the American Association of Clinical Endocrinologists and the American College of Endocrinology stated: "As representatives of physicians caring for the increasing number of people with type 1 diabetes we salute Judge Sotomayor for her nomination to the Supreme Court. We applaud Judge Sotomayor for successfully meeting the challenges that must be overcome by people with type 1 diabetes and trust that many will be inspired by her."

FDA Issues Advisory Regarding Insulin Detemir
The US Food and Drug Administration (FDA) has learned that some stolen vials of the long-acting insulin detemir (Levemir, Novo Nordisk Inc.) have reappeared and are being sold in the US market.

Three lots or a total of 129,000 vials of this product were stolen in all, according to an FDA news release. These stolen insulin vials may not have been stored and handled properly and may be dangerous for patients to use. The FDA has received one report of a patient who suffered an adverse event due to poor control of glucose levels after using a vial from one of these three lots.

According to the news release, the agency is advising patients who use this insulin to: (1) Check your personal supply of insulin to determine if you have insulin from one of the following lots: XZF0036, XZF0037, and XZF0038. The lot number appears on the side of the box of insulin and also on the side of the vial. (2) Do not use the insulin if it is from one of these lots. Replace it with a vial of insulin from another lot. Patients should first contact their health care provider before switching to another insulin for any reason, as another product may require adjustments in dosing. (3) Always visually inspect insulin before using it, it should be a clear and colorless solution. (4) Contact the Novo Nordisk Customer Care Center at 800-727-6500 regarding what to do with vials from these lots or with any other questions.

Intensive Glucose Control in Type 2 Diabetes Reduces MI
A meta-analysis of five trials has shown that more intensive glucose control in type 2 diabetes leads to fewer myocardial infarctions (MI), and coronary heart disease events (CHD)—but has no significant effect on stroke or mortality from all causes. The findings are reported in The Lancet, by Kausik Ray, MD, University of Cambridge, UK, and colleagues.

To date, individual studies of intensive glucose control have failed to show consistent benefits on cardiovascular events, and some have even suggested possible harm. The investigators said this could be because each trial was underpowered to show clinical benefit. This meta-analysis combined five large trials, with the authors hoping to provide definitive evidence of a significant benefit of more intensive glucose control compared with standard care.

The five studies looked at more than 33,000 patients and provided information on 1,497 MIs, 2,318 CHD events, 1,127 strokes, and 2,892 deaths. The mean A1C was assessed in the patients. More intensive glucose control was achieved in the studies using additional medications and/or higher doses as shown by the lower levels of A1C that were achieved.

The researchers found that A1C was 0.9% lower in those patients given more intense treatment than those given standard treatment (6.6% vs 7.5%). Increased intensity of treatment resulted in a 17% reduction in nonfatal MI, and a 15% reduction in events of CHD (fatal and nonfatal MI). Increased intensity treatment had no effect on stroke rates or all-cause mortality, Dr. Ray reported.

"Our findings provide reassurance about the effectiveness of glycemic control for cardiovascular risk reduction, but we have not proven a clear benefit to all-cause mortality," Dr. Ray said in a news release from the journal. "By contrast, strong evidence suggests that lipid-lowering treatment and blood pressure reduction does benefit all-cause mortality, which reinforces the crucial importance of these treatments to reduce cardiovascular events and all-cause mortality in individuals with type 2 diabetes. The optimum methods to achieve glycemic control need to be established and guidelines drawn up with specific recommendations for reduction of A1C concentration in a range of patient populations."

In an accompanying comment, Theodore Mazzone, MD, of the University of Illinois at Chicago, said: "Intensive glucose-control efforts might need to be started sooner after onset of diabetes, and extended follow-up could be required. The benefit of glucose control on CHD in type 2 diabetes will certainly not be as great as that produced by blood pressure control or statin treatment. However, on the basis of current information, and the urgent need to address residual risk of CHD in a rapidly expanding population with type 2 diabetes, it is premature to conclude that glucose control has no part to play."

