Continuous Glucose Monitoring System CGMS

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Continuous Glucose Monitoring System (CGMS)

• Chien-Wen Chou MD
• Division of Endocrinology Metabolism
• Chi-Mei Medical Center
• 30 June 2006

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Continuous Glucose Monitoring System

• A continuous glucose monitoring system (CGMS) is
  an FDA-approved device that records glucose
  levels throughout the day and night.
• only approved device -- Medtronic's MiniMed
  device-can provide up to 288 glucose measurements
  every 24 hours.
• The system is used to measure an average blood
  glucose for up to 3 days, while the person with
  diabetes continues daily activities at home

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How Does the Device Work? (1)

• First, a tiny glucose-sensing device called a
  "sensor" is inserted just under the skin of your
  abdomen.
• Tape is used to hold it in place.
• The sensor measures the level of glucose in the
  tissue every 10 seconds and sends the information
  via a wire to a pager-sized device called a
  "monitor" that you attach to a belt or the
  waistline of your pants.
• The system automatically records an average
  glucose value every 5 minutes for up to 72 hours.

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How Does the Device Work? (2)

• Results of at least four finger stick blood
  glucose readings taken with a standard glucose
  meter and taken at different times each day are
  entered into the monitor for calibration.
• Any insulin taken, exercise engaged in, and meals
  or snacks consumed are both entered into a
  paper-based "diary" and recorded into the monitor
  (by pushing a button to mark the time of the
  meals, medication, exercise, and other special
  event you wish to record).
• After 3 days, the sensor is removed at the
  doctor's office and the information stored in the
  CGMS is downloaded into a computer.
• The information will be presented as graphs or
  charts that can help reveal patterns of glucose
  fluctuations.

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When Is the Device Used?

• The CGMS is not intended for day-to-day
  monitoring or long-term self-care and it is not a
  replacement for standard blood glucose
  monitoring.
• The main advantage of continuous glucose
  monitoring is that it can help identify
  fluctuations and trends that would otherwise go
  unnoticed with standard HbA1c tests and
  intermittent finger stick measurements.
• For example, the device can capture dangerously
  low overnight blood glucose levels which often go
  undetected, reveal high blood sugar levels
  between meals, show early morning spikes in blood
  sugar, evaluate how diet and exercise affect
  blood sugars, or provide up to a 72-hour complete
  review of the effects of changes
• Continuous monitoring is reimbursed by Medicare
  and covered by many private insurance plans

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Continuous Glucose Monitoring Roadmap for 21st
century diabetes therapy

• David C. Klonoff, MD, FACP
• Diabetes Care 281231-1239, 2005

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Purposes

• provides information about the direction,
  magnitude, duration, frequency, and causes of
  fluctuations in blood glucose levels.
• provides much greater insight into glucose levels
  throughout the day.
• help identify and prevent unwanted periods of
  hypo- and hyperglycemia.

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Technologies (1)

• Five CGMs have been approved by the U.S. Food and
  Drug Administration (FDA) for use in the U.S. or
  carry CE marking for use in Europe.
• Continuous Glucose Monitoring System Gold (CGMS
  Gold Medtronic MiniMed, Northridge, CA)
• GlucoWatch G2 Biographer (GW2B Cygnus, Redwood
  City, CA)
• Guardian Telemetered Glucose Monitoring System
  (Medtronic MiniMed)
• GlucoDay (A. Menarini Diagnostics, Florence,
  Italy)
• Pendra (Pendragon Medical, Zurich, Switzerland)
• FreeStyle Navigator Continuous Glucose Monitor
  (Abbott Laboratories, Alameda, CA) -- premarket
  approval application has been submitted to the FDA

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Technologies (2)

• minimal invasiveness through continuous
  measurement of interstitial fluid (ISF) or with
  the
• noninvasive method of applying electromagnetic
  radiation through the skin to blood vessels in
  the body.
• bringing a sensor into contact with ISF include
  inserting an indwelling sensor subcutaneously
  (into the abdominal wall or arm) to measure ISF
  in situ or harvesting this fluid by various
  mechanisms that compromise the skin barrier and
  delivering the fluid to an external sensor
• After a warm-up period of up to 2 h and a
  device-specific calibration process, each
  devices sensor will provide a blood glucose
  reading every 110 min for up to 72 h with the
  minimally invasive technology and up to 3 months
  with the noninvasive technology.
• Results are available to the patient in real time
  or retrospectively.
• Every manufacturer of a CGM produces at least one
  model that sounds an alarm if the glucose level
  falls outside of a preset euglycemic range.

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Target Populations

• The ideal time to calibrate is either after
  fasting or at least 3 h postprandially, but not
  right after exercise or when the blood glucose
  level is likely to be rising or falling.
• Without such calibration, continuous readings may
  be inaccurate.
• Currently available CGMs that provide real-time
  readings should not be used to make therapeutic
  decisions, such as whether to dose insulin or
  eat, because they are not sufficiently accurate.
• Instead, an abnormal reading should prompt a
  finger-stick blood glucose measurement whose
  value can be acted upon.
• Patients require a thorough training program to
  calibrate and operate a CGM.

