1. Early insulinization - Clore

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 (%

)


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


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


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


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

1. Early insulinization - Clore

Documents

insulin deficiency

t2dm

ffa