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Diabetes and cardiovascular disease are closely linked, with a high percentage of those with diabetes dying of a cardiovascular illness or event. This is well-recognized, but the relationship between the two diseases is obviously complex. And the understanding of that relationship got muddier, rather than clearer, with the results of two recent trials looking at aggressive glucose control with the use of drug therapy and its relationship to other factors, such as cardiovascular disease.

Diabetes is associated with a shorter life span, and high blood sugar is a known risk factor for both microvasculature events kidney and eye trouble and macrovasculature events heart attacks and strokes. But it has been unclear how much of an effect lowering blood sugar would have on the risk of heart attack and stroke. Hence, the two trials set out to test whether rigorously bringing blood sugar down to near-normal levels, and levels lower than those recommended in current practice guidelines, would reduce the number of heart attacks and strokes suffered by diabetics.

In February, the Control Cardiovascular Risk in Diabetes (ACCORD) trial, a large study evaluating the effects of tight glucose control on heart attack and stroke risk was halted due to excess deaths in the treatment arm, which aimed to radically lower blood glucose levels to near-normal levels so-called "tight glucose control."

ACCORD investigators in early June gave a press briefing about their data and conclusions following that trial halt, at the annual meeting of the American Diabetes Association (ADA; Alexandria, Virginia) in San Francisco, along with investigators from another diabetes trial, Action in Diabetes and Vascular Disease (ADVANCE).

The two trials had contradictory results, but the same bottom line: that to reduce the risk of heart attacks and strokes in patients with diabetes, it is more useful to focus on blood pressure (BP) and blood lipid levels than blood sugar. But aside from that, the studies raise as many questions as they answer: the ADVANCE trial did not see the increased risk of death associated with tight blood sugar control; the ACCORD trial produced data indicating increases in cardiovascular disease, that increase leading to the early halting of part of the ACCORD trial.

Further, subsequent analyses have not uncovered any one smoking gun that is responsible for the roughly 20% increase in overall risk of death or the 35% increase in risk of death due to cardiovascular causes in the ACCORD trial.

"At this point in time, none of our analyses have identified any one reason" for the higher death rate, in patients with tight glucose control, Hertzel Gerstein of the ACCORD study group said at the briefing. He said, rather, that it was "the strategy in its totality" that likely was the cause of the higher death rate.

The two trials differ in the details, but both used a mixture of drugs to get patients down to the desired blood glucose level, including thiazoledinediones, sulfonylureas, metformin, and insulin.

ADVANCE showed no sign of the excess deaths that produced a halt in the ACCORD trial's tight control arm cold this winter, but also showed no positive effect of tighter blood glucose control on either cardiovascular complications or overall death rate, though it did show a roughly 20% reduced risk of kidney disease with tight blood sugar control.

The reasons for the differences between the two trials are no clearer than the reasons for the high death rate in ACCORD. At the press briefing, Anushka Patel, ADVANCE director, said that the differences were perhaps not surprising. "These two studies are very different studies, and the populations in the studies are very different," she said.

Investigators noted that participants in the ACCORD trial had poorer blood sugar control to begin with, which also means that they experienced greater changes in blood sugar over the course of the study. Also, more patients in the ACCORD trials used the drug rosaglitazone, which itself has been linked to cardiovascular risk, though there was no difference in rosaglitazone use between the different experimental arms.

Beyond their direct findings, the trials illuminate a larger point about clinical trials: that focusing on risk factors, while often a useful approach and sometimes the only one available, also brings with it the risk of missing the forest for the trees.

Simultaneously with their presentation at the ADA meeting, the trial results were published in the New England Journal of Medicine.

In a Perspectives article that accompanied the papers, Harlan Krumholz and Thomas Lee wrote that current treatment goals are often formulated in terms of the level of a risk factor without paying any attention to how that level is achieved.

And they pointed to other recent examples where a trial, despite having the desired effect on a risk factor, showed that a treatment was undesirable in terms of patient outcomes. Hormone replacement in post-menopausal women raises the risk of a heart attack despite lowering bad cholesterol levels; in 2006, Phase III trials of Pfizer's (New York) cholesterol-lowering agent torcetrapib were halted when it became clear that patients receiving the compound had higher death rates despite its desirable effects on levels of both good and bad cholesterol.

"A clinical trial is ultimately a test of a strategy, and we should not be surprised that different strategies may have different effects on patients beyond their effect on risk-factor levels," they wrote. "ACCORD, ADVANCE and other recent trials remind us that practice is complex and that ultimately we need to understand a strategy's effect on people, not just on surrogate endpoints."

Patel, at the briefing, said that a longer follow-up might still show significant patient benefits as well as surrogate endpoints. Patients have been followed for five years to date in ADVANCE, and for 3.5 years in ACCORD before the study halt.

Diabetes test gives 5-year prediction window

There is an old saying that seems appropriate when describing Tethys Bioscience's (Emeryville, California) PreDX Diabetes Risk Test: Forewarned is forearmed. The company presented clinical results of the test and reported expanding the test's availability during the ADA meeting.

The PreDX Diabetes Risk Test serves as a predictive tool that is said by the company to deliver an accurate assessment of an individual's risk of developing Type 2 diabetes within the next five years. The test is performed exclusively by the Tethys Bioscience Clinical Laboratory on routinely collected blood samples.

The new blood test is designed to help physicians identify patients at highest risk of developing Type 2 diabetes so that they can promote lifestyle changes or initiate treatment plans to prevent or slow progression to Type 2 diabetes. Numerous studies have demonstrated that such interventions can reduce the incidence of new onset diabetes by 30% to 60%.

