intensive insulin therapy robert e. jones, md, facp, face professor of medicine university of utah...
TRANSCRIPT
Intensive Insulin Therapy
Robert E. Jones, MD, FACP, FACE
Professor of Medicine
University of Utah School of Medicine
Objectives
1. Define intensive insulin therapy
2. Explore the basis of insulin therapeutics:• Insulin dosing (just where did the “Rule of 1700”
come from and how does it relate to my patients?)
• Insulin kinetics
3. Discover how to modify a mathematically crafted (and otherwise perfect) insulin regimen to match the needs of our patients
4. Understand that nothing is perfect
Intensive Insulin Therapy
Insu
lin E
ffe
ct
B DL HS
Bolus insulinBasal insulin
Physiologic Insulin Therapy
Adapted with permission from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
Biological Actions Of Insulin
• Glucose lowering• Anabolic properties
– Storage of lipids, protein, carbohydrate
• Anti-catabolic properties• Mitogenic properties• Growth factor• Promote endothelial function• Anti-inflammatory
Basic Insulin Regimen: Split-Mixed Regimen or Premix
Regular
NPH
B DL HS B
Endogenous insulin
Basal vs Bolus Insulin
BASAL INSULIN• Suppress hepatic glucose
production (overnight and intermeal)
• Prevent catabolism (lipid and protein)– Ketosis– Unregulated amino
acid release• Reduce glucolipotoxicity
BOLUS INSULIN• Meal-associated CHO
disposal
• Storage of nutrients
• Help suppress inter-meal hepatic glucose production
The Mathematics
The Systems
• Accurate Insulin Management– Rule of 1700– CIR
• Body Weight Only– Assumes insulin requirements are predicted
only on the basis of weight
• 400/500 Rule– CIR = 400-500/TDD
Davidson PC et al. Endocr Pract 14:1095-1101 (2008)
Accurate Insulin Management
• Combines 1700 Rule and Rule of 3
• 1500 Rule (Davidson, 1983)– Refined as 1700 Rule– CF = 1700/TDD
• Rule of 3 (Steed, 1998)– CIR = 3 * BWlb/TDD
Davidson PC et al. Endocr Pract 14:1095-1101 (2008)
Regression Models
Davidson PC et al. Endocr Pract 14:1095-1101 (2008)
Regression Models
Davidson PC et al. Endocr Pract 14:1095-1101 (2008)
Regression Models
Davidson PC et al. Endocr Pract 14:1095-1101 (2008)
Regression Models
Davidson PC et al. Endocr Pract 14:1095-1101 (2008)
Regression Models
Davidson PC et al. Endocr Pract 14:1095-1101 (2008)
AIM Equations
• When insulin requirements are known:– CF = 1700/TDD
• Glucose lowering per unit of insulin
– CIR = 2.8 * BWlb/TDD• G rams CHO covered per unit of insulin
– Basal = 0.47 * TDD
• When insulin requirements are NOT known– TDD = 0.24 * BWlb
Davidson PC et al. Endocr Pract 14:1095-1101 (2008)
Simple Equations
• TDD = Basal + Bolus (50:50)
• CF = 1700/TDD
• CIR = 0.33 * CF
UDPRs, 2008IHC Diabetes Care Model, 2010
Comparisons
Parameter Simple AIM 400/500
Eqn Result Eqn Result Eqn Result
Basal TDD*0.5 15 TDD*0.47 14.1 TDD*0.5 15
CF 1700/TDD 56.7 1700/TDD 56.7 1700/TDD 56.7
CIR CF*0.33 1:18.7 2.8*BWlb/TDD
1:14 441/TDD 1:14.7
25 year old 150 lb woman who requires 30 U/day
Comparisons
Parameter Simple AIM 400/500
Eqn Result Eqn Result Eqn Result
Basal TDD*0.5 25 TDD*0.47 23.5 TDD*0.5 25
CF 1700/TDD 34 1700/TDD 34 1700/TDD 34
CIR CF*0.33 1:11.2 2.8*BWlb/TDD
1:8.4 441/TDD 1:8.8
25 year old 150 lb woman who requires 50 U/day
Comparisons
45 year old 200 lb man who requires 110 U/day
Parameter Simple AIM 400/500
Eqn Result Eqn Result Eqn Result
Basal TDD*0.5 55 TDD*0.47 51.7 TDD*0.5 55
CF 1700/TDD 15 1700/TDD 15 1700/TDD 15
CIR CF*0.33 1:5.0 2.8*BWlb/TDD
1:5.1 441/TDD 1:4.0
Comparison Conclusions
• Equations assume everyone is average– There is a wide variability that defines
“average”
• Basal insulin requirements– No significant differences
• Bolus requirements– The “Simple Method” seems to under estimate
CIR in more insulin-sensitive patients
Insulin Kinetics
Euglycemic Hyperinsulinemic Clamp
Glu
cose
(m
g/dL
)
110
70
50
90
80
40
0
Insu
lin
(U
/mL
)
48
36
24
12 Glu
cose
Inf
usio
n R
ate
(m
ol/m
ink
g)
Time (min)80600
An IV bolus of insulin is given at time 0 followed by a constant infusion of 1 mU/min/kg or 40 mU/min/m2. Yields insulin levels of ~ 70 U/mL.
HGO is effectively suppressed (in normals) and an exogenous glucose infusion is started to maintain target glucose levels. Labeled glucose may
be used to completely assess endogenous glucose production.
