Originally Published MDDI July 2004

William Leventon

July 1, 2004

17 Min Read
Glucose Monitors Promise More Help, Less Hassle

Originally Published MDDI July 2004

In Vitro Diagnostics



New technologies offer diabetes patients easier and better testing options—and the hope of a near-normal life.

William Leventon

The Paradigm Link diabetes management system enables the meter's blood glucose readings to be sent, via radio-frequency signals, to an insulin pump.

People with diabetes must keep a close watch on their blood sugar levels. Helping them do so is a multibillion-dollar industry that turns out a variety of devices designed to precisely monitor glucose while easing the burden of frequent blood tests.

The traditional blood glucose testing process begins when a patient pricks a finger with a lancet, causing a small drop of blood to form on the surface of the skin. The blood is drawn into a test strip attached to a meter, which determines the glucose level and displays the results on a screen.

Looking more like consumer gadgets than medical devices, cutting-edge glucose meters come in compact packages that are easy to handle and carry around. But size and appearance considerations are not purely aesthetic. Rather, the trends toward smaller size and ease of use also represent attempts by manufacturers to improve patient accuracy. Featuring components that require less time and blood to make a glucose measurement, for instance, will help ensure the monitors' efficiency. Similarly, wireless meters that strive to reduce the reliance on the patient will make testing results more reliable.

By the same token, more-frequent testing also enables better overall blood glucose control. But many patients balk at the thought of performing 10 or 15 tests per day. To address this concern, manufacturers are expanding their efforts to make glucose meters that take continuous measurements. Rather than a single measurement, a busier type of monitor produces a continuous stream of glucose readings. Some continuous monitors rely on under-the-skin sensors; others do their sensing outside the body, thanks to exotic schemes that minimize or eliminate the invasive aspects of glucose testing. Continuous monitors can also operate deep inside patients, sending wireless signals to implanted treatment devices.

Manual Coding Not Required

Meters must be calibrated to each new batch of test strips. Calibration is done by entering a code into the meter. Some meter designs require patients to enter the calibration code, but patients often forget to code or make a mistake in the process. As a result, glucose test results may be 20–30% off the mark, says Olaf Weishaupt, the global marketing manager for the Ascensia Contour, a glucose meter introduced by Bayer HealthCare (Elkhart, IN).

To improve accuracy, Bayer's new meter offers a special coding technology. The electrode at the end of each strip comes with a built-in code, which is automatically entered when the electrode is inserted in the meter. This automatic coding technique makes testing more accurate and easier for the patient, Weishaupt says.

Accuracy also gets a boost from an underfill-detection design that relies on an extra electrode at the end of the test strip. Blood reaches this electrode only after it covers the measurement electrodes on the strip. If the underfill electrode doesn't sense blood, the device concludes that an insufficient quantity has been drawn for the test.

The Ascensia Contour needs only 0.6 µl of blood to perform a glucose test. With the very small sample sizes required by this meter and others on the market, patients can draw the necessary amounts of blood from other parts of the body besides the fingers. This so-called alternate-site testing can be done on the forearm, palm, abdomen, or thigh. Pricking these areas is less painful because they don't have as many nerve endings as the fingers, Weishaupt notes.

Small or Too Small?

The Ascensia Contour glucose meter offers 
special technology that automatically reads the code when the strip is 
inserted. Coding errors may result in test results that are 20–30% off.

Small sample sizes, as little as 0.6 µl of blood, enable patients to draw blood from other parts of the body besides the fingers.

Like other new monitors, the Ascensia Contour is small enough to carry easily. But some meters may be too small for some diabetes patients, who may have dexterity problems, Weishaupt notes. “When it comes to handling, pushing buttons, and inserting strips, it's actually a pain to have a very small device,” he says.

With these difficulties in mind, Bayer unveiled the Ascensia Contour's larger cousin, the Ascensia Breeze. Though still small enough to fit in the palm of a hand, the Ascensia Breeze “goes against the trend” toward ever-smaller meters. Smaller meters often have more functions assigned to fewer buttons, notes Michael Wilcox, project manager for the product. With more meter real estate, the designers were able to increase the button count. In addition, they could switch from multifunction buttons to buttons with single functions illustrated by icons.

Larger meter size also lets designers increase the size of the screen, making it easier for users to read the information being displayed. Adequate display size is crucial, as many diabetes patients suffer from retinopathy, notes Robert Singley, vice president of sales and marketing for the diabetes care unit of BD Medical (Franklin Lakes, NJ).

