Biomedical Business & Technology Contributing Editor
Technology keeps expanding to deal with the devastating, chronic disease of diabetes, but these efforts may not be able to keep up with this illness.
CHICAGO — Diabetes is one of the most rapidly growing chronic diseases in incidence and prevalence worldwide, increasing 5% annually since 1990 in the U.S., based on the most recent statistics from the U.S. Centers for Disease Control and Prevention (Atlanta). The total prevalence of diabetes in the U.S. is 20.8 million, or 7% of the population, of which 14.6 million are diagnosed and another 6.2 million have diabetes but are unaware of their disease.
Worldwide, diabetes prevalence is estimated at 180 million, and the number is estimated to likely double by 2030. About 225,000 deaths occur annually in the U.S. due to diabetes, and a new case of diabetes is diagnosed every 21 seconds. Before it kills, the disease produces hugely debilitating effects, amputations of feet and legs, blindness and overall poor quality of life. Even if these worst-case results are put off or delayed, the person with diabetes must undertake a continuing battle to manage the disease.
Short of finding a cure, however, medical science is likely to have a difficult time keeping up with the growth of this illness. According to Larry Deeb, MD, who discussed trends in diabetes prevalence at the annual conference of the American Diabetes Association (ADA; Alexandria, Virginia) here in June, the prevalence of this disease has increased by 30% in the U.S. over the past four years alone. This huge explosion in prevalence is not believed to be due to improved disease detection, but rather a real increase probably linked to the growing prevalence of obesity in the U.S. and life style changes. Because diabetes is a chronic disease, it produces significant ongoing costs. Deeb estimated these to be more than $100 per month for medical supplies required, an average, for a child with Type 1 diabetes, including about $60 per vial for insulin, $1 per day for glucose test strips, and $4 per day for oral agents. These costs are increasing with the development of new technologies such as continuous glucose monitors and advanced insulin pump, and these are creating large market opportunities.
Improvements in glucose monitoring
The key focus of diabetes management is the monitoring of glucose as a guide for the administration of needed insulin, and the ADA conference provides an overview of the continuing advancements in this technology. Continued advances in glucose self-testing technology were also introduced at the conference, targeting improved convenience in glucose monitoring and easier methods for conveying test results to the patient’s physician for disease management. Technologies for continuous monitoring of glucose levels in diabetics are evolving rapidly, including new sensors with extended lifetimes and completely non-invasive monitoring devices that promise to make continuous monitoring more attractive for a wider range of patients.
OrSense (Nes Ziona, Israel) received a CE mark for its NBM-200G continuous non-invasive glucose monitoring system on June 21 and will launch the product in Europe next year. The NBM-200G is based on the use of Occlusion Spectroscopy, which uses spectroscopic analysis of optical signals from the fingertip following local occlusion and re-establishment blood flow, similar to the technique employed in blood pressure measurement.
A poster presentation describing a 28-patient clinical study of the NBM-200G system presented at the ADA conference revealed acceptable accuracy compared to invasive fingerstick glucose measurements, with a mean relative absolute error of 15.9% and 96.9% of all points in the A+B zones of the Clarke error grid. The NBM is now under evaluation in broader clinical settings.
Another continuous non-invasive glucose monitoring system was described at the conference by researchers from GlucoLight (Bethlehem, Pennsylvania). The GlucoLight monitor uses optical coherence tomography to continuously monitor changes in blood glucose non-invasively.
A study presented at the conference by Robert Gabbay, et al. of Glucolight showed that the company’s SENTRIS-100 OCT glucose monitor produced results equivalent in accuracy to other continuous glucose monitors such as the Dexcom STS and Guardian from Medtronic (Minneapolis).
Non-invasive monitoring obviously is preferred vs. invasive continuous monitors because it avoids issues with sensor insertion and insertion site maintenance. In addition, devices such as the NBM-200G are designed to measure blood glucose, not interstitial fluid glucose as measured by existing continuous glucose monitoring systems, leading to improved accuracy for blood glucose determinations.
