Originally Published MX September/October 2001
MARKET ANALYSIS
Diabetes Management: New Technologies, New MarketsNoninvasive and continuous blood-glucose monitoring and alternative insulin-delivery systems are simplifying diabetes control.
Tracy A. Schaaf
According to the American Diabetes Association (ADA; Alexandria, VA), diabetes, a disorder in which the body does not produce or properly use the hormone insulin—which is needed to convert sugar, starches, and other food into energy—affects 16 million Americans. Five million of them don't know they have it. An additional 20–30 million Americans have impaired glucose tolerance, a potentially prediabetic condition. The Centers for Disease Control and Prevention's National Center for Injury Prevention and Control (Atlanta) pronounces diabetes to be the sixth-leading cause of death by disease in the United States (see sidebar).
Diabetes is estimated to cost the country $44 billion annually in direct medical costs and $54 billion in productivity losses attributable to lost workdays, disability, and premature death. Effective management of glucose levels in sufferers is paramount in controlling the condition.
The Diabetes Control and Complications Trial study, conducted from 1983 to 1993 by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; Bethesda, MD), showed that maintaining plasma glucose and hemoglobin A1c (HbA1c) levels as close to normal as possible decreased risk of the development and progression of microvascular complications such as eye, kidney, and nerve disease by 50–75%. Technological innovations fueled by the findings of this influential study continue to make glucose regulation more accurate, more comfortable, and easier for patients, thus improving diabetics' health and productivity and reducing the need for ambulance services, hospitalization, and even doctor visits.
The outlook for growth in the glucose-monitoring market is very promising owing to the growing patient population and a rising percentage of glucose-testing patients. And current glucose-testing patients are also testing more. This trend is being fueled by heavy educational efforts inspired by the results of long-term, large-scale clinical trials showing that frequent testing and better glucose control leads to enhanced quality of life and fewer health complications—not to mention a lower cost of care.
Patients and physicians are ready to accept any effective new minimally invasive (thus less painful) glucose-testing technology, and industry has obliged. This new class of devices is beginning to take away market share from traditional meter products. The worldwide market for glucose monitoring comprises almost 20% of the total $20 billion market for in vitro diagnostic products. According to Merrill Lynch (New York City), approximately $3.8 billion in global sales in 2000 indicated a rise of more than 10% from the previous year.1
"The new glucose sensors really open up the world in terms of blood-sugar control," says Anne Peters, MD, a professor of clinical medicine at the University of Southern California (Los Angeles) and director of the Los Angeles County–USC Diabetes Program. "The next step, which is quickly approaching, is real-time glucose monitoring, with alarms that identify for the diabetic an impending high- or low-blood-sugar episode. Eventually, we will be able to couple these systems with automatic insulin pumps."
Another important segment of this market involves insulin delivery. Industry has been working to address the need to alleviate patients' painful needle experiences through the development of minimally invasive and noninvasive drug-delivery technologies. Products being developed include inhalation-based, oral, and transdermal insulin-delivery systems. The obstacle that innovative systems must surmount is that insulin is ineffective unless it reaches the bloodstream directly.
Current research is also assessing the potential of bioartificial pancreas technology that would essentially enable diabetics to live a normal life. Peters notes that the ideal "cure" for diabetes would be islet-cell transplants engineered not to require immunosuppression. Encapsulated stem cells are another possibility.
Device companies, anxious to cash in on this very lucrative and growing market opportunity, have recently developed and introduced many new technologies into the diabetes market. And more are on the way.
|
Area of Body Affected
|
Specific Complications
|
| Cardiovascular system | Atherosclerosis of the heart and vessels in the extremities |
| Eyes | Glaucoma Cataracts Retinopathy |
| Feet | Foot ulcers Poor circulation Neuropathy Amputation |
| Kidneys | Kidney disease and dialysis |
| Mouth | Gum disease |
| Skin | Bacterial infections Fungal infections Itching Diabetic dermopathy Necrobiosis lipoidica diabeticorum Allergic reactions Diabetic blisters Eruptive xanthomatosis |
Table I. Diabetes can result in complications affecting various areas of the body. Source: American Diabetes Association (Alexandria, VA).