Blood Pressure-Lowering Drug Therapy Should Not Be Limited to Those With Hypertension
Blood pressure-lowering drugs should be offered to anyone old enough to be at risk of an MI or stroke (or who is otherwise known to be at risk), regardless of their blood pressure, according to the largest analysis of blood pressure trials to date.

Cardiovascular disease (CVD) is the leading cause of death throughout the world. For individuals aged ³65 years in England and Wales, the risk of having an MI in the next 10 years is about 10% for men and 5% for women, according to a news release from the British Medical Journal. The increase in blood pressure during a person's life, which affects nearly everyone, is one of the main reasons for strokes and MIs being so common.

Despite the widespread use of blood pressure-lowering drugs and the results of many randomized trials, uncertainty remains about which drugs to use and whom to treat. For example, does the preventive effect of drugs differ in people with and without a history of heart disease? And should blood pressure-lowering drugs be limited to people with high blood pressure?

To answer these questions, Prof. Malcolm Law and colleagues from the Wolfson Institute of Preventive Medicine at Barts and The London School of Medicine analyzed the findings of 147 blood pressure trials published between 1966 and 2007, involving 464,000 people. The results reported in the British Medical Journal show that using any one of the main classes of blood pressure-lowering drugs at standard dose reduced fatal and nonfatal MIs by about 25% and stroke by about one-third. Heart failure was also reduced by about a quarter. The reductions in disease were similar in people with and without clinical CVD and regardless of blood pressure before treatment, stated the news release.

In an accompanying editorial, Profs. Richard McManus from the University of Birmingham and Jonathan Mant from the University of Cambridge, said that these findings reinforce the view that treatment to lower blood pressure should be offered on the basis of risk, regardless of blood pressure. These data support the use of a "polypill" to lower the risk of CVD in people at high risk without first checking their blood pressure, they added.

Type 1 Diabetes in Young Children to Double By 2020
Cases of type 1 diabetes in children aged <5 years across Europe will double by 2020—from 2005 levels—if present trends continue. Numbers in children aged >5 years will also increase substantially. The findings are discussed in The Lancet, by Chris Patterson, MD, Queen's University, Belfast, UK, and Prof. Gyula SoltŽsz, PŽcs University, PŽcs, Hungary, and colleagues.

In the general population, type 1 diabetes cases represent only 10% of total diabetes cases; however, among children, the numbers of cases of type 1 diabetes is higher than type 2 in most countries. To predict the future burden of type 1 diabetes, the authors analyzed diabetes data from 20 centers in 17 European countries, which had registered 29,311 cases of type 1 diabetes during the period 1989 to 2003, according to a news release from The Lancet.

The researchers found that the overall increase in incidence of type 1 diabetes was 3.9% per year; while the annual increase in children aged 0 to 4 years was 5.4%, with a 4.3% rise in the 5- to 9-years-old age group, and a 2.9% rise in 10- to 14-year-olds. There were estimated to have been approximately 15,000 new cases in Europe in 2005, divided among the three groups at 24%, 37%, and 34%, respectively. A total of 24,400 new cases is predicted in 2020, with a doubling in the number of cases in children aged <5 years and a more even distribution across age groups than at present (29%, 37%, and 34%, respectively). The news release stated that if present trends continue, the total number of cases in European children aged <15 years is predicted to rise from 94,000 in 2005 to 160,000 in 2020—a 70% increase.

Because the changes over time are so rapid, they clearly cannot be because of genetic factors alone, the authors wrote. They discuss modern lifestyle habits as possible contributory factors, such as increased weight and height development and increased caesarean section births. The higher increases are seen in Eastern Europe, where lifestyle habits are also changing more rapidly than in the richer European countries.

