Early Insulinization
John N Clore MD
Virginia Commonwealth University
Richmond Virginia
T2DM Is Characterized by Insulin Deficiency and Insulin Resistance
FFA, free fatty acid; T2DM, type 2 diabetes mellitus®.
Yki-Järvinen H. In: Pickup JC, Williams G, eds. Textbook of Diabetes 1. 3rd ed. 2003:22.1-22.19.
Gluco-lipotoxicity
Production of Glucosein the Liver
Overweight, Inactivity(Inherited/Acquired)
FFA
T2DM
Inherited/Acquired Factors
GlucoseUptake
Insulin Deficiency Insulin Resistance
Hyperglycemia
Glucolipotoxicity
Hyperglycemia and lipemia aggravate
– Impaired -cell function
– Insulin resistance
Agents which reduce glucose and lipid levels would be expected to improve beta cell function and enhanceglucose control
? Insulin
HbA1c
cohort, median values
06
7
8
9
0 2 4 6 8 10
HbA
1c (%
)
Years from randomisation
ChlorpropamideConventional GlibenclamideInsulin Metformin
overweight patients
ADA Recommendations
• HbA1c < 7.0%
• Preprandial plasma glucose 70-130 mg/dL (3.9-7.2 mM)
• Peak postprandial plasma glucose
< 180 mg/dL (<10 mM)
Diabetes Care 2008
Achievement of Targets
• HbA1c < 7.0% 38.3%
• LDL < 100 35.0%
• BP < 140/90 42.5%
NHANES 2002
HbA1c
cohort, median values
06
7
8
9
0 2 4 6 8 10
HbA
1c (%
)
Years from randomisation
ChlorpropamideConventional GlibenclamideInsulin Metformin
overweight patients
0.0
0.2
0.4
0.6
0 3 6 9 12 15
Pro
porti
on o
f pat
ient
s w
ith e
vent
s
Years from randomisation
Conventional (411)
Intensive (951)
Metformin (342)
UKPDS-Any diabetes related endpoint
M v Ip=0.0034
overweight patients
M v C p=0.0023
EASD, European Association for the Study of Diabetes; TZD, thiazolidinedione.
Adapted from Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Strategies for Management of T2DM ADA/EASD Consensus Statement
Add TZD
If A1C ≥ 7%
Add sulfonylurea— if A1C < 8%
If A1C ≥ 7% after 2-3 months
Add sulfonylurea
Add basal insulin
Add basal insulin orintensify insulin
If A1C ≥ 7%If A1C ≥ 7%
Intensive insulin + biguanide ± T2D*
Intensifyinsulin
Add basal insulin
If A1C ≥ 7%
Add TZD—if A1C < 8%
If A1C ≥ 7%
Diagnosis
Lifestyle intervention + biguanide
04/07/23 06:11 PM Cardiovascular 10
Type 2 Diabetes is a Progressive Disease
Adapted from UKPDS Group. Diabetes. 1995;44:1249-1258.
0
20
40
60
80
100
-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6
Time (years)
-ce
ll f
un
ctio
n (
%)
Kaplan-Meier Estimates of the Cumulative Incidence of Monotherapy Failure at 5 Years
Kahn SE et al. N Engl J Med 2006;355:2427-2443
Choices in Medication
05
10
1520
2530
3540
4550
1997 1998 1999 2000 2001 2002 2003
OralInsulinI + Oral
Percentages of adults
Treatment in Type 2 Diabetes
• Monotherapy– 44.9% Metformin 43.7% SU
• 2nd-Drug– 36.3% Metformin 36.0% SU
• 3rd Drug– 37.6% TZD 33.0% Insulin
Delay in Treatment Escalation
• 4365 patients with Type 2 Diabetes
• Baseline HbA1c 8.4%
• Addition of SU + Metformin 50.8% < 7.0
• HbA1c increased above 7% within 11 months
• HbA1c averaged 8.4% for another 32.8 months without intervention
Kaiser Permanente 2007
Barriers to Insulin therapy
• Injections
• Weight Gain
• Hypoglycemia
• Lack of confidence
Insulin Requirements
Clore et al, 1989
Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on A1C Quintiles
Monnier L et al. Diabetes Care. 2003;26:881–885.
0
20
40
60
80
100
<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2
Postprandial glucose Fasting glucose
A1C
Co
ntr
ibu
tio
n,
%
Insulin Preparations
Rapid-Acting– Insulin lispro (analogue)– Insulin aspart (analogue)*– Insulin glulisine (analogue)
Short-Acting– Regular (soluble)
Intermediate-Acting– NPH (isophane)
Long-Acting– Insulin glargine (analogue)– Insulin detemir
Continue oral agents
● Add 0.2 U/kg basal insulin
● Titrate every 4-7 days based on home glucose monitoring until the fasting glucose is 100 mg/dl.
Based on available data, the total basal insulin dose required will be ~ 0.4-0.8 U/kg.
A Basal Insulin Strategy
Insulin Dosage and FPG During Study(Both treatment groups)
Preliminary data.Preliminary data.
*Week 0 based on a starting dose of 10 units.*Week 0 based on a starting dose of 10 units.
Adapted from Rosenstock et al. ADA Annual Meeting. June 2001, Philadelphia, PA; Abst. 520-P.Adapted from Rosenstock et al. ADA Annual Meeting. June 2001, Philadelphia, PA; Abst. 520-P.
Tota
l D
aily D
ose,
Un
its (
±SE)
*Mean
FP
G,
mg
/dL (
±S
E)
3736
3331
2825
16
3941
43 44
10
0
10
20
30
40
50
0 2 4 6 8 10 12 14 16 18
Weeks in Study
*100
150
200206
125128135135
142153
175
121 118 117 116
Comparison of Glargine and Detemir
Comparisons of clinical efficacy of basal insulin preparations in patients with type 2 diabetes mellitus during 24-week insulin titration studies
Insulin HbA1c reduction
Weight gain,
kg/24 wk
Nocturnal hypoglycem
ia
(Baseline 8.6%) (RR vs NPH)
NPH 1.7 2.8 —
Glargine 1.7 3 0.66 [24]
Detemir 1.8 1.2 0.63 [24]
Clore and Thurby-Hay, 2007
Insulin vs SU in Newly Diagnosed Type 2 diabetes
• Small study in 51 patients
• Subjects randomized to two injections of 70/30 insulin or glibenclamide
• Glucagon stimulated C-peptide
• Similar HbA1c reductions (7.2 to 6.3%)
• Greater C-peptide response with insulin after 1 and 2 years of treatment
Diabetes Care 26:2231, 2003
INSIGHT
• 405 patients with Type 2 diabetes mellitus
• Inadequately controlled on oral medications (baseline HbA1c 8.6%)
• Randomized to – Baseline orals + glargine at bedtime– Up-titration of oral medications
Diabetic Medicine 23:736, 2006
INSIGHT
0
5
10
15
20
25
30
35
40
45
HbA1c < 6.5% HbA1c < 7.0 %
GlargineConventional
Diabetic Medicine 23:736, 2006
INSIGHTFall in Metabolic Parameters
HbA1c % FPG (mM) Tg (mM) TC (mM) Non-HDL
Glargine 1.55 3.89 1.08 0.38 0.37
Control 1.25 2.31 0.47 0.11 0.13
Diabetic Medicine 23:736, 2006
Early (Basal) Insulin Therapy
• More effective to achieve HbA1c targets– ? Decreased gluocolipotoxicity– Must be used in sufficient dosage (>0.4 units/kg)
• Cost effective alternative to multiple oral agents
• Patient acceptance higher than appreciated
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