Pain-Free and Alternate-Site Glucose Monitoring
The annual ADA meeting held in Philadelphia this June generated great excitement about low-pain or painless blood-glucose monitoring devices and new alternate-site testing, in which samples are taken from areas of the body that are less pain-sensitive than the fingertips, such as the forearm and thigh. So far, privately held Amira Medical (Scotts Valley, CA) is the front-runner in this field, with a combination sampling device and glucose meter that received industry notice for design innovation when it won a Medical Design Excellence Award in 2000.
TheraSense (Alameda, CA), another private company, has also entered the fray. It launched a 510(k)-approved device last August. An integrated lancing and sampling system from Abbott Laboratories/ MediSense (Abbott Park, IL) received 510(k) clearance in November 2000. Merrill Lynch reports that these alternate-site and pain-free glucose meters are expected to command as much as 10% of the new meter market this year, with huge anticipated consumer demand.
 |
| Figure 1. The AtLast blood-glucose system by Amira Medical (Scotts Valley, CA) combines a sampling device with a glucose monitor. |
No Pain—AtLast. The microtechnology-based AtLast blood-glucose system developed by Amira Medical enables end-users to obtain a blood sample from the forearm, thigh, or upper arm—areas with fewer nerve endings than the fingertips—and measure the glucose in it (see Figure 1). The system received FDA marketing approval in late 1998 via the 510(k) process.
AtLast works by creating a small break in the skin using a custom-made lancet designed with a mechanism to help bring blood to the surface. The mechanism adapts to variations in skin texture. A capillary test strip touched to the minute 2-µl blood sample results in a chemical reaction and associated color change that a built-in meter converts into a digitally displayed glucose reading in as little as 15 seconds. Accumulated data are retrievable.
"The number one comment we hear from consumers is that there is no pain," says Pam Hetrick, health professional representative at Amira. "Also, the batteries are built into the device, so after 2500 tests or within three years of product purchase, the patient returns the device free of charge for a new one that will contain any updates that have been made to the technology. This is an inventive approach to encouraging frequent monitoring among patients."
Amira is also developing home glucose-monitoring tests that employ interstitial-fluid technology from Inverness-acquired Integ (Waltham, MA) through a strategic alliance with that company. The device, LifeGuide, combines meter and test-strip technology with interstitial fluid–collection technology. Its operation is similar to that of the AtLast system. In-house trials involving use by professionals under routine conditions were promising, but further studies have been deemed necessary.
Smaller Samples. The FreeStyle blood-glucose monitoring system from TheraSense was designed to require only a pinhead-sized sample taken from a minimally painful body site such as the forearm. The system employs proprietary sampling technology that can measure glucose volumes in the nanoliter range. It reads the entire yield of glucose in the blood coulometrically, whereas other meters, using amperometric technology, measure the rate of the electrical charge of glucose, and thus require a larger sample. The technology is available to end-users as well as professionals, but there is concern that the ultrasmall sample will be difficult for many diabetics with dexterity and vision problems to see and target.
Portability. An alternate-site meter about to vie for a slice of the glucose-monitoring pie is the Sof-Tact diabetes-management system from Abbott/ MediSense. About the size of a Walkman, the Sof-Tact is a self-contained testing device that is easy and, says its manufacuturer, virtually painless to use. It is designed to enable another person to help a patient with dexterity problems, and its vacuum function allows samples to be drawn from the arm, thigh, or abdomen. Like the AtLast and FreeStyle systems, the Sof-Tact stores results that can be downloaded to a PC. It provides average glucose readings for the past 7, 14, and 28 days on its own display.
Making It Easier. Another alternate-site device intended to relieve the pain involved in blood sampling is the One Touch Ultra system from LifeScan, a Johnson & Johnson company (Milpitas, CA). The device, which received 510(k) clearance in 2000 and was released to the U.S. market in February 2001, requires a tiny, 1-µl drop of blood that can be taken from the arm. In a clinical study, 78% of participants reported that testing on the arm with this system was either painless or significantly less painful than fingertip testing.
The One Touch Ultra system provides clinically accurate results in just five seconds. Like the products previously described, it offers a variety of features designed to support better diabetes management: a memory of time- and date-labeled test results, periodic glucose-measurement averaging, no necessity for cleaning, and the option to download test data to a personal computer.
Such products make glucose monitoring easier for tech-ready patients interested in logging a variety of personal health parameters (see sidebar).