The authors conclude: "The predicted rise in childhood type 1 diabetes in Europe during the next 20 years, and the raised proportion of cases diagnosed at younger ages than were before, could result in more cases presenting with ketoacidosis and needing hospital admission. More patients with severe diabetes complications presenting at younger ages than before are also likely, and appropriate care from diagnosis and maintenance of good metabolic control are crucial for delay or prevention of these adverse complications. In the absence of any effective means to prevent type 1 diabetes, European countries need to ensure appropriate planning of services and that resources are in place to provide high-quality care for the increased numbers of children who will be diagnosed with diabetes in future years."

In an accompanying comment, Dana Dabelea, MD, of Colorado School of Public Health, University of Colorado, Denver, said findings from this and other studies suggest "that the incidence of type 1 diabetes is increasing even faster than before, pointing toward harmful changes in the environment in which contemporary children live." She also discussed the findings specific to children aged <5 years and the concerns that younger age of onset of type 1 diabetes is usually associated with more acute symptoms. The consequences of longer exposure to altered metabolism due to diabetes and the increasing economic costs of the disease are also examined.

Bovine Blood Improved Neuropathy Symptoms
Patients with diabetic polyneuropathy experienced improvement of their symptoms following treatment with sequential IV and oral protein-free bovine blood extract.

Dan Ziegler, MD, of the Institute for Clinical Diabetology, German Diabetes Center at the Heinrich Heine University, and colleagues reported in Diabetes Care results from a multicenter, randomized, double-blind trial, of 567 type 2 diabetes patients who received 20 IV infusions of Actovegin (Nycomed, Shanghai) (2,000 mg/day) or placebo once daily followed by three tablets of Actovegin (1,800 mg/day) or placebo three times daily for 140 days.

Coprimary outcome measures included total symptom score (TSS) of the lower limbs and vibration perception threshold (VPT). Secondary endpoints included individual TSS symptoms, Neuropathy Impairment Score of the Lower Limbs (NIS-LL), and quality of life (SF-36).

TSS was significantly improved during Actovegin treatment versus placebo (as assessed by area under the curve [AUC] -0.56 points, 95% confidence interval [CI]: -0.85, 0.27; P=.0003) and from baseline to 160 days (-0.86 points, 95% CI: -1.22, -0.50; P<.0001), according to the report. VPT decreased by 3% more with Actovegin versus placebo as assessed by AUC (95% CI: 0%, 6%; P=.084) and by 5% more after 160 days (95% CI: 1%, 9%; P=.017). NIS-LL sensory function as assessed by AUC was also significantly improved with Actovegin versus placebo (-0.25, 95% CI: -0.46, -0.04; P=.021), as was the SF-36 mental health domain.

Treatment with Actovegin for 160 days improved neuropathic symptoms, VPT, sensory function, and quality of life in patients with diabetic polyneuropathy.

Antihypertensive Therapy Beneficial in Dialysis Patients
Randomized trials suggest a benefit of antihypertensive therapy among dialysis patients, according to a meta-analysis published in Hypertension.

Rajiv Agarawal, MD, and Arjun D. Sinha, MD, from Indiana University School of Medicine wrote that although epidemiological studies have shown that lower blood pressure is associated with higher mortality in dialysis patients, randomized controlled trials lack the power to establish benefits of antihypertensive therapy.

Their meta-analysis looked at patients on long-term dialysis participating in randomized, controlled trials and receiving antihypertensive drug thereapy. They identified 1,202 patients from five trials and found the overall benefit of therapy versus control or placebo had a hazard ratio (HR) for cardiovascular events of 0.69 (95% CI, 0.56–0.84) using a fixed-effects model and 0.62 (95% CI, 0.45–0.86) using a random-effects model.

A sensitivity analysis showed that the hypertensive group had a pooled HR of 0.49 (95% CI, 0.35–0.67), but when normotensives were included, less protection was observed (HR, 0.86 [95% CI, 0.67–1.12]). There was significant heterogeneity between hypertensive and included normotensive patients, the authors wrote. The risk ratio for death and cardiovascular events was similar.

