Rob Lindsay, M.D.
The Beantown Beacon
American Diabetes Association
74th Scientific Sessions
Boston, June 2015
The annual meetings were held in Boston this year. Boston is a wonderful town and I
thoroughly enjoyed walking down some of its backstreets and through the Boston Common but it
is a poor choice for meetings since the cost is so tremendous. We spent a good deal more money
in Boston than we do at a lot of the other cities. I stayed at the Parker House Hotel which is the
oldest continually functioning hotel in Boston. It had all the wonderful old brass work and
facades that you would expect and is the home of Parker House rolls. And yes, I did go to a Red
Sox game in Fenway even though they are terrible this year. We went to the game where the
woman unfortunately was hit in the face with a bat. Fortunately, she survived. The meetings
this year welcomed 18,400 participants so you can imagine the crowd and bustle at the
convention center. They also usually had six sessions going simultaneously and 2,936 abstracts,
posters and presentations so you can tell how much information there was from which I had to
choose to present to you.
Closed Loop Artificial Pancreas in Youth
I decided to start with an interesting joint ADA/JDRF symposium that was presented in
the late afternoon on Saturday. It was entitled “Closed-Loop Technology in Youth-Real Estate,
Alarms and Challenges”. Before I get into his talk, I thought I had better refresh your memory
that the artificial pancreas is a combination of a continuous glucose monitor and an insulin
pump that communicate and control the diabetes. The continuous monitor radios the pump,
currently through a Smartphone, as to what the blood sugars are and what to do with the insulin.
There are no such devices available yet (although the Medtronic Enlite is the first step) but I
suspect we will be seeing it on the market in the fairly near future. Dr. Weinzimer first pointed
out the challenges of an artificial pancreas in children. First, there are variations in insulin
sensitivity that can be week-to-week or even day-to-day. Thus what works one day may not
work the next day. Second is the variable exercise, particularly in our younger children which
has a profound effect on insulin sensitivity and glucose utilization. Third, he listed meals since
children can be very picky and unpredictable. I do not think I need to tell any of you parents
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about this. Fourth, he mentioned the susceptibility to hypoglycemia which is certainly present in
adults but seems to be more variable in children. Finally, he mentioned developmental issues
which included the size of the site, the alarms and the interfaces all of which have an effect on
the child. He noted that overnight control (as is being achieved with the Medtronic Enlite) is the
easiest but it will be necessary to have meal announcement or true hybrid pumps. A hybrid pump
is a pump that controls blood sugars in the normal non-eating state. The patient still has to
count carbs and dial in the insulin necessary for food so the system is not truly automatic. He
showed that the process is truly a continuum with sensor augmented pump control at one end,
followed by the auto suspend program, followed by hybrid closed loop systems, followed by true
closed loop systems and concluding with multi-hormonal systems. He stated that the first two
steps have already been started. We certainly have sensor augmented pump therapy where
patients can use information from their CGM to direct the pump. The second step is the autosuspend systems. Right now we have a low threshold suspend which signals the pump to shut
down for up to two hours if the patient reaches hypoglycemic states. This system is usually most
effective at night. The next step would be the predictive low glucose suspend where the system
can stop insulin infusion before hypoglycemia occurs. These systems obviously could
significantly lower the rate and risk of nighttime hypoglycemia. He quoted a DAIS study at
camp where they found a significant drop in hypoglycemia and likewise a significant increase in
time to target. Time to target merely means the amount of time that the patient stayed within the
range predetermined by the patient and the care provider. At the camp the time to target
increased from 50% to 72% of the time. Obviously they were still not in range all of the time but
this is a significant improvement. He quoted some other studies but did not give the statistics.
Fifteen adolescents in a camp in Colorado moved from an open standard pump therapy to closed
and had a significant decrease in blood sugars over night. There as an increased time to target
both day and night. Another study used a bionic pancreas (this is the use of two pumps one of
which provides insulin and the other glucagon) and found again a decrease in average glucose
and decrease in hypoglycemia. Some of these studies will be quoted later.
Laurel Messer, a nurse and educator from Colorado talked about the practical translation
for closed loop pump technology. She spoke from a diabetes educator perspective. She said that
the desires include a small pump that is effective and has minimal individual involvement. She
talked of the low glucose suspend which lowered hypoglycemic events of two hours or more by
53% in 4 to 10-year-old children and 62% in 11 to 14-year-old children. She also pointed out
that there was a change in patient behavior. The younger patients were much more likely to
check glucose levels when on this system. On the other hand, young adults were three times less
likely to check. She states that the children in the 3 to 6-year-old category wore the pump a
median of 120 hours while the 7 to 10 year olds wore it 138 hours and the 11 to 25 year olds 110
hours. Sixty-four percent of the youngest children had skin reactions and 36% of those were
moderate to severe. One hundred percent of the families whose children were in the 3 to 6 year
old range stated that they would definitely use this system if available, whereas 87% of the 7 to
10 year olds, 78% of the 11 to 14 year olds and 66% of the 13 to 25 year olds were enthusiastic.
The main concerns were accuracy, the time consumption and the frequency of the alarming. She
stated that some of the problems in the 11 and older group included the need for increased
autonomy with frustration of the technology. They also had a much higher burnout rate. She
suggested that these patients may well need breaks from a closed system. Dr. Aaron Kowalski
discussed the artificial pancreas roadmap update and basically the question, when does my child
get one? He quoted some data from the Type I Diabetes Exchange (I have discussed this
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program in each of the last two or three years and several of our patients are enrolled) where he
pointed out that the children less than 6 years old achieved the A1c goal of less than 7.5% 21%
of the time, the 6 to 13 year olds 21% of the time and the 13 to 18 year olds 17% of the time.
The data shows that the average 8 to 14 year old spends 10.6 hours per day with a blood sugar
greater than 180 mg/dL and 3.9 hours greater than 250 mg/dL. Likewise 5% of the time is spent
under 60 mg/dL. He also pointed out that there is a rate of ketoacidosis of about 8% to 10% per
year. Thus he felt that our progress to this point is obviously too slow. He stated that the
timeline in this case starts with research then moves to commercial development, then to
regulatory evaluation, then to reimbursement, then to clinical acceptance and finally to improved
clinical outcome. We are still in the research category although the others will be coming in the
not-too-distant future. He felt that the researchers and developers were targeting 2017 to 2018 as
the launch of the hybrid systems.
Then Dr. Stayce Beck, PhD talked about pediatric patient’s safety and patient products
from the FDA perspective. She pointed out that artificial pancreas systems must be evaluated in
kids to be approved. There is no mandate, however, that adults should be approved first. She
said it was not “easier” to get a device approved for adults and that ideally it should be approved
in children at the same time. She pointed out that CGMs do not work as well in children due to
body fat differences, activity differences, increased glucose variability, hormonal changes,
smaller real estate and difficulty maintaining adherence. She stated that the first studies would
be feasibility studies showing safety but that the pivotal studies will show performance. I came
away feeling that the FDA was certainly open to these systems being used in children but that the
developers still have a ways to go before acceptance. Dr. Edward Damiano, PhD gave a talk on
the pathway to the pediatric bionic pancreas. It has evolved that the term bionic pancreas
usually means combined insulin and glucagon infusion. The bionic pancreas is ideally the way
to go in that the insulin will bring the blood sugars down but the glucagon can bring the blood
sugars up if there should be hypoglycemia. This way we would not be reliant on suspension but
actual intervention when a child dropped low. He discussed the Dexcom G4-Apple iPhone with
apps and the t:slim pumps system that they have been using. They are very automated and what
impressed me was that the app was based solely on body weight and then adapts in one day to
the patient’s needs. They only need to provide the body weight of the patient to start the system.
This is the first time that I have heard of this approach. It would take much of the guesswork out
of initiating such a system if it could truly work safely. Such an approach would relieve a lot of
the stress on old diabetes care providers. He reported on two camp studies and four center
studies with adults. The first camp study included 32 teens with five days on an open loop pump
and then five days on a bionic pump. The average blood sugar with the open loop was 158
ng/dL whereas it was 142 ng/dL on the bionic system. The time spent less than 60 mg/dL was
2.2% in the open loop patients and 1.3% in the bionic patients. The time spent greater than 180
mg/dL was 31% in the open loop time and 21% with the bionic system. It also reduced intersubject variability from 7.5% to 6.4%. He stated that the predicted hemoglobin A1C of these
patients had they stayed on the system long enough would have dropped from 7.1% to 6.6%.
