The Art and Science of Insulin

1
The Art and Science of Insulin

• Thomas Repas D.O.
• Diabetes, Endocrinology and Nutrition Center,
  Affinity Medical Group, Neenah, Wisconsin
• Member, Inpatient Diabetes Management Committee,
  St. Elizabeths Hospital, Appleton, WI
• Member, Diabetes Advisory Group, Wisconsin
  Diabetes Prevention and Control Program

Website www.endocrinology-online.com
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Overview

• Goals and Purpose of Insulin Therapy
• Barriers to the use of Insulin
• Current Concepts in Insulin Therapy
• Basal/Bolus Insulin
• Sliding Scales
• Insulin Pump Therapy
• Future of Insulin
• Conclusion

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Purpose of Insulin Therapy

• Prevent and treat fasting and postprandial
  hyperglycemia
• Permit appropriate utilization of glucose and
  other nutrients by peripheral tissues
• Suppress hepatic glucose production
• Prevent acute complications of uncontrolled
  diabetes
• Prevent long term complications of chronic
  diabetes

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The Goal of Insulin TherapyAttempt to Mimic
Normal Pancreatic Function
Schade, Skyler, Santiago, Rizza, Intensive
Insulin Therapy, 1993, p. 131.
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WHAT!? Did you say INSULIN?!
Barriers to the Use of Insulin
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Patient Concerns About Insulin

• Fear of injections
• Perceived significance of need for insulin
• Worries that insulin could worsen diabetes
• Concerns about hypoglycemia
• Complexity of regimens

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Help Patient Accept and Prepare for Insulin
Therapy

• Address patient concerns
• Dispel fear by countering misconceptions
• Review rationale for insulin use
• Explain that insulin
• Can be incorporated into lifestyle
• Causes only modest weight gain
• Is a common course of treatment for this
  progressive disease
• Promise patient support and close follow-up
• Monitoring can prevent hypoglycemia
• Todays technology can facilitate daily
  injections and readings

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Barriers to Insulin Therapy Common Medical
Concerns

• Insulin therapy in type 2 diabetes might cause
• Worsening Insulin Resistance?
• More Cardiovascular Risk?
• Weight Gain ?
• Hypoglycemia?

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10
Insulin Sensitivity in Glucose Clamp Studies
Improved by Insulin Treatment
Baseline
After Insulin
100
87
80
80
67
57
60
53
Glucose Disposal of Matched Control Values
40
40
20
0
Garvey
Andrews
Scarlett
Scarlett, et al. Diabetes Care. 19825353-363
Andrews, et al. Diabetes. 198433634-642
Garvey, et al. Diabetes. 198534222-234.
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11
Cardiovascular RiskMortality After MI Reduced by
Insulin Therapy in the DIGAMI Study
IV Insulin 48 hours, then
4 injections daily
All Subjects
.7
.7
Low-risk and Not Previously on Insulin
(N 620)
(N 272)
.6
.6
Risk reduction (51)
Risk reduction (28)
.5
.5
P .011
P .0004
.4
.4
.3
.3
.2
.2
.1
.1
0
0
0
1
2
3
4
5
0
1
2
3
4
5
Years of Follow-up
Years of Follow-up
Malmberg, et al. BMJ. 19973141512-1515.
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Reassurance About Common Concerns

• Insulin Therapy in Type 2 DM
• Improves Insulin Sensitivity by Reducing
  Glucotoxicity
• Reduces Cardiovascular Risk
• Causes Modest Weight Gain
• Rarely Causes Severe Hypoglycemia
• Patients fears and concerns can be addressed by
  education

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Current Concepts in Insulin Therapy
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Comparison of Human Insulins and Analogues

• Insulin Onset of Duration ofPreparations
  Action Peak Action
• Lispro/Aspart 5-15 minutes 1-2 hours 3-5 hours
• Human Regular 30-60 minutes 2-4 hours 4-8 hours
• Human NPH/Lente 1-4 hours 4-12 hours 10-20 hours
• HumanUltralente 6-8 hours Unpredictable 16-20
  hours
• Glargine 2-3 hours Flat 24 hours

