BBI Contributing Editor

SAN FRANCISCO, California — One of the major focuses of the American Diabetes Association's (ADA; Alexandria, Virginia) 62nd annual scientific sessions, held here in mid-June, was a review of the ADA's efforts to educate diabetics about their high risk of cardiovascular disease (CVD) and stroke. The ADA gathering, which was attended by more than 15,000 participants, focused on the need of the pre-diabetes population to control their diets and to exercise as a means of stemming the growth of this disease. There are an estimated 17 million diabetics in the U.S., of whom 65% will die from a heart attack or stroke. Diabetes itself is the fifth-leading cause of death in the U.S.

Diabetes ranks higher than smoking, high blood pressure, elevated cholesterol or obesity as a risk factor for CVD. Diabetics are twice as likely to have heart disease and five times more likely to suffer strokes than non-diabetics. A survey revealed that 68% of diabetics are ignorant of the link between diabetes and CVD. The ADA and the American College of Cardiology (Bethesda, Maryland) have joined in a three-year campaign entitled "Make the Link! Diabetes, Heart Disease and Stroke" that emphasizes the need for comprehensive diabetes care that goes beyond lowering of blood glucose and targets other CVD risk factors. Their program promotes controlling the ABCs of diabetes — hemoglobin A1c test, blood pressure and cholesterol.

Pre-diabetics at risk for diabetes, heart problems

Pre-diabetes is a state when a person's glucose levels are in the range of 110 to 125 mg/dl, which is above normal levels but not high enough for a diagnosis of diabetes. This condition also is known as impaired glucose tolerance or impaired fasting glucose. These are an estimated 16 million pre-diabetics in the U.S. They have a 50% greater likelihood of having a heart attack or stroke compared to people with normal blood glucose levels. Studies have shown that most people with pre-diabetes develop Type 2 diabetes within 10 years.

Several papers at ADA presented a link between inflammation and Type 2 diabetes, thereby creating potentially new pathways for the prevention and treatment of diabetes. Joshua Barzilay, MD, of the division of endocrinology at Kaiser Permanente of Georgia (Atlanta, Georgia) cited several studies that have shown that markers of inflammation are predictive of the development of diabetes. One of these markers, C-reactive protein (CRP), appears to be elevated in the presence of diabetes as well as heart disease and obesity. Vivian Fonesca, MD, of Tulane University Health Science Center (New Orleans, Louisiana), reported that inflammation may be a common link for developing insulin resistance, diabetes and heart disease, and it may therefore be desirable to monitor CRP levels. Professor Nabila Abdella of Kuwait University reported that diabetics having the highest 20% in CRP values were four times more likely to suffer from CVD compared to those having the lowest 20% CRP values, making it a potentially useful marker of high risk CVD among diabetics. Bruce Duncan, MD, of the School of Medicine of the Federal University of Rio Grande do Sul in Brazil, reported an association between developing diabetes and a series of inflammatory markers, especially sialic acid. The use of HMG-CoA reductase inhibitors, a class of drugs commonly known as "statins," are used to reduce high cholesterol levels and has also been found to reduce inflammation. Jeffrey Johnson, PhD, of the University of Alberta (Edmonton, Alberta), found that the use of statins by diabetics was associated with an average 10-month delay before starting insulin therapy.

Insulin pump/infusion set competition grows

The use of insulin pumps among the 1 million Type 1 diabetics in the U.S. continues to grow. Patients using insulin pump therapy were shown to have 85% fewer incidents of severe hypoglycemia. Competition is increasing in the insulin pump market and among suppliers of infusion sets that are used with these pumps. The infusion set disposable market is estimated at $200 million and growing at an annual rate of 25%.

Medtronic Minimed (Northridge, California), the leading supplier of insulin pumps in the U.S., featured its Paradigm insulin pump. Launched earlier this year, it is the smallest insulin pump on the market. It is designed for greater ease of use, has multiple bolus and basal options, is watertight and can be operated by remote control. The company is marketing the MIP, Minimed Implantable Pump, in Europe and has filed with the FDA for obtaining marketing clearance in this country.

Dr. Eric Renard from Montpellier University (Montpelier, France) has collaborated with researchers from Medtronic Minimed on the development of an implanted closed-loop system that monitors blood glucose and pumps insulin into the bloodstream. A study using an implanted monitor and pump was conducted on five Type 1 diabetes patients. He noted that such a device that mimics the human pancreas could be commercialized in Europe or the U.S. in three to five years.