Because HGO is suppressed and glucose levels are clamped, the rate of exogenous glucose infusion must equal the rate of tissue glucose uptake.
Analog Insulin Profiles
Rosenstock J. Clin Cornerstone. 2001;4:50-61.
0 2 4 6 8 10 12 14 16 18 20 22 24
Pla
sma In
sulin
Levels
Time (hr)
NPH (10–20 hr)
Regular (6–10 hr)
Glargine (~24 hr)
Aspart, Lispro, Glulisine (4–5 hr)
Detemir ~18-24hr
What Can Influence Insulin Kinetics?
Effect of Dose (Lispro) (PK)
Healthy 10 U
Obese 50 U
Obese 30 U
Obese 10 U
Gagnon-Auger M et al. Diabetes Care. E-pub Sept 14, 2010.
Effect of Dose (Lispro) (PD)
Obese 10 U
Healthy 10 U
Obese 50 U
Obese 30 U
Gagnon-Auger M et al. Diabetes Care. E-pub Sept 14, 2010.
Effect of Dose (Detemir)
Plank J et al. Diabetes Care 28:1107-1112 (2005).
Detemir
NPH 0.3 IU/kg
0.2 U/kg
0.1 U/kg
0.4 U/kg
0.8 U/kg
1.6 U/kg
1. Hedman CA et al. Diabetes Care 2001;24:1120-1121 2. Home PD et al. Eur J Clin Pharm 1999;55:199-201 3. Novo Nordisk, data on file
Time (min)-60 0 60 120 180 240 300 360 420 480 540
Aspart 1,2
Pla
sma
Insu
lin
Lev
els
Effect of Premixing on Rapid-Acting Analog Properties
Tmax 49-53 min
70/30 NovoLog Mix 3Tmax 2.4 hours
mg/dl
0.3 U/Kg NPH s.c.
Plasma Glucose908070
5.0
4.5
4.0 mm
ol/l
Lepore M. et al., unpublished data
4.0
3.0
2.0
1.0
0
24
20
16
12
8
4
0
0 1 2 3 4 5 6 7 8 9Time (hours)
µm
ol/K
g/m
in
mg/
Kg/
min
PEN UP
PEN DOWN
MIX
Effect of Insulin Suspensions on GIR
What Else Can Influence Insulin Kinetics?
• Site of injection
• Local blood flow– Exercise– Obesity
• Inherent variability
• Absentmindedness
• Effect of food
Effect of Food
Mondo Mama’s Pizza
Or Think Outside the Box...
Mondo Mama’s Pizza
Effect of Food
Mondo Mama’s Pizza
Or Think Outside the Box...
DUAL WAVE BOLUSMondo
Mama’s Pizza
Effect of Food
Mondo Mama’s Pizza
Or Think Outside the Box...
RAA + RHI (50/50 Mix)
Mondo Mama’s Pizza
Difficult Questions That Were Not Asked
• When do you split the basal insulin?– NPH– Detemir– Glargine
• How do you time a bolus in relationship to eating?
Cases
Case #1
45 year old man is seen with complaints of polyuria and polydipsia of several weeks duration. He has had an associated 30 lb weight loss. He weighs 250 pounds.
Lab results:
RBS 397 mg/dl; A1C 12.6%; Na+ 133 mEq/l; CO2 19 mEq/L
What does he have and how would you treat him?
Case #1
• The practice of medicine is an art…but we base our decisions on science (and experience)
• Oral agents?
• Insulin?– Premix– Basal only– Basal-bolus
Case #2
56 year old woman returns for follow up. She has had diabetes for 10 years and has intermittently struggled with her glucose control (A1C range 6.4 -8.8%). Her current A1C is 8.9% and her fasting glucose (SMBG) is 210 mg/dL. She is presently taking metformin 1500 mg/d, glyburide 15 mg/d; sitagliptin 100 mg/d, exenatide 10 mcg BID
How would you alter her therapy?
If you chose insulin, how would you start it?
B DL HS
Insu
lin E
ffe
ct
Metformin Basal InsulinSecretogogue
Case 2
Case 3
A 25 year old woman is sent to you because her glucose control is poor (A1C 9.7%). She really wants to improve her control, but doesn’t know how, and, by the way, she is recently married.
She is currently on 25 IU glargine per day and 5 to 15 IU aspart given before meals. She tests her glucose levels 3-4 times a day.
Florentine Arch
Hypoglycemia
Severe insulin reactions per 100 patient-yr
7.8
3
2.3
110
62
0 20 40 60 80 100 120
VA IIIP
VA CSDM
UKPDS
SDIS
DCCT Type 1 diabetes
Type 2 diabetes
Adapted with permission from McCall A. In: Leahy J, Cefalu W eds. Insulin Therapy. New York, NY:Marcel Dekker, Inc.; 2002:193
0.5
0
1
1.5
2
Weight v Delta A1C
Studies with Type 2 Diabetes
1 2 3 4
Glargine
NPH
1
14
2
2
3 3
4
2
6
5
6
5
Detemir1. Yki-Jarvinen Diabetes Care 2000;23:1131 2. Rosenstock Diabetes Care 2001;24:631 3. Riddle Diabetes Care 2003;26: 3079 4. Fritsche Ann Int Med 2003;138: 952 5.Raslova Diab Res Clin Pract 2004;66:193 6. Haak Diab Obes Clin Pract 2005;7:56 R
educ
tion
in A
1C (
%)
Weight Gain (kg)
7. Study 1530 8. Study 1337 9. Study 1373; Rosenstock, 2006
77
8
8 99