DexCom (San Diego) introduced a new version of its continuous in-dwelling glucose monitor that extends the useful life of the sensor from three days to seven. The new Seven system is priced at $450 for a starter kit that includes the Receiver, Transmitter and Sensor Applicator. Single-use sensors are priced at $60 each, making the cost per day of $8.57 substantially less than that for the company’s first-generation STS sensor of $11.67, and with the added convenience of a longer time between sensor replacement.
The new Seven monitor provides vibratory or audible High and Low alarms with selectable thresholds; a trend line that shows a history of glucose levels over a selectable interval of one, three or nine hours; and a USB data port. The 26-gauge implantable sensor, which can be inserted by the user or by a physician using the DexCom self-adhesive pad and applicator, requires a two-hour stabilization period before valid readings are produced. The sensor must be recalibrated using a fingerstick glucose reading once every 12 hours.
Another new continuous monitor that recently received a CE mark — but not yet available in the U.S. — is the FreeStyle Navigator from Abbott Diabetes Care (Abbott Park, Illinois). The Navigator performs a glucose reading once per minute, includes arrows showing the trend in glucose level, provides high and low alarms as well as an alarm for rapidly changing glucose level, and offers a five-day sensor life.
Although a 10-hour equilibration period is required for the Abbott Navigator sensor before valid readings are available, only four fingerstick measurements are required over the five-day lifetime of the sensor to maintain calibration. The interval between recalibration starts at 10 hours and gradually increases, on average, to 72 hours.
Another important advantage of the Navigator, distinguishing it from others now on the market — such as the Medtronic Guardian and CGMS and the DexCom STS and Seven — is that diabetics will be able to use the Navigator readings directly to decide upon changes in insulin dosage. With existing monitors, the user must first confirm the glucose level indicated by the monitor with a separate fingerstick measurement prior to changing therapy.
Glucose, ISF not in sync
All existing continuous glucose monitors, with the exception of the new OrSense non-invasive monitor, measure glucose levels in interstitial fluid (ISF) via a subcutaneous sensor rather than blood glucose levels. While there is a close correlation between ISF and blood glucose levels, it is not exact and significant differences exist, particularly when blood glucose levels are changing rapidly.
According to Howard Wolpert, MD, of Joslin Diabetes Center (Boston), who discussed continuous glucose monitoring technologies at the conference, there is a five to 30-minute delay between blood glucose and ISF glucose levels, which can prove problematic when recalibrating the continuous sensor using a fingerstick reading. While that drawback may be addressed to some extent with future subcutaneous monitoring systems through the application of more sophisticated software algorithms, the primary tactic used to avoid calibration errors at present is extensive training of diabetic users. A study of patient outcomes comparing diabetics using continuous glucose monitoring and insulin pump therapy to manage their glucose levels to controls using fingerstick glucose testing and insulin pump therapy, the STAR 1 study, was presented by Irl Hirsch, MD, of the University of Washington School of Medicine (Seattle).
The results showed a direct correlation between the extent of sensor utilization and the likelihood of achieving a decrease in hemoglobin A1c levels, which reflect average blood glucose levels over a 90-day window. For each 10% increase in sensor utilization, there was a 41% increase in the probability of a 0.5% hemoglobin A1c decrease. The trial, with 138 participants enrolled, had few exclusion criteria, thus making the results applicable to most of the diabetic population.
The STAR 1 results provide evidence for a real benefit of continuous glucose monitoring in improving glycemic control, albeit on a relatively small number of patients. Previous studies using the Medtronic Guardian RT continuous glucose monitoring system have also shown benefit in reducing HbA1c levels compared to fingerstick testing.
TGC protocols improve control
Continuous glucose monitoring is also expected to play a role in the hospital setting to help manage patients on Tight Glycemic Control (TGC) protocols. At present, TGC is generally implemented using fingerstick blood glucose testing, creating a significant workload for nurses who must perform testing at intervals as often as every 30 minutes.
