The Art and Science of The Art and Science of InsulinInsulin
Thomas Repas D.O.Thomas Repas D.O.Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, WisconsinDiabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin
Member, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WIMember, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WIMember, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program
Website: www.endocrinology-online.comWebsite: 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:The Goal of Insulin Therapy:Attempt to Mimic Normal Pancreatic FunctionAttempt to Mimic Normal Pancreatic Function
Schade, Skyler, Santiago, Rizza, “Intensive Insulin Therapy,” 1993, p. 131.
0
60
30
100
60
140
15
1930
HO URS
2330 0330 073015301130330
80
40
120
75
160
PLA SM AG LUC O SE
m g /d l
B L S HS
PLA SM A FREEIN SULIN
u/m l
WHAT!?Did you say
INSULIN?!INSULIN?!
Barriers to Barriers to the Use of the Use of
Insulin 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
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.
57
80
53
87
40
67
0
20
40
60
80
100
GarveyAndrewsScarlett
BaselineAfter Insulin
Glu
cose
Dis
pos
al%
of
Mat
ched
Con
trol
Val
ues
6-9
Cardiovascular RiskMortality After MI Reduced by Insulin Therapy in the DIGAMI Study
Malmberg, et al. BMJ. 1997;314:1512-1515.
All Subjects(N = 620)Risk reduction (28%)
P = .011
Standard treatment
0
.3
.2
.4
.7
.1
.5
.6
0 1Years of Follow-up
2 3 4 5
Low-risk and Not Previously on Insulin(N = 272)Risk reduction (51%)
P = .0004
IV Insulin 48 hours, then 4 injections daily
0
.3
.2
.4
.7
.1
.5
.6
0 1Years of Follow-up
2 3 4 5
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 Current Concepts in Insulin TherapyInsulin Therapy
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.
6-22
Twice-daily Split-mixed Regimens
Regular
NPH
B SL HS
Insu
lin
Eff
ect
B
6-23
Multiple Daily Injections (MDI)NPH + Regular
Regular NPH
NPH at AM and HS + Regular AC NPH at HS + Regular AC
Insu
lin
Eff
ect
B SL HS B
Insu
lin
Eff
ect
B SL HS B
Regular NPH
6-24
Multiple Daily Injections (MDI)Ultralente + Regular
Regular
Ultralente
B SL HS
Insu
lin
Eff
ect
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 InsulinsBasal 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
6-20
Ideally, for insulin replacement therapy, each component should come from a different insulin with a specific
profile
Insulin and Glucose Patterns: Normal and Type 2 Diabetes
Polonsky, et al. N Engl J Med. 1988;318:1231-1239.
100
200
300
400
Glucose Insulin
0600 1000 18001400 02002200 0600
Time of Day
0600 1000 18001400 02002200 0600
Time of Day
20
40
60
80
100
120
B L SB L S
Normal
Type 2 Diabetes
mg/
dL
U/m
L
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
Rapid-acting Insulin Analogues: Lispro and Aspart
400
350
300
250
200
150
100
MealSC injection
50
00 30 60
Time (min)90 120 180 210150 240
Lispro
Regular Human
500450400350300250
150
50
200
100
00 50 100
Time (min)150 200 300250
Aspart
Regular Human
Pla
sma
Insu
lin
(p
mol
/L)
Pla
sma
Insu
lin
(p
mol
/L)
MealSC 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
Insu
lin
Eff
ect
B SL HS B
Insu
lin
Eff
ect
B SL HS B
LisproNPH
LisproNPH
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
Lispro
NPH
Mealtime Lispro + NPH and NPH at HS
B SL HS
Insu
lin
Eff
ect
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
Glargine
NPH
Ultralente
CSII
n = 20 T1DMn = 20 T1DMMean Mean ± SEM± SEM
SC insulin
4.04.0
3.03.0
2.02.0
1.01.0
00
2424
2020
1616
1212
88
44
0000 44 88 1212 1616 2020 2424
Time (h)
mg
/kg
/min
mo
l/kg
/min
µ
SC=subcutaneous; CSII=continuous subcutaneous insulin infusionSC=subcutaneous; CSII=continuous subcutaneous insulin infusionLepore M et al. Lepore M et al. Diabetes.Diabetes. 2000;49:2142-2148. 2000;49:2142-2148.
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 DiabetesAction Profiles by Glucose Clamp
Lepore, et al. Diabetes. 1999;48(suppl 1):A97.