Calling it Quits. Not every company is able to negotiate the rapids of product development to a succesful conclusion. After advancing its system to limited clinical studies, Technical Chemicals & Products Inc. (TCPI; Pompano Beach, FL) determined that it lacked sufficient resources to complete develpoment. TCPI's TD glucose monitoring system uses a transdermal approach to noninvasive glucose monitoring. The device draws dermal glucose into a patch that is placed on the forearm for approximately five minutes. A specially designed meter optically deciphers the color change in a chemical-impregnated membrane in the patch to produce a glucose reading.
Although TCPI has suspended further development of the monitor, the company hopes to pick up the project again when additional funding becomes available.
The Big Four in Glucose Monitoring
The glucose-monitoring market is largely a retail market, according to Merrill Lynch. Roughly 60% of sales occur in pharmacies. Therefore, strong relationships with the big chains are a top priority for companies contending to win shelf space and reach patients. The second factor critical to product success is securing managed-care contracts. For these reasons, four large players with the necessary critical mass and clout have long dominated the glucose-monitoring market: Roche (Basel, Switzerland), Johnson & Johnson (J&J; New Brunswick, NJ), Bayer (Leverkusen, Germany), and Abbott (see Table II). Smaller companies are now entering the market with either a private-branding strategy (e.g., Home Diagnostics [Ft. Lauderdale, FL]) or differentiated technology, as discussed above.
|
Company
|
Worldwide Sales ($ millions)
|
Market Share (%)
|
Year-to-Year Change (%)
|
| Roche |
1065
|
28
|
16
|
| Johnson & Johnson |
975
|
26
|
(5)
|
| Bayer |
675
|
18
|
11
|
| Abbott |
495
|
13
|
21
|
| Home Diagnostics |
100
|
3
|
54
|
| Inverness |
90
|
2
|
27
|
| Others |
370
|
10
|
19
|
| Total |
3770
|
100
|
-
|
Table II. Estimated worldwide glucose-monitoring market for 2000. Source: Merrill Lynch (Boston).
Roche: We're Number One. Merrill Lynch reports that Roche generated considerable momentum with its new Accu-Chek product family. In 2000, the company claimed the mantle of sector leader from J&J. Roche's Accu-Chek system and new Comfort Curve test strips feature sampling ease, small sample requirements, and good readability of results. Roche does not yet offer a system that uses alternate test sites for blood sampling.
J&J: Rebounder? The market leader in 1999, J&J's LifeScan saw sales of its glucose-monitoring products fall 5% to $975 million in 2000. The introduction of new products from other major competitors, particularly Roche, took a toll, and J&J was the last major player to reach the market with an electrochemical/biosensor-based system. FastTake, launched behind schedule in April 1998, uses wicking-strip technology that allows for collection of very small samples, a short test time of 15 seconds, and alternate testing sites. The launch of the One Touch Ultra system this February puts J&J in a position to rebound.
Bayer: Acquiring Minds. Bayer is a solid competitor in the glucose-monitoring market. Its Glucometer Elite and Elite XL products use the same test strips, their meters turn on automatically when the strip is inserted, and they provide complete, rapid, no-button testing. Bayer also offers a lancing system for both meters, the higher-end Glucometer DEX meter that provides the diabetic with a discreet option to test away from home, as well as Glucofacts home-use and Glucofacts Pro doctor's-office diabetes management software that works with the Elite XL and DEX.
In April 2000, Bayer acquired exclusive rights to the blood-sampling technology from Kumetrix (Union City, CA). Kumetrix has developed a microneedle device that withdraws a 0.1-µl sample into a microcuvette containing test reagents that produce a color change. A laser device measures the color shift to determine glucose levels.
Abbott: After a Bigger Share. The fourth big market presence, Abbott Labs, offers more than the well-received Sof-Tact diabetes-management system. The company is aiming to command a 13% share of the worldwide glucose-testing market with the January 2001 U.S. launch of its Precision Xtra, designed specifically for type I diabetics (frequent testers).
The Xtra offers the ability to test quantitatively for blood ketones, the earliest predictors of the potential for diabetic ketoacidosis (DKA). Type I diabetics must test for DKA when they are sick, have a glucose level above 240, or are pregnant. Most DKA testing is currently done via qualitative urine strips. Offering the test on the Precision Xtra platform allows the patient to receive real-time results at home (the test can also be administered by a physician), thus saving valuable time in detecting what could be a life-threatening condition.
