intensive insulin treatment issues in type 1 diabetes · intensive insulin treatment issues in type...
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Intensive Insulin Treatment Issues in Type 1 Diabetes
Jay S. Skyler, MD, MACPJay S. Skyler, MD, MACPDivision of Endocrinology, Diabetes, and MetabolismDivision of Endocrinology, Diabetes, and Metabolism
and Diabetes Research Instituteand Diabetes Research InstituteUniversity of Miami Miller School of MedicineUniversity of Miami Miller School of Medicine
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Commercial InterestsCommercial Interests• Board of Directors Member –Dexcom, Moerae Matrix, Paean
Therapeutics, VasoPrep Surgical• Scientific Advisory Board Member –
Diavacs, Halozyme, Orgenesis, Sekris, Valeritas, Viacyte
• Advisor or Consultant –Boheringer Ingelheim, Bristol-Myers Squibb/Astra-Zeneca, Elcelyx, Eli Lilly, Ideal Life, Intarcia, Julphar, Roche, Sanofi
• Stock or Option Holder –
Dexcom, Ideal Life, Moerae Matrix, Paean Therapeutics, Patton Medical Devices, Tandem Diabetes Care, VasoPrep Surgical
• Research Support (to University of Miami) –
Halozyme, Mesoblast
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• Intensive Management of Type 1 Diabetes: Moshé
Phillip• How Big (Hypoglycemia) Is an Issue in T1D: Hans DeVries• Real Life Diabetes Management Issues Internist’s Perspective:
Richard Bergenstal• Real Life Diabetes Management Issues Pediatrician’s
Perspective: Desmond Schatz• Steps to a Perfect Close-Loop: Irl B. Hirsch• DREAM Project: Moshé
Phillip• Future of AP at Home: Hans DeVries • Role of CGM in Diabetes: Irl B. Hirsch• Role of SMBG and CGM –
REACT Study: Richard Bergenstal• New Basal and Prandial Insulin: Robert Ratner
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Evolution ofEvolution of Intensive Insulin TherapyIntensive Insulin Therapy
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Canadian Medical Association Journal 1922;12:141Canadian Medical Association Journal 1922;12:141--146. 146.
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Toronto Daily Star, March 22, 1922.Toronto Daily Star, March 22, 1922.
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RD Lawrence, 1925RD Lawrence, 1925
““The temperament and usual habits of the patient The temperament and usual habits of the patient should be considered in the type of treatment chosen should be considered in the type of treatment chosen and our object should be to interfere with these as and our object should be to interfere with these as little as is compatible with healthlittle as is compatible with health……
I know that full I know that full
physiological control of severe diabetes physiological control of severe diabetes –– the most the most
continuously normal blood sugar and the least continuously normal blood sugar and the least hypoglycaemia hypoglycaemia ––
can be best obtained with 4can be best obtained with 4––6 small 6 small
injections of soluble insulin in the 24 hoursinjections of soluble insulin in the 24 hours……
RD Lawrence. Diabetic Life, 1st edn. London: J & A Churchill LtdRD Lawrence. Diabetic Life, 1st edn. London: J & A Churchill Ltd, 1925 , 1925
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Characteristics of Insulin PreparationsCharacteristics of Insulin Preparations
Purity of PreparationPurity of Preparation
Species of OriginSpecies of Origin
ConcentrationConcentration
Time Course of ActionTime Course of Action
OnsetOnset
PeakPeak
DurationDuration
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Advances in Insulin PreparationsAdvances in Insulin Preparations
Protamine insulinate Protamine insulinate -- 19361936
Protamine zinc insulin Protamine zinc insulin -- 19361936
Surfen insulin Surfen insulin -- 19381938
Globin insulin Globin insulin -- 19391939
Phenylcarbomoyl insulin Phenylcarbomoyl insulin -- 19441944
Isophane (NPH) insulin Isophane (NPH) insulin -- 19461946
Lente insulins Lente insulins -- 19511951
