Type 1 Diabetes Mellitus Introduction by 7uXYvB

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									Type 1 Diabetes Mellitus

      Introduction
                             Prevalence of Diabetes
                              in the United States
                            US Population: 275 Million in 2000
                    Undiagnosed
                                                                               Diagnosed
                      diabetes
                                                                             type 2 diabetes
                     5.2 million
                                                                                12 million
   Diagnosed
 type 1 diabetes
   ~1.0 million

  Type 1 diabetes
  misdiagnosed as
  type 2 diabetes
     ~1.0 million

Centers for Disease Control. Available at: http://www.cdc.gov/diabetes/pubs/estimates.htm;
EURODIAB ACE Study Group. Lancet. 2000;355:873-876; Harris MI. In: National
Diabetes Data Group. Diabetes in America. 2nd ed. Bethesda, Md: NIDDK;
1995:15-36; U.S. Census Bureau Statistical Abstract of the U.S.; 2001                          1
                      Incidence of Type 1 Diabetes

      • Incidence increasing by 3.4% per year
      • 50% of patients diagnosed before age 20 years
      • 50% of patients diagnosed after age 20 years
           – Often mistaken for type 2 diabetes—may make up 10% to 30% of
             individuals diagnosed with type 2 diabetes
           – Oral agents ineffective; insulin therapy required
           – Autoimmune process slower and possibly different
           – Can usually be confirmed by islet cell antibodies (ICA), glutamic
             acid decarboxylase antibodies (GADA), insulin antibodies (IAA),
             and/or insulinoma-2–associated antibodies (IA-2A)


EURODIAB ACE Study Group. Lancet. 2000;355:873-876;
Naik RG, Palmer JP. Curr Opin Endocrinol Diabetes. 1997;4:308-315                2
           Making the Diagnosis of Type 1 Diabetes

        Symptoms of diabetes                                 Polyuria, polydipsia,
                                                             polyphagia, diabetic
        plus                                                 ketoacidosis (DKA)
        Random plasma glucose                                200 mg/dL*
      or
        Fasting plasma glucose (FPG)                         126 mg/dL*
      or
        Oral glucose tolerance
        test (OGTT) with 2-hour value                        200 mg/dL*
      and confirmed by
        Presence of islet autoantibodies                     GADA, ICA, IA-2A, IAA
*Requires confirmation by repeat testing
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S5-S10                3
                         Differential Diagnosis
                        Type 1 and Type 2 Diabetes
                              Type 1 Diabetes         Type 2 Diabetes
Usual clinical course         Insulin-dependent       Initially non-insulin-
                                                      dependent
Usual age of onset            <20 years (but ~50%     >40 years but
                              over 20 years)          increasingly earlier
Body weight                   Usually lean            Usually obese
Clinical onset                Often acute             Subtle, slow
Ketosis-prone                 Yes                     No
Family history                15% with 1° relative   Common
Ethnicity                     Predominantly white     More common in minorities
Frequency of HLA-DR3,         Increased               Not increased
DR4, DQB1*0201, *0302
Islet autoantibodies          Present                 Absent
(GADA, ICA, IA-2A, IAA)
                                                                                  4
           Natural History of ―Pre‖–Type 1 Diabetes

                        Putative
                         trigger
-Cell                               Cellular autoimmunity
mass 100%
                                               Circulating autoantibodies (ICA, GAD65, ICA512A, IAA)

                                                            Loss of first-phase
                                                         insulin response (IVGTT)

                                                                  Abnormal glucose
                                                                  tolerance (OGTT)        Clinical
                                                                                           onset



              Genetic                   Insulitis               -Cell
           predisposition             -Cell injury          insufficiency     Diabetes

                                        Time
Eisenbarth GS. N Engl J Med. 1986;314:1360-1368                                                      5
Rationale for Intensive Therapy
      of Type 1 Diabetes

   Glucose Control Is Critical




                                  6
                         Retinopathy Progression
                                            DCCT

                                Primary Prevention Cohort
Cumulative 100%
incidence
               80%                     Intensive (n=348)
                                       Conventional (n=378)
               60%

               40%
                                                                              P<0.001

               20%

                0%
                     0     1     2      3      4      5       6   7   8   9
                                              Years
DCCT Research Group. N Engl J Med. 1993;329:977-986                                     7
              Cumulative Incidence of Nephropathy
                                           DCCT

 Cumulative              Combined Primary Prevention and Secondary
 percentage                        Intervention Cohorts
      40%          Intensive
                   Conventional
      30%
                                              Microalbuminuria              P<0.001

      20%


      10%                                                 Albuminuria
                                                                             P=0.006
       0%
            0       1       2        3       4        5      6      7   8     9
                                             Years
DCCT Research Group. N Engl J Med. 1993;329:977-986                                    8
              Risk of Progression of Microvascular
                      Complications vs A1C
                                            DCCT

 Relative 20
 risk                       Retinopathy
           15               Neuropathy
                            Microalbuminuria