The time course of action of any insulin may vary
in different individuals, or at different times
in the same individual. Because of this
variation, time periods indicated here should be
considered general guidelines only.
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Twice-daily Split-mixed Regimens
Regular
NPH
Insulin Effect
B
S
L
HS
B
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Multiple Daily Injections (MDI)NPH Regular
NPH at AM and HS Regular AC
NPH at HS Regular AC
Regular
Regular
NPH
NPH
Insulin Effect
Insulin Effect
B
S
L
HS
B
B
S
L
HS
B
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Multiple Daily Injections (MDI)Ultralente
Regular
Regular
Ultralente
Insulin Effect
B
S
L
HS
B
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Limitations of Human Regular Insulin

• Slow onset of action
• Requires inconvenient administration 20 to 40
  minutes prior to meal
• Risk of hypoglycemia if meal is further delayed
• Mismatch with postprandial hyperglycemic peak
• Long duration of activity
• Up to 12 hours duration
• Increased at higher dosages
• Potential for late postprandial hypoglycemia

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• Basal and Bolus Insulins

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The Basal/Bolus Insulin Concept

• Basal Insulin
• Suppresses glucose production between meals and
  overnight
• Nearly constant levels
• 50 of daily needs
• Bolus Insulin (Mealtime or Prandial)
• Limits hyperglycemia after meals
• Immediate rise and sharp peak at 1 hour
• 10 to 20 of total daily insulin requirement at
  each meal

Ideally, for insulin replacement therapy, each
component should come from a different insulin
with a specific profile
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Insulin and Glucose Patterns Normal and Type 2
Diabetes
Normal
Type 2 Diabetes
Glucose
Insulin
400
120
100
300
80
mg/dL
?U/mL
200
60
40
100
20
0600
1000
1800
1400
0200
2200
0600
0600
1000
1800
1400
0200
2200
0600
B
L
S
B
L
S
Time of Day
Time of Day
Polonsky, et al. N Engl J Med. 19883181231-1239.
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Rapid-acting Analogues Clinical Features

• Insulin profile more closely mimics normal
  physiology
• Convenient administration immediately prior to
  meals
• Faster onset of action
• Limit postprandial hyperglycemic peaks
• Shorter duration of activity
• Reduced late postprandial hypoglycemia
• But more frequent late postprandial hyperglycemia
  
• Need for basal insulin replacement revealed

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Rapid-acting Insulin Analogues Lispro and Aspart
400
500
Aspart
Lispro
450
350
400
300
350
250
300
250
200
Plasma Insulin (pmol/L)
Plasma Insulin (pmol/L)
Regular
200
150
Human
150
Regular
100
100
Human
50
50
0
0
0
30
60
90
120
180
210
150
240
0
50
100
150
200
300
250
Time (min)
Time (min)
Meal SC injection
Meal SC injection
Heinemann, et al. Diabet Med. 199613625-629
Mudaliar, et al. Diabetes Care. 1999221501-1506.
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Multiple Daily Injections (MDI)NPH Mealtime
Lispro
NPH at AM and HS Lispro AC
NPH at HS Lispro AC
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Limitations of Human NPH, Lente, and Ultralente

• Do not mimic basal insulin profile
• Variable absorption
• Pronounced peaks
• Less than 24-hour duration of action
• Cause unpredictable hypoglycemia
• Major factor limiting insulin adjustments
• More weight gain

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The Quest for Basal Insulin Replacement
Mealtime Lispro NPH and NPH at HS
Lispro
NPH
Insulin Effect
B
S
L
HS
B
Bolli, et al. Diabetologia. 1999 421151-1167.
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The Ideal Basal Insulin . . .