Using data generated from thousands of patients who were monitored for up to 17 years, Tethys identified specific proteins and other biomarkers that are most predictive of a person's progression to Type 2 diabetes.

"It's a simple blood test, based on analyzing proteins and an integration of multiple risk-defining biomarkers," Mike Richey, chief business officer of Tethys, told Biomedical Business & Technology. "We then put those through an algorithm we designed. From there a risk score is generated from a scale of one to 10. A person scoring an eight would likely have a 40% chance of developing diabetes in five years."

According to statistics diabetes, a preventable and manageable disease, consumes one in five dollars spent toward healthcare in 2007. The total annual economic cost of diabetes in the U.S. in 2007 was estimated to be $174 billion, an increase of more than 30% in the past five years.

The U.S. and countries throughout the world face a near-epidemic of diabetes. More than 60 million individuals are at risk for Type 2 diabetes in the US alone, with more than 14.6 million diagnosed and 6.2 million remaining undiagnosed.

"It is already known that we are facing a diabetes epidemic that will only grow worse in the next 10 to 20 years," said Sean Sullivan, director of pharmaceutical outcomes research and policy at the University of Washington (Seattle). "The ability to identify patients at high risk years ahead of disease diagnosis may allow us to halt diabetes progression, saving lives and helping to maintain or improve the quality of life for our patients, while also reducing the overall expenses associated with the disease."

Part of the problem lies with predictability test that aren't convenient for the patient or the physician. Richey said that most diabetes tests on the market are too arduous for the patient to take and doctors seldom use the test until symptoms begin to show.

Take, for example, the Oral Glucose Tolerance Test. In it the patient should have been fasting for the previous 8 to 14 hours (water is allowed). Usually the OGTT is scheduled to begin in the morning, as glucose tolerance exhibits a diurnal rhythm with a significant decrease in the afternoon. A zero time (baseline) blood sample is drawn.

The patient is then given a glucose solution to drink. The standard dose since the late 1970s has been 1.75 grams of glucose per kilogram of body weight, to a maximum dose of 75 grams. It should be drunk within five minutes. Blood is drawn at intervals for measurement of glucose (blood sugar), and sometimes insulin levels.

The intervals and number of samples vary according to the purpose of the test. For simple diabetes screening, the most important sample is the 2-hour sample and the 0- and 2-hour samples may be the only ones collected. "[PreDX] just has the physician taking the patient's blood and sending it to our lab. In four to five days the patient has the result," he said.

So far a little more than 100 patients have taken the test in the clinical setting, but in the research setting, that number has been in the thousands. Plans call for the test to be widespread by next year.

"We expect a modest ramp in 2008 and in 2009 ... expect to see a robust adoption of this test," Richey said.

Tethys Bioscience is a personalized predictive medicine company developing novel tests which address the growing global healthcare challenge of chronic diseases such as diabetes. It was founded in 2005.

Product & trial reports

Bayer Diabetes Care (Tarrytown, New York) unveiled the new Contour blood glucose meter with enhanced testing features that can be personalized to best meet patients' individual treatment needs. In addition to the new meter, Bayer also unveiled a redesigned Microlet2 lancing system and new product packaging.

In addition to its No Coding technology, small sample size and fast testing time, Bayer said the updated Contour is the only meter that offers patients the flexibility to choose either "Basic" or "Advanced" levels of testing to keep the management of their diabetes as simple and specific as they would like.

The company said the new, personalized features include programmable testing reminders and pre- and post-meal markers that provide information on how a meal can affect blood glucose, a feature particularly helpful for self-adjusting insulin users. The advanced settings also allow users to set their own high and low blood glucose targets to fit their management needs and provide personal 7, 14 and 30-day testing averages.

The Microlet2 lancing system has been redesigned with a large lancet-release button that is easier to eject. It also features smooth silicone-coated lancets and reduced puncture force.

• Christopher Sorli, MD, an endocrinologist at the Billings Clinic (Billings, Montana), presented initial findings on non-surgical implant of an impermeable liner the EndoBarrier from GI Dynamics (Lexington, Massachusetts) — into a portion of the small intestine, which he said results in rapid weight loss and remission of Type 2 diabetes.

The company said the potential to control diabetes through the use of this non-invasive device means that doctors may be able to reduce or eliminate the need for diabetes drugs, and they may be able to delay or slow the progression of Type 2 diabetes.

The EndoBarrier is being tested in clinical trials around the world as a treatment for obesity and Type 2 diabetes. The EndoBarrier creates a physical barrier between ingested food and the intestinal wall. This mechanical bypass of the small intestine mimics the effects of gastric bypass surgery on a patient's metabolism which results in weight loss and remission of Type 2 diabetes. The EndoBarrier can be easily implanted and removed endoscopically, without the need for surgical intervention.

In the most recent randomized, prospective trial, 12 subjects with Type 2 diabetes were given the EndoBarrier and six underwent a similar endoscopic procedure but did not actually receive the device. The primary endpoint was reduction of HbA1c (average blood glucose level over three months) at 12, 24 and 52 weeks.

At one week follow-up, most device recipients experienced an immediate reduction of fasting and post-prandial blood glucose levels, a key indicator of diabetic status. Some device patients were able to stop taking their diabetes medication as blood sugar levels normalized. As is seen after gastric bypass, this effect occurs in advance of meaningful weight loss. In contrast, patients who did not receive the device experienced no improvement in diabetes status.

"These interim results are very encouraging," said company President/CEO Stuart Randle. "They highlight the EndoBarrier's ability to rapidly restore glycemic control, suggesting that the device mimics the metabolic effects of gastric bypass surgery, without its associated complications and at about one-third of the cost."

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