Disetronic Medical Systems (Burgdorf, Switzerland), the leading supplier of insulin pumps in Europe and the second-largest provider in the U.S., introduced its new Ultraflex infusion set that is compatible with all insulin pumps. Its tapered Teflon cannula can make a 90 insertion without the need for an insertion device.

Animas (Frazer, Pennsylvania), marketer of the R1000 insulin pump, introduced the ezInfusionSystem, an infusion set for insulin pumps that possesses a flexible cannula for angled insertion. Its ezManager Plus diabetes management software package, for use by diabetic patients and professionals, was introduced last January.

Deltec (St. Paul, Minneapolis), a subsidiary of Smiths Group (London), the leading marketer of ambulatory infusion devices for delivering chemotherapy and fertility drugs, plans to introduce its Cozmo insulin pump later this year, upon receipt of market clearance from the FDA. It is a personalized pump that can be adapted to every user's individual lifestyle and will be priced competitively to other insulin pumps on the market.

SpectRx (Norcross, Georgia) featured its SimpleChoice insulin delivery products that came with its acquisition earlier this year of Sterling Medivations (Los Altos Hills, California) to provide several options for users of insulin pumps. The SimpleChoice patch uses soft micro-catheters to deliver insulin through five microneedles that are less than half the length of other insulin pump infusion needles. Reduced penetration is for improved comfort and wearability. The SimpleChoice easy uses a soft catheter for comfort and can be inserted at a 30 angle. The SimpleChoice quick has a 90 insertion angle. These products are designed for use with all commercial insulin pumps. They received FDA clearance in recent months and will be marketed later this year or early in 2003. SpectRx is developing a continuous glucose monitor with Abbott Laboratories (Abbott Park, Illinois) that uses technology licensed from Altea Technologies (Tucker, Georgia).

Proliferation of blood glucose monitors

Blood glucose monitors were the most commonly displayed products on the ADA exhibit floor, with at least a dozen companies featuring their devices and software packages and trying to distinguish their products from the many competitors.

Medisense (Bedford, Massachusetts), a subsidiary of Abbott Laboratories, featured Sof-Tact, its alternate site testing device, along with Precision Xtra and Q-I-D blood glucose monitors. The Sof-Tact can be used to test blood specimens taken from the forearm, upper arm and base of thumb, as well as the fingertip. It is claimed to be the first automated and integrated blood glucose monitor and provides lancing, blood collection and diagnosis by pressing a button.

Home Diagnostics (Fort Lauderdale, Florida) is pursuing a co-branded strategy by marketing its Prestige IQ and Prestige LX glucose monitors to leading chain drug stores. A large portion of the company's business is via mail order sales, with reimbursement by Medicare.

TheraSense (Alameda, California) recently received FDA clearance for its FreeStyle Tracker, an integrated glucose monitor that incorporates a personal digital assistant. It uses the smallest blood specimen needle (0.3 l) for blood glucose testing. The company launched CoPilot, its new web-based data management system, at the ADA gathering.

Bayer Diagnostics (Tarrytown, New York) introduced Ascensia as a new brand to replace the Glucometer name for its Elite, Elite XL, Dex and Dex glucose monitors. These products also have FDA clearance for alternate-site testing.

Roche Diagnostics (Indianapolis, Indiana) showcased its Accu-Chek Compact System, an automated glucose monitor that is loaded with a drum-shaped cartridge containing 17 test strips, thereby eliminating strip handling. The company recently received FDA clearance for Accu-Chek Advantage, which performs blood glucose testing on a Palm Pilot.

LifeScan (Milipitas, California, a unit of Johnson & Johnson (New Brunswick, New Jersey), featured OneTouch UltraSmart, a combination glucose meter and electronic logbook which yields test results in only five seconds on a 1 l blood specimen. It is awaiting marketing clearance from the FDA. LifeScan and Novo Nordisk Pharmaceuticals (Princeton, New Jersey), a subsidiary of Novo Nordisk (Bagsvaerd, Denmark), are jointly marketing the InDuo System, a combined insulin doser and blood glucose monitor that offers added convenience for diabetics that have difficulty monitoring their blood glucose and injecting the appropriate amount of insulin at the right time.

Insulin without injections

The long-awaited delivery of insulin without injection drew attention at the ADA meeting, which included presentations on alterative options such as an oral dosage form, transdermal patch, mouth spray and several pulmonary inhaled versions. An estimated 3.7 million diabetics take one to five daily insulin injections.