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Traditional Insulin PreparationsTraditional Insulin Preparations
ShortShort--actingacting
Regular (Soluble)Regular (Soluble)IntermediateIntermediate--actingacting
NPH (Isophane)NPH (Isophane)
Lente (Insulin Zinc Suspension)Lente (Insulin Zinc Suspension)LongLong--actingacting
Ultralente (Extended Insulin Zinc Suspension)Ultralente (Extended Insulin Zinc Suspension)
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Protein Components in Insulin Preparations Pre-1972
%
Insulin Other
92%
8%
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Purity of Insulin PreparationsPurity of Insulin Preparations
PreparationPreparation
Proinsulin ContentProinsulin Content(ppm)(ppm)
Conventional USPConventional USP
10,00010,000--40,00040,000““Single PeakSingle Peak””
300300--30003000
““Improved Single PeakImproved Single Peak””
< 50< 50““Single ComponentSingle Component””
< 10< 10
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mg
% o
r U
/ml
mg
% o
r U
/ml
100100
00
1212 66 1212 66 1212
GLUCOSEGLUCOSE
INSULININSULIN
Breakfast Lunch Tea DinnerBreakfast Lunch Tea Dinner
Components of Insulin SecretionComponents of Insulin Secretion• Meal Related•• Meal RelatedMeal Related• Basal•• BasalBasal
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Components of Insulin SecretionComponents of Insulin Secretion
Meal relatedMeal related
BasalBasal
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Physiologic Serum Insulin Physiologic Serum Insulin Secretion ProfileSecretion Profile
4:004:00
2525
5050
7575
8:008:00 12:0012:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
Plasma Plasma Insulin Insulin
((µµU/mL) U/mL)
TimeTime8:008:00
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4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
8:008:0012:0012:008:008:00
TimeTime
REGREG REGREGNPHNPHNPHNPH
Classical Classical ““SplitSplit--MixedMixed”” Treatment ProgramTreatment Program
Plasma Plasma InsulinInsulin
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GLUCOSEGLUCOSE
INSULININSULINmU/LmU/L
mg/dLmg/dL
100100
001212 66 1212 66 1212
BreakfastBreakfast LunchLunch SnackSnack DinnerDinner
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4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
8:008:0012:0012:008:008:00TimeTime
REGREG REGREG
NPHNPHNPHNPH
““SplitSplit--MixedMixed”” Program WithProgram With
Bedtime Intermediate InsulinBedtime Intermediate Insulin
Plasma Plasma InsulinInsulin
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Typical Treatment ProgramTypical Treatment Program circa 1970circa 1970
•• Single Daily Injection Single Daily Injection -- NPH or LenteNPH or Lente
(Mixed Beef(Mixed Beef--Pork Pork -- U40 or U80) U40 or U80) ––
2424--25 g25 g
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Typical Treatment ProgramTypical Treatment Program circa 1970circa 1970
•• Single Daily Injection Single Daily Injection -- NPH or LenteNPH or Lente
(Mixed Beef(Mixed Beef--Pork Pork -- U40 or U80) U40 or U80) ––
2424--25 g25 g
•• Meal Plan Meal Plan -- 3 meals, 3 snacks 3 meals, 3 snacks --
40% 40%
carbohyrate, 40% fat, 20% protein carbohyrate, 40% fat, 20% protein -- never skip meals, always eat on timenever skip meals, always eat on time
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ENERGY ENERGY SOURCESOURCE(FOOD)(FOOD)
ENERGYENERGYUTILIZATIONUTILIZATION(ACTIVITY)(ACTIVITY)
INSULININSULIN
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Typical Treatment ProgramTypical Treatment Program circa 1970circa 1970
•• Single Daily Injection Single Daily Injection -- NPH or LenteNPH or Lente
(Mixed Beef(Mixed Beef--Pork Pork -- U40 or U80) U40 or U80) ––
2424--25 g25 g
•• Meal Plan Meal Plan -- 3 meals, 3 snacks 3 meals, 3 snacks --
40% 40%
carbohyrate, 40% fat, 20% protein carbohyrate, 40% fat, 20% protein -- never skip meals, always eat on timenever skip meals, always eat on time
•• Urine Glucose TestingUrine Glucose Testing (first void or (first void or ““double voiddouble void””
?)?)