           10


             5


             0
                 1      5         6         7         8      9   10   11   12

                                                  A1C (%)
A1C=hemoglobin A1c
Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254                      9
              Long-term Microvascular Risk Reduction
                        in Type 1 Diabetes
                                Combined DCCT-EDIC
                                  Intensive       Conventional
 A1C 12%                                 Retinopathy 0.5
                                         progression
                                         (incidence) 0.4
     10%
                                                      0.3


      8%                                              0.2

                                                      0.1

      6%
              P<0.001 P<0.001   P=0.61                   0
                DCCT    EDIC    EDIC                         0   1     2   3    4  5           6     7
                End of Year 1   Year 7                                 Years in EDIC
             randomized                          No. Evaluated
                                                 Conventional    169   203   220   581   158   192   200
              treatment                          Intensive       191   222   197   596   170   218   180


DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569                                                    10
              Long-term Macrovascular Risk Reduction
                        in Type 1 Diabetes
                                Combined DCCT-EDIC

 Mean change in 0.10                                         Intensive (n=618)
 intima-media                         P=0.01                 Conventional (n=611)
 thickness      0.05
 (mm)           0.00

                     -0.05

                     -0.10

                     -0.15
                                                                P=0.02
                     -0.20
                                Common carotid           Combined common and
                                   artery                 internal carotid artery
                                                    Year 6


DCCT/EDIC Research Group. N Engl J Med. 2003;348:2294-2303                          11
                  Cost-Effectiveness of Intensive
                   Therapy in Type 1 Diabetes
                             DCCT Modeling Study
                                                  Years Free From Complication
                                                       (Projected Average)
                                                Conventional         Intensive
                                                 treatment           treatment
    Proliferative retinopathy                       39.1                53.9

    Blindness                                       49.1                56.8

    Microalbuminuria                                34.5                43.7

    End-stage renal disease (ESRD)                  55.6                61.3

    Neuropathy                                      42.3                53.2

    Amputation                                      39.1                53.9


DCCT Research Group. JAMA. 1996;276:1409-1415                                    12
Principles of Intensive Therapy of
         Type 1 Diabetes

          Insulin Options




                                     13
                 Insulin Preparations

Class               Agents
Human insulins      Regular
                    Neutral protamine Hagedorn (NPH)
                    Lente, ultralente

Insulin analogues   Rapid=aspart, glulisine, lispro
                    Long=glargine, detemir

Premixed insulins   Human 70/30, 50/50
                    Humalog mix 75/25
                    Novolog mix 70/30


                                                       14
                               Action Profiles of Insulins

                Aspart, glulisine, lispro 4–5 hours
                  Regular 6–8 hours
  Glucose                   NPH 12–18 hours
  infusion
    rates                                      Detemir 12-24 hours
  in clamp
   studies
                                                                         Glargine >24 hours




               0   1   2   3   4   5   6   7    8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
                                                          Hours
Lepore M. Diabetes. 2000;49:2142-48; Porcellati F. Diabetes Care. 2007;30:2447-52;
Plank J. Diabetes Care. 2005;28: 1107-12; Mudaliar SR. Diabetes Care 1999;22:1501-06;
Becker RHA. Exp Clin Endocrinol Diab 2005;113:435-443                                              15
                Insulin Injection Devices



Insulin pens
• Faster and easier
  than syringes
  – Improve patient
    attitude and adherence
  – Have accurate dosing
    mechanisms, but
    inadequate
    resuspension of NPH
    may be a problem


                                            16
                                Insulin Pumps
     Continuous Subcutaneous Insulin Infusion (CSII)

• For motivated patients
• Expensive
• External, programmable pump
  connected to an indwelling
  subcutaneous catheter
  – Only rapid-acting insulin
  – Programmable basal rates
  – Bolus dose without extra injection
  – New pumps with dose calculator
    function
  – Bolus history
• Requires support system of qualified
  providers

                                                       17
Principles of Intensive Therapy of
         Type 1 Diabetes

 Patient Education and Counseling




                                     18
               Patient Education in Type 1 Diabetes
                    ADA National Standards for DSME*
                       *Diabetes Self-Management Education (DSME)
  Should include                        May include
  DSME team
   Patient, RN, RD, physician           Psychologist, exercise physiologist,
   (endocrinologist where               ophthalmologist, optometrist, pharmacist,
   possible)                            podiatrist, and other health care providers

  Written curriculum
    • Insulin administration            • Diabetes disease process
    • Nutritional management            • Physical activity guidance
    • Glucose monitoring                • Other monitoring (urine ketones, etc)
                                        • Prevention, detection, and treatment of
                                          complications
                                        • Goal setting and problem solving
                                        • Preconception and prenatal care
Mensing C et al. Diabetes Care. 2004;27(suppl 1):S143-S150                            19
   Type 1 Diabetes Lifestyle Considerations

      Physical Activity                  Family Dynamics
• Important for weight            • Tailor nutrition plan to fit within
  management and                    patient’s culture
  cardiovascular health
                                  • Caregiver education essential
• Adjust insulin dosing to
  compensate for activity level     for pediatric and some elderly
                                    patients
• Snack before exercise if
  needed to avoid hypoglycemia