Continuous Glucose Monitoring
Although careful glucose control is critical in avoiding the major complications of diabetes, only about 10% of people in the diabetic population do any form of intensive management. This is because of the enormous amount of commitment required. But with the continuous glucose-monitoring systems recently developed by several companies, tests are taken automatically every few minutes around the clock. This technology makes acquisition of the necessary insulin profile much more likely, and enables trends to be recorded.
Continuous glucose-monitoring systems are intended to replace the point-in-time measurements of traditional glucose meters and strips, providing physicians with glucose-level trend information that can be critical in making therapy decisions. Continuous monitoring systems have a smaller error range than traditional point-in-time meters and offer the additional advantage of reduced pain. Sticks, which are less frequently necessary, are performed typically in the abdominal area. A successful system of this type could significantly improve patient compliance and foster better disease management.
However, according to Merrill Lynch, the prospect of such systems gaining market acceptance remains hard to peg. Not every patient is going to want to be attached to a device. And some doctors may be concerned about the lag time between levels of interstitial glucose (what most continuous systems measure) and levels of blood glucose (what traditional meters and strips measure).
FDA Approved. MiniMed (Northridge, CA), now in the process of being acquired by Medtronic (Minneapolis), was first to market with a continuous-monitoring device for use by healthcare professionals. The company filed a premarket approval (PMA) application for a consumer version of its device in August 2000. Cygnus Inc. (Redwood City, CA) is next up; FDA approved its innovative product in March 2001.
The MiniMed continuous glucose-monitoring system (CGMS) is the only FDA-approved continuous glucose-sensing device. The system, which received PMA approval in June 1999 and is now available only to healthcare professionals, offers an approach resembling that of a Holter monitor, with 72-hour implantation and automatic glucose measurement every five minutes.
The sensor is a tiny electrode inside a small needle introduced under the skin. Once inserted, the sensor remains just under the skin surface while the needle is removed and discarded. The sensor is attached to a small plastic disk about the size of a dime, which is taped to the skin to hold the sensor in place. A thin cable connects the sensor to a pager-sized glucose monitor.
After wearing the sensor for up to three days (the device has a two-week data-storage capability), the patient returns to the doctor's office, where the 864 readings taken over 72 hours are downloaded to a computer. Graphs display the continuous glucose data so that physician and patient can see a detailed blood-glucose history. Markers on the graph designate meals, exercise, and other important events, lending the patient's health profile even greater depth. The CGMS requires an initial calibration-meter finger-stick measurement and four finger-stick measurements from midnight to midnight each day, but perhaps once through the postmarketing trials, the manufacturer may apply for approval of use with less-frequent calibration.
The CGMS has been tested on diabetes patients in a multicenter clinical trial that compared sensor output with more than 7000 finger-stick glucose measurements taken over a total of more than 1100 patient-days. Study results demonstrated close correlation between sensor measurements and blood-glucose values.
MiniMed expects to launch the consumer version of its continuous glucose sensor sometime in 2002. This device will display glucose values on the monitor screen as well as provide hypoglycemia and hyperglycemia analysis.
MiniMed and affiliate Medical Research Group Inc. (also being acquired by Medtronic) have together begun clinical trials with a combination long-term implantable glucose sensor and implantable insulin pump that will be the platform for an implantable prosthetic pancreas. This invention would revolutionize diabetes management. Several patients have already been implanted, and the company claims to have seen impressive sensor correlation. In addition, an automatic control algorithm has been implanted in several dogs with these systems; almost-normal glycemic control has been demonstrated. The company hopes to begin human clinical trials with the augmented system within the next year.
 |
|
Figure
2. The GlucoWatch Biographer by Cygnus (Redwood City, CA) offers pain-free
glucose monitoring.
|
Automatic Noninvasive Reading. Another promising technology in pain-free glucose monitoring appears in the form of the GlucoWatch Biographer from Cygnus Inc. (see Figure 2). FDA granted a PMA for this continuous monitor in March 2001 for adults with diabetes. The device is being marketed as the first and only monitoring system that provides glucose readings automatically and noninvasively up to three times an hour, day or night. The system uses an extremely low electric current to pull interstitial fluid through the skin, from which the glucose is then collected to generate an electric signal that becomes a glucose reading.