(Clinitest tablets with dropper)(Clinitest tablets with dropper)
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Urine Glucose Testing ApproachesUrine Glucose Testing Approaches
0% 2%
Red cuprous oxide
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4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
Plasma Plasma InsulinInsulin
8:008:0012:0012:008:008:00TimeTime
REGREG REGREGNPHNPHNPHNPH
Classical Classical ““SplitSplit--MixedMixed”” Treatment ProgramTreatment Program
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Typical Treatment ProgramTypical Treatment Program circa 1976circa 1976
•• SplitSplit--Mixed Insulin ScheduleMixed Insulin Schedule (Mixed Beef(Mixed Beef--Pork or Pure PorkPork or Pure Pork--
U100)U100)
•• Meal plan Meal plan -- 3 meals, 3 snacks 3 meals, 3 snacks --
4040--60% 60%
carbohyrate, 30% fat, 10carbohyrate, 30% fat, 10--20% protein20% protein•• Urine glucose testingUrine glucose testing
(first void or (first void or ““double voiddouble void”” ?)?)
(Clinitest tablets or Glucose oxidase (Clinitest tablets or Glucose oxidase test strips)test strips)
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Could messy urine be avoided?Could messy urine be avoided?
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Ted Danowski and colleagues
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Diabetes Care. 1978 Jan 1; 1(1):27-33.
The First Article on SMBG
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Karl Sussman – Patients WOULD NOT do it
Philip Felig – Patients COULD NOT do it
Leonard Madison – Patients SHOULD NOT do it
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4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
Plasma Plasma InsulinInsulin
8:008:0012:0012:008:008:00TimeTime
REGREG REGREGNPHNPHNPHNPH
Classical Classical ““SplitSplit--MixedMixed”” Treatment ProgramTreatment Program
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4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
8:008:0012:0012:008:008:00TimeTime
REGREG REGREG
NPHNPHNPHNPH
““SplitSplit--MixedMixed”” Program WithProgram With
Bedtime Intermediate InsulinBedtime Intermediate Insulin
Plasma Plasma InsulinInsulin
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Basal/Bolus Insulin Absorption Pattern:Basal/Bolus Insulin Absorption Pattern:Standard Insulin PreparationsStandard Insulin Preparations
4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
8:008:0012:0012:008:008:00TimeTime
REGREG REGREGREGREG
NPHNPH
Plasma Plasma InsulinInsulin
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Basal/Bolus Insulin Absorption Pattern:Basal/Bolus Insulin Absorption Pattern:Standard Insulin PreparationsStandard Insulin Preparations
4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
8:008:0012:0012:008:008:00TimeTime
REGREG REGREGREGREG
NPHNPHNPHNPH
Plasma Plasma InsulinInsulin
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Intensive Insulin TherapyIntensive Insulin Therapy
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System of Intensive Therapy of Type 1 DiabetesSystem of Intensive Therapy of Type 1 Diabetes
1. Multiple Component Insulin Program1. Multiple Component Insulin Program2. Careful Balance of Food Intake, Activity, & Insulin Dosage2. Careful Balance of Food Intake, Activity, & Insulin Dosage3. Daily Self3. Daily Self--monitoring of Blood Glucosemonitoring of Blood Glucose4. Planned Patient Alterations of Food Intake and of Insulin 4. Planned Patient Alterations of Food Intake and of Insulin
Dosage & TimingDosage & Timing5. Defined Target Blood Glucose Levels (Individualized)5. Defined Target Blood Glucose Levels (Individualized)6. Frequent Contact Between Patient and Staff6. Frequent Contact Between Patient and Staff7. Patient Education & Motivation7. Patient Education & Motivation8. Psychological Support8. Psychological Support9. Assessment (A1c)9. Assessment (A1c)
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HbA1cHbA1c•• Integrated Measure of Glycemic ControlIntegrated Measure of Glycemic Control•• Correlates with Mean Blood GlucoseCorrelates with Mean Blood Glucose•• Patient Independent Assessment ToolPatient Independent Assessment Tool•• Facilitates ControlFacilitates Control•• Predicts ComplicationsPredicts Complications•• Reflects Tissue ChangesReflects Tissue Changes
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Rate of progression of
retinopathy (per 100
patient-years)
5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5
A1c (%)
Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-986.
