Leading Innovations in the Treatment of Juvenile Diabetes

Discovery of Insulin. Frederick Banting and Charles Best discovered the efficacy of treating Juvenile Diabetes with insulin in 1922.

Synthetic Human Insulin. Pure, and without side effects, the first true human insulin was introduced by Eli Lilly in 1982.

Home based blood glucose monitor.  Bayer introduced the first home based blood glucose testing system in 1981.

Infusion Pump.  MiniMed introduced its first commercial insulin infusion pump in 1983.

Diabetes Control and Complications Trial (“DCCT”).  The DCCT Study, completed 1993, determined that tight blood glucose control reduced risk of complications.

Continuous Glucose Monitor.  Medtronic introduced the first consumer grade CGM in 2003.

History of Innovations in the Treatment of Juvenile Diabetes

i.  Before 1920.  The Dark Ages.

Prior to Frederick Banting’s discovery of insulin in 1921, Juvenile Diabetes was a near certain death sentence.   A ten year old in 1900 with Juvenile Diabetes had a life expectancy of less than one year.  Patients were treated using near starvation diets.

ii.  1925 – 1979.  The Enlightenment Era.

Diabetes treatment during this period was limited by the available technology – crude by today’s standards.  From the discovery of insulin in the early twenties until the late 1970’s, the diabetic’s basic health care plan was to avoid dangerously low or high blood sugar levels – tighter control of blood glucose was not possible. There were several reasons for this.  First, the only means of testing for blood sugar were urine tests, which were complicated, and yielded little useful information (essentially whether you were hyperglycemic – nevertheless most could already recognize this from related sickness and symptoms).  Home based urine tests were not introduced until the 1960’s and yielded the same poor information.  Second, insulin therapy relied on animal insulin that was inconsistent in quality and efficacy.   Third, insulin treatments were dispensed based upon rules of thumb and trial-and-error because “carb counting” was not yet widely understood and blood sugar concentrations could not be adequately measured.

Because of the impurities and lack of quality of the insulin at this time, the number of injections throughout the day was limited. This was accomplished by adding substances to the insulin formulation that would slow its rate of absorption and prolong its duration. Insulin shots were given only once daily and no distinction was made between a bolus dosage (insulin provided before a meal to reduce the resulting blood glycemic rate) and basal dosage (insulin provided via either long acting insulin or continuous infusion through an insulin pump to provide a continuous baseline level of insulin).

Despite the crude technology and a lack of a reliable glucose measurement system, with the widespread availability of insulin in the late 1920’s, Juvenile Diabetes became a chronic but manageable condition.  Even though diabetes had ceased to be a death sentence it remained a considerable foe – as late as the 1950’s twenty percent of diabetics died within twenty years of the disease’s onset.  Although not understood at the time, serious complications would become a major health problem for most of the remaining 80% who survived.

In 1942 the American Diabetes Association, an advocacy and sponsor of research, was created.  In 1970, the Juvenile Diabetes Research Foundation was created to fund research. The NIDDK Special Diabetes Program (SDP) began funding research in 1998.

iii.  1980 – 1999.   The Renaissance Period.

Since 1980, a primary goal of the management of Juvenile Diabetes has been the achievement of closer-to-normal blood glucose levels. The benefits include a reduction in the occurrence and severity of long-term complications from hyperglycemia as well as a reduction in the short-term, potentially life-threatening complications of hypoglycemia.  The ability to reach near-normal blood glucose levels was made possible by a number of innovations including:  improved insulin, accurate home based blood glucose testing meters, improved insurance coverage and dramatically improved insulin infusion capabilities.

The pace of innovation increased dramatically during this twenty-year period.  And innovation was widespread from improvements in the speed and miniaturization of electronics to the dramatic breakthroughs in biotechnology and even included improved education about such simple tasks as “carb counting”.  A summary of the major breakthroughs is summarized below.

a.  Biotechnology

Human Insulin.   With the advent of synthetic human insulin or so-called insulin analogs (recombinant DNA human insulin) in the 80’s, achieving closer to human physiological blood glucose levels became a reality.  The human analog had near perfect consistency in quality and, as a result, there were fewer insulin related side effects.   Pharmaceutical companies also perfected “short acting” insulin (which works like native insulin) and “long acting” insulin (which provides a baseline or “basal” level of insulin throughout the day).  Human insulin was made possible by genetic engineering technology pioneered by Genentech.

b.  Blood Glucose Measurement.

The home blood glucose monitor (sometimes referred to as SMBG for “self monitoring of blood glucose”), introduced in 1981, was a major milestone in dramatically improving the day-to-day care for diabetics.  Amazingly it took nearly sixty years after the discovery of insulin to create an affordable home-based system to simply and accurately measure blood sugar levels.  Today’s blood glucose meters are remarkably similar to these original models.