To illustrate the point, Singley notes that one tiny, penlike monitor was “a huge flop” because users couldn't read the values on the small screen. “Companies have demonstrated the ability to miniaturize to the point where they can make meters whatever size they want,” he explains. “But the size of the display—and the patient's ability to read the display—is going to dictate optimal meter size.”

Wireless Linkage

Recently, Singley's firm partnered with Medtronic MiniMed (Northridge, CA) to introduce its new Paradigm Link diabetes management system. In this system, the meter's blood glucose readings are sent via radio-frequency signals to an insulin pump. The wireless link relieves patients of the task of manually entering test data into the pump. By eliminating human error, it also makes data entry more accurate, notes Jeffrey DuBois, vice president of business development for Nova Biomedical Corp. (Waltham, MA), which designed the wireless communication link.

The company also developed the technology for the BD Logic blood glucose monitor, a key part of the Paradigm Link system. Marketed by BD Medical, the BD Logic requires a blood sample measuring just 0.3 µl. Such small sample sizes were probably inconceivable to people designing meters in the industry's early days.

“When I first got into this business 15 years ago, 20-µl sample sizes weren't uncommon,” Wilcox recalls. “So we thought we were doing pretty good when we got them down to 10 µl.” According to Wilcox, dramatic sample-size reductions are the result of several factors, including electronics advances and tight control of test strip chemistry.

Besides a supersmall sample size, the BD Logic also features a fast 5-second test time. The meter was the first to offer best-in-class status in both sample size and test time, Singley claims.

Though the strides ahead won't be as big as those already taken, meter manufacturers are still moving toward smaller sample sizes and faster test times. Singley says the impetus comes from users. “As people manage their diabetes more aggressively, they're doing tests in nontraditional locations like restaurants and the workplace,” he explains. “So they want to be done with it as fast as they can and get on with whatever they're doing.”

No matter how fast and easy it becomes, pinprick blood testing will always have major shortcomings. For one thing, pinprick tests only give patients a snapshot of their blood sugar level at one moment in time. These snapshots provide no trend data such as how quickly or slowly glucose levels are changing, Weishaupt notes.

What's more, a few discrete glucose readings could lead a patient to mistakenly conclude that the condition is under control. In fact, there's about a 40% chance that patients will miss a potentially serious hypoglycemic event even if they do four pinprick tests a day, according to Deanne McLaughlin, a spokesperson for Medtronic MiniMed. 

Appealing Alternatives

These shortcomings underscore the appeal of so-called continuous glucose monitors, which check blood sugar levels scores of times a day. By taking many readings, continuous monitors can spot dangerous fluctuations and trends that would be nearly impossible to detect through conventional pinprick tests.

Several years ago, Medtronic MiniMed introduced a continuous glucose monitor that's now being prescribed by hundreds of physicians. The CGMS Gold features a sensor that's slipped under the patient's skin, usually in the stomach area. The sensor is composed of a microelectrode coated with a thin layer of glucose oxidase enzyme, which is covered by several layers of biocompatible membrane. The enzyme causes a reaction that converts glucose from the patient's interstitial fluid into an electronic signal, which has a strength proportional to the amount of glucose present. Studies show that blood glucose levels correlate to glucose levels in interstitial fluid, which is found between cells in the body.

The sensor is connected by wire to a Holter-style monitor that stores data gathered at 5-minute intervals. During a 24-hour period, the device takes the equivalent of 288 pinprick readings, according to McLaughlin. That's significantly more than the four daily readings that diligent patients would get from conventional tests. “It's almost like watching a feature-length movie, as opposed to seeing only a few frames of the movie,” she says.

After 3 days, the accumulated blood glucose data are downloaded into a computer in a doctor's office. The data can be presented in graphs and charts showing glucose trends. By analyzing the data, physicians and patients can make diet and treatment adjustments.

On the down side, the CGMS Gold is a physician tool that doesn't provide patients with real-time glucose data. Nor would it allay the fears of parents who wake their diabetic children in the middle of the night to be sure they haven't fallen victim to an undetected hypoglycemic event.
So Medtronic MiniMed will be introducing two new continuous monitoring products designed for diabetes patients. Recently approved by FDA, the Guardian is similar to the CGMS Gold, but it also includes an alarm feature. Patients will be able to set high and low glucose thresholds that trigger the alarm. The alarm will go off before the threshold points are reached, giving patients a chance to take appropriate action.