   Psychological Support                  Barriers to Care
• Decrease risk and impact of     • Provide education and support
  associated neurobehavioral        to overcome
  problems                           – Fear of hypoglycemia
  – Depression                       – Patient/caregiver lack of
  – Anxiety                            knowledge
  – Eating disorders                 – Reimbursement challenges
                                                                          20
Integrating Insulin Therapy With Lifestyle in
              Type 1 Diabetes

      Integrate insulin with eating and exercise habits




 Intensive Insulin Therapy       Traditional Insulin Therapy




 • Flexible insulin dose          • Fixed insulin dose
 • Adjust insulin dose to         • Adjust diet and exercise
   compensate for diet              to compensate for
   and exercise                     insulin dose

                                                               21
                                    Nutrition Plan
                              ADA Recommendations

                                                           Energy Intake
      Saturated fat                                        <10%
      Protein                                              15%–20%
      Carbohydrates and                                    60%–70%
      monounsaturated fat
       – Amount of monounsaturated fat varied
         according to metabolic needs and
         weight management goals
       – Carbohydrates from whole grains,
         fruit, and vegetables
       – Total amount of carbohydrate more
         important than source or type—
         sugar acceptable in moderation

American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S36-S46     22
Principles of Intensive Therapy of
         Type 1 Diabetes

        Glucose Monitoring




                                     23
Self-Monitoring of Blood Glucose
               (SMBG)

 • Modern meters
   – Small blood volume (0.3 to 4 L)
   – Ability to use alternate sites
     (eg, arm, thigh, calf, palm)
   – Shorter results time: 5 to 10 seconds
   – Very accurate if maintained properly




                                             24
                           SMBG in Type 1 Diabetes
                        Blood Glucose Goals and Timing


                                    Goals                Timing
       Fasting                      80–120 mg/dL         Test on waking to evaluate basal
                                                         insulin
       Premeal                      70–130 mg/dL         Test before each meal to
                                                         determine bolus doses

       Peak postmeal                <180 mg/dL           Test 2 hours after a meal to
                                                         confirm adequate bolus
       10:00 PM–6:00 AM             80–120 mg/dL         Test at bedtime and/or in middle
                                                         of the night to make adjustments
                                                         in basal insulin*

*2:00–4:00 AM if nocturnal hypoglycemia is suspected
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S15-S35; Costello M.
In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker; 2002:
21-45                                                                                       25
                                  Hemoglobin A1c
                                             (A1C)

          Significance                                Reflects mean glucose
                                                      over 2 to 3 months

          Target                                      Lowest possible
                                                      without
                                                      unacceptable
                                                      hypoglycemia*

          Recommended                                 Every 3 months†
          frequency of testing

*CADRE target. ADA target <7.0%; AACE/ACE target 6.5%
†In-office fingerprick testing available, with almost immediate results


American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S91-S93        26
Complications of Insulin Therapy




                                   27
                               Hypoglycemia
                                  Risk Factors

            Patient Factors                           Behavioral Factors
•   Hypoglycemia unawareness                 • Dietary inconsistency
•   History of previous hypoglycemia           – Prolonged fasting
•   Defective glucose counterregulation        – Missed meal or snack
•   Long duration of diabetes                • Strenuous exercise
•   Erratic insulin absorption
•   Age less than 5 to 7 years


                                    Medical Factors
                        •   Drug side effects (-blockers)
                        •   Dosing errors
                        •   Unpredictable insulin kinetics
                        •   Inappropriate insulin distribution
                                                                           28
               Balancing Risk of Severe Hypoglycemia
                 Against the Risk of Complications
                                                           DCCT

                        Severe Hypoglycemia                                              Retinopathy Progression


100      120                                                       100        16

patient- 100                                                       patient-   14
years                                                              years
                                                                              12
          80
                                                                              10

          60                                                                   8

                                                                               6
          40
                                                                               4
          20
                                                                               2

           0                                                                   0
               5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5                   5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5
                                  A1C (%)                                                               A1C (%)


DCCT Research Group. N Engl J Med. 1993;329:977-986                                                                                    29
                       Treatment of Hypoglycemia

    Blood       Treatment                            Further Management
    Glucose
    (mg/dL)
    50–70       Oral carbohydrates (12–15 g) Observe for improvement


    <50         • Oral carbohydrates if              Hospitalize patient until stabilized
                  mental status permits, or          if:
                • Intramuscular injection of          • Unresponsive to treatment
                  glucagon, or                        • Persistent neuroglycopenia
                • Intravenous (IV) glucose            • Blood glucose remains
                                                        <50 mg/dL
                                                      • Patient will be alone for the next 12
                                                        hours

Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY:
Medical Information Press; 2004                                                                 30
                      Weight Gain


• Insulin therapy reverses catabolic effects of
  diabetes
   – Glycosuria reduced
   – Normal fuel-storage mechanisms restored
• Risk of hypoglycemia often causes patients to
  increase caloric intake and avoid exercise
• Risk of weight gain decreases with more
  physiologic insulin administration
   – Flexible insulin dosing to meet dietary and exercise
     needs
                                                            31
        Weight Gain With Intensive Insulin Therapy
                                              DCCT