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5
4
3
2
1
00 10
Time (h) After SC Injection
End of observation period
20 30
Glargine
NPH
Glu
cose
Uti
liza
tion
Rat
e(m
g/k
g/h
)
6-34
Bedtime Glargine vs NPH, With Mealtime Regular
*P < .01 (change from baseline to endpoint within each group)**P < .02 (compared to NPH)
Rosenstock, et al. Diabetes. 1999;48(suppl 1):A100.
Baseline8.5 ± 1
* **
*
8.8 ± 1 11.1 ± 4 10.6 ± 4Baseline
4
3
2
1
0
1
2
48
36
24
12
0
NocturnalHypoglycemia
FPG(mmol/L)
HbA1c(%)
NPH Glargine
**
Patien
ts (%)
6-51
Bedtime Glargine vs NPH, With Mealtime Regular
4
3
2
1
0
48
36
24
12
0Nocturnal
HypoglycemiaWeight Gain
*
**
Wei
ght
(kg)
NPH Glargine
Patien
ts (%)
*P < .0007**P < .02 (compared to NPH)
Rosenstock, et al. Diabetes. 1999;48(suppl 1):A100.
6-52
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
6-35
AllAllType 1 diabetics should be on aType 1 diabetics should be on a
basal / bolus insulin regimenbasal / bolus insulin regimento control glucose while minimizing to control glucose while minimizing
hypoglycemiahypoglycemia
6-19
However over time,However over time,most type 2 diabetics will also needmost type 2 diabetics will also need
both basal and mealtime insulinboth basal and mealtime insulinto control glucoseto control glucose
6-19
Beginning Insulin TherapyBeginning 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…
Typical Diagnosis of Diabetes
Severity of Glucose Intolerance
Years to Decades
Normal Blood Normal Blood GlucoseGlucose
Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes
Risk of Macrovascular ComplicationsRisk of Macrovascular Complications
Insulin Insulin ResistanceResistance
IGTIGT
Insulin SecretionInsulin Secretion
Postprandial GlucosePostprandial Glucose
Risk of Microvascular ComplicationsRisk of Microvascular Complications
Fasting Blood GlucoseFasting Blood Glucose
Frank Frank DiabetesDiabetes
NGTNGT
Worsens with Time
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
patient’s 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…
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
B SL HS B
Insu
lin
Eff
ect
Metformin
Glargine
TZD
B SL HS B
lispro
Glargine
Insu
lin
Eff
ect
Glargine at HS + Oral Agents or Mealtime Lispro
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 Changing from Other regimens to Basal/Bolus InsulinBasal/Bolus Insulin
~50%
Basal*
Total Daily DoseTotal Daily Dose(~70-75% of prior insulin regimen TDD)(~70-75% of prior insulin regimen TDD)
~50%
Bolus*
Usually divided into 3 premeal dosesUsually divided into 3 premeal doses*Range: 40 to 60%*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 DosesFine 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 pointfor 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
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
Determination of Insulin to Carb Ratio: Method 3
*Walsh, Pumping Insulin, 2nd ed.Weight Based Method
Premeal Insulin and Carb Premeal Insulin and Carb CountingCounting
Macronutrient Conversion to Blood Glucose
Carbohydrate Counting
BenefitsAllows 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
Sample Meal 1 c. orange juice 30 g2 slices toast 30 g½ c. oatmeal 15 g1 soft-cooked egg1 tsp margarineCoffee & 1 T cream_____________________Total CHO: 75 gInsulin bolus: 5 units
Sample Meal2 slices wheat bread 30 g2 oz. turkey breastLettuce leaf, tomato slice1 tsp mayonnaise6-8 3-ring pretzels 15 g2 small choc cookies 15 gDiet soda, 16 oz__________Total CHO: 60 gInsulin bolus: 4 units
Insulin-to-Carb Ratio
EXAMPLE: 1 unit insulin: 15 grams CHO
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 Correction Boluses for HyperglycemiaHyperglycemia
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
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
Use to high blood glucose
Insulin Sensitivity FactorEXAMPLE
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 A Quick Word on using Sliding Scale Insulin….Scale Insulin….
Don’t!Don’t!
Instead of Sliding 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!
Think Supplementation or Correction Scale…
The Solution:
•If one must use an insulin scale in an outpatient or stable inpatient setting:
• In acutely ill hospitalized diabetics: use continuous IV insulin
• 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 FutureThe Futureof of
Insulin TherapyInsulin 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
*P < .001
Weiss, et al. Diabetes. 1999;48(suppl 1):A12.
10
9
8
7
5Baseline
(0)Follow-up
(12)
Oral Agents +Inhaled InsulinOral Agents Alone
Baseline(0)
Follow-up(12)
2.3%*
Weeks
6
Hb
A1c
(%
)
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