“As people manage their diabetes more aggressively, they're doing tests in nontraditional locations like 
restaurants and the workplace.” 

Still under development, the other product, called the Guardian 2, will supplement the alarm with real-time readings that are viewed on a screen. The screen will also show graphs that give patients a picture of how their glucose levels have changed over time.

While they provide much useful information, the Guardian products and the CGMS Gold are designed to supplement, rather than replace, pinprick glucose testing. In fact, the Medtronic MiniMed sensor requires at least four calibrations per day using blood glucose readings from a conventional meter.

Pinprick Replacement?

Supplemental status isn't good enough for Abbott Diabetes Care (Alameda, CA), which is seeking FDA approval for a continuous glucose monitor meant to replace pinprick testing. The key to replacing conventional blood tests is sensor accuracy, explains Tim Goodnow, the unit's vice president of research and development. In Abbott's Freestyle Navigator, the sensor features Abbott's “wired enzyme” technology, which isn't sensitive to oxygen levels that vary within the body. This helps boost sensing accuracy to the point where Abbott believes glucose data from the Freestyle Navigator are as accurate as the results from finger-stick tests.

Like the CGMS Gold, the Freestyle Navigator relies on a tiny sensor placed under the skin for 3 days. During that time, sensor data are wirelessly transmitted from a small device worn on the arm to a pager-like unit with a display. The system can check glucose levels and display results every 60 seconds. The display also shows whether glucose levels are rising or falling, as well as the rate of change.

In addition, the system includes alarms for hyperglycemia and hypoglycemia. It also has alarms that notify patients when blood glucose is at a certain level and dropping rapidly.

Abbott is hoping the Freestyle Navigator will reach the market in 12–18 months. If and when it does, though, it won't mean the end of pinprick blood tests—despite the product's billing as a finger-stick replacement. Like the CGMS Gold, the Freestyle Navigator requires conventional blood tests for calibration. Three pinprick tests must be performed during the first 24 hours. No additional calibration is required during hours 25 through 72.

The Holy Grail

Though continuous monitors may be an improvement over other testing devices, they are a far cry from what Weishaupt calls the “holy grail” of glucose monitoring: noninvasive testing. How long will diabetes patients have to wait for a glucose monitor that completely eliminates the pain and annoyance of invasive procedures? “When I started working in the diabetes field 8 years ago, people were saying that noninvasive testing was 5 years away,” Weishaupt says. “And that's what people are saying now.”

Nevertheless, there is a glucose monitor on the market that's billed as noninvasive. Developed by Cygnus Inc. (Redwood City, CA), the GlucoWatch G2 Biographer uses an electrical current to extract glucose molecules through the skin. Worn like a watch, the device includes a sensor that lasts up to 13 hours. But each time the sensor is changed, the replacement must be calibrated using data from conventional pinprick tests, notes Kevin Xie, director of business development for Bayer HealthCare.

“If people have to stick themselves once or twice a day—or even once every two days—I think it's going to be a big hassle to convince them to use your noninvasive system,” Xie says.

Cost is also a factor in marketing noninvasive monitoring devices. In the case of the GlucoWatch, Xie believes the device's price tag may put it out of reach of some diabetes patients. “You have to lower the cost for your product to have a broader appeal,” he says.

On the other hand, lowering the cost of a product limits the technology that can be put into it, he notes. “So the question is: Do you have a cost-effective technology that will make the product work?”

Some in the field have high hopes for optical detection methods that involve picking up a glucose signal from the body. But Xie compares this to looking for a needle in a haystack. In the body, “you have many molecules that emit signals,” he says. “And there are a whole bunch of molecules that emit signals that are close to [that of] glucose, which is typically pretty weak. So it's really difficult to pick up the right signal without expensive electronics and computer power.”

A Minimally Invasive Approach

Mark Samuels thinks a minimally invasive approach may have the best shot at doing away with pinpricks. Samuels's company, SpectRx Inc. (Norcross, GA), is developing a continuous glucose monitoring device that will be worn on top of the skin. The device will measure the glucose in interstitial fluid accessed using the company's patented microporation technology.