Emisphere Technologies (Hawthorne, New York) presented data on a capsule containing insulin combined with the company's oral delivery agent. Maximum insulin concentrations in systemic circulation were observed in 15 to 25 minutes, mimicking the physiological production and excretion of insulin from the pancreas. In a Phase I study, insulin combined with the delivery agent provided insulin absorption at clinically significant levels.

Nobex (Research Triangle Park, North Carolina), in collaboration with GlaxoSmithKline (London), is in Phase II trials with hexyl-insulin monoconjugate (HIM2) for oral administration. It uses patented polymer technology to resist enzymatic degradation of the hormone and to promote its absorption into the bloodstream. Stephen Clement, MD, of Georgetown University (Washington), reported that HIM2 yielded insulin-lowering benefits equal to injected insulin when multiple doses were given over a three-day period.

Alan Smith, PhD, described the system used by Altea Technologies for the transdermal delivery of insulin. An electronic adhesive patch is applied to the skin and is activated for a millisecond to painlessly vaporize cells on the skin surface, thereby creating microscopic openings. This is followed by the application of a small insulin patch containing a reservoir of insulin. Altea's research has shown that insulin is steadily absorbed over a 12-hour period and the company is working on a 24-hour version.

TransDermics (Ashdod, Israel) has conducted a Phase IIa clinical trial on 43 Type 1 diabetic patients using a transdermal insulin patch that uses its patented emulsion technology for transdermal delivery of large molecules.

Generex Biotechnology (Toronto, Ontario) gave several presentation on Rapid Mist, its oral spray device for administering Oralin, an aerosolized insulin, which is absorbed by the mucous membranes in the inner cheek walls, tongue and throat. Research results were reported which showed that Oralin was identical to an insulin injection in its ability to lower blood glucose levels and that it served as a mealtime boost by diabetics that are have failed on oral hypoglycemic drugs.

A series of presentations were made by the developers of pulmonary insulin delivery systems. An overview of these development programs was provided by Jay Skyler, MD, of the University of Miami (Coral Gables, Florida). They include the Exubra inhaled insulin by Inhale Therapeutic Systems (San Carlos, California) with Pfizer (New York) and Aventis Pharma (Frankfurt, Germany); the AIR System by Alkermes (Cambridge, Massachusetts) with Eli Lilly (Indianapolis, Indiana); the AeroDose inhaler by AeroGen (Sunnyvale, California) with Disetronic Medical Systems (Burgdorf, Switzerland); the AERx system by Aradigm (Hayward, California) with Novo Nordisk; Insulin Technospheres by Pharmaceutical Discovery Corp. (Danbury, Connecticut), a subsidiary of Mannkind (Los Angeles, California). Each of these developments employs different features for delivering a dose of insulin in liquid or dry powder form through the mouth and directly into the lungs, where it enters blood circulation as a rapid-acting insulin. Regulatory approval is still several years away. Skyler emphasized that research must now determine whether the pulmonary route is safe, cost effective and viable for long-term insulin delivery.

BioSante Pharmaceuticals (Lincolnshire, Illinois) has had positive results from preclinical trials of its Bio-Air calcium phosphate nanoparticles containing insulin for administration by inhalation Bio-Air extended the hypoglycemic effect of insulin from four to five hours to 10 to 15 hours compared with insulin alone. The company is seeking a strategic corporate partner.

Diabetic peripheral neuropathy

More than half of all diabetics are affected by diabetic peripheral neuropathy (DPN), according to the International Diabetes Federation. DPN is the second-leading cause of chronic falls in the elderly. There are no drugs currently approved in the U.S. for treating the underlying process of microvascular (small blood vessel) damage that leads to this condition. Eli Lilly reported that its protein kinase C beta (PKC beta) inhibitor was found in a Phase II trial to improve symptoms, vibratory sensation and other measures of diabetic peripheral neuropathy. PKC beta inhibitor also is being studied as a possible treatment for other diabetic microvascular complications including diabetic retinopathy and diabetic macula edema which can lead to blindness. Lilly is expanding the number of its Phase III trials of PKC beta and plans to file in 2004 in the U.S. for regulatory approval for the treatment of symptoms of diabetic peripheral neuropathy.

Boston Medical Technologies (Wakefield, Massachusetts) exhibited its Anscore System, which is used to diagnose autonomic neuropathy, a dysfunction of the autonomic nervous system that is said to occur in 30% of diabetic patients.

MedAssist (Tampa, Florida) markets the Anodyne Therapy System that applies infrared light for treating DPN and claims that a clinical study has shown that 12 half-hour treatments in a month restored protective sensation in all treated Type 1 diabetic patients.