• Mimics normal pancreatic basal insulin secretion
• Long-lasting effect around 24 hours
• Smooth, peakless profile
• Reproducible and predictable effects
• Reduced risk of nocturnal hypoglycemia
• Once-daily administration for convenience

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Profiles of Various Basal Insulins
SCsubcutaneous CSIIcontinuous subcutaneous
insulin infusion Lepore M et al. Diabetes.
2000492142-2148.
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Long-Acting Insulins Ultralente and Glargine

• Ultralente
• Injected once or twice daily
• Onset within 68 hours
• Peak effect within 1020 hours
• Glargine
• 24-hour, long-acting recombinant human insulin
  analogue has no peak
• Cannot be diluted or mixed with other insulins or
  solutions
• Administered once daily
• In combination therapy, glargine given at
  bedtime rapid- or short-acting given during the
  day

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Glargine vs NPH Insulin in Type 1 DiabetesAction
Profiles by Glucose Clamp
6
5
4
NPH
Glucose Utilization Rate (mg/kg/h)
3
2
Glargine
1
0
0
10
20
30
Time (h) After SC Injection
End of observation period
Lepore, et al. Diabetes. 199948(suppl 1)A97.
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Bedtime Glargine vs NPH, With Mealtime Regular
4
48
Glargine
NPH
3
36

Patients ()
2
24
1
12
Baseline
Baseline
8.5

1
8.8

1
11.1

4
10.6

4
0
0

?1


?2

Nocturnal
FPG
HbA1c
()
Hypoglycemia
(mmol/L)
P lt .01 (change from baseline to endpoint
within each group)P lt .02 (compared to
NPH) Rosenstock, et al. Diabetes. 199948(suppl
1)A100.
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Bedtime Glargine vs NPH, With Mealtime Regular
48
4
Glargine
NPH
36
3

24
2
Weight (kg)
Patients ()
12
1

0
0
Nocturnal
Weight Gain
Hypoglycemia
P lt .0007P lt .02 (compared to
NPH) Rosenstock, et al. Diabetes. 199948(suppl
1)A100.
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Insulin GlargineSummary of Completed Trials

• Glucose-insulin clamp studies of Glargine vs NPH
• Smooth, continuous release from injection site
• Longer duration of action with effect for about
  24 hours
• Peakless profile
• Equivalent absorption rates at various injection
  sites
• Clinical efficacy equivalent to NPH, with
  significantly less nocturnal hypoglycemia

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• All
• Type 1 diabetics should be on a
• basal / bolus insulin regimen
• to control glucose while minimizing hypoglycemia

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• However over time,
• most type 2 diabetics will also need
• both basal and mealtime insulin
• to control glucose

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Beginning Insulin Therapy
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When Oral Medications Are Not Enough

• Watch for the following signs
• Increasing BG levels
• Elevated A1C
• Unexplained weight loss
• Traces of ketonuria
• Poor energy level
• Sleep disturbances
• Polydipsia
• Next steps
• Make a decision to start insulin
• Offer patient encouragement, not blame

Remind the patient of disease progression
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Natural History of Type 2 Diabetes
IGT
Frank Diabetes
NGT
Normal Blood Glucose
Risk of Microvascular Complications
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Initiating Insulin Therapy in Type 2 Diabetes

• Let blood glucose levels guide choice of insulins
• Select type(s) of insulin and timing of
  injection(s) based on pattern of patients sugar
  (fasting, lunch, dinner, bedtime)
• Choose from currently available insulin
  preparations
• Rapid-acting (mealtime) lispro, aspart
• Short-acting (mealtime) regular insulin
• Intermediate-acting (background) NPH, lente
• Long-acting (background) ultralente, glargine
• Insulin mixtures
• Provide long-acting or intermediate-acting as
  basal
• and rapid-acting as bolus
• Titrate every week

Goal to approximate endogenous insulin secretion
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Starting With Basal Insulin Advantages

• 1 injection with no mixing
• Slow, safe, and simple titration
• Low dosage
• Limited weight gain
• Effective improvement in glycemic control

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Glargine at HS Oral Agents or Mealtime Lispro
TZD
lispro
Metformin
Glargine
Glargine
Insulin Effect
Insulin Effect
B
S
L
HS
B
B
S
L
HS
B
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Starting with Basal Insulin

• Continue oral agent(s) at same dosage (eventually
  stop secretegogue)
• Add single, evening insulin dose (around 10 U)
• Glargine (bedtime or anytime?)
• NPH (bedtime)
• 70/30 (evening meal) or 75/25
• Adjust dose by fasting BG
• Increase insulin dose weekly as needed
• Increase 4 U if FBG gt140 mg/dL
• Increase 2 U if FBG 120 to 140 mg/dL
• Treat to target (usually lt120 mg/dL)