It consists of two integrated parts, the Biographer and the single-use AutoSensor. The Biographer, worn like a watch, calculates, displays, and stores glucose readings. The AutoSensor, which snaps into the back of the Biographer and adheres to the skin, creates the electric signal from the glucose it collects. It provides up to 12 hours of automatic readings. A built-in alarm alerts the wearer of beyond-limit high and low blood-glucose levels, and also sounds if the latest reading is 35% or more below the previous one. The GlucoWatch Biographer is not yet being distributed directly to U.S. consumers, but that is expected to happen by the end of 2001.
Cygnus introduced its product with a controlled launch in mid-2000 in the United Kingdom. The company is now finalizing an agreement for direct-to-consumer distribution in Europe. It is expected to begin clinical trials shortly to evaluate the device for expanded indications in the United States, including adolescents and pregnant women.
Reports from early users suggest that the watch-like monitor is effective but tends to irritate the skin somewhat. Other concerns relate to the three-hour warm-up required (which prevents a critical early-morning reading), the need for frequent calibration, and the inability to take a reading if the patient is sweating.
Up-to-the-Minute Monitoring. Roche Diagnostics GmbH (Mannheim, Germany) has developed a subcutaneous continuous glucose-monitoring (SCGM) system that consists of a microdialysis catheter and a miniaturized portable extracorporeal electrochemical glucose sensor. This system measures glucose concentration and displays one value every minute.
In a study, the system was tested on patients with type I and type II diabetes.2 The study concluded that the SCGM system allows one-point-calibrated continuous glucose monitoring. Immediate data display was found to be sufficiently precise over the 72-hour study period. All patients tolerated the SCGM system well during the three days of the study. It did not limit their daily activities, and no adverse event occurred except for mild skin irritation caused by the dressing tape.
Wireless Transmission.TheraSense is also working on a continuous glucose-monitoring system, and has completed preliminary work with 30 human study subjects. The company's device consists of a small coil transmitter percutaneously inserted in the abdomen and a receiver that takes readings from the transmitter via a radio-frequency wireless link. The transmitting coil uses FreeStyle technology to determine glucose levels. The monitor needs to be calibrated once daily, and the transmitter in the skin is changed every 36 hours. The company submitted results from its study to FDA in December 1999. Merrill Lynch expects U.S. market entrance sometime in 2002.
Advances in Insulin Delivery
The National Diabetes Information Clearinghouse, an information service of the NIDDK, lists several new insulin-delivery systems under development that may eliminate the need for needle-based introduction. These include jet injectors, external pumps, implantable pumps, skin patches, and inhaled-insulin systems. All of these approaches are designed to be more user-friendly than injection, and thus to improve patient compliance with health-maintenance regimens.
Pulmonary Insulin Delivery. Inhaling insulin brings the drug directly into contact with the large surface area of the lungs. Insulin is absorbed into the bloodstream through the thin alveolar wall of these organs. Pulmonary absorption appears to be the most promising alternative approach for insulin delivery at this time. The most critical element in successfully delivering a drug to the extensive surface area of the lungs is to create a particle small enough to get past the back of the throat, yet large enough not to be exhaled after being inhaled.
One company working on a pulmonary delivery vehicle for insulin is Aradigm Corp. (Hayward, CA). Its AERx pulmonary drug-delivery platform incorporates innovative aerosol-production, inhalation-control, and other technologies that make the noninvasive delivery of traditionally injected drugs possible. These include liquid insulin formulations that facilitate correct particle sizing, electronic breath control that allows delivery only if the rate of breathing is correct, one-insulin-unit dosing, and data-downloading systems for reviewing the accuracy of device use and patient compliance. Aradigm's inhaled-insulin product is currently in phase-II trials, with phase III expected later this year.
According to Richard Thompson, president, CEO, and chairman of Aradigm, the company expects its technology to be applied first to those diabetics who have been unwilling to take insulin despite recommendations from their doctors. Market research indicates that patients refusing to take insulin by injection are far more likely to take it by inhalation. The worldwide insulin market amounts to some $2 billion by Aradigm's calculation, and many analysts believe that, with the advent of pulmonary delivery, it could grow to several times that size.