A blood glucose meter works as follows. The user pricks his finger with a small lancet and places a small amount of blood on a disposable test strip inserted into an electronic meter (typically about the size of a pack of cards).  A chemical reaction on the test strip enables the meter to display the resulting blood sugar levels.  The resulting measurement is typically expressed in mg/dl with 100 being normal. To put this measurement in context and provide some perspective on how sensitive the human blood supply is to small amounts of sugar consider the following examples. The average human has 5 liters of blood. If one packet of sugar is dissolved in 5 liters of blood, then the resulting concentration of blood sugar is 100 mg/dl; if only a half pack of sugar is dissolved in that same blood supply, then the glycemic index would be only 50 mg/dl, which would be considered hypoglycemic.

Today’s meters are accurate within 5% (which implies that the meter’s reading of 100 would indicate an actual reading of between 95 and 105 which is statistically insignificant for insulin management). Once the blood sample is placed on the strip, the resulting reading is displayed almost immediately.  This technology is the predominate means of testing blood sugar today and is widely available, affordable and covered by nearly all insurance plans (including Medicaid and Medicare).

Roche, Abbott, Bayer and J&J are the dominant suppliers of HBGM devices with a reported annual volume of 10 to 15 million units per year in the US.   While the original cost of a meter was about $500, today meters are essentially free because the manufactures want to sell the test strips (which range in price up to $1.00 per test strip or $2,200 per year for one who tests his blood sugar six times per day with no waste or errors).

c.  Injection Devices.

Insulin Injections.  An important innovation around 1985 was Novo-Nordisk’s introduction of the first insulin “pen” – a disposable, insulin injection device that came with a prefilled insulin vial, a much smaller needle and a “dial a dose” capability for the user to accurately set and dispense the correct dose of insulin.   The insulin pen replaced, for the first time, the use of hospital grade syringes for insulin infusion.

Insulin Pumps.  Commercially available insulin infusion pumps were first introduced in the late 1980’s. This was, in our opinion, one of the most revolutionary changes in the treatment of diabetes since the discovery of insulin and the blood glucose monitor.  An insulin infusion pump works as follows. The pump contains a small vial of insulin that is automatically dispensed via a motorized thumbscrew at the bottom of the vial.  A modern insulin pump can infuse insulin for three to five days – thus freeing the diabetic from multiple daily injections.  Perhaps more importantly the infusion pump supplies a continuous basal rate of insulin while the patient can bolus additional insulin to reduce blood sugar associated with meals and snacks.

Today the physician sets the programing for these devices to best match their care plan.  There is a great deal of trial-and-error to get these settings correct.  Unfortunately this work to adjust the pump and the associated patient training is rarely reimbursed by insurance companies.  While insulin pumps are a dramatic improvement to multiple daily injections, insulin pumps require considerable user involvement.  For example,  the user inputs his “carb count” and blood sugar levels into the pump and it calculates the bolus infusion for the patient.   Insulin pumps can also be adversely impacted by user errors in estimating carb intake or errors from his blood glucose measurement.  The result can lead to hypoglycemia or hyperglycemia despite the pump’s advanced features.

d.  Education

Complications Research. Another important innovation was a leap forward in understanding the long-term side effects of Juvenile Diabetes.  A National Institute of Health (“NIH”) sponsored study, the Diabetes Control and Complications Trial (“DCCT”), was a longitudinal study following the care and complications of more than 1,400 Juvenile Diabetics from nearly 30 medical centers from 1983 through 1993.   This was the first study to document the serious side effects of Juvenile Diabetes:  blindness, kidney failure and amputation of lower limbs (as a result of nerve damage).  Among the study’s most important findings was that the tighter the patient’s blood glucose control, the lower the risk of serious complications.   The study results showed that proper management reduces risk complications significantly for eye disease (76%), kidney disease (50%) and nerve disease (60%).  For the first time research emphasized the importance of tight glycemic control which was now possible thanks to simple home-based blood glucose monitors and improved insulin.  Repeated daily blood glucose tests and multiple daily injections were, for the first time, medically recommended as the “gold standard” for diabetes care.

e.  Carb Counting – Patient Education.

For most diabetics estimating their carbohydrate consumption is challenging.  Thankfully, a simple book published around the time of the completion of the DCCT study, made carb counting easy.  The Calorie King, Calorie, Fat and Carbohydrate Counter by Allan Borushek is the “bible of carb counting” and is one of the first things a diabetic is encouraged to buy (although some endocrinologist actually give the book away for free).  The book also has carb counts for most popular restaurants.  A simple ten-dollar investment makes it was easy to accurately estimate your carb intake (and therefore more accurately dose your insulin therapy).

iv.  Post 2000.  Modern Era – Technological Revolution.

The pace of innovations over the last twelve years parallels those of the unprecedented innovation in consumer electronic technologies – new smaller, smarter devices like the iPhone.

a.  Continuous Glucose Monitors.