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Advancing Bolus/ Adding Bolus Insulin

• Indicated when FBG acceptable but
• HbA1c not at goal and/or
• Postprandial BG not at goal (lt140mg/dl)
• Insulin options
• To Glargine, add mealtime Regular or Lispro
• To bedtime NPH, add morning NPH and mealtime
  Regular or Lispro
• To suppertime 70/30 or 75/25, add morning 70/30
  or 75/25
• Oral agent considerations
• Usually stop secretagogue (it is redundant to be
  on insulin and secretagogue)
• Continue metformin and TZD for additional
  glycemic and other benefits

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Changing from Other regimens to Basal/Bolus
Insulin
Total Daily Dose (70-75 of prior insulin
regimen TDD)
50 Basal
50 Bolus
Usually divided into 3 premeal doses
Range 40 to 60
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An Example

• Mr. M 58 yo with history type 2 diabetes for 8
  years
• In addition to oral meds, he is on 70/30 insulin
  30 u AM and 15 u PM
• Current Total Daily Dose 45 u of 70/30
• However, he has been having difficulty with wide
  glycemic excursions
• After discussing his options in detail, he is
  willing to begin basal/bolus regimen
• New TDD 45 u x .75 33.75 34 u
• Basal 17 u Lantus at bedtime
• Bolus 17 u total / 3 5.6 u 5 u Humalog with
  meals

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Another method

• Same patient Mr. M on 70/30 insulin 30 u AM and
  15 u PM
• Current Total Daily Dose 45 u of 70/30
• Instead, some clinicians prefer to instead
  calculate the new basal/bolus doses independently
  of each other
• Current Basal 0.70 x 45 u TDD 31.5 u N
• Current Bolus 0.30 x 45 u TDD 13.5 u R
• Then, use 70 to 75 of prior NPH, but divide
  prior short acting into 3 premeal doses
• New Basal 0.75 x 31.5 u N 24 u Lantus
• New Bolus 13.5 u R / 3 4.5 u (round up or
  down) premeal Humalog

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So which method is best?

• This is where the Art of Medicine comes in
• If patient has been having difficulty with
  hypoglycemia, then start any new insulin regimen
  with conservative doses
• If patient, on the other hand, has been having
  hyperglycemia, then one can be more aggressive

Remember every patient is an individual!
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Fine Tuning of Bolus Doses
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Bolus Dose Insulin

• Premeal boluses
• Taken before meals
• Covers mealtime carbohydrate intake
• Prevents postprandial hyperglycemia
• Correction or supplementation boluses
• Used to Correct and treat hyperglycemia
• May be given alone between meals for
  hyperglycemia
• May be given to supplement already scheduled
  insulin to cover premeal hyperglycemia

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Calculation of Premeal Bolus Doses

• Methods
• Estimate patients individual insulin-to carb
  ratio
• Formula 500 Rule
• Weight based Method

Bode et al Diabetes Care 1994 19 324-7
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Determination of Insulin to Carb Ratio Method 1

• EXAMPLE Estimate 1 unit of insulin 15 gm carb
• Note 1 unit 15 gm is often a safe starting
  point
• for most patients . . .

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Determination of Insulin to Carb Ratio Method 2

• Use the 500 Rule
• Divide 500 by TDD 1 unit insulin to ___ gm CHO
  as bolus
• EXAMPLE 500 34 u 15
• Bolus ratio is 1 u insulin 15 gm CHO

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Determination of Insulin to Carb Ratio Method 3
Weight Based Method
Walsh, Pumping Insulin, 2nd ed.
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Premeal Insulin and Carb Counting
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Macronutrient Conversion to Blood Glucose
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Carbohydrate Counting

• Benefits
• Allows for variation in appetite and preferences
• Increases variety of food choices
• Can be used to match insulin bolus doses to food
  intake

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Carb Counting and Insulin Bolusing
Insulin-to-Carb Ratio EXAMPLE 1 unit insulin
15 grams CHO