"Adequately powered randomized trials are required to confirm these observations, especially among those with hypertension," Drs. Agarawal and Sinha concluded.

Blood Test Reduces False-Positives in Prostate Screening
A new blood test used in combination with a conventional prostate-specific antigen (PSA) screening sharply increases the accuracy of prostate cancer diagnosis and could eliminate tens of thousands of unneeded, painful, and costly prostate biopsies annually, according to a study reported at the annual meeting of the American Society of Clinical Oncology.

William K. Oh, MD, and Robert W. Ross, MD, Dana-Farber Cancer Institute, Boston, reported at a poster presentation that the six-gene molecular diagnostic test, when combined with a PSA test, accurately detected prostate cancer more than 90% of the time. Earlier studies suggest that the conventional PSA test is 60% to 70% accurate in detecting cancer. The 2-year study involved 484 participants and found that "the six-gene model was more accurate than PSA alone at predicting cancer if you had it and no cancer if you didn't," said Dr. Oh in a news release from the Dana-Farber Cancer Institute. The test's accuracy improved even more when PSA measurements were added. Combined, the two tests achieved a diagnostic accuracy of more than 90% in specificity and sensitivity and eliminated most of the false-positives yielded by the PSA test. Based on these findings, the researchers are planning to conduct a larger, multicenter trial involving approximately 1,000 men to determine if the findings remain valid.

Less Sleep Associated With High, Worsening Blood Pressure
Middle-aged adults who sleep fewer hours appear more likely to have hypertension and to experience adverse changes in blood pressure over time, according to a study published in the Archives of Internal Medicine.

"Identifying a novel lifestyle risk factor for high blood pressure could lead to new interventions to prevent or reduce high blood pressure," the authors wrote. "Laboratory studies of short-term sleep deprivation have suggested potential mechanisms for a causal link between sleep loss and hypertension."

Kristen L. Knutson, PhD, University of Chicago, and colleagues examined 578 adults (mean age, 40.1 years) who first had their blood pressure and other clinical, demographic, and health variables measured between 2000 and 2001. In 2003 and 2005, sleep duration was measured using surveys and wrist actigraphy. Blood pressure, demographic, and self-reported sleep information were measured again in 2005 and 2006, according to a news release from the journal.

Participants slept an average of 6 hours per night; only 1% averaged ³8 hours of sleep. After excluding patients taking medication for hypertension and controlling for age, race, and sex, the researchers found that individuals who slept fewer hours were significantly more likely to have higher systolic and diastolic blood pressure.

Sleeping less also predicted increases in blood pressure over 5 years, along with the onset of hypertension. Each hour of reduction in sleep duration was associated with a 37% increase in the odds of developing hypertension.

OSA and Retinopathy Linked in Diabetes Patients
Research presented at the International Conference of the American Thoracic Society (ATS), held in San Diego, suggests that patients with diabetes who have retinopathy should also be screened for obstructive sleep apnea (OSA).

"We know from our earlier research that 23% of men with type 2 diabetes have OSA, and this is underrecognized and undertreated," said lead researcher Sophie D. West, MD, Oxford Centre for Respiratory Medicine, UK. "This study suggests that OSA is linked to retinopathy in type 2 diabetes."

According to an ATS news release, the researchers analyzed data from 118 men who had participated in the earlier study on the prevalence of OSA in type 2 diabetes in Oxford, UK, and who also had retinal images to review. (All UK patients with type 2 diabetes are offered annual retinal screening to look for signs of retinopathy.) Ophthalmology graders studied the images for evidence of retinopathy, and the sleep study data were reviewed to determine the presence or absence of OSA.

The researchers found that retinopathy was present in 54% of those who had OSA, compared to 31% of those without OSA, independent of the effects of glucose control, age, body mass index, hypertension, and the duration of the diabetes. This was statistically significant.