The second study in camp took 19 pre-teens and was again five days on an open loop pump and
five days on a bionic pump. The average glucose with the open loop was 168 mg/dL versus 137
mg/dL with the bionic. Two point eight percent of the patients dropped below 60 mg/dL on the
open loop pump whereas only 1.2% did so on the bionic pump. Thirty-six percent of the patients
on the open loop were at some point greater than 180 mg/dL versus 17% with the bionic. There
was no significant change in insulin dose. In the first study the open loop period required 0.79
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U/kg/day versus 0.82 U/kg/day on the bionic. In the second study the patients required 0.68
U/kg/day of insulin in both parts of the study. The adult studies showed that the patients wore
the bionic pump for 11 days and the average glucose dropped from 162 ng/dL to 141 ng/dL. The
time spent less than 60 ng/dL was 1.9% versus 0.6% and the time spent greater than 180 ng/dL
changed from 34% to 20%. The adults again had very little change in their insulin going from
0.63 U/kg/day to 0.66 U/kg/day on the bionic pump. One of the questions still remains the use
of soluble glucagon. He stated that several companies have come up with several different
solutions that have stability up to one year. They are in phase 1 to 3 testing right now. Thus this
question should be answered relatively soon. He felt the systems were good enough without
faster insulins (we will discuss newer insulins later) and without pre-meal announcement. He
stated, however, that it would be better and safer had we faster insulins. He stated that the
artificial pancreas is not a cure but it is a bridge to a cure. This would buy time for the ultimate
cure to be developed. Finally, he said the ultimate goal is building a single pump that could
control both glucagon and insulin with a single cannula. That is not in the works at the moment
as far as I could tell. I come away from these sessions much more hopeful than I did in the past.
I felt that these were dreams that would occur long after my career ended but now I am not so
sure. The timeline discussed by Dr. Kowalski shows that we still have a long way to go.
Technology still needs to be improved and the safety has to be demonstrated. The cost will be a
tremendous deterrent initially I suspect. I can foresee many battles with insurance companies
that simply do not want to pay for the newer technologies. However, this is a process that we
have gone through before. You remember that I have been around a long time and remember the
fights that occurred with each step in our advance in diabetes management. The first time I
appeared in court was in support of a patient wanting to do blood glucose monitoring rather
than urine testing. That seems a long time ago and in fact it was. We have made each step thus
far and I can see no reason that we will not progress again as the glitches are worked out and
the safety and efficacy can be proved. Thus I think there is definitely hope for this system in the
next few years.
As you can imagine, there were many different abstracts and posters presented on various
approaches to closed loop pumps and artificial pancreases. First, we have a study from Bruce
Buckingham at Stanford using the DAIS system. This system includes a Dexcom G4 sensor, a
Roche Accu-Chek pump and an Android based DAIS controller. They used this system at camp
with a primary outcome of percentage of time in the target range of 70 to 180 mg/dL. The
control group used a sensor augmented pump, using CGM and telling the pump what to do. The
primary outcome was greater with DAIS, 78.6% versus 65.4%. There also was a reduction in the
time spent less than 70 mg/dL and greater than 180 mg/dL. The results are on the following
table.
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This study is very similar to the others which is encouraging. If most of them show the same
results then there is some consistency. The next study came from Cambridge, United Kingdom.
The title was “Day and Night Closed Loop Insulin Delivery in Young People with Type I
Diabetes: A Free Living, Randomized Clinical Trial”. This study was important because they
looked at 12 children and adolescents with Type I diabetes that had been on insulin pump
therapy. Their average age was 15.4 years and their hemoglobin A1c was 8.3%. They all
underwent two seven-day periods using sensor augmented insulin pump therapy or closed loop
therapy. During the closed loop period, a predictive algorithm automatically directed insulin
delivery between meals and overnight. Prandial boluses were administered by participants using
a bolus calculator (so this is a hybrid closed loop system). They found the mean glucose and
time spent above target were lower during closed loop therapy without a change in total daily
insulin amount. The time spent in the hypoglycemic range was low and comparable between the
two. Their results are in the following charts.
They concluded “unsupervised day and night closed loop at home is feasible and safe in suboptimally controlled young people with Type I diabetes”. I wonder if free living is the same as
free range? A late breaking abstract from Australia was entitled “It is Definitely a Game
Changer: Closed Loop Technology in the Home Experienced by Adults with Type I Diabetes”.
This study explored participant’s experiences after four nights of home closed loop insulin
delivery. They had been using sensor augmented pump therapy with lower glucose suspend
previously. “When asked about the four nights closed loop experience, the most common
observation was the ‘flat line’ showing stable overnight glucose levels. Although most reported
technical glitches during one or more nights, few safety concerns were raised”. The participants
reported the following benefits when compared with their current insulin pumps and sensors:
less decision making resulting in fewer errors; fewer alarms as the closed loop kept glucose
levels within target overnight; not having to cope with the consequences of hypo- and
hyperglycemia due to less glucose variability. The participants found closed loop was easy to
use but that “this might be different for people who are less tech savvy”. The conclusion was
that the participants gave a very positive evaluation of closed loop in the home. The group from
Boston that I quoted extensively last year had an oral presentation on outpatient glycemic control
with a bionic pancreas in pre-adolescents with Type I diabetes. Glucose regulation was by an
automated bi-hormonal (insulin and glucagon) bionic pancreas and was compared to insulin
pump therapy under supervision by camp staff. Of interest to me was the fact that the bionic
pancreas was initialized only with subject weight and no other information. “After 24 hours of
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autonomous adaptation, the bionic pancreas produced a lower mean continuous glucose monitor
glucose level versus competitor (138 versus 168 mg/dL), less time under 60 mg/dL (1.2% versus
2.8%) and more time in the 70 to 180 mg/dL range (80.6% versus 57.6%).” They concluded
“the same bi-hormonal bionic pancreas used for previous studies in adolescents and adults, in all
cases initialized only with body weight, achieved similar results in pre-adolescents,
demonstrating safety and efficacy for ages 6 through 75 years and body masses 21 to 128 kg.”
Their results are nicely demonstrated in the next graph.
A group from Virginia and Italy found “artificial pancreas improves glycemic control in a
multi-night, multi-center outpatient/home study of patients with Type I diabetes”. Their
hypothesis was “overnight closed loop control with a system designed to aim tight glycemic
control every morning and ‘reset’ the patient to normal glycemia before wake up may have
positive impact on glycemic control overnight and on the next day”. They did a randomized
crossover trial using 36 subjects on sensor augmented pumps and closed loop pumps for five
consecutive nights. They found “overnight closed loop control at home and in supervised
outpatient settings achieved similar results. Compared to sensor augmented pump therapy, both
closed loop conditions resulted in significant improvement in hypoglycemia and glycemic
control, with potential to improve daytime control when glucose levels are reset to normal
glycemia each morning”. Their results are in the following chart; remember SAP is sensor
augmented pumps, O is outpatient and H is home closed loop systems.
A group from Montreal reported their results of outpatient overnight glucose control with dual
and single hormone artificial pancreas systems in Type I diabetes. Half of the patients were
adolescents at diabetes camp and the other half were adults. Their results are in the following
chart. (Please remember in Canada they use mmol/L versus ng/dL so merely multiply all of their
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results by 18 and it will be more understandable to you). They concluded that although sensor
augmented pump therapy significantly improves overnight control compared to pump therapy
(CSII) further improvements in overnight glycemia may be achieved with dual pump artificial
pancreas.
The same group did an open label randomized crossover study comparing sensor augmented
pumps (SAP) and dual hormone artificial pancreas (DAP) in 12 adults. They looked at both
moderate intensity continuous exercise and high intensity interval exercise. With SAP, exercise
induced hypoglycemia (glucose ≤ 3.3 mmol/L) was 27% versus 9% with the DAP. The
percentage of time with a glucose less than 4 mmol/L was 19.9% with SAP and only 2.4% with
DAP. They concluded “DAP is offering a tighter control and a better potential to prevent
hypoglycemia during two types of exercise in adults with Type I diabetes”. A group from
Portland used a bi-hormonal closed loop pump to look at its effect on exercise in order to prevent
hypoglycemia. They used a wireless bi-hormonal artificial pancreas system that delivered both
insulin and glucagon and adjusted the dosing after exercise was announced. This is a formal way
of saying that they had let the pump know that the patient was going to have exercise. “Exercise
announcement stopped insulin for 30 minutes then 50% reduction for 60 minutes and increased
glucagon by twofold for one and one half hours.” They found that the automated delivery of
glucagon prevented blood glucose values from dropping below 70 mg/dL in 100% of the cases.