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  Accuracy (1)

• A real-time CGM can be programmed to sound an
  alarm for readings below or above a target range
• The most important use of an alarm is to detect
  unsuspected hypoglycemia (such as during sleep)
  so that glucose can be administered to prevent
  brain damage.
• There is a trade-off between an alarms
  sensitivity and specificity.
• In general, if the alarm is set to sound at a
  lower level than the hypoglycemic threshold, then
  the specificity will be good but the sensitivity
  may be poor.
• If the alarm is set to sound at a glucose level
  higher than the hypoglycemic threshold, then the
  sensitivity will be good but the specificity may
  be poor.
• The greater accuracy a continuous monitor can
  provide, the less of a trade-off is necessary

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Accuracy (2)

• The Diabetes Research in Children Network
  (DirecNet) is a U.S. network of five clinical
  centers and a coordinating center dedicated to
  researching glucose monitoring technology in
  children with type 1 diabetes
• The networks investigators, the DirecNet Study
  Group, assessed the accuracy of the first- and
  second-generation CGMS and the GW2B in children
  with type 1 diabetes in concurrently published
  studies
• The second-generation CGMS Gold, compared with
  the first-generation CGMS, had a lower median
  relative absolute difference (RAD) between CGMS
  glucose and reference serum glucose paired values
  (11 and 19, respectively)
• For the GW2B, the median RAD between GW2B glucose
  and reference serum glucose paired values was 16
  
• Similar RAD values of 21 have been reported for
  the first-generation CGMS by Kubiak et al.
• RAD values of 12.8 and 12.815.7 have been
  reported for the second-generation CGMS Gold
  system by Goldberg et al. and Guerci et al.
  respectively.

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Accuracy (3)

• The DirecNet Study Group found the CGMS Gold
  system, which is the second generation of CGMS
  technology, as well as the GW2B, which is the
  second generation of GlucoWatch technology, to
  have inversely proportional sensitivity and
  specificity rates during hypoglycemia in children
  and adolescents with type 1 diabetes.
• A series of alarm settings were selected for a
  reference blood glucose of 60 mg/dl.
• For CGMS Gold, the settings with sensitivity and
  specificity were 60 mg/dl, 49 and 42 80 mg/dl,
  84 and 36 100 mg/dl, 100 and 25 and 120
  mg/dl, 100 and 16.
• With the GW2B, the settings were 60 mg/dl, 23 and
  49 80 mg/dl, 59 and 33 100 mg/dl, 84 and 20
  and 120 mg/dl, 92 and 15.
• The authors concluded, "These data show that the
  GW2B and the CGMS do not reliably detect
  hypoglycemia.
• Both of these devices perform better at higher
  glucose levels, suggesting that they may be more
  useful in reducing HbA1c levels than in detecting
  hypoglycemia"

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Accuracy (4)

• The International Organization for
  Standardization (ISO) standards for accuracy of
  point blood glucose tests require that a sensor
  blood glucose value be within 15 mg/dl of
  reference for a reference value 75 mg/dl and
  within 20 of reference for a reference value gt75
  mg/dl.
• Sensor accuracy by this definition is expressed
  as the percentage of data pairs meeting these
  requirements.
• The DirecNet group found that for hypoglycemic
  blood glucose levels (determined by a reference
  blood glucose monitor, the OneTouch Ultra), the
  CGMS Gold met the ISO standards in only 48 of
  readings and the GW2B met these standards in only
  32 of readings
• The percentage of data points attaining ISO
  accuracy standards climbed as the blood glucose
  level rose, topping out for the highest segment
  of reference blood glucose levels (i.e., blood
  glucose values 240 mg/dl).
• In this glycemic category, the CGMS Gold and
  GW2B, respectively, met ISO accuracy for 81 and
  67 of data points.
• In a separate series of 15 healthy nondiabetic
  children undergoing continuous glucose monitoring
  over 24 h, the DirecNet Group reported that the
  median absolute difference in concentrations for
  the GW2B was 13 mg/dl and for the CGMS was 17
  mg/dl.
• Furthermore, 30 of the values from the GW2B and
  42 of the values from the CGMS deviated by gt20
  mg/dl from the reference value

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Clinical Indications (1)

• when adjusting therapy
• quantifying the response in a trial of a diabetes
  therapy
• assessing the impact of lifestyle modifications
  on glycemic control
• monitoring conditions where tighter control
  without hypoglycemia is sought (e.g., gestational
  diabetes, pediatric diabetes, in the intensive
  care unit)
• diagnosing and then preventing hypoglycemia
  (e.g., during sleep, with hypoglycemia
  unawareness)
• diagnosing and preventing postprandial
  hypoglycemia.
• facilitate adjustments in therapy to improve
  control (most important use)

