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. Elizabeth’s Hospital, Appleton, WI
Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program
Website: www.endocrinology-online.com
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
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
The Goal of Insulin Therapy:
Attempt to Mimic Normal Pancreatic Function
B
L
S
HS
160
140
PLASMA
GLUCOSE
m g/dl
120
100
80
60
75
60
PLASMA FREE
INSULIN
u/m l
40
30
15
0
330
1130 1530
Schade, Skyler, Santiago, Rizza, “Intensive Insulin Therapy,” 1993, p. 131.
1930 2330 0330 0730
HOURS
WHAT!?
Did you say
INSULIN?!
Barriers to
the Use of
Insulin
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
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
– Today’s technology can facilitate daily injections and readings
Barriers to Insulin Therapy :
Common Medical Concerns
Insulin therapy in type 2 diabetes might cause:
• Worsening Insulin Resistance?
• More Cardiovascular Risk?
• Weight Gain ?
• Hypoglycemia?
6-8
Insulin Sensitivity in Glucose Clamp Studies:
Improved by Insulin Treatment
Baseline
After Insulin
Glucose Disposal
% of Matched Control Values
100
87
80
80
60
67
57
53
40
40
20
0
Scarlett
Andrews
Garvey
Scarlett, et al. Diabetes Care. 1982;5:353-363; Andrews, et al. Diabetes. 1984;33:634-642; Garvey, et al. Diabetes.
1985;34:222-234.
6-9
Cardiovascular Risk
Mortality After MI Reduced by Insulin Therapy in the DIGAMI Study
Standard treatment
IV Insulin 48 hours, then 4 injections daily
.7
All Subjects
.7
.6
(N = 620)
Risk reduction (28%)
P = .011
.6
.5
.4
.3
.3
.2
.2
.1
.1
0
0
1
2
3
4
Years of Follow-up
(N = 272)
Risk reduction (51%)
P = .0004
.5
.4
0
Low-risk and Not Previously on Insulin
5
0
1
2
3
4
Years of Follow-up
5
Malmberg, et al. BMJ. 1997;314:1512-1515.
6-11
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
6-15
Current Concepts in
Insulin Therapy
Comparison of Human Insulins and Analogues
Insulin
Preparations
Onset of
Action
Duration of
Action
Peak
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
Human
Ultralente
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.
6-22
Twice-daily Split-mixed Regimens
Insulin Effect
Regular
NPH
B
L
S
HS
B
6-23
Multiple Daily Injections (MDI)
NPH + Regular
NPH at AM and HS + Regular AC
NPH at HS + Regular AC
Regular
NPH
Insulin Effect
Insulin Effect
Regular
NPH
B
L
S
HS
B
B
L
S
HS
B
6-24
Multiple Daily Injections (MDI)
Ultralente + Regular
Insulin Effect
Regular
Ultralente
B
L
S
HS
B
6-25
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
6-26
Basal and Bolus Insulins
6-16
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
6-20
Insulin and Glucose Patterns: Normal and Type 2 Diabetes
Normal
Glucose
Type 2 Diabetes
400
120
100
U/mL
300
mg/dL
Insulin
200
80
60
40
100
20
0600 1000 1400 1800 2200 0200 0600
B
L
S
Time of Day
0600 1000 1400 1800 2200 0200 0600
B
L
S
Time of Day
Polonsky, et al. N Engl J Med. 1988;318:1231-1239.
6-17
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
6-27
Plasma Insulin (pmol/L)
400
Lispro
350
300
250
200
150
100
50
0
Regular
Human
0
30
Meal
SC injection
60
90 120 150 180 210 240
Time (min)
Plasma Insulin (pmol/L)
Rapid-acting Insulin Analogues: Lispro and Aspart
500
450
400
350
300
250
200
150
100
50
0
Aspart
Regular
Human
0
50
100
150 200
Time (min)
250
300
Meal
SC injection
Heinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care.
1999;22:1501-1506.
6-28
Multiple Daily Injections (MDI)
NPH + Mealtime Lispro
NPH at AM and HS + Lispro AC
NPH at HS + Lispro AC
Insulin Effect
Lispro
NPH
Insulin Effect
Lispro
NPH
B
L
S
HS
B
B
L
S
HS
B
6-29
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
6-30
The Quest for Basal Insulin Replacement
Mealtime Lispro + NPH and NPH at HS
Insulin Effect
Lispro
NPH
B
L
S
HS
B
Bolli, et al. Diabetologia. 1999; 42:1151-1167.
6-31
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
6-32
Profiles of Various Basal Insulins
4.0
mg/kg/min
NPH
24
20
3.0
Ultralente
16
CSII
2.0
12
8
1.0
4
Glargine
0
0
0
4
8
12
16
Time (h)
SC=subcutaneous; CSII=continuous subcutaneous insulin infusion
Lepore M et al. Diabetes. 2000;49:2142-2148.