They were planning to use rescue doses of carbohydrate for blood glucose values below 70
mg/dL but in none of the five studies did they have to use it. They concluded “preliminary
results show that automated insulin and glucagon delivery effectively controlled glucose levels
and prevented hypoglycemia, including during and after exercise”. These algorithms are
becoming more and more sophisticated and are certainly more sophisticated than this poor old
care provider. Finally, a group from Northridge, California used the Medtronic hybrid closed
loop system in evaluation meal dosing. “Medtronic’s hybrid closed loop system requires that
patients provide an estimate of the carbohydrate content of upcoming meals; the system then
calculates an appropriate meal bolus based on pre-specified insulin to carbohydrate ratio.” They
hypothesized that the use of standardized carb ratios could significantly improve the system’s
performance by reducing post prandial hyperglycemia. They had their subjects consume
standardized meals on day 2 with the open loop pump and day 6 with a closed loop pump with
the previous pump carbohydrate ratios. They found “the use of a standardized and relatively low
carbohydrate ratio resulted in higher pre-meal bolus doses and greater reductions in post prandial
hyperglycemia. This was achieved without increasing the risk of hypoglycemia”. There were a
few other posters and abstracts on closed loop pumps that I chose not to review. Most of them
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showed the same type of results as the ones that I have presented to you. The bottom line is that
people are becoming more and more sophisticated with this system and are achieving
remarkable results. I firmly believe that this will be the wave of the future in the next three to
four years. Again, we have to resolve the financial issues before it can become truly available to
our patients. I certainly hope that those problems can be overcome because these systems
appear to be remarkable. I should emphasize again that they are not foolproof and require
active intervention from the patients. If our patients truly want good control and not just to be
relieved of all diabetes responsibilities, these systems will be outstanding.
New Insulins and Old Friends
Although the artificial pancreas is fun to think about, it is still in the future. Some of the
newer insulins hopefully will be available considerably before we start worrying about closed
loop pumps. Saturday afternoon I went to an oral session on basal insulin analogs. Satish Garg
from the Barbara Davis Center in Denver presented a talk on greater hemoglobin A1c reduction
with basal insulin PEG lispro versus insulin glargine in Type I patients. This is a study known as
the IMAGINE 1 in which they are looking at PEG lispro. If you refer back to the last couple of
years you will know that PEG lispro (or BIL-basal insulin lispro) is a basal insulin with a flat
activity profile with hepatic and peripheral action more like endogenous insulin. Basically, it is
lispro (Humalog) insulin bound to polyethylene glycol. The large hemodynamic size leads to
slower degradation and has a preferential action in the liver. The half life of this insulin is
approximately two to three days. The IMAGINE 1 study has included 455 patients with Type I
diabetes. They were randomized to bedtime BIL or glargine (Lantus). The primary endpoint
was to follow these patients for 26 weeks but then they were followed to a total of 78 weeks.
The baseline hemoglobin A1c was 7.9% and the patients on BIL had an A1c of 7.0% at 26 weeks
and 7.3% at 78 weeks. The Lantus patients had an A1c of 7.5% at 26 weeks and 7.6% at 78
weeks. At 26 weeks the average fasting glucose was 138 in the BIL patients and 160 in the
Lantus patients. At 78 weeks the fasting glucose was 140 for BIL and 160 for Lantus. They also
found that there was a significant reduction in glucose variability as determined by CGM. The
patients using BIL had significantly less nighttime hypoglycemia but interestingly had a slightly
higher rate of hypoglycemia overall. Five point seven percent of the BIL patients had severe
hypoglycemia (losing consciousness or requiring help) versus 11.3% in the glargine group.
There was more fat noted in the liver with BIL than with glargine (glargine actually reduced the
liver fat content) but the levels were still within the normal range. There were also more site
reactions with BIL than there were with Lantus. Finally, there was a significantly greater rise in
liver function (ALT and AST) with BIL but not with Lantus. The conclusions drawn were “BIL
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provided greater reduction in hemoglobin A1c, less nocturnal hypoglycemia, less weight gain
and higher triglycerides compared to glargine, consistent with reduced peripheral action and a
hepato preferential effect of BIL”. Next a group from Lilly demonstrated reduced intra-subject
variability of basal insulin PEG lispro (BIL) compared with insulin glargine in patients with
Type I diabetes. They found that BIL showed a flatter time action profile than glargine with a
more even distribution of the glucodynamic effect over the first and second 12 hours of the
study. Intra-subject was statistically significantly lower with BIL. They concluded “BIL has a
flatter and more predictable time action profile with less day-to-day intra-subject variability
compared to Lantus”. Their results are on the following chart.
As you can see the lower curve which is BIL is significantly flatter than Lantus. This would be a
tremendous benefit to our patients since there is quite a bit of variability from hour to hour with
Lantus. I have told virtually all of you that Lantus is not as flat as we would like it and thus has
more effect early on than later. BIL seems to overcome that problem. The session went on to
discuss other types of insulin but I think it is probably best to continue on with some of the other
presentations of BIL so that we can group them effectively. A group reporting from Minneapolis
gave the results of the IMAGINE 3 study. This was a study of 11,014 adults with Type I
diabetes that were randomized to either bedtime BIL or Lantus along with prandial Humalog. At
52 weeks the results were quite interesting and are demonstrated in the chart below. Their
conclusion was that treatment with BIL versus glargine in patients with Type I diabetes gave
superior hemoglobin A1c reduction, lower nocturnal hypoglycemia and better weight loss. They
also found that there were increases in ALT (the liver enzyme), triglycerides and injection site
reactions.
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These results are very interesting. You can see that the hemoglobin A1c was lower in BIL and
that a greater percentage of the patients achieved the goal of a hemoglobin A1c of less than 7%.
The body weight change was the equivalent of about two pounds between the two insulins. BIL
also produced nighttime hypoglycemia at about half the rate of glargine but again there were
more total hypoglycemia events with BIL than with glargine. On the other hand, as with
IMAGINE 1, the severe hypoglycemia rate was lower with BIL than with Lantus. Notice also
that the between day variability was definitely improved with BIL and the within day variability
also was improved with BIL.
Another study from Indianapolis looked at the effect of exercise on the pharmacokinetics
of BIL. They found that BIL concentrations increased during exercise, reaching a peak at one
hour and returning to pre-exercise levels within three hours after starting the exercise. The
patients with glargine found none of these changes. Interestingly, the blood glucose level did not
seem to be particularly affected by these changes. They found that over the three hour period
after exercise starts, the blood glucose levels were similar with or without exercise following
both BIL and glargine dosing. They concluded “while exercise transiently increased systemic
exposure following BIL but not glargine dosing, this did not appear to effect blood glucose to a
clinically significant extent”. I will have to see more studies on BIL with exercise before I know
how to translate that to those of you who actually do exercise. This will be particularly
important for our athletes and dancers. Another report was on IMAGINE 7. This was a phase 3
crossover study in which 212 patients received BIL for 12 weeks. One hundred and eighty-two
were then randomized to two 12-week treatment periods comparing fixed time evening dosing
and variable time dosing with dosing intervals anywhere from 8 to 40 hours. The following table
shows the results in which both the variable time and fixed time groups were similar in
hemoglobin A1c, fasting glucose, glucose variability, total and nocturnal hypoglycemia and
basal and bolus insulin doses.
They concluded that BIL permits 8 to 40 hours dosing intervals with similar hemoglobin A1c
compared to fixed time dosing in Type I diabetes. What this study shows is that if you forget
your dose of BIL at bedtime, you can give it the next morning and have no appreciable change in
control. I think this is probably both a good and bad thing. For those who are conscientious
and just occasionally forget a dose, being able to dose the following morning would be
wonderful. For those who are pretty random in how they approach insulin in the first place (I
know who you are), this would just give them more leeway to be even more erratic with their
insulin dosing. Overall, however, I think this would prove to be a very valuable aspect of BIL
therapy. But remember: they were not saying just on Sunday.
