Initiation and Intensification insulin therapy

in type 2 diabetes
Hikmat Permana
Division Endocrinology and Metabolism
Department of Internal Medicine
Padjadjaran University Medical School/
Hasan Sadikin Hospital
Bandung
1

Causes of Death in People With Diabetes

50

65%

40
40

of Diabetic Patients Deaths

are from CV Causes

30

20
10
0

15

13

13

10
4

UKPDS: Glucose Control Study Summary

The intensive glucose control policy maintained a lower
HbA1c by a mean of 0.9% over a median follow up of
10 years from diagnosis of type 2 diabetes with
reduction in risk of:

12% for any diabetes related endpoints

p=0.029

25% for microvascular endpoints

p=0.0099

16% for myocardial infarction

p=0.052

A1c : Myocardial Infarction and Microvascular

Complication
80

Microvascular
disease

Incidence per
1000 patient-years

60

Myocardial infarction

40

20

0
0 5
UKPDS 35. BMJ 2000; 321: 405-12.

10

11

Mean HbA1c (%)

A1c & Microvascular Complications

60 70 % Reduction of Complications
Retinopathy

15

Nephropathy

Relative Risk

13

11
9

Neuropathy

7
5
Microalbuminuria

3
1
6

10

HbA1c (%)
Skyler JS. Endocrinol Metab Clin. 1996;25:243254.

11

12

Can long-term glycemic control reduce

the risk of cardiovascular disease?

ACCORD ADVANCE and VADT- No Significant Effect on

Macro or Micro Vascular Outcomes
ACCORD

ADVANCE

VADT

No. of participants

10,251

11,140

1791

Participant age ,years

62

66

60

Duration of diabetes at
study entry, years

10

11.5

HbA1C at Baseline, %

8.1

7.5

9.4

Participants with prior

cardiovascular event, %

35

32

40

Duration of follow-up,
years

3.4

5.0

Summary of ACCORD, ADVANCE and VADT

ACCORD

ADVANCE

VADT

10,251

11,140

1791

Participant age ,years

62

66

60

HbA1C at Baseline, %

8.1

7.5

9.4

Significant Effect on
Macrovascular
Outcomes?

No

No

No

Significant Effect on
Microvascular
Outcomes?

NA

Significant for
nephropathy, not
retinopathy

No

90% vs. 58%

17% vs. 11%

85% vs.
78%

3.4

5.0

No. of participants

Rosiglitazone use,
(intensive vs. standard)
Duration of follow-up,
years

UKPDS: Legacy Effect of Earlier Glucose Control

After median 8.5 years post-trial follow-up
Aggregate Endpoint

1997

2007

Any diabetes related endpoint

RRR: 12%
P: 0.029

9%
0.040

Microvascular disease

RRR:
25%
P: 0.0099

24%
0.001

Myocardial infarction

RRR:
P:

16%
0.052

15%
0.014

All-cause mortality

RRR:
P:

6%
0.44

13%
0.007

N Eng J Med 2008

RRR = Relative Risk Reduction, P = Log Rank

Can long-term glycemic control reduce

the risk of cardiovascular disease?

Yes
If early and sustained glycemic control started
before atherosclerosis is established

ADA: Position statement:

Need for early treatment

Patients with shorter duration of Type 2 diabetes

and without established atherosclerosis might reap
cardiovascular benefits
from intensive glycaemic control

Skyler JS, et al. J Am Coll Cardiol. 2009;53(3):298-304.

Glycemic control & A1c Target

ADA

AACE

<7

<6.5

Preprandial (mg/dl)

80-120

<110

Postprandial (mg/dl)

140-180

<140

Bedtime (mg/dl)

100-140

100-140

A1c (%)

ADA: American Diabetes Association

AACE: American Association of Clinical Endocrinologists

Two-thirds of Type 2 Patients are not

Achieving Glycemic Control

NHANES1

44.5%

35.8%

1988-1994
N=1215

AACE survey
2003-20042

A1c <7%

1999-2000
N=372

33%

A1c 6.5%

N=157,000 type 2 patients

39 US states included
NHANES = National Health and Nutrition Examination Survey.
1Koro

et al. Diabetes Care. 2004;27:17-20; 2 State of Diabetes in America, American Association of Clinical
Endocrinologists, 2003-2004. Available at: http://www.aace.com/public/awareness/stateofdiabetes/
DiabetesAmericaReport.pdf. Accessed January 6, 2006.

Clinical Inertia:
Failure to Advance Therapy When Required
Percentage of subjects advancing when A1C >7% < 8%
100

% of Subjects

80

At insulin initiation, the average patient had:

5 years with A1C > 8%
10 years with A1C > 7%
66.6%

60

44.6%

35.3%

40
18.6%

20
0
Diet

Sulfonylurea

Brown JB et al. Diabetes Care 2004;27:1535-1540.

Metformin

Combination

ADA/EASD Position Statement

Initial drug monotherapy
Efficacy (A1C)
Hypoglycemia
Weight
Side effects
Costs

Combination therapy:
2 drugs
Efficacy (A1C)
Hypoglycemia
Weight
Side effects
Costs

Combination therapy:
3 drugs

More-complex
insulin strategies
Reprinted with permission from Inzucchi SE et al. Diabetes Care. 2012;35:
1364-1379. Copyright 2012 American Diabetes Association. All rights reserved.