          Body        35                     Intensive     Conventional
         mass          30                                                  *
         index         25
         (BMI) (%)
                       20
                                                             *
                       15                                                          *
                       10                       *
                         5                              *            *
                         0
                         -5              *
                       -10
     Weight  quartile               1              2            3             4
     Final BMI (kg/m2)          24       24     25 24       27 25          31 27
*P<0.001 vs baseline
Purnell JQ et al. JAMA. 1998;280:140-146                                               32
                    Lipid Changes Associated With
                       Intensive Insulin Therapy
                                                 DCCT
         mg/dL    15                Intensive                       Conventional
                                                                                        * *
                   10
                                                      *                  *    *
                    5


                    0


                   -5                                     *

                  -10       *              Triglycerides      LDL      HDL

                  -15
                        *
   Weight  quartile            1   2        3       4          1        2        3           4
   Mean A1C (%)             7.3     7.2      7.1    7.3        9.5      9.2       9.1     8.9

*P<0.01 vs baseline
Purnell JQ et al. JAMA. 1998;280:140-146                                                          33
Principles of Management of
      Type 1 Diabetes




                              34
                    Elements of Intensive Therapy

     • Multiple component insulin regimen
     • Insulin algorithm to adjust for variations in food and
       exercise
     • Frequent daily SMBG with use of correction doses of
       insulin and recording of values for trend analysis
     • Frequent patient contact
     • Patient education and motivation
     • Psychological support
     • Hemoglobin A1C to measure outcome


Hirsch I. Med Clin North Am. 1998;82:689-719                    35
           A1C Targets for Diabetes Management
                            The CADRE Position


      • Action recommended*                  A1C >7.0%
      • Target                               Lowest A1C possible
                                             without unacceptable
                                             hypoglycemia
      • Normal (nondiabetic)                 A1C ~4% to 6%




*Different targets may apply in children, the elderly, and
other patients with comorbidities                                   36
                       Glucose Targets in Diabetes


                                                                          AACE/ACE
                                      Normal         ADA Goal               Goal
    Preprandial PG                      <110            90–130              <110     mg/dL
    Postprandial (2-h) PG               <140             <180*              <140     mg/dL




*Peak value. Different targets may apply in children and the elderly
PG=plasma glucose
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S15-S35;
AACE/ACE medical guidelines. Endocr Pract. 2002; 8(suppl 1):40-82                            37
                  Normal Daily Plasma Insulin Profile
                         Nondiabetic Obese Individuals

    U/mL
           100
                          B          L                D
             80

             60

             40

             20


                  0600   0800       1200              1800   2400   0600

                                               Time of day
B=breakfast; L=lunch; D=dinner
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239                        38
   Physiologic Multiple Injection Regimens
            The Basal-Bolus Insulin Concept

• Basal insulin
   – Controls glucose production between meals and overnight
   – Near-constant levels
   – Usually ~50% of daily needs
• Bolus insulin (mealtime or prandial)
   – Limits hyperglycemia after meals
   – Immediate rise and sharp peak at 1 hour postmeal
   – 10% to 20% of total daily insulin requirement at each meal
• For ideal insulin replacement therapy, each component
  should come from a different insulin with a specific profile
  or via an insulin pump (with one insulin)

                                                                  39
                    Basal-Bolus Insulin Treatment
                              NPH + Regular Insulin

                        Regular Regular    Regular
   U/mL
           100
                          B      L            D
            80     NPH                               NPH
            60
                                                           Normal pattern
            40

            20


                 0600     0800   1200         1800         2400       0600

                                          Time of day

B=breakfast; L=lunch; D=dinner                                               40
                     Basal-Bolus Insulin Treatment
                NPH + Rapid-Acting Insulin Analogues

                      Aspart, glulisine, or lispro with each meal
 U/mL
       100                                            NPH at bedtime
                NPH B         L          D
         80

         60

         40                                                 Normal pattern
         20


              0600   0800    1200        1800       2400            0600
                                     Time of day

B=breakfast; L=lunch; D=dinner                                               41
                    Basal-Bolus Insulin Treatment
            Long- and Rapid-Acting Insulin Analogues

                       Rapid-acting insulin


                      B          L          D         Long-acting insulin




             0600    0800        1200       1800      2400        0600
                                        Time of day

B=breakfast; L=lunch; D=dinner                                              42
                    Overnight Plasma Glucose and
                       the Dawn Phenomenon
                              Glargine vs NPH Insulin
                                       47 Patients With Type 1 Diabetes
                                                                 NPH (n=24)
 Mean plasma               Injection                             Glargine (n=23)
                  220
 glucose
 (mg/dL)
                  200

                                                                                       P<0.05
                  180


                  160


                  140


                                   24:00                 04:00                     08:00
                                                 Time (hours)
Rosenstock J et al. Diabetes Care. 2000;23:1137-1142                                            43
                  Basal and Prandial Insulin Needs
                         in Type 1 Diabetes
                              Glargine vs NPH Insulin

      NPH twice daily (n=199)         Glargine once daily (n=195)     Preprandial regular insulin


                   40
   Mean daily
   insulin (IU)    35
                   30
                   25
                   20
                   15
                   10
                    5
                    0
                           Baseline        Endpoint       Baseline         Endpoint