Inhale Therapeutic Systems Inc. (ITS; San Carlos, CA) and Pfizer Inc. (New York City) have developed the inhaled-insulin product Exubera. Exubera is a dry-powder form of insulin that is inhaled directly into the lungs through a delivery device created by ITS. The company has experience in protein delivery, and was able to create a micron-sized particle containing 20% insulin suitable for deep lung delivery. It also developed the dry-powder blister packs that are loaded into the delivery device. Squeezing a trigger on the device disperses the insulin powder into a clear chamber from which a slow, deep breath brings the finely powdered air cloud into the lungs. Only one or two breaths are required for delivery.
Exubera is being developed for patients with type I and type II diabetes through a collaboration between Pfizer and Aventis Pharma (Frankfurt, Germany), which have entered into a global agreement to jointly develop, promote, and manufacture inhalable insulin.
The drug is meant to allow diabetes patients to take insulin conveniently at mealtimes to control excessive blood sugar. But because it is not long acting, patients taking inhaled insulin must still take one insulin injection at bedtime to control glucose levels overnight.
According to a study reported by ITS and Pfizer, diabetes patients taking Exubera controlled their blood-sugar levels as well as diabetics taking only standard injections of insulin.3 The phase-III trial of Exubera involved 299 patients with type II diabetes. One group received both the powder insulin prior to meals and a long-acting shot of insulin at bedtime. The other group received insulin injections only. Side effects were similar in both groups, but those receiving Exubera developed more natural antibodies against their insulin than those taking injections only. Exubera patients did not appear to suffer any harm from the higher levels of antibodies.
Although patients in both groups had similar blood-sugar levels after six months, significantly more patients treated with Exubera met target blood-glucose levels established by ADA: 46.9% of patients on Exubera achieved target levels of HbA1c glucose of less than 7%, compared with only 31.7% in the injection-only group.
 |
| Figure 3. The Injex 30 jet-delivery device by Equidyne Systems (San Diego) offers an alternative to insulin delivery by needle. |
Jet-Injection Technology. Another alternative to insulin delivery via needle is jet injection, by which pressure forces the drug molecules through the skin quickly and painlessly. Equidyne Systems (San Diego) received FDA approval in July 2001 for its Injex 30 jet- delivery system (see Figure 3).
Injex is a stainless-steel device measuring 4 in. long with a small, 26-lb spring in the back. The spring exerts force on a plunger through a piston process, pushing the insulin through an orifice in the skin in a split second and depositing it in the subcutaneous tissue; the skin closes back immediately. The process has proven to be safe and effective.
J. Randall Nelson, chairman, president, and CEO of Equidyne, attests that the insulin is in no way harmed during the jet-delivery process, a past concern with respect to this method. The company has conducted many studies with insulin from Eli Lilly (Indianapolis) and Novo Nordisk a/s (Copenhagen, Denmark), the two main suppliers of insulin in the United States, and it has observed no destruction or shearing of the molecule, and no destruction of the disulfide bonds between the A and B chains. This suggests that the potency of the insulin remains undegraded.
Earlier injectors penetrated the patient's skin at about 10,000 psi, but the Injex applies pressure between 1800 and 2000 psi. Using one-fifth the pressure, the new device manages to get the insulin into the patient without hurting either the drug or its recipient.
The Injex 30 will deliver as much as 30 insulin units at one shot, or as little as 5 units. Equidyne is working on a second product that delivers up to 50 insulin units, and on a third, the Injex 15, for delivering minute amounts of insulin to small children. The company is talking with pharmaceutical manufacturers and regulatory agencies about other possible applications for the product.
Other companies with insulin jet injectors on the market are Medi-Ject Corp. (Minneapolis), Activa (Charlottetown, PE, Canada), and Vitajet Corp. (Laguna Hills, CA).
Ultrasonic Transdermal-Patch Technology. An ultrasonic transdermal insulin-delivery system now in development at Penn State University (University Park, PA) with the collaboration of Encapsulation Systems Inc. (Broomall, PA) is designed to maximize patient compliance, ease of use, and the safety of insulin delivery.4 It is expected to effectively regulate glucose levels. The portable U-Strip, consisting of an electronically controlled ultrasonic device and a transdermal patch containing human insulin, transmits 20- to 50-kHz pulses through the patch, allowing the insulin to permeate the skin layers.
The developers' primary focus at present is to improve the efficiency of the system's low-frequency transducers and transducer arrays to produce a rugged, portable device for accurate insulin delivery and ultrasound transmissions. The noninvasive delivery system would be electronically programmed to deliver the insulin according to an individualized drug regimen consisting of a basal rate and large doses before meals.