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Now we are going to look at the other long acting insulin that will soon be on the market,
insulin Degludec from Novo. The first poster I wanted to mention came from Japan looking at
the efficacy of switching from insulin glargine (Lantus) to insulin Degludec in patients with
Type I diabetes. They looked at 45 adult patients who were on once or twice daily Lantus and
then switched to Degludec. With the switch, there was a significant decrease in total basal
insulin from 17.8 U/day to 15.3 U/day. The episodes of hypoglycemia had a tendency to
increase temporarily but it was not considered significant. The hemoglobin A1c in four weeks
dropped from 8.3% to 8.0%. The fluctuation in blood glucose values did not change
significantly with the switch. They concluded that “insulin Degludec once daily improves
glycemic control in patients with Type I diabetes to a greater extent than insulin glargine without
increasing the risk of hypoglycemia”. There were a few other abstracts using Degludec but they
all showed pretty much the same results. You remember that Degludec was supposed to come
out last year but was sent back for further study because Novo had not included cardiovascular
risk data. I think that that is why there were few studies with Degludec this year since most of
the studies had already been done. The only ones that came out were from Europe and Asia
where Degludec has already been released. There was one study from Japan looking to estimate
the long acting effect of insulin Degludec. They were looking at the subject primarily to see
when it would be safe for a patient on Degludec to start insulin pump therapy in its place. What
they found was 50% of the patients could start or restart the pump at 36 hours and 100% at 48
hours after the last injection of Degludec. They concluded “the duration of insulin Degludec
action on Type I diabetes might attenuate within 36 hours in the real clinical field”. There is
some good news for our patients in that it appears insulin Degludec may be released by the FDA
at the end of this year or the beginning of next year. Novo was able to get the cardiovascular
risk data in very quickly. I do not know if there will be any age restrictions but I would hope not
because it certainly would be an interesting insulin to replace some of the problems that we are
experiencing with Lantus. Likewise, I do not know what the cost would be which is critical to
many of our patients since Lantus has been raised so many times over the last 12 months.
There were two very preliminary studies looking at very long acting insulins. A group
from Germany described Hn12470 which they found showed a flat profile of action that lasted
for a full week. A group from Menlo Park, California described insulin AB101 which also is a
once weekly basal insulin. These insulins are in the very earliest stages of development and have
not been tried on humans that I am aware of. It sounds lovely to be able to give basal insulin
every Sunday and not have to worry until the next Sunday. On the other hand, if the dose is not
right then the patient is stuck with that amount of insulin for seven days. That makes calculating
dosages very, very important and would mean that we would have to titrate up very slowly. I
really do not know if these insulins will ever come out on the market and I do not know if they
would ever be considered safe enough for the use in our children. Nevertheless, it is interesting
to see these studies and to see the direction that various researchers are going.
There were some reports on more rapid acting insulins also which are of equal
importance to me since the timing of the insulin has become such a necessity and yet is such a
bugaboo for many of our patients. A group from Neuss, Germany looked at BioChaperone
insulin lispro which has been described in the reviews last year and the year before. They were
looking at 38 male patients with Type I diabetes. The graph below shows the concentration of
insulin over time comparing different doses of BioChaperone insulin lispro versus standard
lispro. As you can see there is a much more rapid rise and fall which is of tremendous help for
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our patients preventing post prandial (after meal) hyperglycemia but also preventing pre-prandial
hypoglycemia at the next meal.
Their conclusion was fairly obvious: “because of its ultra-fast action BCLIS has the potential to
improve post prandial glucose control”. A group from Denmark looked at faster-acting insulin
Aspart. This is NovoLog in a new formulation containing two additional components,
nicotinamide and arginine. It results in a faster initial absorption after subcutaneous injection.
This study was looking at the mechanisms in which nicotinamide elicits its effect. They found
“these studies reveal that nicotinamide efficiently augments the rate at which insulin aspart
(NovoLog) permeates across the endothelium; likely via promotion of the monomeric state and
supports observations in human subjects that faster aspart elicits a faster onset and higher earlier
exposure compared to insulin aspart”. Another study from Hanover, Germany looked at fasteracting insulin aspart in children, using adolescents and pre-adolescents. They found that faster
aspart had a significantly faster onset of appearance (in children 5.2 minutes versus 9.8 minutes
with regular aspart, in adolescents 5.3 minutes versus 11 minutes and in adults 5.5 minutes
versus 12.3 minutes). As the chart below shows, faster aspart had a greater glucose lowering
effect versus regular aspart. They concluded “faster onset and higher early insulin exposure with
faster aspart versus aspart led to a larger glucose lowering effect, though only significant for
children, who are prone to rapidly fluctuation glucose levels and unplanned food intake”.
This chart is hard to understand but it does show that faster acting insulin aspart certainly has a
beneficial effect for our children and would reduce the need for having significant time between
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the shot and when a child eats. Another study from Atlanta and Denmark looked at the use of
faster acting insulin aspart using pump therapy. They compared it with regular aspart
(NovoLog). They found “faster aspart had significantly greater glucose lowering effect than
insulin aspart after a standardized meal, with findings confirmed by CGM for all meals, and less
time spent with lower glucose levels”. Another study from Neuss, Germany looked at faster
acting insulin aspart in pump therapy also. They were measuring the time it took to get to 50%
of the total insulin level in the blood after bolusing. They also looked at the time max where
they reached the maximum insulin level. The t-50% max occurred 36% (12 minutes) earlier than
regular insulin aspart and reached its maximum level 31% earlier at 26 minutes. They found that
the early insulin exposure in the first two hours was greater with the newer insulin. They
concluded “faster aspart showed enhanced early exposure and action compared with insulin
aspart in CSII”. There was another insulin formulation described from a group in Chula Vista,
California using BIOD-531, which is a U400 Humalog insulin combined with EDTA, citrate and
magnesium sulfate. This study was in Type II diabetics and I am not going to bother you with
the results. I just wanted you to be aware that there are other insulins being looked at also.
I did not want to conclude this section without mentioning inhaled insulin. Technosphere
inhaled insulin is now on the market for adults and patients with Type II diabetes. A group from
Boston did a meta-analysis on its use. I will only give their conclusion. “Until long-term safety
data are available, Technosphere insulin should be reserved for non-pregnant, non-smoking adult
patients with diabetes, free of pulmonary disease who are needle phobic and would otherwise
delay initiating or intensifying insulin therapy. For patients who are needle tolerant,
subcutaneous insulin appears to be a better option”. Another group from Baltimore looked at the
use of Technosphere insulin in patients who had upper respiratory tract infections, since that was
considered to be a real worry since it might affect the absorption. They found URTIs had no
impact on pharmacokinetics/pharmacodynamic properties of Technosphere insulin. They
warned, “however, study observations are limited to patients with URTI, as individuals with
lower respiratory tract infection were not studied”. They also pointed out that if a patient is
unable to conduct proper inhalation, they should administer insulin subcutaneously. This insulin
is not available for our patients and I do not think will ever be particularly useful since it is not
easy (probably impossible) to achieve the variations in dose that our patients employ every day.
They only come out at 4 and 8 unit doses. It is interesting, however, to see what is being done
and to see how people are progressing. The Technosphere inhaler is about the size of an
albuterol inhaler for someone with asthma so it is much more convenient than the earlier model.
I know of very few adult patients who are using it but then I do not deal with Type II adult
patients. Finally, a group from Jerusalem, Israel looked at oral insulin ORMD-0801. This
insulin is deposited directly into the portal vein following its release from enteric coated capsules
in the gastrointestinal tract and was tried in adult patients with Type I diabetes in a double blind
study. (This type of study makes it so that neither the doctor nor the patients know if they are
using the medication or placebo.) They found that “the use of pre-prandial ORMD-0801 reduced
the exogenous insulin demands required to maintain euglycemia in Type I diabetic patients and
proved safe and well tolerated as the tested regimen”. This insulin did not fully take the place of
rapid acting insulin but reduced the amount needed. I have no idea if this insulin will ever be
useful for patients or for children. Again, I just wanted you to be aware that people are still
studying alternative forms of insulin.
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I mentioned earlier that I went to an evening seminar that was obviously designed to
introduce the concept of BIL, the long acting insulin from Lilly. The seminar spent much of its
time talking about studies in dogs and very complicated testing, which I do not want to bore you
with. They did have a couple of interesting slides that I wanted to show. The first one is just
looking at PEG lispro and some of it characteristics.