                                 Glargine                            NPH

Hershon KS et al. Endocr Pract. 2004;10:10-17                                                       44
                    Long-term A1C Reductions With
                         Basal-Bolus Therapy
                         Glargine + Lispro vs NPH + Lispro
                                       121 Patients With Type 1 Diabetes
   Mean A1C       7.6
                                                                     NPH qid + lispro (n=60)
   ± SEM (%)
                  7.4                                                Glargine + lispro (n=61)

                  7.2

                  7.0

                  6.8                               *            *
                                                          *                          *
                  6.6
                                                                           *
                   6.4

                            0          2            4     6      8       10         12
                                                        Months
*P<0.05 vs baseline and vs NPH

Porcellati F et al. Diabet Med. 2004;21:1213-1220                                               45
                    Basal Insulin and Hypoglycemia
                               Glargine vs NPH Insulin
                               Nocturnal and Symptomatic Hypoglycemia

 Episodes per 14                         P<0.05
 patient-month
                   12                         13.2
                                                        Glargine + lispro
                   10                                    NPH + lispro
                    8

                    6              7.2

                    4                                          P<0.05

                    2                                                   3.2
                                                            1.2
                    0
                                   Symptomatic               Nocturnal

Porcellati F et al. Diabet Med. 2004;21:1213-1220                             46
                    Glucose Profiles With Different
                          Prandial Insulins
                               Aspart vs Regular Insulin
           1070 Adult Type 1 Diabetes Patients After 6 Months of Treatment

                  190                                            Aspart (n=707)
       SMBG                     *
       (mg/dL)                                                   Human insulin (n=358)
                  180
                  170
                                                           *
                  160      *                 *
                  150
                                                      *
                  140
                  130
                  120
                  110
                  100
                        Pre- Post-     Pre- Post-   Pre- Post-    Bedtime   2:00 AM
                         Breakfast       Lunch        Dinner
*P<0.01 between insulin regimens
Home PD et al. Diabet Med. 2000;17:762-770                                               47
        Mealtime Insulin and Severe Hypoglycemia
                            Aspart vs Regular Insulin

                                                        Favors
                                             Favors     Regular
                                             Aspart     Insulin    P Values
        All severe hypoglycemia                                           NS
                  Nocturnal event                                       0.076
  Nocturnal, glucagon required                                         <0.050
              4–6 hours postmeal                                       <0.005

                                      0.1           1             10
                                              Relative risk




Home PD et al. Diabet Med. 2000;17:762-770                                      48
      Typical Daily Insulin Requirements in Adults

       • Total daily dosage affected by body size, adiposity,
         physical activity, and remaining endogenous insulin
       • Daily dosage usually 0.3 to 0.8 U/kg in adults*
       • Daily dosage usually 50% basal / 50% bolus insulin
                                              Example
       Patient                                                   Dosage
       50 kg (110 lb) active                                     12–24 U/day
       70 kg (154 lb) somewhat active                            30–40 U/day
       100 kg (220 lb) obese inactive                            80–120 U/day
*Children and adolescents may need 1.0–1.5 U/kg
Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York,
NY: Marcel Dekker Inc; 2002:87-112                                              49
            Typical Insulin Distributions
 Multiple Injection Regimens With Insulin Analogues

Regimen                        Example
Glargine AM, PM, or bedtime    Glargine 18 U at bedtime
Rapid-acting analogue with     Lispro ~6 U before breakfast,
each meal                      lunch, and dinner

Detemir at PM or bedtime, or   Detemir 8 U before breakfast
in AM plus PM or bedtime       Glulisine ~6 U before breakfast,
Rapid-acting analogue with     lunch, and dinner
each meal                      Detemir 10 U at bedtime


                                                                  50
              Insulin Dose Changes
                 Pattern Adjustments

• Based on glycemic pattern over several days
• Generally change only one component of
  insulin at a time
Morning fasting glucose         Increase/decrease basal
too high/too low                 insulin by 10%
Postprandial glucose (PPG)      Adjust carbohydrate-to-
too high/too low                 insulin ratio
PPG too low                     Decrease bolus insulin
Correction dose insufficient    Adjust correction factor

                                                            51
  Adjusting Bolus and Correction Doses
          Carbohydrate-to-Insulin Ratio


Based on three questions before meals
1. How much carbohydrate am I going to eat?
2. What is my insulin dose for this amount of
   carbohydrate?
3. Should I lower the dose because I plan to be very
   active or have recently been active?




                                                       52
      Adjusting Bolus and Correction Doses
                      Correction Doses


• Individually determined                   Example
• Based on prevailing blood
                                Blood Glucose   Rapid Insulin
  glucose
                                <50 mg/dL       Decrease 2 units, or
• Questions to ask:                             consume 10–15 g
  – What is my blood glucose                    oral carbohydrate
    now?                        50–69 mg/dL     Decrease 1 unit
  – What is my target glucose   70–120 mg/dL    Usual dose
    (eg, 100 mg/dL)?            121–160 mg/dL   Increase 1 unit
  – How much insulin do I       161–200 mg/dL   Increase 2 units
    need to reach my target
    glucose?
                                                                       53
        Adjusting Bolus and Correction Doses
               Sample Correction Dose Calculation