Slide Source:
Lipids Online Slide Library
www.lipidsonline.org

Barriers to Insulin Initiation

Several myths, misperceptions, and negative attitude
that act as barriers about the use of insulin among
people with type 2 diabetes as follows:
Insulin causes blindness, renal failure, amputations, heart
attacks, strokes, or early death,
Sense of personal failure
Low self-confidence
Low confidence in therapy
Injection phobia
Hypoglycemia concerns
Feeling that diabetes is a serious cause of concern
Negative impact on social life and job
Inadequate health literacy,
Health care provider inadequately explaining risks/benefits
Limited insulin self-management training

The physicians barriers to timely initiate insulin

are as follows:

Concerns over patients with comorbidities

Excess weight gain in already overweight patients
Concerns about patient non-compliance
Risk of severe hypoglycemia/adverse effects on QoL
Lack of resourcesdrug costs, staff, skills
Patient refusal
UKPDS study:
27% of patients initially declined insulin and
a survey of 708 insulin-nave patients found that 28% said
they would be unwilling to take insulin if it was prescribed.

Pathophysiological basis of
management of diabetes
Optimization of OHA (T2DM)
Addition of GLP-1 RA (T2DM)
Timely initiation of insulin(T2DM)
Basal insulin analogs
Premixed analogs
NPH (pregnancy)

Slide 21

To normalise blood glucose both FPG and PPG

must be reduced

% contribution to HbA1c

Most insulin is
initiated when
HbA1c >8.5%
100

PPG

80
60

45%

40%

50%

55%

60%

7.38.4

8.59.2

9.310.2

50%
70%

40
20

30%

70%

30%

0
<7.3

HbA1c range (%)

Adapted from Monnier L et al. Diabetes Care 2003;26:8815

>10.2

FPG

Treatment options in type 2 diabetes

Basal insulin therapy

long-acting insulin
+/- OAD

Targets:
- HbA1c
- Fasting glucose

Conventional
Insulin Therapy

Prandial/Intensified
Insulin Therapy

Usually 2 injections
of a mixture of regular
insulin/short-acting insulin
analog and long-acting
insulin

Short acting insulin or

insulin analog prandially
+
long-acting insulin ad lib

Targets:
- HbA1c
- Fasting glucose
- Postprandial glucose

Normal Secretory Pattern of Insulin

in Eating Patients
Prandial Insulin

Insulin
Level

Basal Insulin

SLEEP
Breakfast

Lunch

Dinner

Basal Insulin

(mmol)

6
3

0
7

10

11

12

AM

7
PM

time

Can lower HbA1clevel, but can not improve PPG

Basal Insulin

Fasting Hypos
(mmol)

6
3

0
7

10

11

12

AM

PM

time

Can lower HbA1clevel, but can not improve glucose spike?

FIX THE FASTING FIRST !!!

Options for basal insulin

Glargine

Levemir insulin
Pre mix insulin
NPH

If the A1c remains >7%, despite

control of fasting glucose (90-120)..

the problem is post prandial

Pre meal control
Basal Insulin
Glargine

Fix the Fasting First

Find the meal associated
the highest
2 hour PP

Cover that ONE meal

with rapid acting
STEP THERAPY

Regimen Basal Bolus

REGIMEN BASAL-BOLUS
Kelebihan :

----

Insulin endogen
Basal Insulin

----

Rapid Insulin

1. Sangat ideal, dapat menghasilkan terapi yang

menyerupai profil insulin endogen
2. Sangat mudah mengatur dosis insulin basal
maupun bolusnya

Kelemahannya :
Makan
Makan
Makan
Sebelum tidur
1. Pasien
tidak
menyukainya
karena
4 x suntik
Pagi
Siang
Malam

2. Pasien harus menggunakan 2 jenis insulin (berisiko

pasien salah suntik) dan biaya terapi lebih mahal

In-Hospital Basal-Bolus Insulin Therapy

Basal

suppresses hepatic glucose production

QD dosing, based on weight & estimated
insulin secretion/sensitivity
start @ 0.2-0.3 units/kg/day or convert
from current insulin dose.

Bolus

prandial insulin blunts postprandial BG spikes

TID AC dosing, based on carbs in meal, weight,
estimated insulin secretion/sensitivity

start @ 0.05 units/kg/meal

Correction
corrects pre-meal hyperglycemia
QID dosing, based on BG & sensitivity

TID-

BOLUS INSULIN USED IN THE INDONESIA

Novorapid
Apidra

humalog

Humulin R
Actrapid

PREMIXED INSULIN ANALOGS

COMMONLY USED IN THE INDONESIA

Novomix
70/30
Humalog Mix
75/25

Humulin
70/30: Mixtrad
70/30

Summary
Insulin therapy provides many benefits to patients with
T2DM
Timely Initiation of Insulin Is Critical
Early initiation of insulin therapy, as insulin acts to
significantly lower plasma glucose levels while minimizing
the long-term complications associated with chronic
hyperglycemia Basal Insulin
Early intensification of diabetes therapies can minimize the
risk of long-term complications associated with exposure to
chronic hyperglycemia Basal bolus

Terima kasih

The distance is nothing;

it is only the first step that is difficult.

DIABETES can be controlled!!!