Another showed the milestones in insulin development and I thought that you would be
interested to see it. Those of us who have been around a fair number of years (I think fair is the
appropriate adjective) experienced many of these different insulins. I just thought it might be fun
to put it into perspective for you.
Finally, I wanted to show the graph on Degludec versus Lantus.
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Remember that the lower dose of Degludec (0.4 U/kg/day) is close to what we traditionally use
with our patients.
So there you have it on new insulins. We are making progress and I think that we will be
seeing rapid changes in the next few years. It will be very much like that brief span when
Humalog, NovoLog and Lantus all came out and our approach to diabetes changed totally.
Degludec probably will be out within the next nine months. BIL has been withdrawn from the
FDA and has probably been put back about two years. I hope that maybe that can be speeded up
because I like having options since that may help with cost. Finally, the rapid acting insulins are
going to be a little bit later but it is reassuring to know that we will have some alternatives to
Humalog, NovoLog and Apidra in the near future which will make life much more comfortable
for our patients. Three cheers for the pharmaceutical companies, even if they are costing an arm
and a leg.
To conclude this section I wanted to go back to some of the insulins that we are currently
using because there were a few interesting studies that I thought you would like to know about.
First there was a study from Germany looking at insulin injection into regions of
lipohypertrophy. As you know, we have been harping on you to give shots in multiple sites for
many years. When you give shots in the same place too frequently, you frequently get “build
up” which is a combination of fatty tissue and scar tissue. The official term for this phenomenon
is lipohypertrophy. These people were looking at how insulin is absorbed and what effect it has
on the blood glucose levels when insulin is injected into these areas. The first curve shows the
insulin concentrations after giving Humalog insulin. The solid line is the insulin given into
lipohypertrophy whereas the dotted line is given into normal adipose tissue. As you can see,
there is a higher insulin level in unaffected sites thus giving a greater insulin effect.
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The second curve looks at the blood glucose levels when insulin is given into the two different
sites. Again it is obvious that the insulin works considerably better in normal adipose tissue as
opposed to the area of lipohypertrophy.
Another study from the same group showed the same effect looking at fancier parameters. Gosh
darn it looks like maybe we knew what we were talking about when we asked that you spread the
insulin around so that you do not get build up. It really does have an effect on your insulin
absorption and your control. The next study from Syracuse, New York looked at a problem that
we probably do not emphasize enough: “Incorrect Insulin Administration: A Poorly Recognized
Problem”. They watched 60 of their adult patients with diabetes to judge their skill accuracy in
diabetes injections. They were observed injecting in pillows and were rated on preparation,
injection and drawing up of insulin skills. What they found was overall 81.9% of the patients
were observed to have correct technique. Insulin preparation was correct in 80.2% of
observations with pen users significantly worse than syringe users. The pen users dialed the
correct number of insulin units in 78.5% of observations versus 81.2% for syringe users. Eightysix point seven percent of injections steps were correct with pen users again significantly worse
than syringe users. Interestingly studies last year showed pens to be more accurate when used
properly. Overall 38% had skin problems at injection sites and only 28.3% answered all three
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diabetes numeracy problems correctly (numeracy is their ability to do the math for calculating a
dose). Correct timing of injections and confidence in choosing correct insulin dose but not skill
scores related to better hemoglobin A1c and blood glucose levels. They concluded “errors in
self-administering insulin may be common, including errors in choosing the correct insulin dose.
Injection site selection and diabetes numeracy were also concerns. Providers should attend to
reviewing/re-educating patients in proper insulin self-administration”. I found this study very
interesting. As care providers we tend to assume that our patients know what they are doing and
are doing them correctly. Our teens particularly are allowed to go off and calculate doses and
dial them up with very little supervision. This study was in adults but I suspect that we would
find similar problems in our pre-teens and teens. I think it would be a very interesting study to
try sometime. I am afraid that it would be very humbling to both the care providers and the
parents and would probably explain some of the variability that frustrates us as we try to achieve
adequate control.
A study from Iowa City was titled “Improved Glycemic Control with Lesser Daily Dose
with Insulin Glargine on Re-Transition from Insulin Detemir”. Their background was “we
documented lapse of glycemic control, despite higher daily dose insulin dose, two subcutaneous
injections and increased number of daily blood glucose monitoring with less convenience on
switching from insulin glargine to insulin detemir in patients with Type I and Type II diabetes”.
This apparently was a study done with Iowa Medicaid. The objective of this study was looking
to see what happens when patients were re-transitioned from detemir back to glargine (Lantus).
What they found was the daily insulin dose of 58 units on detemir declined significantly to 48
units on glargine. The bolus insulin with one of the analogs was not significantly altered. The
hemoglobin A1c was not significantly changed with the re-transition being 7.2% with glargine
and 7.4% with detemir. There was no significant change in body weight or incidence of
hypoglycemia. They concluded “insulin glargine is more cost effective than insulin detemir due
to lower daily dose and less equipment (syringes, needles, alcohol pads) needed for once daily
administration”. They also felt it was more convenient with once daily injections as opposed to
twice daily as they had to have with the detemir. I do wish that Altius and Aetna reviewers
would look at this abstract. We have fought them bitterly (we meaning virtually every pediatric
endocrinologist in the country) for years but they insist that detemir is just as good as Lantus.
This study again shows that that is not true and that detemir is not a once daily insulin. Cost
effectiveness apparently does not register with these people. Thank goodness we will have other
options in the near future with BIL and with Degludec so that we can get away from this very
tiresome and detrimental fight. Finally there was a study from the Netherlands looking at the use
of a needle-free jet injection device for rapid acting insulins. They pointed out that earlier
studies showed that insulin administered by jet injection is more rapidly absorbed than when
injected by conventional pen. They felt that this would be advantageous for the correction of
substantial and potentially hazardous post prandial hyperglycemias. They found that the time to
achieve maximum insulin absorption was 40.5 minutes with the jet injector and 76.8 minutes
with an insulin pen. They also found that the hyperglycemic burden during the first two hours
after injection was significantly lower with the jet injector. The risk for hypoglycemia was not
altered, however. They concluded “using jet injection for administration of rapid acting insulin
accelerates the correction of substantial hyperglycemia in patients with insulin requiring
diabetes”. We used the jet injector many years ago (in the 1990s) with little success. The noise
of the injectors scared the younger patients and the older patients found that they bruised more
which did not sit well with our teenage girls. I am not aware of any jet injectors currently
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available in the United States. We will certainly look to see how they function and what they
cost should they arrive. Certainly the increased rate of absorption would be useful but I do not
know that it supersedes the drawbacks that we have encountered in the past. We will certainly
let you know if we encounter such a device.
Pumps and Pumps with Continuous Monitoring
First I would like to report on two talks given early Saturday morning (I promise I was
awake) in the diabetes care symposium. The first was by Bruce Buckingham from Stanford. He
was talking about how predictive low glucose insulin suspension reduces duration of nocturnal
hypoglycemia without increasing ketosis. He first gave some interesting statistics. Fifty-five
percent of all severe hypoglycemia events occur during the night and 75% of all seizures occur at
night. Patients who have continuous glucose monitors ignore the alarm for hypoglycemia 71%
of the time. I take it they sleep through the alarm or just choose to ignore it. Fortunately many
parents are not as able to sleep through. Finally he pointed out that seizures from hypoglycemia
usually occur approximately two hours after the start of the hypoglycemia. It is not at the onset
of the hypoglycemia but with persistence. He was describing the Medtronic Enlite system in
which the Enlite continuous glucose monitor will suspend the pump when the blood sugar
reaches 80 mg/dL. That system starts when the hypoglycemia is reached but the newer system,
which Is the predictive low glucose insulin suspend, starts 30 minutes before hypoglycemia
should occur. There are no alarms and thus the patient and the parents get a good night’s sleep.
It just shuts down the pump so that there is no more insulin being infused. The study he quoted
had 1,900 nights in children 11 to 14 years of age and 1,500 nights in children 4 to 10 years of
age. The number of children who dropped below 60 mg/dL dropped from 8% with an open loop
pump to 3% in the 11 to 14-year-old group and from 5% to 1% in the 4 to 10-year-old group.