One of most significant innovations was the introduction of the continuous glucose monitor (CGM) in 2003.  A CGM works as follows.  These devices require a small catheter (inserted by a needle which is then withdrawn) worn just under the skin.  The catheter is connected to a small device, typically about the size of a nickel that “reads” the user’s blood sugar levels every five minutes.  The CGM can be worn for five to seven days.  CGM accuracy has historically been a problem (in fact the FDA only allows the use of a CGM as a “backup” measurement device) with error rates historically as high as 25%.  A CGM reading of 100 mg/dl may indicate an actual blood glucose level between 75 mg/dl and 125 mg/dl; the lower number is approaching hypoglycemia while the upper bound is normal.  Therefore, insulin therapy decisions made based upon CGM readings could lead to hypoglycemia or hyperglycemia.  Newly introduced CGM’s have reduced the error rates to 15% (which improves the implications of a 100 mg/dl reading to an actual range of 85 mg/dl to 115 mg/dl). Meanwhile the accuracy of SMBG’s continued to improve with newer state-of-the-art meters having error rates of less than 5%. Two dominant CGM manufacturers, Medtronic and Dexcom, control substantially all of the U.S. CGM market.  Today less than 5% of Juvenile Diabetics wear a CGM.   The largest obstacles are insurance coverage, undesirability of wearing “another device”, the pain of the needle insertion and the perception that they are not accurate.

b.  Infusion Pump Improvements

Pumps continued to innovate with users now able to wear them for as long as five days.  Onboard memory and computer intelligence enabled the pump to perform automated calculations for the patient.  A related innovation was the connectivity of CGM’s, blood glucose meters and insulin pumps.  Using wired, and in some cases wireless, connectivity these devices can share information (such as a blood glucose reading from a meter to an infusion pump) and can share information with caregivers (for example, uploading blood sugar readings and infusion therapy dosing directly to a physician). OmniPod (made by Insulet, a startup) introduced the first “patch pump” adhering directly to the patient’s body in 2006.  Three vendors control 90% to 95% of the infusion pump market:  Medtronic, Insulet and J&J.   Today the adoption of insulin infusion pumps is around 27% of all Juvenile Diabetics.  The largest obstacles are cost and lack of insurance reimbursement, perceptions that they are complicated to use and a lack of acceptance by physicians (who are required to train patients without any reimbursement).

c.  Implantable Infusion Pump.

In 1980, the first research grade implantable insulin pump was used for a human study by a Minnesota group. Later in 1986, the first MiniMed pump was implanted by Dr. Christopher Saudek and received CE mark approval by 1995.  We believe nearly two dozen American patients had these pumps before Medtronic/MiniMed discontinued its U.S. clinical trials in 2007, apparently they feared the high cost (because of the major surgery) would restrict the available market and possible complications of surgery could lead to lawsuits.  Nevertheless as infusion pumps get smaller and smarter the prospects of an affordable implantable infusion pump seems possible.

d.  The Edmonton Protocol – Islet Cell Transplantation.

One of the first attempts at a true “cure” for Juvenile Diabetes was the islet cell transplantation procedure first utilized in 2000 at the University of Alberta (the so-called “Edmonton Protocol”).  This was the first experimental treatment that resulted in patient insulin independence, albeit for a relatively short duration. Six months after their last infusion of islets, more than half of recipients were free of the need for insulin injections, but at the two-year follow-up, the proportion dropped to about one-third of recipients and by the fifth year anniversary, fewer than 10% were free of daily insulin.

The procedure involves recovering islet cells from a cadaver pancreas.  The resulting islet cells are infused into the diabetic’s liver through a surgically placed catheter near the portal vein where they can travel to the liver, develop a blood supply and begin producing insulin, partly due to the capability of the liver to regenerate, build new blood vessels and make new supporting tissue when damaged.

Islet cell transplantation has a number of shortcomings that make it unlikely, at least as it is currently implemented, to be a compelling solution for most diabetics.

First, patients are required to use immunosuppressive drugs that have a number of adverse side effects.  The immune system is programmed to destroy bacteria, viruses, and tissue it recognizes as “foreign,” including transplanted islets. In addition, the diabetic’s autoimmune response that destroyed transplant recipients’ own islets in the first place can attack the transplanted islets. As a result, immunosuppressive drugs are needed to protect the transplanted islets. These immunosuppressive or anti-rejection medications must be taken for life.  These drugs have several adverse side effects including damage to the liver and kidneys, heightened risk of cancer and damage to women’s reproductive abilities.

Second, the cost of islet cell transplant is approximately $140,000 and is not typically covered by insurance. Coverage is generally restricted to those rare diabetics who have become completely insulin intolerant or who have severe and uncontrollable hypoglycemia.  Some diabetics are “hypoglycemic unaware” in other words they cannot sense that their blood sugar levels are low or declining rapidly.

Third, the current supply of islet cells is severely limited.  Today there are only enough islet cells derived from cadaver pancreases to perform islet cell transplants on 1,500 patients per year.