The GlucoLight device, for example, is being developed first for use in TGC protocols in hospitals to provide improved control of glucose. Another system, the GlucoScout continuous blood glucose monitor from International Biomedical (Austin, Texas), is also available for TGC monitoring at the hospital bedside. TGC has been shown to result in reduced mortality and morbidity in hospitalized patients, particularly those undergoing cardiac surgery, including reduced incidence of central venous catheter-related infections, resulting in reduced length of stay and a consequent reduction in the cost of hospitalization.
Continuous monitors such as the GlucoLight system could alleviate the burden on nurses who must perform the TPG testing by providing automated glucose readings at intervals as short as one minute. However, accuracy will need to be improved compared to that available from existing continuous glucose monitors in order for the technology to be accepted by hospitals.
Other technologies that are playing an important role in enabling the most efficient TGC in hospitals include new software programs that determine the proper insulin dose adjustments needed to maintain a patient’s blood glucose within the desired range, typically between 80 and 120 mg/dL.
Available products include the EndoTool glucose management system from MD Scientific (Charlotte, North Carolina), and the G+ glucose management system from GlucoTec (Greenville, South Carolina). The G+ system is based on the Glucommander software algorithm for directing intensive IV insulin therapy, developed by Paul Davidson and others at Atlanta Diabetes Associates (Atlanta). The G+ was cleared by the FDA in June 2006 for use in TGC protocol management, and GlucoTec has generated $1.3 million in sales of the product in 2007 to date.
The software is proving to be quite valuable in managing pediatric and neonatal patients, since their inherent glucose and insulin control may not be fully developed, and the consequences of hypoglycemia, which can include cerebral edema, are often serious.
The EndoTool software from MD Scientific has been used in the management of more than 4,000 patients and is also FDA-cleared. Evaluations of the software in intensive care units have shown that glucose levels are well controlled with a minimal (0.13%) incidence of severe hypoglycemia.
Glucose self-testing continues to be an important component of diabetes management, with continuous advances in meter and test strip technology driving a growing global market.
As shown in Table 1, the market for whole blood glucose self-testing products approached $7.5 billion in 2006 and is forecast to grow at 10.7% annually through 2011. The large and expanding market is attracting a number of new companies, making it one of the most attractive segments of the in vitro diagnostics market worldwide.
One indication of the attractiveness of the market is that in two major divestitures in the in vitro diagnostics industry within the past two years, the sale of the Bayer Diagnostics (Tarrytown, New York) business to Siemens Medical Solutions (Munich, Germany) and the sale of Abbott’s diagnostics business to GE Healthcare (Waukesha, Wisconsin), both Bayer and Abbott retained their glucose self-testing business units.
New products exhibited at the ADA conference included Abbott’s FreeStyle Lite, new models of the Ultra Mini meter from LifeScan/J&J (New Brunswick, New Jersey), and the Nova Max glucose test system from Sanvita (Clearwater, Florida). In addition, new products were announced that are slated for launch in the U.S. market in the future including AccuChek Smart Pix data management software from Roche Diagnostics (Indianapolis), and the Precision Xtra Fast blood glucose and ketone test system from Abbott Diabetes Care.
The new FreeStyle Lite system from Abbott Diabetes Care represents the first glucose test system from Abbott that incorporates a no-coding feature. No-coding or automatic coding is rapidly becoming an important product feature in the glucose self-testing products market.
Bayer Diabetes Care was the first to introduce no-coding technology and now offers the feature on both its Breeze meters via a coded label on the test strip cartridge employed in the Breeze, and via a meter-readable code on each test strip in the Contour system.
Studies highlighted by Bayer show that up to 43% of errors associated with blood glucose self-testing are due to mis-coding of meters, and that up to 41% of all users make coding errors when using glucose meters that require user coding.