      Target                      100 mg/dL
      Total daily insulin dose    36 U
      Correction factor           1 U lowers BG by 50 mg/dL
        ―Rule of 1800‖            (1800 ÷ 36 = 50)
      Premeal glucose             280 mg/dL



                      280 – 100 = 180 ÷ 50 = 3.6 U
                     in addition to usual mealtime
                              insulin dose

BG=blood glucose
                                                              54
 When Intensive Insulin Therapy With Target
      A1C <7% May Be Inappropriate
                   Patient Characteristics
• Lack of access to diabetes management team
• Unwillingness or inability to use flexible insulin regimen
  – Cognitive dysfunction or learning disability
  – Visual impairment
• Age <5 to 7 years
• Age >75 years with numerous comorbidities or reduced
  life expectancy
• High risk of death from hypoglycemia due to, eg, severe
  coronary, cerebrovascular, or hepatic disease
                    A1C goal: 8% to 9%

                                                               55
                        ―Traditional‖ Insulin Therapy
       Alternative to Intensive Therapy for Select Patients

                        Integrate insulin with eating and exercise habits



           Intensive Insulin Therapy                   ―Traditional‖ Insulin Therapy
    • Most patients                                • Patients with limited ability to
                                                     manage glucose


                                                   • 2- or 3-injection insulin regimen
    • Physiologic, multiple injection                with fixed insulin dose
      regimen or CSII
                                                   • Use either self-mixed or premixed
    • Adjust insulin dose to                         insulin
      compensate for diet and exercise
                                                   • Adjust diet and exercise to
                                                     compensate for insulin dose
CSII=continuous subcutaneous insulin infusion                                            56
Pharmacokinetic Barriers to Intensive Therapy


  • Differences between insulin formulations
    and regimens
  • Mixing insulins—crystallization slows
    absorption of short-acting insulin
  • Timing of premeal insulin
  • Insulin absorption variability
  • Injection sites


                                                57
               Insulin Injection Sites


• Regional differences in insulin absorption
  (variation in blood flow)
  – Abdomen > arm > buttocks > thigh
• Discourage random site rotation
  – Rotate sites within regions
  – Use specific sites for particular times of day




                                                     58
                  Continuous Subcutaneous
                    Insulin Infusion (CSII)
                   Benefits and Disadvantages
             Benefits                        Disadvantages
• Programmability                    • Risk of ketosis and DKA from
   – Meals                             interruption
   – Overnight                       • Complexity—additional patient
• Pharmacokinetic advantage            education required
   – Reproducible insulin
     absorption
   – No subcutaneous depot, so
     less exercise-related
     hypoglycemia
• Greater flexibility of lifestyle
• Fewer injections
• Control as good as multiple
  daily injections (MDIs) if not
  better
                                                                       59
                    CSII vs Multiple Daily Injections
                    Reductions in A1C and Insulin Dose

                 32 Patients With Type 1 Diabetes Previously Treated With
                                       NPH + Lispro

Baseline A1C       9.2%            8.5%
            0                                                      0
  A1C    -0.2
                                                   Insulin dose    -2               -0.9 U
 (%)                                               (units/day)     -4
          -0.4
                                  -0.6%
          -0.6                                                     -6
          -0.8                      *                              -8
                    -1%                                                   -10.3 U
          -1.0                                                    -10
          -1.2       *                                            -12        †
Achieved A1C       8.2%           7.9%

                    CSII with lispro (n=16)          MDI with glargine + lispro (n=16)


*P<0.001 vs baseline; †P<0.001 vs glargine
Lepore G et al. Diabetes Care. 2003;26:1321-1322                                             60
                    CSII vs Multiple Daily Injections
                    Reduction in Severe Hypoglycemia

                32 Patients With Type 1 Diabetes Previously Treated With
                                      NPH + Lispro
          Severe             0.5
          hypoglycemic
          episodes per       0.4
          patient/year
                             0.3

                             0.2                                         *
                                                   *
                             0.1

                               0
                                     Baseline CSII with   Baseline    MDI with
                                               lispro                glargine +
                                               (n=16)                  lispro
                                                                       (n=16)
*P<0.05 vs baseline
Lepore G et al. Diabetes Care. 2003;26:1321-1322                                  61
                CSII vs Multiple Injections of Insulin
                                      Meta-analyses

                                              Injection         Pump
                                              Therapy          Therapy
                                                Better          Better
         Blood glucose concentration
         Glycated hemoglobin
         A1C
         Insulin dose

                                      -2       -1     0      1           2
                                               Mean difference
                   Pickup et al. 12 RCTs               Weissberg-Benchell et al. 11 RCTs
RCT=randomized controlled trial
Pickup J et al. BMJ. 2002;324:1-6;
Weissberg-Benchell J et al. Diabetes Care. 2003;26:1079-1087                               62
         CSII Technologic Developments
          Since Beginning of the DCCT
• Smaller, highly reliable pumps
• Multiple basal rates; multiple bolus types
• Quick-release infusion sets
• Automatic infusion set insertion devices
• Faster acting insulins
• ―SMART‖ pumps
   – Dose calculator: carbohydrate/insulin correction dose
   – Direct transmission of bolus glucose value
   – Insulin-on-board function
   – Multiple preprogrammed basal profiles
   – Bolus history and bolus reminders