20
24
µmol/kg/min
n = 20 T1DM
Mean ± SEM
SC insulin
Long-Acting Insulins:
Ultralente and Glargine
Ultralente
• Injected once or twice daily
• Onset within 6–8 hours
• Peak effect within 10–20 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
Glargine vs NPH Insulin in Type 1 Diabetes
Action Profiles by Glucose Clamp
Glucose Utilization Rate
(mg/kg/h)
6
5
4
NPH
3
2
Glargine
1
0
0
10
20
Time (h) After SC Injection
30
End of observation period
Lepore, et al. Diabetes. 1999;48(suppl 1):A97.
6-34
Bedtime Glargine vs NPH, With Mealtime Regular
4
3
**
2
1
0
1
36
24
Baseline
8.5 ± 1 8.8 ± 1
*
*
0
*
2
HbA1c
(%)
12
Baseline
11.1± 4 10.6± 4
Patients (%)
NPH
48
Glargine
*
FPG
(mmol/L)
Nocturnal
Hypoglycemia
*P < .01 (change from baseline to endpoint within each group)
**P < .02 (compared to NPH)
Rosenstock, et al. Diabetes. 1999;48(suppl 1):A100.
6-51
Bedtime Glargine vs NPH, With Mealtime Regular
48
4
Glargine
NPH
36
Weight (kg)
**
2
24
1
12
Patients (%)
3
*
0
Weight Gain
*P < .0007
**P < .02 (compared to NPH)
Nocturnal
Hypoglycemia
0
Rosenstock, et al. Diabetes. 1999;48(suppl 1):A100.
6-52
Insulin Glargine
Summary 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
6-35
All
Type 1 diabetics should be on a
basal / bolus insulin regimen
to control glucose while minimizing
hypoglycemia
6-19
However over time,
most type 2 diabetics will also need
both basal and mealtime insulin
to control glucose
6-19
Beginning Insulin Therapy
6-36
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…
Natural History of Type 2 Diabetes
Severity of Glucose Intolerance
NGT
IGT
Frank
Diabetes
Insulin
Resistance
Insulin Secretion
Postprandial Glucose
Normal Blood
Glucose
Risk of Microvascular Complications
Risk of Macrovascular Complications
Years to
Decades
Typical Diagnosis of Diabetes
Worsens
with Time
Initiating Insulin Therapy in Type 2 Diabetes
•
Let blood glucose levels guide choice of insulins
–
•
Choose from currently available insulin preparations
–
–
–
–
–
•
•
Select type(s) of insulin and timing of injection(s) based on pattern of
patient’s sugar (fasting, lunch, dinner, bedtime)
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…
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
6-37
Glargine at HS + Oral Agents or Mealtime Lispro
TZD
lispro
Metformin
Glargine
Insulin Effect
Insulin Effect
Glargine
B
L
S
HS
B
B
L
S
HS
B
6-56
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 >140 mg/dL
– Increase 2 U if FBG = 120 to 140 mg/dL
• Treat to target (usually <120 mg/dL)
6-59
Advancing Bolus/ Adding Bolus Insulin
• Indicated when FBG acceptable but
– HbA1c not at goal
and/or
– Postprandial BG not at goal (<140mg/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
6-60
Changing from Other regimens to
Basal/Bolus Insulin
Total Daily Dose
(~70-75% of prior insulin regimen TDD)
~50%
~50%
Basal*
Bolus*
Usually divided into 3 premeal doses
*Range: 40 to 60%
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
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
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!
Fine Tuning of Bolus Doses
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
Calculation of Premeal Bolus Doses
Methods
1.
Estimate patient’s individual insulin-to carb ratio
2.
Formula: 500 Rule
3.
Weight based Method
* Bode
et al: Diabetes Care 1994: 19: 324-7
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 . . .
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
Determination of Insulin to Carb Ratio: Method 3
Weight (lb)
Insulin u: CHO gm *
100-109
1: 16
110-129
1: 15
130-139
1: 14
140-149
1: 13
150-169
1: 12
170-179
1: 11
180-189
1: 10
190-199
1: 9
200+
1: 8
Weight Based Method
*Walsh, Pumping Insulin,
2nd
ed.
Premeal Insulin and Carb
Counting
Macronutrient Conversion to Blood
Glucose
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
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
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
Correction Boluses for
Hyperglycemia
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
Insulin Sensitivity Factor
Use to  high blood glucose
1 unit of insulin will  blood glucose by:
Regular:
Humalog:
mg/dl
1500 Rule
1800 Rule
1500 or 1800 divided by TDD= amount of blood glucose
lowered by 1 unit insulin
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
Combining Correction and Premeal Boluses
If a patient’s insulin to carb ratio is 1:15gm and the insulin
correction factor is 1: 50 mg/dl and their premeal BG goal
is < 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
A Quick Word on using Sliding
Scale Insulin….
Don’t!
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 diabetic’s FBG is <150
does not mean that they need no insulin!
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
The Future
of
Insulin Therapy
6-53
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)
6-54
Oral Agents + Mealtime Inhaled Insulin: Effect on HbA1c
Oral Agents Alone
Oral Agents +
Inhaled Insulin
10
HbA1c (%)
9
2.3%
*
8
7
6
5
Baseline Follow-up
(0)
(12)
Baseline Follow-up
(0)
(12)
Weeks
*P < .001
Weiss, et al. Diabetes. 1999;48(suppl 1):A12.
6-55
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