Other meters with no-coding or autocoding features now on the market worldwide in addition to the Bayer meters and Abbott’s new FreeStyle Lite include the SideKick from Home Diagnostics (Ft. Lauderdale, Florida), the Evolution from Infopia Co. (Kyunggi, Korea), the AccuChek Compact Plus from Roche Diagnostics, and the Sanvita Nova Max, and the X-Meter from Arkray (Kyoto, Japan).
Biosensor, fluorescence, AGE accuracy
Another important trend in the glucose self-testing market is improved result accuracy.
AgaMatrix (Salem, New Hampshire) exhibited the WaveSense glucose system, which uses advanced biosensor technology developed in Korea. In addition to measuring glucose, the meter also measures hematocrit and temperature, and uses that information to correct the glucose reading for improved accuracy. The meter requires a 0.5 uL blood sample and performs a test in about three seconds. Clinical studies have shown a high degree of correlation between the WaveSense and reference methods such as the YSI analyzer from Yellow Springs Instruments (Yellow Springs, Ohio).
Two new devices for diabetes screening were exhibited at the conference that could help to reduce the number of persons with diabetes who are unaware of their condition. VeraLight (Albuquerque, New Mexico) is developing the Scout DS system, a non-invasive screening device that is designed to detect individuals with diabetes by measuring skin fluorescence due to advanced glycation end products (AGEs) that are known to be present in most diabetics. The product will be sold on a cost-per-test basis, and a screening test, typically reimbursed at between $12 and $18, can be performed in one minute. VeraLight (a spin-out from the former Rio Grande Medical), expects to receive FDA clearance for the Scout DS in 2008.
DiagnOptics (Groningen, the Netherlands) also exhibited an AGE reader. The DiagnOptics AGE Reader has received the CE mark and has been accepted for use by the Ministry of Health in the Netherlands for screening of the general public. The reader is priced at €20,000, and performs a screening test in 30 seconds. According to the company, high AGE levels in the skin are not a definitive marker for the presence of diabetes, but are highly correlated with the risk of diabetes complications.
Glucose, combined with ketone testing
Abbott’s new Precision Xtra Fast, due to be released in the U.S. in the near future, offers both blood glucose and ketone testing with a 0.3 uL blood volume requirement and 3 second test time for glucose and a 1.5 uL volume and 10 second test time for ketones. The Xtra Fast will also feature no-coding technology via Smart Chip technology that encodes calibration data on each test strip which is uploaded to the meter.
The new Nova Max system from Sanvita received FDA clearance in late May 2007, and is based on the Logic blood glucose testing technology from BD (Franklin Lakes, New Jersey). Sanvita has acquired the BD Logic blood glucose business, which had estimated calendar 2006 sales of $93 million, and, in partnership with Nova Biomedical (Waltham, Massachusetts), developed the new Nova Max which features a 0.3 uL test volume and a 5 second test time.
Sanvita has a 175-person sales force serving the U.S., giving the company a significant market presence, and it will also supply test strips that are compatible with the Paradigm Link glucose meter which is integrated into the Paradigm insulin pump, marketed by Medtronic.
Internet and algorithms
Advances beyond improved glucose testing and glucose self-management discussed at the ADA conference included new technologies for physiological and neurological monitoring, such as devices to track physical activity and to assess diabetic neuropathy, as well as advances in insulin delivery and diabetes screening.
Exhibited at the conference were new non-invasive technologies for diabetes screening that promise to facilitate disease detection, allowing treatment to begin earlier when it is most effective.
A variety of these new developments in patient monitoring and diagnosis of diabetes and its complications were introduced at the conference by companies including BodyWear (Pittsburgh) and GlucoTel Scientific (Bad Wildungen, Germany), a unit of BodyTel Scientific (Reno, Nevada).
BodyWear introduced a web-based clinical weight management product at the ADA exhibition called SenseWear WMS, based on the company’s wearable body monitoring technology. The SenseWear platform is designed to track metabolic activity using an armband that measures skin temperature, galvanic skin response, heat flux and motion via a two-axis accelerometer. The combined outputs from all four sensors can be analyzed using a patented algorithm to provide data on metabolic activity having a 95% correlation with gold standards.