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Clinical Indications (2)

• Specific therapeutic adjustments include changing
  from regular to a synthetic ultrashort-acting
  insulin analog at mealtime, changing from NPH to
  a synthetic ultralong-acting insulin once or
  twice per day, increasing or decreasing the
  mealtime insulin bolus dosage, increasing or
  decreasing the basal insulin rate, altering the
  treatment of intermittent hypoglycemia or
  hyperglycemia, changing the insulin-to-glucose
  correction algorithm for premeal hyperglycemia,
  changing the insulin-to-carbohydrate ratio at
  mealtime, changing the method for counting
  carbohydrates, changing the carbohydrate
  composition of the diet, changing the discount in
  short-acting insulin dosage for exercise,
  changing the nighttime regimen because of the
  dawn phenomenon, changing the target preprandial
  or postprandial blood glucose values, or before
  referring a patient for psychological counseling
  to improve adherence to the treatment regimen.
• The most frequent therapy adjustment by Sabbah et
  al.(out of eight adjustments) was to increase the
  mealtime bolus dosage.
• The most frequent therapy adjustment by Kaufman
  et al.(out of nine adjustments) was to modify the
  type of basal long-acting insulin.

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Advances in Glucose Monitoring

• As recently as July 2003, the FDA approved the
  first wireless combination system, consisting of
  a glucose monitor and an "intelligent" insulin
  pump (co-developed by Medtronic MiniMed and
  Becton, Dickinson and Company).
• The next phase of advances will allow insulin
  pumps to not only simply recommend proper insulin
  dosages, but actually automatically deliver them.
• More recently, in August 2005, Medtronic has
  expanded its CGMS line and announced FDA approval
  of its newest device, called the Guardian RT.
• This system works just like the MiniMed device
  but instead, displays the "real-time" glucose
  levels every five minutes. This information
  alerts the patient immediately to glucose levels
  that are too high or low, allowing for
  adjustments in therapy

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Light Waves Instead of Finger Pricks

• Several companies are developing non-invasive
  glucose monitoring devices that rely on light
  waves.
• The monitors shine infrared (or near-infrared)
  light onto the skin of the patient's forearm and
  analyse the light that is reflected back to
  determine the concentration of glucose in the
  tissue.
• The company Sensys has made progress in
  developing a commercial, portable version of an
  infrared monitor.
• Their latest model, the Sensys Medical Glucose
  Tracking System is about the size of a computer
  tower and is over 90 accurate.
• CME Telemetrix has developed a product called
  GlucoNIR, a non-invasive infrared system which
  may also be able to non-invasively measure HbA1c.
  
• Animas is developing an implantable version of an
  infrared optical sensor, intended to be implanted
  in the body for up to 5 years, but the device is
  not expected to be available until 2005.

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A Glucose-Monitoring Skin Patch

• SpectRx and Abbott Laboratories are developing a
  continuous glucose monitor which will be worn as
  a skin patch.
• This monitor would measure glucose levels in
  interstitial fluid, collected through microscopic
  holes created by a laser in the dead outer layer
  of skin, and measured through glucose oxidase
  reaction/electrical current generation in a patch
  containing a glucose sensor.
• This device is currently being assessed in human
  trials in adults and children.

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Glucose-Sensing Contact Lens

• Researchers at the University of Texas and Ciba
  Vision are developing glucose sensing contact
  lenses which are designed to be used in
  conjunction with a palm-sized light source.
• The contact lens is made using a meshwork that
  traps fluorescent molecules inside the lens.
• The patient inserts the contact lenses in the
  usual way, holds the light device up to the eye
  and activates it, sending a small burst of
  glowing light into the contact lens.
• The fluorescent molecules in the lens bind to and
  react with the glucose in the users tears.
• The device reads the wavelength of the
  fluorescence reflected from the contact lens and
  translates the reading into a measure of the
  glucose.
• Higher levels of fluorescence mean higher levels
  of glucose.
• There is a seven-minute delay before a hand-held
  device stores the glucose data.
• This device also includes an alarm that signals a
  patient if the glucose levels rise too quickly.
• Clinical trials are underway.

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A Smart Tattoo

• A collaboration between Texas AM University and
  Penn State University is developing a "smart
  tattoo" that could provide accurate blood glucose
  readings.
• Polyethylene glycol beads coated with fluorescent
  molecules are injected beneath the skin surface
  and interact with the interstitial fluid.
• In low glucose, the tattoo is highly fluorescent.
  
• In high glucose, the fluorescence beads are
  displaced by glucose binding and the overall
  fluorescence of the tattoo decreases.
• Fluorescence can be read by a detection light.
• Preliminary data in tattooed rats have yielded
  promising results.