0
2
4
6
8
10
DCCT: Absolute Risk of Sustained Retinopathy DCCT: Absolute Risk of Sustained Retinopathy Progression by Mean A1cProgression by Mean A1c
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DCCT. N Engl J Med 1993;329:977DCCT. N Engl J Med 1993;329:977--8686
DCCT: Absolute Risk of Severe DCCT: Absolute Risk of Severe Hypoglycemia by Mean A1cHypoglycemia by Mean A1c
Rat
e of
sev
ere
Hyp
ogly
cem
ia(p
er 1
00 p
atie
nt-y
ears
)R
ate
of s
ever
e H
ypog
lyce
mia
(per
100
pat
ient
-yea
rs)
2020
4040
6060
8080
120120
100100
Glycosylated Hemoglobin (%)Glycosylated Hemoglobin (%)
005.05.0 10.510.55.55.5 6.06.0 6.56.5 7.07.0 7.57.5 8.08.0 8.58.5 9.09.0 9.59.5 10.010.0
DCCT: 1986 to 1993DCCT: 1986 to 1993
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Flexible Insulin TherapyFlexible Insulin Therapy
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Principles of Flexible TherapyPrinciples of Flexible Therapy
Patient lifestyle determines treatment Patient lifestyle determines treatment programprogram
Meal pattern totally flexibleMeal pattern totally flexible——including including number of meals, timing of meals, content of number of meals, timing of meals, content of meals, variations from day to daymeals, variations from day to day
Unrestricted activity patternUnrestricted activity pattern——totally flexible, totally flexible, including sporadic exerciseincluding sporadic exercise
Unrestrained creativity in treatment optionsUnrestrained creativity in treatment options
Insulin program should be tailored to patient Insulin program should be tailored to patient lifestyle on ongoing basislifestyle on ongoing basis
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4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
Ideal Basal/Bolus Insulin Ideal Basal/Bolus Insulin Absorption PatternAbsorption Pattern
8:008:0012:0012:008:008:00TimeTime
Plasma Plasma InsulinInsulin
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Advances in Insulin PreparationsAdvances in Insulin Preparations
Protamine insulinate Protamine insulinate -- 19361936
Protamine zinc insulin Protamine zinc insulin -- 19361936
Surfen insulin Surfen insulin -- 19381938
Globin insulin Globin insulin -- 19391939
Phenylcarbomoyl insulin Phenylcarbomoyl insulin -- 19441944
Isophane (NPH) insulin Isophane (NPH) insulin -- 19461946
Lente insulins Lente insulins –– 19511951
Rapid Acting Insulin Analogs Rapid Acting Insulin Analogs –– 1995 1995
Basal Insulin Analogs Basal Insulin Analogs –– 2000 2000
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4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
RapidRapid--acting Insulin Analogs Provideacting Insulin Analogs ProvideIdeal Prandial Insulin ProfileIdeal Prandial Insulin Profile
8:008:0012:0012:008:008:00TimeTime
Lispro Lispro LisproLispro Lispro LisproAspart Aspart AspartAspart Aspart Aspart
oror orororor
Glulisine Glulisine GlulisineGlulisine Glulisine Glulisineoror ororororPlasma Plasma
InsulinInsulin
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Four Questions Before Each MealFour Questions Before Each Meal
1.1.