The average glucose level over 24 hours was increased by only 6 mg/dL. There were no seizures
or ketoacidosis. However, 10% of the 4 to 10 year olds did have ketones present the following
morning while 2% of the 11 to 14 year olds had ketones present the following morning. We will
discuss this system further later in the section. Dr. Trang Ly talked about day and night closed
loop control using the integrated Medtronic hybrid closed loop system at diabetes camp. She
was using a fourth generation sensor from Medtronic. The meal bolus used a calculation of 500
divided by the total daily dose of insulin. The correction dose was calculated by 1,800 divided
by the total daily dose. The basal rates were given in five minute micro boluses throughout the
day. She studied 20 campers for six days aged anywhere from 14 to 40 years. She compared the
hybrid system versus the sensor augmented suspend system. During the day the readings were
similar between the two systems but at night 96% of the readings were within range with the
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hybrid system whereas as 80% of the readings were in range with the low dose suspend system.
The mean glucose for both groups was 147 mg/dL with overall 73% in range. She found no
improvement in control with the hybrid system versus the sensor augmented system.
There were no sessions specifically designated for pump therapy. I think that this was
because the major new players in pump therapy have been out now for about two or three years
and there was nothing truly new or innovative other than the sensor augmented and closed loop
systems. A group from Manchester, United Kingdom looked at a large cohort of patients with
Type I diabetes that were treated with continuous subcutaneous insulin infusion (CSII). These
patients were adults with a mean age of 45 years. They used a variety of insulin pumps
including the Medtronic, OmniPod, Animus and Accu-Chek. They found that there were no
hemoglobin A1c differences when comparing the different pump users or those using catheter
pumps versus the OmniPod. Less than one third of the patients achieved the desired control of a
hemoglobin A1c of less than 7.5%. “Contrary to our expectations more than a third had poor
control (hemoglobin A1c greater than 8.5%) and 11% had very poor control (hemoglobin A1c
greater than 10%).” They concluded “our data highlight the challenges of managing Type I
diabetes in real live conditions which may vary when compared to research settings”. Their
results are in the following chart.
I suspect that we would find the same kind of results with our patients on pumps with a slight
shift in each percentage. We certainly have those patients that simply do not use their pumps
properly. As we try to tell our patients when they start pump therapy, the pump is a tool and is
only as good as the patient who controls it. There is no magic to pump therapy and we have to
be very careful as to who is allowed pump use. Because pumps are easier than injections, some
of our patients just decide to let the pump take care of their diabetes with disastrous results. I
guess, in a somewhat perverted way, it is nice to see that other centers have the same problems
that we do. Looking at the subject from a different standpoint, a group from Boston looked at
the patient perspective as far as insulin pump use. They recruited current pump users, former
pump users and multiple daily injection patients to complete an online survey which they hoped
would identify the attributes of insulin pumps and integrated technology that create barriers to, or
enhance, a person’s ability to manage Type I diabetes. Their results are in the following table.
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They found “in this population, pump use was associated with higher income and the use of
CGMS and diabetes related web applications”. They found, however, that the choice of insulin
delivery was not related to a recent hemoglobin A1c level. This study was not designed to
compare the groups as to efficacy. They were merely trying to understand who used pumps and
who gave up on them and who never chose to go on pump in the first place. A group from
Toronto looked at pump use in Canada. They found that the prevalence of pump use was
approximately 44%. Pump users tended to be younger (these are adults that they are surveying),
more educated, more physically active and had less chronic kidney disease. The pump users had
a slightly lower hemoglobin A1c level but it was not significant (7.4% versus 7.6% for nonpump users). They found that “daily glucose tests (6.0 versus 4.0), use of carbohydrate ratios
(84% versus 34%), use of insulin sensitivity factor (95% versus 85%), use of computer data
uploads (37% versus 12%) and use of continuous glucose monitors (22% versus 72%) were
significantly greater among pump users”. They concluded “despite a trend toward lower A1c
among pump users that is comparable in magnitude to that observed in clinical trials, the only
modifiable factor independently associated with better glycemia was a greater frequency of daily
glucose tests”. Thus they found that the number of blood tests was the only variable that
correlated with the lowered hemoglobin A1c level. I hate to point out that this is something that
we have been preaching for years. You remember that studies have shown that for each blood
test that a patient increases per day on average, the hemoglobin A1c will drop. It continues to
drop until a total of seven tests per day. The message I take here is DO YOUR TESTS. A group
of combined Stanford and Barbara Davis researchers looked at early detection of infusion set
failure during pump therapy. They pointed out that infusion set failures can result in prolonged
hyperglycemia or ketoacidosis. Set failures are frequently characterized by variable and
unpredictable patterns of higher sugar levels despite more insulin being given. They developed a
“novel algorithm for early detection of the onset of a set failure”. This algorithm used only the
CGM and insulin data without any information on food intake or the cause or timing of the
failures. They had 23 patients using a Dexcom G4 sensor and a Teflon infusion set for seven
days or until there was a failure which was defined as a glucose level greater than 250 mg/dL
that failed to decrease at least 50 mg/dL in one hour and/or serum ketones. Because the system
was being used for seven days they had a greater chance of set failure. They found that the
algorithm identified failure 2.52 days ahead of the actual event as recorded by the clinical team.
They felt that this algorithm could potentially lower the time spent with a blood sugar greater
than 180 mg/dL by 29%. A group from Japan looked at the three current rapid acting insulins to
see if one provided better hemoglobin A1c levels than the others. They used Apidra, Humalog
and NovoLog and found no difference in hemoglobin A1c results. Interestingly, the only
variable that they found that had a direct effect on hemoglobin A1c levels was the frequency of
site rotations and the number of sites that were used. They concluded “the education of site
rotations is a major subject for Type I diabetes patients with CSII”. Do not say that we have not
mentioned this in the past. Using proper site rotation so there is not scar tissue or
lipohypertrophy makes a significant difference according to this study. Please listen to us when
we plead that more area be used for infusion. A group from North Carolina looked at a novel
continuous subcutaneous insulin infusion set that had ports that allowed for a flow stabilizing
infusion of insulin with reduced infusion pressure. They used MRI studies to look at the
effectiveness and found “catheter porting creates an auxiliary tissue flow pathway that may
reduce occlusion and stabilize flow”. Anything that will enable us to infuse better with fewer
problems is welcome. Another study from the same group looking at the same infusion set
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concluded “compared to a commonly used infusion set, the investigational set had fewer flow
interruptions/silent occlusions and less time with interrupted flow. Decreasing flow interruptions
may benefit CSII patients by providing more consistent insulin delivery and reducing
hypoglycemic episodes caused by infusion set failures and/or temporary blockage”. I have not
actually seen this device but I certainly hope that it proves to be feasible. Again we can always
benefit from better infusion sets.
I wanted to finish this section with a few posters or presentations on sensor augmented
pump use, using a pump and a continuous glucose monitor. A study from the Barbara Davis
Center in Denver looked at the effects of SAP on hemoglobin A1c and c-peptide production in
the first year of Type I diabetes. They were working on the hypothesis that “intensive control on
onset of Type I diabetes has been suggested to preserve c-peptide production”. C-peptide is a
marker for insulin production and the thought is that the more insulin a patient produces, the
easier and better the control. They studied 48 patients and found that there were no significant
differences in hemoglobin A1c level or c-peptide level when comparing patients on SAP from
the onset of their diabetes or usual care. However, they did find that one year after diagnosis, the
hemoglobin A1c level was lower in the patients who had a high frequency of use of the
continuous monitor versus the patients that had low CGM use (6.8% versus 7.9%). Interestingly,
however, there was no difference in c-peptide production between these two groups. They
concluded “in those with more frequent CGM use, early intensive control with SAP improved
hemoglobin A1c levels at one year follow-up. Although c-peptide improvement was not
statistically significant in this analysis, it deserves further study”. I suspect that this group is not
different from any of the other groups that have been reported over the last few years. You
remember from last year it was noted that the hemoglobin A1c level would drop in patients using
CGM only if they wore it for five to seven days per week. Intermittent use has no benefit in terms
of diabetic control. There were several studies reporting on automatic pump suspend in response
to continuous glucose monitoring levels. Medtronic had a study reporting on the ASPIRE InHome study which evaluated the threshold suspend feature of SAP therapy. The pump will
automatically suspend insulin delivery at a programmed sensor glucose value. The Home study
showed that there was a 32% reduction in rate and a 38% reduction in area under the curve of
nighttime hypoglycemic events. Patients with the low threshold suspend had an average glucose
level of approximately 4 mg/dL higher than the group with SAP alone. The mean glucose values
were 158 mg/dL in the SAP plus threshold suspend group versus 154 mg/dL in the SAP group.