                                                             63
Pediatric Treatment Considerations




                                     64
Treating Diabetes in Children and Adolescents
         Challenges by Developmental Stage

 Infant/Toddler/Preschool        Adolescent

 Unpredictable eating            Insulin resistance
 Hypoglycemia recognition        Independence/dependence
  Risk of hypoglycemia events   Noncompliance
 Number of injections            High-risk behaviors

 Preadolescent
 Irregular appetite
 Irregular sleep activity



                                                           65
                Challenges in Intensive Therapy of
                      Adolescents vs Adults
                                  DCCT Experience

      A1C levels higher

      Adults                             7.1%
      Adolescents                        8.1%*

      Risk of severe hypoglycemia greater

      Adults                             57 events/100 patient-years
      Adolescents                        86 events/100 patient-years†
*P<0.001 vs adults; †P=0.004 vs adults
DCCT Research Group. J Pediatr. 1994;125:177-188                        66
        Overcoming Obstacles to Optimal Treatment
             in Children With Type 1 Diabetes
  Hvidøre Study
  Across 21 centers, grand mean A1C 8.67%                                 RR severe hypoglycemia
   • A1C similar to or significantly above mean                           Higher
   • A1C significantly below mean                                         Lower

  Yale Program for Children With Diabetes
  Increased education and support from diabetes                           A1C decreased by 1.6%
  care team
   • Changing treatment goals
   • Modifying insulin regimens
   • Changing patients’ and parents’ beliefs about
     acceptable glucose goals
RR=relative risk
Ahern JA et al. Diabetes Educ. 2000;26:990-994; Danne T et al. Diabetes Care. 2001;24:1342-1347    67
Elderly Treatment Considerations




                                   68
              Special Considerations in the Elderly
                      With Type 1 Diabetes

      • Intensive therapy/tight control for otherwise
        healthy elderly patients
      • Less strict glycemic goals for elderly patients
        with severe complications or comorbidities or
        with cognitive impairment
         – FPG <140 mg/dL
         – PPG <220 mg/dL



Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY: Medical
Information Press; 2004                                                              69
               Treatment Challenges in the Elderly
                     With Type 1 Diabetes
      • Lack of thirst perception predisposes to hyperosmolar state
      • Confusion of polyuria with urinary incontinence or bladder
        dysfunction
      • Increased risk of and from hypoglycemia
         – Altered perception of hypoglycemic symptoms
         – Susceptibility to serious injury from falls or accidents
      • Compounding of diabetic complications by effects of aging
      • Frequent concurrent illnesses and/or medications
      • More frequent and severe foot problems


Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY: Medical
Information Press; 2004                                                              70
Monitoring Outcomes and
 Managing Risk Factors




                          71
                                 Follow-up Visits
                         Monitoring of Target Values:
                         Cardiovascular Risk Factors
                              Frequency                   Goal

     Blood pressure           Quarterly                   <130/80 mm Hg
     HDL cholesterol          Annually (more often        >40 mg/dL, males
                              if control poor)            >50 mg/dL, females

     LDL cholesterol          Annually (more often        <100 mg/dL
                              if control poor)            May be different in young
                                                          children
     Triglycerides            Annually (more often        <150 mg/dL
                              if control poor)

     Creatinine               Annually                    <1.3 mg/dL


Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY:
Medical Information Press; 2004                                                       72
                                 Follow-up Visits
                              Quarterly Evaluations

                                 Frequency                Assessment

     General checkup             Quarterly                General health
     (including
     weight/BMI, A1C)

     Foot exam                   Quarterly                Peripheral neuropathy
                                 (or every visit)         and infection




Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY:
Medical Information Press; 2004                                                   73
                                 Follow-up Visits
                                Annual Evaluations

                              Frequency                          Assessment

  Skin examination            Annually                           Peripheral neuropathy
  Neurologic examination      Annually                           Autonomic and peripheral
                                                                 neuropathy
  Dilated eye examination     Annually (in adolescents and       Retinopathy
                              >3 years after type 1 diagnosis)
  Microalbuminuria            Annually (in adolescents and       Target <30 mg/g creatinine
                              >3 years after type 1 diagnosis)
  Cardiac examination         Annually (more often if CVD        Development/
                              present)                           progression of CVD
  Screening for other         Annually                           Thyroid disease,
  autoimmune conditions                                          celiac disease, etc
CVD=cardiovascular disease
Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY:
Medical Information Press; 2004                                                               74
    Management of Cardiovascular Risk in Diabetes
                              Blood Pressure Control

         Treatment target: Blood pressure <130/80 mm Hg
   Standard                   • Angiotensin-converting enzyme (ACE)
   methods                      inhibitor
   (1, 2, or 3 agents         • Angiotensin-receptor blocker (ARB)
   may be needed)             • Thiazide
                              • -Blocker

   Individualized             • -Adrenergic blocker or central adrenergic
   options                      agent
                              • Long-acting calcium channel blocker (CCB)
                              • Loop diuretic
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S65-S67;
Arauz-Pacheco C et al. Diabetes Care. 2002;25:134-147                        75
      Management of Cardiovascular Risk in Diabetes
                                           LDL Control