The microporation process begins when a patch with a laser target is laid on the skin. Then an electric-shaver-size laser is placed on top of the target. When the laser is activated, it hits the target, transferring some energy to the top layer of skin. According to Samuels, this energy painlessly creates an array of micropores—holes with a diameter about that of a human hair—in the outer dead layer of skin cells.

After the tiny holes are created, the patient takes the laser off the patch and replaces it with a sensor. For 3 days, the sensor measures the amount of glucose in the interstitial fluid flowing through the holes. A transmitter sends the sensor data to a wireless handheld display device.

Samuels believes the SpectRx approach to continuous monitoring has several advantages. For one thing, it doesn't require anything to be placed under the patient's skin. “When you implant a foreign object under the skin, the body wants to attack it,” he says. “Our system doesn't perturb the body and cause a huge reaction. We just make little holes and take a little bit of fluid.”

In addition, the SpectRx system doesn't try to draw glucose through the skin. Samuels contends that the GlucoWatch process significantly dilutes the glucose before it gets to the sensor. “So it needs a sensor that's probably 1000 times more sensitive than everyone else's,” he maintains.

Samuels's plan is to introduce a product that doesn't have to be used with conventional blood tests. “No one has a product on the market that will let people throw away their lancets,” he says. “We believe ours has the capacity to do that.”

But the company will need help. According to Samuels, SpectRx has effective technology for taking samples from the body. But it will have to partner with a firm that can provide a highly accurate, mass-producible sensor. (In tests so far, the sensors used delivered less-than-adequate repeatability.) Once SpectRx finds a suitable sensor partner, Samuels thinks it will take another 18–20 months to get a product ready for submission to the FDA.

Artificial Pancreas on the Way

A continuous monitor of some kind will be a key element in another much-anticipated diabetes device that has yet to reach the market: the so-called artificial pancreas, which is supposed to keep tabs on blood glucose levels and deliver accurate insulin doses when necessary. The purpose of such a system is to reduce or eliminate human intervention in diabetes management and maintain tight glucose control.

Besides a continuous monitor, Medtronic MiniMed's artificial pancreas systems include an insulin pump that communicates with the monitor via RF telemetry. The systems also include a mathematical control algorithm that automatically regulates insulin delivery based on blood glucose readings from the sensor.

The company is working on what it calls semiautomated and closed-loop artificial pancreas systems. Semiautomated systems recommend an insulin dose to the patient, who must approve the recommendation before the dose is administered by the pump. In a closed-loop system, the pump automatically dispenses the insulin dose determined by the algorithm. 

Worldwide, about 350 people have been fitted with a Medtronic MiniMed artificial pancreas in clinical trials, according to McLaughlin. She believes that an artificial pancreas system will be on the market in 4 to 5 years. In the meantime, the company will be developing both external and internal versions of the device. The fully external option will be available for people who don't want a device implanted in their bodies. The system includes the subcutaneous sensor used in the CGMS Gold and a Paradigm-series pump worn outside the body. 

The fully implanted system frees patients from attached devices, making it easier to move around. It also eliminates the need to change sensors every few days.

The implantable sensor is inserted in the right vein leading to the heart. Like the subcutaneous sensor, the vascular sensor is based on glucose oxidase technology. Designed to last a year in the body, the sensor automatically communicates with an implanted insulin pump measuring about 3 in. in diameter. The pump delivers insulin based on sensor data and in response to signals from a communicator held by the patient. Designed to program insulin delivery, the pager-size communicator stores and displays glucose data received via wireless signals.

At present, the system is implanted in more than 40 people in the United States and Europe. Their stories have been heartening, according to McLaughlin. “A few of them have gone from external pumps to implantable pumps,” she reports. “And they say, ‘External pumps were great. But now it's all inside me; I feel normal again.'”

Conclusion

Though old-fashioned blood tests remain the gold standard in glucose monitoring, today's pinprick meters do faster tests with less blood than ever. Manufacturers will continue to shrink sample sizes and reduce test times, but the biggest strides have already been made in these areas. Challenges still lay ahead for continuous monitoring, which provides a wealth of diabetes management data but is still dependent on pinprick tests. Pinpricks may be banished by minimally invasive and noninvasive monitoring techniques, but the technology is elusive, and these options are years away from the market. Also down the road is the artificial pancreas, an automated pump-sensor combination meant to free diabetes 
patients from most or all monitoring and treatment tasks.  

Copyright ©2004 Medical Device & Diagnostic Industry

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