There was no difference in hemoglobin A1c between the two groups. They concluded that “the
data suggests that the reduction in hypoglycemia seen with a threshold suspend feature was not
associated with a significant increase in hyperglycemia, including after maximum insulin
suspensions lasting two hours”. This same group along with researchers from London looked at
the Mini-Med 640G system which provided the predictive low glucose suspend feature. In this
case the pump is stopped before the patient reaches the threshold that the earlier system was
using. Instead the system predicts that the blood sugars will drop and suspends insulin sooner.
They found that the serum glucose values avoided the low program threshold following 87% of
the pump stoppages. They concluded that the Mini-Med 640G system helped to prevent
hypoglycemia in patients with Type I diabetes. Finally, a group from Australia compared
overnight home closed loop insulin delivery versus sensor augmented pump therapy with low
glucose suspend. They found that the sensor time between 4.0 and 10.0 mmol/L (remember this
is the European measurement and should be multiplied by 18 so we are talking 72 to 180 ng/dL
in American terms), area under the curve of sensor glucose above and below target were all
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significantly better with the closed loop system. They concluded the closed loop system “at
home improved nocturnal glycemia and reduced symptomatic hypoglycemia compared to SAP
low glucose suspend”. For those of you who like to look at the data I have included in the chart
below.
The sensor augmented pump therapy with low glucose threshold is the first step on our way to a
closed loop pump. That system is already available via the Mini-Med 540G system. The next
step, which is predictive low glucose suspend will be available I suspect in the not-too-distant
future. These are all small steps on our way to the ultimate goal of an artificial pancreas. This
last study is not surprising in that it is a much more sophisticated system than either of the SAP
systems I described. Each step is important, however, to our ultimate goal of a safe, automated
system for our patients and children.
The second session that I went to (when I was still fresh) was a Meet the Expert session
with Dr. Bruce Buckingham from Stanford discussing pumps and continuous glucose monitoring
in youth. He quoted some statistics from the Type I Diabetes Exchange. Forty-three to fiftythree percent of the patients in the pediatric section were now on pumps and 15% were on
continuous glucose monitors. The Medtronic pump was still being used by greater than 50% of
the members. Patients on insulin pumps bolused 6.2 times per day among the pediatric patients
and 6.8 times per day among adults. On average they were using a three day insertion for their
pump. Seventy-two to seventy-eight percent used the bolus wizard. (I do not know what our
number is but Sheri Hardy despairs of many of our patients for not using the bolus wizard). He
stated that there are rarely infections from the continuous glucose monitoring sensors and that
almost all of the infections come from the infusion sets for pumps and that we need at least 14
days to heal before using that area again. Sixty-six percent of patients have occlusions or
unexplained hyperglycemia while on pumps. He stated that with pump users NovoLog and
Humalog are identical and that a study showed there was no difference in their use. When
comparing steel versus Teflon catheters at seven days they were about equal but there was a
higher kinking rate earlier with the Teflon catheters. He stated that 1 to 3% of pediatric families
will stop using a pump within three months of starting. He also stated that there is less DKA and
pump use than in multiple daily injections. This has not been our experience at Primary.
Catheter failures seem to be the greater cause of DKA in our patients. He did say that with the
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use of continuous glucose monitoring, the rate of ketoacidosis dropped about 50%. He felt that
severe hypoglycemia was equal between pump users and multiple daily injection users. He
stated worldwide 16% to 40% of patients use CSII while it is 47% in the United States. Thirtythree percent of our patients less than 6 years of age are on pumps, 46% of the 6 to 9-year-old
children, 50% in the 10 to 14-year-old children and 58% of the adolescents between 14 and 18
years of age are on pumps. He also stated that 40% of patients with self glucose monitoring now
download. I am sure that this is higher than in our population. I am not quite sure where those
numbers came from because I cannot think that our patients are worse than the overall
population. He made a big emphasis that timing is critical in bolusing for meals. He suggested
that half of the meal bolus should be given over the first 30 minutes and all should be given over
the first 60 minutes. He reported also that 65% of patients on pumps missed more than one meal
bolus per week. It increased the hemoglobin A1c by 0.5% if a patient misses two boluses per
week. I have been mentioning this for years and maybe quoting an expert will be helpful. It is
simply impossible to maintain good control and miss boluses. An interesting point was made
also that if you place the continuous glucose monitor sensor on an area of lipohypertrophy, it has
no effect on the accuracy of the monitor. Maybe we should do this frequently because then
patients will not give insulin into the lipohypertrophy. Please look at the section on insulins as
to why I say this. He went through some of the closed loop studies that I have already quoted so
I will not repeat that. He mentioned the problem with glucagon in the bi-hormonal pumps and
that the glucagon has still not been FDA approved. It turns out that it was eating the tubing but
now they have new tubing which is resistant to its effect. Finally, he pointed out that we can
improve continuous glucose monitoring use if we set wider alarms initially so that patients are
not bombarded with rings. He also said that CGM is much better when patients have better
education. I am afraid that all of us jump to new technology quickly and assume that it is
relatively easily managed. Again we should consider that full education is a critical part of
using any of these devices properly.
Self Blood Glucose Monitoring
Just as I reported with insulin pumps, there were few studies presented on self blood
glucose monitoring this year. I suspect that it stems from the fact that there were no new meters
out this year and also that continuous glucose monitoring is much sexier. People want to devote
their time to the new kid on the block rather than the old timer. The first study that I wanted to
report was from San Diego and looked at the imprecision of self blood glucose monitoring
values used for continuous glucose monitoring calibration, comparing optimal conditions and
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home use. They pointed out that real time continuous glucose monitoring requires twice daily
calibrations with self monitored blood glucose values that the patients obtain at home. Thus the
accuracy of the continuous glucose monitor is dependent on the accuracy of the meter used.
They compared the differences between two initial calibration self blood glucose monitoring
values performed during clinic sessions in which subjects washed their hands, were instructed on
proper blood application and used fresh strips versus home use. In the studies there were 69
adults and 24 pediatric patients. They did not report what meters were being used but since there
were 11,026 finger stick pairs evaluated I suspect that there were a variety of meters. They
found that subjects in the clinical study demonstrated errors of greater than 10%, 7.6% of the
time and greater than 20%, 3.3% of the time. During home use the subjects demonstrated an
error of greater than 10%, 17.6% of the time and greater than 20%, 3.6% of the time. They
concluded “patients self blood glucose monitoring testing demonstrates significantly more
variability at home than when conducted in the optimized clinical environment highlighting the
lack of precision of self blood glucose monitoring during actual use”. This is an interesting
thought. Since the CGM is based on self blood glucose monitoring, we may be compounding
errors more than we like to admit. Another study from Boston looked at the comparative
accuracy of 17 different glucometers. This was done in a clinic setting where the results were
compared to the lab machinery. They compared the results to ISO 2003 criteria and then ISO
2013 criteria which demand a smaller error than it did in 2003. They found that seven of the 17
meters met ISO 2003 criteria for accuracy but only two met ISO 2013 criteria. I am afraid that
the chart is going to be very difficult to read but you can look at the overall graph. If you look at
the chart underneath, you can figure out which meter they are reporting.
The Contour Next had the most accurate reading with OneTouch Verio third and FreeStyle
Freedom Lite fourth. The OneTouch Ultra2 was well down the line as was the Bayer Breeze.
The ReliOn was very close to the bottom. Those are the main meters that our patients are using.
Blood glucose monitoring has been a staple since the early 1980s. With each new generation,
the accuracy is better but we still have significant problems. Fortunately the main meters that
we use (the OneTouch Verio and the FreeStyle Freedom) were among the best meters. Many of
those other meters, I have never heard of or very rarely use. Another study from Spain
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compared the Contour Next, FreeStyle InsuLinx and OneTouch Verio IQ using error grid
analyses and an insulin dosing error model. I am not going through the gruesome statistics but
what they found was that the Contour Next demonstrated the highest accuracy of the meters.