Insulin Delivery via Mouth Spray. Another delivery method for insulin now under investigation is a buccal (mouth) spray. Generex Biotechnology Corp. (Toronto) is developing a platform technology for the buccal delivery of large-molecule drugs that historically have been administered only by injection. The first application for the technology is an insulin formulation to be delivered as a fine spray into the oral cavity. In September 2000, Generex entered into an agreement with Eli Lilly to develop this insulin product.
Generex says its buccal-delivery technology will have application for many large-molecule drugs besides insulin, including fentanyl, morphine, estrogen, and heparin.
Study results indicate that Oralin, Generex's proprietary oral insulin formulation, may be used safely and effectively in place of injected insulin to treat type I and type II diabetes.5–8 Oralin is administered via the company's Rapidmist device and is rapidly absorbed through the mucous lining of the mouth.
Artificial Pancreas Technology
The large and growing number of diabetic patients requiring daily insulin suggests a real need for an implantable device that could reduce and potentially eliminate dependence on exogenous insulin, or insulin from outside the body. Human islet-cell transplantation appears to be a successful approach, but the supply of donor organs is quite limited.
To address this huge need, researchers are developing an implantable technology that is, in effect, an artificial pancreas. It monitors blood levels automatically and injects insulin as needed by means of an implanted pump. Artificial pancreas systems could potentially enable diabetics to live essentially normal lives with good glucose control and to avoid complications arising from high-glucose states—blindness, kidney failure, and cardiovascular disease among them—and acute complications from low glucose levels, such as the loss of mental acuity, coma, and untimely death. The patient would simply visit the doctor every three or four months for an insulin refill and a check-up.
Someday, a bioartificial pancreas may be able to act as a substitute for the human endocrine pancreas.9 Four major requirements for success have been cited. First, a steady supply of islet cells is necessary. Potential sources include human islets, islets from pigs, and engineered cells. Second, islet-cell viability must be maintained through an adequate oxygen supply and appropriate growth factors. The islets also must be protected from immune-mediated destruction; that is, they must not be rejected. Finally, a practical procedure for implantation must exist—one that would be minimally invasive with low associated risk. The implanted device should be unobtrusive and easily retrievable.
The inventions currently undergoing testing by MiniMed, Disetronic (St. Paul, MN), and other companies contain encapsulated, seeded islets that are shielded from the immune system by a semipermeable membrane within an acrylic casing. The devices also feature pores to permit glucose and insulin exchange. They must be implanted into a place well supplied with blood in order to achieve an adequate level of function.
The most popular experimental design consists of islets embedded within microcapsules that are surgically implanted in the abdominal peritoneum. An alternative design involves islets layered between flat sheets of hollow fibers pretreated with a synthetic extracellular matrix protein. The sheets can be sutured to the liver capsule or to the peritoneum.
Good results with bioartificial pancreas implantation have been achieved in rodents. A bioartificial pancreas has not yet been approved for human testing in the United States, but several biotechnology companies and research facilities promise bioartificial devices over the horizon.
Issues still to be addressed in this research include the safety of the islet cells, both long term and after repeated doses; the length of time the cells remain functional; the biocompatibility and durability of the device; the strength of the vascular grafts used to attach the device to blood vessels; the need for immunosuppression; and the risk of developing immunity against donor antigens. According to researchers, no device will be available for clinical testing and use in the United States for at least another five years.
Conclusion
The trend in diabetes management is toward developing technologies that will enable diabetics to live normal lives. Research is even trying to determine whether the progression of diabetes can be reversed. But for now, many new glucose-monitoring and insulin-dosing techniques are changing the way diabetics approach their condition.
Says Richard Eastman, MD, medical director for Cygnus, "Patients have many more options now to help them manage their diabetes. Only technology is limiting growth in this area right now. Patients are ready to use the technology when it comes out."
