Early Insulinization

John N Clore MD
Virginia Commonwealth University
Richmond Virginia
 T2DM Is Characterized by Insulin
Deficiency and Insulin Resistance
Overweight, Inactivity
Inherited/Acquired Factors (Inherited/Acquired)

Insulin Deficiency  FFA Insulin Resistance

Gluco-
lipotoxicity  Glucose
Uptake

 Production
of Glucose
in the Liver

Hyperglycemia

T2DM

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.
 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 enhance
glucose control

? Insulin
 HbA1c
overweight patients cohort, median values
9 Conventional Insulin Chlorpropamide Glibenclamide Metformin

8
HbA 1c (%)

6
0 0
2 4 6 8 10
Years from randomisation
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
overweight patients cohort, median values
9 Conventional Insulin Chlorpropamide Glibenclamide Metformin

8
HbA 1c (%)

6
0 0
2 4 6 8 10
Years from randomisation
UKPDS-Any diabetes related endpoint
overweight
patients 0.6
Conventional (411)
Intensive (951)
Proportion of patients with events

Metformin (342)
0.4 M v C
p=0.0023

0.2

MvI
p=0.0034
0.0
0 3 6 9 12 15
Years from randomisation
 Strategies for Management of T2DM
ADA/EASD Consensus Statement
Diagnosis

Lifestyle intervention + biguanide

If A1C ≥ 7% after 2-3 months

Add basal Add sulfonylurea Add TZD

insulin
If A1C ≥ 7%
If A1C ≥ 7% If A1C ≥ 7%

Intensify Add TZD—if Add basal

insulin Add sulfonylurea—
A1C < 8% insulin
if A1C < 8%

If A1C ≥ 7% If A1C ≥ 7%

Add basal insulin or

Intensive insulin + biguanide ± T2D* intensify insulin

EASD, European Association for the Study of Diabetes; TZD, thiazolidinedione.

Adapted from Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
 Type 2 Diabetes is a Progressive
Disease
100

80
-cell function (%)

60

40

20

0
-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6
Time (years)
12/08/21 07:46 PM Cardiovascular 10
Adapted from UKPDS Group. Diabetes. 1995;44:1249-1258.
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
Percentages of adults
50
45
40
35
30
Oral
25
Insulin
20
I + Oral
15
10
5
0
1997 1998 1999 2000 2001 2002 2003
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
Postprandial glucose Fasting glucose
100
Contribution, %

80

60

40

20

0
<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2

A1C
Monnier L et al. Diabetes Care. 2003;26:881–885.
 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
A Basal Insulin Strategy
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.
 Insulin Dosage and FPG During Study
(Both treatment groups)
50
Total Daily Dose, Units ( SE)

43 44

*Mean FPG, mg/dL (±SE)

± 41
39
40 206 37
36
200
33
31
30 175 28
25

153
20 16 142 150
10 135 135
128 125
10 121 118 117 116

0 100
0* 2 4 6 8 10 12 14 16 18

Weeks in Study
Preliminary data.
*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.
 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

Weight gain, Nocturnal

Insulin HbA1c reduction kg/24 wk hypoglycemia
  (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
45
40
35
30
25
Glargine
20 Conventional
15
10
5
0
HbA1c < 6.5% HbA1c < 7.0 %

Diabetic Medicine 23:736, 2006

 INSIGHT
Fall 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