The monitor in effect works like a metabolic Holter device that, using the new web platform, allows patient data to be viewed and analyzed remotely by a clinician to quantitatively track metabolic activity. Patients can track the number of calories they burn compared to clinician-set goals on a watch-type display.
The SenseWear system, priced at $599, is protected by patents covering the data processing algorithms used in the device. Clinicians can obtain reimbursement for patient coaching using the system under existing codes.
GlucoTel is a telehealth system using wireless technology to report values from glucose self-testing measurements back to a clinician. The system will be launched in Europe in late summer 2007 and will be introduced in the U.S. in late 2007, pending FDA clearance. The system consists of a glucose meter/cellular phone used to perform glucose readings and report the data to a secure website. The meter is placed at no charge, and the company sells test strips to users.
The current version of the test strip has a sample volume requirement of 0.6 uL and test time of 10 seconds, but by the end of 2007 a newer version will be introduced having a 0.25 uL sample volume requirement and a 5 second test time. In addition to recording glucose test results, the meter/cell phone can be used to store events in the on-line database such as insulin dose, carbohydrate intake, and stress events.
Advances in insulin delivery
Complementing, as it were, glucose monitoring is the insulin delivery sector. The sector includes insulin pumps, insulin pens, insulin syringes and other types of injectors and infusion devices for insulin delivery. Table 2 describes trends in the insulin pump market in the U.S., which totaled $532 million in 2006, and represents one of the largest and fastest growing segments of the insulin delivery products market.
The most revolutionary new insulin delivery method, launched in the U.S. at the ADA exhibition in 2006, is inhaled insulin, a technology developed and introduced as Exubera by Nektar Therapeutics (San Carlos, California) in partnership with Pfizer (New York,). The acceptance of Exubera in the market has, however, been disappointing for Pfizer.
Although sales have not been disclosed by Pfizer, sales of Exubera to Pfizer by Nektar — which developed and manufactures the inhaled form and the inhaler to deliver it — totaled about $110 million in 2006, as shown in Table 3.
Nektar projects only slightly higher sales in 2007 of between $110 million and $130 million. Furthermore, the 1Q2007 Exubera sales figure for Nektar included 60 days of sales deferred from 2006, indicating a downward trend in purchases of Exubera by Pfizer. Sales of Exubera by Nektar to Pfizer do not represent end-user sales, so Pfizer’s Exubera sales may be lower.
Pfizer has said it plans to increase its marketing and education efforts in 2007 in an effort to boost Exubera sales. However, as discussed by Carol Hamersky in a session covering new technologies at the conference, use of Exubera has so far been limited, in her experience, to the relatively small number of insulin-requiring diabetics who have an extreme aversion to self-injection of insulin.
Citing four case studies of patients who now use Exubera, Hamersky noted that for many diabetics there is not a significant concern with the use of needles for injection, limiting applications for Exubera to those patients who either refuse to perform injections or who simply would like to temporarily avoid injecting.
Another factor limiting the adoption of Exubera is the physical size of the inhaler delivery device, which makes its use somewhat cumbersome compared to devices such as insulin pens. Hamersky said that she believes that future versions of the device will be smaller in size.
Innovations in pumps
Insulin pumps represent an active market segment characterized by rapid new product innovations though the uptake in insulin pumps is slow growing. Key trends include integration of pumps with glucose meters and continuous glucose monitors, easier-to-apply infusion sets, advanced software features such as food databases that simplify calculation of dose requirements, and simpler user interfaces.
For example, Sooil Development (Seoul, Korea) is planning to introduce a new version of its IIs insulin pump family, the IISG, later in 2007 that will have an integrated glucose meter. The IISG is already available in Europe and Korea, and more than 50,000 patients have been treated with Sooil insulin pumps since the company entered the market in 1979.