All the new systems have the goal of decreasing and ultimately eliminating
the serious complications of diabetes that make the disease such a devastating
problem. The healthcare cost savings and business productivity advantages of
dramatically improved health outcomes for people afflicted with diabetes would
be colossal.
|
Keeping It under Control Diabetes, strictly speaking, is a collection of syndromes. The form of diabetic condition addressed in this article is diabetes mellitus, which is generally divided into two major types: type I (insulin-dependent) and type II (non-insulin-dependent). Type I diabetes is characterized by the body's failure to produce any insulin. It most often arises in children and young adults. People with type I diabetes must inject insulin daily to stay alive. Type I diabetes accounts for 5–10% of diabetic cases. Type II diabetes is a metabolic disorder resulting from the body's inability to make enough or properly use insulin. It is the most common form, accounting for 90–95% of cases. Type II diabetes is nearing epidemic proportions in the United States, partly because the population of older Americans is burgeoning, and partly owing to a greater prevalence of obesity and of sedentary lifestyles. The percentage of Americans diagnosed as having diabetes has doubled over the past 20 years, a trend that is expected to continue. Many of the health complications from diabetes contribute to a high rate of morbidity and mortality in sufferers, and place costly demands on the U.S. healthcare system (see Table I). Maintenance of glycemic control by close monitoring of blood sugar is the best defense against their development and progression. Researchers and device companies are answering the need to encourage this practice by developing glucose-monitoring and alternative insulin-delivery systems that eliminate finger-pricking as the necessary source of blood samples. |
|
Personal Diabetic Assistant Glucose control has entered the computer age. A host of Web-based device and software companies are trying to capture the attention of computer-savvy diabetics and health-conscious consumers.
One such company, HealtheTech Inc. (Golden, CO), is an innovator in the area of consumer health-monitoring devices, disposables, software, and services that facilitate the measurement and tracking of personal health concerns such as diet, exercise, weight, metabolism, and blood-glucose levels. Through an agreement last year with Palm Inc. (Santa Clara, CA), the company markets the GlucoPilot diabetes-management application for Palm computing-platform devices. GlucoPilot gives diabetic patients who are able to use a personal digital assistant (PDA) enhanced control over their condition by helping them track blood sugars, insulin, and carbohydrate intake. It allows patients to filter and categorize blood-sugar records and to compile reports, charts, and graphs (see figure). The PDA-based portable tool makes keeping an accurate log of glucose levels easy and convenient. "Consumers want easy-to-use technologies, as they make their lives easier," says Teresa Barnes, public relations manager for HealtheTech. "And they are more compliant with their therapies when that is made easier for them." |
REFERENCES
1. SV Lisa et al., In Vitro Diagnostics [annual industry
outlook report] (New York City: Merrill Lynch, 2000).
2. K Jungheim et al., "Subcutaneous Continuous Glucose Monitoring: Feasibility
of a New Microdialysis-Based Sensor System," Diabetes 50, supp. 2 (2001):
A3.
3. P Hollander, "Efficacy and Safety of Inhaled Insulin (Exubera) Compared to
Subcutaneous Insulin Therapy in Patients with Type-2 Diabetes: Results of a
Six-Month Randomized, Comparative Trial" (paper presented at the 61st Scientific
Sessions of the American Diabetes Association, Philadelphia, June 22–26,
2001).
4. S McElligott et al., "Ultrasonic Transdermal Insulin Delivery," Diabetes
50, supp. 2 (2001): A429.
5. P Modi, "Long-Term Efficacy of Oral Insulin and Pioglitazone Combination
Therapy for Treatment of Type II Diabetes," (paper presented at the 61st Scientific
Sessions of the American Diabetes Association, Philadelphia, June 22–26,
2001).
6. P Modi, "Replacement of Failing Sulfonylurea Drugs with Oral Insulin, a Long-Term
Efficacy Study in Treatment of Type II Diabetes" (paper presented at the 61st
Scientific Sessions of the American Diabetes Association, Philadelphia, June
22–26, 2001).
7. P Modi, "Replacement of S.C. Injections with Oralin in Treatment of Diabetes"
(paper presented at the 61st Scientific Sessions of the American Diabetes Association,
Philadelphia, June 22–26, 2001).
8. P Modi, "Combination Therapy with Oral Insulin and Metformin for Treatment
of Type II Diabetes" (paper presented at the 61st Scientific Sessions of the
American Diabetes Association, Philadelphia, June 22–26, 2001).
9. DA Geller, "Current Status of Bioartificial Organs" (paper presented at the
Annual Joint American Transplant Meeting, Chicago, May 11–16, 2001)..
Tracy A. Schaaf is senior research analyst at Medtech Insight (Mission Viejo, CA), a market intelligence firm for the medical technology industry.
Copyright ©2001 MX