            Treatment target:                  LDL <100 mg/dL, no CVD
                                               LDL <70 mg/dL, with CVD

   Standard                    • HMG-CoA reductase inhibitors (statins)
   method
   Individualized              • Intestinal cholesterol absorption inhibitors
   options                     • Bile acid–binding resins
                               • Nicotinic acid

HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S68-S71;
Grundy SM et al. Circulation. 2004;110:227-239; Haffner SM. Diabetes Care.
1998;21:160-178; Lindgärde F. J Intern Med. 2000;248:245-254                    76
      Management of Cardiovascular Risk in Diabetes
                                   Triglyceride Control

                         Treatment target: <150 mg/dL

      Standard treatment                  Fibric acid derivative (fibrate)

      Individualized option               Nicotinic acid


                 Caution is needed with combinations
        Combining statins with fibrates or nicotinic acid can cause
        rhabdomyolysis or myositis, especially in elderly patients
                    or those with renal insufficiency


American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S68-S71;
Haffner SM. Diabetes Care. 1998;21:160-178                                   77
The Future of Type 1 Diabetes Care




                                     78
            Emerging Type 1 Diabetes Therapies

Insulins
  Aerodose®             Inhaled liquid aerosol insulin; portable device delivery

  AERx®                 Inhaled liquid aerosol insulin; portable device delivery
  Exubera®              Particulate cloud inhaled insulin; portable device
                        delivery
  Oralin®               Buccally absorbed, liquid aerosol insulin; portable
                        device delivery
  Technosphere®         Inhaled dry powder insulin; portable device delivery
  insulin
Pramlintide (Symlin®) Injectable amylin analogue; slows gastric emptying,
                      suppresses glucagon, and increases satiety
Islet cell transplant   Transplantation of donor pancreatic -cells; restores
                        endogenous insulin secretion
                                                                                   79
     Alternative Insulin Delivery Systems


Pfizer/Aventis/Nektar     Exubera (inhaled insulin)
Aradigm/NovoNordisk       AERx (NN1998)
MannKind (formerly PDC)   Technosphere insulin
Aerogen/Disetronic        Aerodose insulin inhaler
Alkermes/Lilly            AIR insulin
Kos Pharmaceuticals       Inhaled insulin
Coremed                   Alveair insulin
BMS/QDose                 Microdose DPI/Quadrant insulin
Dura/Lilly                Discontinued
Generex/Lilly             Oralin (buccal insulin)

                                                           80
                   Inhaled Insulin in Type 1 Diabetes

            73 Patients Taking Inhaled Insulin TID in Addition to Injected
                                 Long-Acting Insulin

                                                                 Subcutaneous insulin:
          A1C (%)     10
                                                                 16 U regular + 31 U
                                                                 long-acting
                       9
                                                                 Inhaled insulin:
                                                                 12 mg inhaled + 25 U ultralente
                       8


                       7


                       6
                                0           4           8   12
                                                Weeks

Skyler JS et al. Lancet. 2001;357:331-335                                                      81
Continuous Glucose Monitoring

     • Benefits of continuous glucose monitoring
       – More complete glucose profile than with
         traditional SMBG
       – Tracking of meal-related glycemic trends
       – Detection of nocturnal hypoglycemia
       – Facilitation of changes in insulin regimens
       – Alarm for highs and lows (GlucoWatch)
     • Remaining challenges
       –   Daily SMBG still required
       –   Not suited to many patients
       –   Limited accuracy, especially for hypoglycemia
       –   Glycemic pattern results confusing, subject to
           interpretation

                                                            82
                       Future Glucose Monitors

 Guardian™ CGMS                                External Closed-Loop
                        • Minimally invasive
                          continuous glucose
                          monitors
                        • Implanted glucose
                          sensors
Freestyle Navigator™                           Implanted Closed-Loop
                        • Implanted insulin
                          pumps
                        • ―Closed-loop‖
                          systems

                                                                  83
                 Can Type 1 Diabetes Be ―Cured?‖
                              Islet Cell Transplantation
            7 Type 1 Patients, Aged 29 to 54 Years, With History of Severe
                       Hypoglycemia and Metabolic Instability
Mean 9                                     Mean        6                           *
A1C                                        C-peptide                              5.7
(%)  8               8.4%                  (ng/mL)     5

                                                       4
        7
                                                       3
        6
                                                                        *
                                      *                2                2.5
                                    5.7%
        5
                                                       1
                                                             0.48
        4                                              0
                   Baseline       6 months                 Baseline   Fasting    90 min
                               after transplant                                 postmeal
                                                                            6 months
*P<0.001 vs baseline                                                     after transplant
Shapiro AMJ et al. N Engl J Med. 2000;343:230-238                                           84
                   Opportunities for Intervention in
                          Type 1 Diabetes
                                    TrialNet

                                           Multiple antibody positive
         Genetically at risk

-Cell                                                   Loss of first-phase
mass                                                     insulin response



                                                                   Newly diagnosed
                                                                   diabetes

                Genetic          Insulitis            -Cell
             predisposition    -Cell injury       insufficiency   Diabetes


                                   Time
                                                                                85

								
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