Smiths Deltec, a unit of Smiths Group (London) is also developing an integrated pump/glucose monitor system, partnering with Abbott for development of the continuous monitor.
At the ADA conference, Smiths exhibited new meal calculation software for its Cosmo insulin pump, which will be made available without charge to current Cosmo users whose pumps are still in warranty.
Animas (West Chester, Pennsylvania), a business unit of J&J, exhibited the 2020 insulin management system, which includes a flat-panel screen, a 500-item food database, a waterproof design, and a simplified user interface that eliminates icons in favor of text messages.
A new all-in-one infusion set, the Inset from Unomedical (Birkerod, Denmark), is also available for the 2020 that inserts the 6 mm cannula and attaches the self-adhesive pad in one step. Another exhibitor at the ADA conference, Diamesco Co. (Seoul, Korea) is planning to introduce the Best Life insulin pump in the U.S. market in 2008.
Patches and ports
Other new developments in insulin delivery technology described at the conference included transdermal patches, insulin ports, and remotely-controlled insulin “pods.” Encapsulation Systems (Broomall, Pennsylvania) exhibited the U-Strip, a programmable transdermal patch designed to provide insulin delivery equivalent to that available from an insulin pump, but that is non-invasive and will be significantly less costly. The U-Strip uses ultrasound energy to dilate skin pores, allowing large molecules such as insulin to be delivered transdermally.
The device consists of two components, an insulin patch and the ultrasonic transducer. It is typically worn on the bicep, secured with an arm band, or on the abdomen attached with a self-adhesive patch. The U-Strip hold from 20-100 units of insulin, and the patient can control the dose.
The company is focusing on Type 2 diabetics as the target users of the device, allowing them to avoid the need for injections. Cost of the U-Strip, which is still in development, is estimated at $2.50 per day, or less than $1,000 per year, much below the cost of an insulin pump, which costs more than $1,500 per year for infusion sets and catheters plus the annualized cost of the pump. Insulin pumps typically cost over $5,000. The combination of lower cost and non-invasive insulin delivery could make the U-Strip an attractive alternative to insulin pumps.
Venture-funded, Encapsulation Systems recently received funding sufficient to take the company through Phase II clinical trials.
Patton Medical (Austin, Texas) exhibited the I-Port Injection Port, a self-adhesive drug delivery port with a soft cannula that is attached to the abdomen for insulin delivery. Rather than injecting insulin directly with a syringe multiple times per day, a new port is attached only once every 72 hours. While the port is attached, insulin can be injected into the port through a resealable septum. The product was introduced in February of 2007, and costs about $120 per month.
The ultimate solution
The ultimate solution for treatment of diabetes, addressed in multiple sessions at the conference, is the development of stem cell therapy or renewable islet cell transplants to restore the ability of diabetics to produce insulin. Although some successes have been achieved with implantation of donor-derived islet cells, the transplanted cells eventually lose their ability to produce insulin over time.
Recent developments described at the conference include various drug therapies aimed at preventing transplant rejection by suppression of the immune system, coating of implanted cells with substances such as heparin and low molecular weight dextran sulfate to eliminate adverse immune responses, and implantation of cells in sites other than the intraportal vein (the usual site for implantation) without direct blood exposure.
A major limitation for the use of islet cell transplantation in diabetes, however, is the scarcity of donor cells. Attempting to solve this particular problem, Novocell (San Diego) is developing technology to produce replenishable islet cells, avoiding the need for donated cells.
As discussed by Anne Bang, PhD, of Novocell at the ADA meeting, the company has developed a technique for transforming stem cells into islet cells in-vitro, and coating the newly formed islet cells with a conformal polyethylene glycol layer.
Novocell is now studying the characteristics of the replenishable islet cells to determine their ability to produce insulin at levels comparable to native islet cells and to release factors such as C-peptide in response to changes in glucose level. Although human experiments have not yet begun, the company believes that it can create viable beta cells that function in vivo like normal islet cells, resulting in a new therapeutic approach for diabetes.