What is my blood glucose level now?What is my blood glucose level now?2.2.
Do I plan to eat a larger or smaller Do I plan to eat a larger or smaller meal than usual?meal than usual?
3.3.
Will I be more or less active than Will I be more or less active than usual?usual?
4.4.
What has happened previously in What has happened previously in these circumstances?these circumstances?
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4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
Ideal Basal/Bolus Insulin Ideal Basal/Bolus Insulin Absorption PatternAbsorption Pattern
8:008:0012:0012:008:008:00TimeTime
Plasma Plasma InsulinInsulin
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4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
Plasma Plasma InsulinInsulin
LongLong--acting Insulin Analogs Provideacting Insulin Analogs ProvideIdeal Basal Insulin ProfileIdeal Basal Insulin Profile
8:008:0012:0012:008:008:00TimeTime
GlargineGlargineoror
DetemirDetemir
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4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
8:008:0012:0012:008:008:00TimeTime
GlargineGlargineoror
DetemirDetemir
Basal/Bolus Treatment Program WithBasal/Bolus Treatment Program With RapidRapid--acting and Longacting and Long--acting Analogsacting Analogs
Lispro Lispro LisproLispro Lispro LisproAspart Aspart AspartAspart Aspart Aspart
oror orororor
Glulisine Glulisine GlulisineGlulisine Glulisine Glulisineoror ororororPlasma Plasma
InsulinInsulin
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4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
8:008:0012:0012:008:008:00TimeTime
Basal/Bolus Treatment Program WithBasal/Bolus Treatment Program With RapidRapid--acting and Longacting and Long--acting Analogsacting Analogs
Plasma Plasma InsulinInsulin
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4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
8:008:0012:0012:008:008:00TimeTime
Basal/Bolus Treatment Program WithBasal/Bolus Treatment Program With RapidRapid--acting and Longacting and Long--acting Analogsacting Analogs
Plasma Plasma InsulinInsulin
SnackSnack
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4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
Variable Basal Rate ContinuousVariable Basal Rate ContinuousSubcutaneous Insulin Infusion (CSII) ProgramSubcutaneous Insulin Infusion (CSII) Program
8:008:0012:0012:008:008:00TimeTime
Basal InfusionBasal Infusion
BolusBolus BolusBolus BolusBolusPlasma Plasma InsulinInsulin
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Dexcom G4 PlatinumDexcom G4 PlatinumContinuous Glucose MonitorContinuous Glucose Monitor
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Change in A1c from Baseline to 26 Weeks in Change in A1c from Baseline to 26 Weeks in ≥≥7.0% HbA1c Cohort7.0% HbA1c Cohort
-0.50
0.02
-0.18 -0.21
-0.37
-0.22
-0.6-0.5-0.4-0.3-0.2-0.1
00.1
CGM Control CGM Control CGM Control
P<0.001P<0.001≥≥ 25 yr olds25 yr olds 1515--24 yr olds24 yr olds 88--14 yr olds14 yr olds
P=0.52P=0.52 P=0.29P=0.29
Cha
nge
in H
bA1c
Cha
nge
in H
bA1c
New Engl J Med 2008: 359: 1464New Engl J Med 2008: 359: 1464--14761476
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Diabetes Care. 2009;32:1947-5193.