• Sample Meal
• 1 c. orange juice 30 g
• 2 slices toast 30 g
• ½ c. oatmeal 15 g
• 1 soft-cooked egg
• 1 tsp margarine
• Coffee 1 T cream
• _____________________
• Total CHO 75 g
• Insulin bolus 5 units

• Sample Meal
• 2 slices wheat bread 30 g
• 2 oz. turkey breast
• Lettuce leaf, tomato slice
• 1 tsp mayonnaise
• 6-8 3-ring pretzels 15 g
• 2 small choc cookies 15 g
• Diet soda, 16 oz__________
• Total CHO 60 g
• Insulin bolus 4 units

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Fine Tuning Meal Bolus Doses

• Adjust bolus based on post-meal BGs
• Carbohydrate counting or pre-determined meal
  portion
• Individualize insulin to carbohydrate dose or
  insulin to premeal dose

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Correction Boluses for Hyperglycemia
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Correction Bolus Insulin

• To be taken to correct for hyperglycemia
• Based on insulin sensitivity factor
• Goal is for correction bolus to lower blood
  glucose to within 30 to 50 mg/dl of target value

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Insulin Sensitivity Factor
Use to ? high blood glucose

• 1 unit of insulin will ? blood glucose by
  mg/dl
• Regular 1500 Rule
• Humalog 1800 Rule
• 1500 or 1800 divided by TDD amount of
  blood glucose lowered by 1 unit insulin

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Insulin Sensitivity Factor

• EXAMPLE
• TDD is 34 units
• 1500 Rule 1500 34 44
• 1 unit of Regular ? bg 44 mg/dl
• 1800 Rule 1800 34 53
• 1 unit of Humalog ? bg 53 mg/dl

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Combining Correction and Premeal Boluses

• If a patients insulin to carb ratio is 115gm
  and the insulin correction factor is 1 50 mg/dl
  and their premeal BG goal is lt 110 mg/dl..

• What dose of Humalog would you give premeal if
  their actual premeal BG 210 mg/dl and they are
  about to eat a turkey sandwich (30 gms carbs)?
• 210 mg/dl 110 mg/dl 100/50 2 u for
  correction
• 30 gms carbs/15 2 u for mealtime carb coverage
• Premeal total insulin bolus dose 4 u

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A Quick Word on using Sliding Scale Insulin.

• Dont!

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Instead of Sliding Scale....
Think Supplementation or Correction Scale

• Basal insulin is necessary even in the fasting
  state
• Sliding scales do not provide physiologic insulin
  needs
• Sliding scales often result in chasing of
  blood sugars
• There can be wide glycemic excursions

Remember Just because a diabetics FBG is lt150
does not mean that they need no insulin!
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The Solution

• In acutely ill hospitalized diabetics use
  continuous IV insulin

• If one must use an insulin scale in an outpatient
  or stable inpatient setting

• Insulin scale should only supplement a routine
  scheduled regimen of basal and premeal insulin
• May use to correct for hyperglycemia between
  scheduled doses of insulin
• It should NEVER be ordered such that the scale is
  the only source of insulin for the patient

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• The Future
• of
• Insulin Therapy

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The Future of Insulin

• Inhaled Insulin Exubra, others
• Oral / Buccal Insulin Oralin
• New basal insulin Insulin Detemir
• New Rapid Acting Insulin Analogue
• Other Closed Loop Systems (Artificial pancreas)

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Oral Agents Mealtime Inhaled Insulin Effect on
HbA1c
Oral Agents
Oral Agents Alone
Inhaled Insulin
10
9
?2.3
8

HbA1c ()
7
6
5
Baseline
Follow-up
Baseline
Follow-up
(0)
(12)
(0)
(12)
Weeks
P lt .001 Weiss, et al. Diabetes. 199948(suppl
1)A12.
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Summary Insulin Therapy

• Replaces complete lack of insulin in type 1
  diabetes
• Supplements progressive deficiency in type 2
  diabetes
• Basal insulin added to oral agents can be used to
  start
• Full replacement requires basal-bolus regimen
• Hypoglycemia and weight gain are main medical
  risks
• New insulin analogues and injection devices
  facilitate use