Another study from San Diego looked at the accuracy of six different monitoring systems,
looking at Accu-Chek Active, Accu-Chek Performa, Contour, FreeStyle Lite, OnCall Vivid and
OneTouch Ultra2 meters. They were again comparing it with the lab glucose results. They
found “the results showed that more than 95% of results were within plus or minus 15% of the
comparison method at results greater than 100 mg/dL or within plus or minus 15 mg/dL of the
comparison method at results less than 100 mg/dL for Accu-Chek Active, Accu-Chek Performa,
and OnCall Vivid but less than 95% of results satisfied the same criteria for Contour, FreeStyle
Lite and OneTouch Ultra”. They did point out, however, that all of the systems in the study
showed 100% of the results within zones A and B of the Clarke Error Grid. Unfortunately they
did not study the OneTouch Verio that most of our patients are now using. In the previous study
it was more accurate than the OneTouch Ultra2. Nevertheless, these results again show that we
are not as close as we really want to be or should be. Our meters are still not meeting the
criteria of the organizing bodies that monitor these kinds of things. Fortunately, the new
generation Dexcom continuous monitor that will be out in probably one to two years (the Gen6
or 7 model) will be accurate enough that it no longer will require blood glucose calibration. I
am not sure that it will be more accurate than the blood glucose meters but at least we will not
have compounded errors with an initial error from the self blood glucose monitoring and then
with the continuous glucose monitor. That was all that I could find on continuous glucose
monitoring so you can see that it was not a topic of interest this year.
Social Media and Making Sense of Technology
I need you to understand from the beginning that I am the worst person in the world to be
reporting on these aspects of the meetings. As many of you know, I have a flip top phone that I
can charge once a year and survive. I use it so infrequently that it never runs down. It has no
apps and cannot text nor receives texts. This should give you an idea of my ability as I wade
through these next few sessions.
The Council on Youth in Diabetes met on Sunday at lunch and the topic this year was an
update of social media. Joyce Lee is the social media editor of Jama Ped. She talked about
Nightscout which many of you know is an app that can be used with Dexcom so that parents can
have real time surveillance of their child’s continuous glucose monitoring readings. It was
started by John Kostick who had a 4-year-old son with diabetes and was frustrated waiting for
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Dexcom to get through the FDA with their Share program. His hash tag was #wearenotwaiting.
It now allows continuous glucose monitoring in the cloud and there are 12,000 members. It is
parent run and there are volunteers monitoring 24 hours per day. The parents created their own
app and the FDA approved it two months ago. She said that diabetes needs more patient-topatient involvement. It needs to be active, collaborative and open. There are many very bright
parents who can create solutions to problems for which industry has to take much longer to deal.
She mentioned that there are some closed loop pump systems being run by parents already
although she discouraged this use since they really do not know all of the pitfalls. She did point
out that Nightscout finally allows patients and parents to sleep at night; thus there is a
tremendous benefit. Jeff Hitchcock discussed the web as a resource from a patient and parent
perspective. He said the reason the parents reach out is for support (to get answers to real life
questions), self expression (oftentimes catharsis) and advocacy. Many reach out because they
want to be involved in research. He mentioned several different online sites of interest. First
was Children with Diabetes which is an online magazine for kids, families and adults. It has
various websites and forums. It is free and anonymous. He said that something like this is
important because if you just google, “Type I diabetes in children,” you will pull up 41,900,000
results. He mentioned TuDiabetes.org, diaTribe.org, youandthisproject.com, insulinnation.com
and a few others that I was not able to write down quickly enough. He states that Facebook has
just exploded with diabetes. You must petition to join and he warned that some administrators
are capricious and that people are not always who they say they are. He mentioned the
“disinhibition effect” which means that many people respond online on about the level of a
seventh grade recess. He also wanted to emphasize once again that what works for one person
may not work whatsoever for another. He warned that the internet is forever and can be tracked
down. His recommendation was to give the child a false name when involved in these forums.
George Serbedzija talked primarily about MyGlu.org. This is a site put up by the Type I
Diabetes Exchange and is now about two years old. I mentioned it in the handout two years ago
but I do not know how many patients are taking advantage of it. You need to know that you do
not have to be a member of the Type I Registry in order to participate. There are about 13,500
participants, 8,000 of which are patients with Type I diabetes and 3,500 of which are parents and
guardians. It has continuous monitors to make sure that the exchange is civil and has some basis
in reality. They include a number of articles on various topics. There are open forums to parents
and children. They list a question of the day which sounds very interesting. They also have
closed forums on sports and fitness and parents with children and they give updates on research.
They have a one-on-one with Dr. Nick (I am not quite sure who Dr. Nick is but was assured that
it is a valid program) and there is quite a bit of data collection that can be obtained through
MyGlu. They oftentimes have study recruitments and they have research surveys. The thing
that he emphasized most was the term “sharenting” which is parents sharing information. This
enables parents to learn what not to do in particular situations, worry less about things that they
might be concerned about and to get advice from more experienced parents. I have been a big
believer in MyGlu.org since its inception. As you can tell, I am not one who goes and
participates in forums or needs to violently express my opinions each time. I do like to lurk at
times, however, and can learn quite a bit even if I do not actively participate. I think that this
one in particular is useful for our parents and patients and should be used. The other resources
that I listed earlier certainly have their place but I cannot specifically address them myself and
everyone will need to see what they offer and see if it is what they would like.
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Early on in the early afternoon on Friday there was a symposium on using technology for
better outcomes. First to speak was Kelly Close, MBA who is the editor of diaTribe.org. Her
goal is to have a patient perspective in all of the changes that go on in diabetes management. She
pointed out several things from a parent’s standpoint: 1) hypoglycemia is the limiting factor in
glycemic management point blank, 2) a hemoglobin A1c alone is not sufficient but time in range
indicates much more stability than a hemoglobin A1c by itself, 3) patients need to evaluate who
is excluded from studies because this can oftentimes bias the results. She stated that mental
health provision is horribly underfunded and should be a goal for all national planners. She also
felt that we need to better allocate resources to help those who are at risk. We need face-to-face
contact for those at higher risk whereas email and text oftentimes is sufficient for the well
controlled. Margaret Powers, PhD from the International Diabetes Center in Minneapolis talked
about what to do with all that data? Using the ambulatory glucose profile. She emphasized
patient log books which we still use. She also emphasized meter downloads and continuous
glucose monitoring downloads. Again, she emphasized that a hemoglobin A1c does not tell the
whole story. The data really needs to include food, exercise and medication. She emphasized
(as I have many times to you) that the more a patients tests the blood sugar, the lower drops the
hemoglobin A1c. She mentioned a study where patients began testing seven times per day and
the average hemoglobin A1c dropped from 8.5% to 7.5%. She emphasized that what we really
need is a standard report for glucose data which would include all the different meters so that
they all provided the same information. She is working on one now called the Ambulatory
Glucose Profile which organizes glucose data and makes it into a standard and easily understood
report. It includes 1) a visual display showing the variability over a 24-hour period (as she
pointed out, this is usually due to carb counting difficulties). It would 2) include a daily view so
that patients could compare day-to-day and 3) it would have a statistical summary showing
glucose exposure and glucose variability and would include glucose ranges and the number in
target. This system would summarize key glucose data and would have a dynamic display which
can be changed with changing targets. It would not be owned by any device company but would
be used by all and most importantly would be easy to read and interpret. This system should be
used for both continuous glucose monitoring and self blood glucose monitoring. Their plan is to
have it so it could be placed in a kiosk and could be downloaded in one to two minutes. The
ultimate goal of course is better understanding of glucose variations and to give the patient more
confidence in managing their own diabetes. This system is only in study mode now but
hopefully will become available in the next couple of years. It is extremely frustrating when we
try to download various pumps and various meters and monitors. We get a different type of data
from each one of them and it makes it very difficult to compare patient to patient. I think this
type of system would be very nice if all of the companies would agree. I think that agreement
will be very difficult to come by, however.
Chandra Osborn, PhD looked at using technology for patient engagement and education.
The message I got from her was that it is very hard to evaluate since research moves slowly but
technology changes quickly. Just as they start to evaluate one form of technology it becomes
obsolete and everyone is moving on to the next one. Finally, Tara Cushman, RN talked about
Choosing Continuous Glucose Monitoring-What Patients Need to Know to Make a Good
Personal Choice. I did not make many notes from this talk since it was all very self-evident. She
did point out, however, that CGM is not for everyone because there can be information overload
that can be very difficult for patients. She said the ones who most need CGM are 1) those not
meeting A1c goals (I think that would be about 60% of our patients), 2) those who keep glucose
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