0.2
0.1
0
-0.1
-0.2
-0.3
-0.4
-0.5
-0.6
-0.7
-0.8
P = 0.02P = 0.002
P <0.001
n = 1
n = 6 n = 43 n = 10 n = 29 n = 17 n = 7 n = 21 n = 28
Age ≥25 Age 15-24 Age 8-14
Change in A1C by Sensor UseC
hang
e in
A1C
Age (Years)
<4.0 days/week sensor use4.0-<6.0 days/week sensor use≥6.0 days/week sensor use
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DCCT. N Engl J Med 1993;329:977DCCT. N Engl J Med 1993;329:977--8686
DCCT: Absolute Risk of Severe DCCT: Absolute Risk of Severe Hypoglycemia by Mean A1cHypoglycemia by Mean A1c
Rat
e of
sev
ere
Hyp
ogly
cem
ia(p
er 1
00 p
atie
nt-y
ears
)R
ate
of s
ever
e H
ypog
lyce
mia
(per
100
pat
ient
-yea
rs)
2020
4040
6060
8080
120120
100100
Glycosylated Hemoglobin (%)Glycosylated Hemoglobin (%)
005.05.0 10.510.55.55.5 6.06.0 6.56.5 7.07.0 7.57.5 8.08.0 8.58.5 9.09.0 9.59.5 10.010.0
DCCT: 1986 to 1993DCCT: 1986 to 1993
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DCCT: 1986 to 1993DCCT: 1986 to 1993
DCCT. N Engl J Med 1993;329:977DCCT. N Engl J Med 1993;329:977--8686
Two Eras of Diabetes ManagementTwo Eras of Diabetes Management
Rat
e of
sev
ere
Hyp
ogly
cem
ia(p
er 1
00 p
atie
nt-y
ears
)R
ate
of s
ever
e H
ypog
lyce
mia
(per
100
pat
ient
-yea
rs)
2020
4040
6060
8080
120120
100100
Glycosylated Hemoglobin (%)Glycosylated Hemoglobin (%)
005.05.0 10.510.55.55.5 6.06.0 6.56.5 7.07.0 7.57.5 8.08.0 8.58.5 9.09.0 9.59.5 10.010.0
Control Group Control Group 20062006--20072007JDRF CGM StudyJDRF CGM Study
♦♦
JDRF. N Engl J Med JDRF. N Engl J Med 2008;359:14642008;359:1464--7676
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■■■■
♦♦
■■♦♦ ♦♦
DCCT. N Engl J Med 1993;329:977DCCT. N Engl J Med 1993;329:977--86; JDRF. N Engl J Med 86; JDRF. N Engl J Med 2008;359:14642008;359:1464--76; Diabetes Care 2009: 32:137876; Diabetes Care 2009: 32:1378--1383 1383
Impact of Continuous Glucose Monitoring on Rate Impact of Continuous Glucose Monitoring on Rate of Severe Hypoglycemia Compared to DCCTof Severe Hypoglycemia Compared to DCCT
Rat
e of
sev
ere
Hyp
ogly
cem
ia(p
er 1
00 p
atie
nt-y
ears
)R
ate
of s
ever
e H
ypog
lyce
mia
(per
100
pat
ient
-yea
rs)
2020
4040
6060
8080
120120
100100
Glycosylated Hemoglobin (%)Glycosylated Hemoglobin (%)
005.05.0 10.510.55.55.5 6.06.0 6.56.5 7.07.0 7.57.5 8.08.0 8.58.5 9.09.0 9.59.5 10.010.0
■■ Age Age ≥≥ 25 years with A1C < 7.0% 25 years with A1C < 7.0% ■■ Age 8Age 8--14 years with A1C < 7.0 % 14 years with A1C < 7.0 % ■■ Age 15Age 15--24 years with A1C < 7.0% 24 years with A1C < 7.0% ♦♦ Age Age ≥≥ 25 years with A1C 25 years with A1C ≥≥ 7.0%7.0%♦♦ Age 15Age 15--24 years with A1C 24 years with A1C ≥≥ 7.0% 7.0% ♦♦ Age 8Age 8--14 years with A1C 14 years with A1C ≥≥ 7.0%7.0%
♦♦
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Intensive Insulin TherapyIntensive Insulin Therapy WeWe’’ve Come A Long Wayve Come A Long Way