"These results suggest an association between OSA and retinopathy that should be further investigated," said Dr. West. "While the study only analyzed data from men, there is no reason to believe that gender would play a role in the results."

"While there is clearly more research to be done, there is an immediate implication to consider," said Dr. West. "Our message would be for doctors and nurses who see patients with type 2 diabetes to consider whether they could have OSA and whether they should therefore be referred for a sleep study."

Future research will try to determine whether the treatment for OSA, that is continuous positive airway pressure, can delay the development or progression of retinopathy, associated with diabetes, the ATS said.

FDA Approves Biyearly Zoledronic Acid Injection
The FDA has approved zoledronic acid 5-mg injection (Reclast, Novartis) to prevent postmenopausal osteoporosis for 2 years with a single dose.

"It is very important to treat postmenopausal women with low bone mass to prevent them from progressing to osteoporosis," said Mone Zaidi, MD, Mount Sinai Bone Program, Mount Sinai School of Medicine, New York, NY. "The dosing of [zoledronic acid injection] for the prevention of postmenopausal osteoporosis offers an advance over existing therapies since it can be given once every 2 years, instead of daily, weekly, or monthly."

According to a Novartis news release, the new indication to prevent bone loss in postmenopausal women with osteopenia was based on a 2-year randomized, multicenter, double-blind, placebo-controlled study of 581 postmenopausal women aged older than 45 years. The primary endpoint was the change in bone mineral density (BMD) at 2 years relative to baseline. This study included women in early and late menopause. Patients were divided into three groups and received either zoledronic acid injection at the beginning of the study and again at 1 year, zoledronic acid injection at the beginning of the study and placebo at 1 year, or placebo at the beginning of the study and placebo again at 1 year.

Zoledronic acid significantly increased lumbar spine BMD relative to placebo at the end of the 2-year study. Treatment with zoledronic acid injection given as a single dose at the beginning of the study increased lumbar spine BMD by 6.3% in the early menopause group and by 5.4% in the late menopause group at 2 years (both P<.0001).

Bromocriptine Approved for Type 2 Diabetes
VeroScience, in collaboration with S2 Therapeutics, Inc., announced the FDA approval of first-in-class drug bromocriptine (Cycloset) for the treatment of type 2 diabetes. Bromocriptine improves glycemic control across a broad patient population as a monotherapy or as an adjunctive therapy to sulfonylurea, metformin plus sulfonylurea, and single or dual oral hypoglycemic agent therapies, according to the company news release.

Bromocriptine represents a new therapeutic approach in the management of type 2 diabetes by targeting the body's dopamine activity within the nervous system. The specific mechanism by which bromocriptine improves glycemic control in humans is unknown. The development of bromocriptine for type 2 diabetes treatment was based on preclinical studies that have shown brain dopamine activity to be low in metabolic disease states and that this factor contributes to multiple metabolic dysfunctions such as insulin resistance. Preclinical studies of diabetic animals have shown that treatment with a dopamine agonist as in bromocriptine acts upon the central nervous system to reset and improve control of peripheral metabolism.

The company stated that bromocriptine is the first drug to be approved subsequent to the FDA's new guidelines that require studies demonstrating that diabetes drugs do not increase cardiovascular risk. A 52-week, double-blind safety trial of 3,000 patients treated with bromocriptine did not show an increase in prespecified and independently adjudicated adverse cardiovascular outcomes compared with patients taking placebo (HR, 0.58; CI, 0.35-0.96).

"For patients newly diagnosed with type 2 diabetes or those who cannot adequately control their blood sugar with currently available medications, [bromocriptine] provides a completely new approach to treating diabetes," said J. Michael Gaziano, MD, Associate Professor, Division of Aging, Brigham & Women's Hospital and principal investigator of the Cycloset Safety Trial. "In addition, patients with type 2 diabetes are at high risk for cardiovascular events, so it's important that Cycloset has been demonstrated not to increase the risk of cardiovascular events such as [MIs] and may actually have potential to lower this risk."