Initiation and Intensification insulin therapy

in type 2 diabetes

1

Hikmat Permana

Division Endocrinology and Metabolism Department of Internal Medicine

Padjadjaran University Medical School/ Hasan Sadikin Hospital

Bandung

40

15 13 13

10

4 5

0

10

20

30

40

50

Causes of Death in People With Diabetes

of Diabetic Patients Deaths

are from CV Causes 65%

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

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

A1c : Myocardial Infarction and Microvascular Complication

0

20

40

60

80

0 5 6 7 8 9 10 11

Myocardial infarction

Microvascular disease

Mean HbA1c (%)

Inci

de

nce

pe

r 1000 p

atie

nt-ye

ars

A1c & Microvascular Complications

60 70 % Reduction of Complications

Rela

tive R

isk

Retinopathy

Nephropathy

Neuropathy

Microalbuminuria

HbA1c (%)

15

13

11

9

7

5

3

1 6 7 8 9 10 11 12

Skyler JS. Endocrinol Metab Clin. 1996;25:243 254.

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

8

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

6

Summary of ACCORD, ADVANCE and VADT

ACCORD ADVANCE VADT

No. of participants 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

Rosiglitazone use, (intensive vs. standard)

90% vs. 58% 17% vs. 11% 85% vs. 78%

Duration of follow -up, years

3.4

5.0

6

After median 8.5 years post-trial follow -up

Aggregate Endpoint 1997 2007

Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040

Microvascular disease RRR: 25% 24 % P: 0.0099 0.001

Myocardial infarction RRR: 16% 15 % P: 0.052 0.014

All-cause mortality RRR: 6% 13 % P: 0.44 0.007

RRR = Relative Risk Reduction, P = Log Rank

UKPDS: Legacy Effect of Earlier Glucose Control

N Eng J Med 2008

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

2 diabetes and without established atherosclerosis might reap

cardiovascular benefits from intensive glycaemic

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

Glycemic control & A1c Target

AACE ADA

< 6.5

Two -thirds of Type 2 Patients are not Achieving Glycemic Control

NHANES = National Health and Nutrition Examination Survey.

1Koro et al. Diabetes Care. 2004;27:17 -20; 2

Endocrinologists, 2003 -2004. Available at: http://www.aace.com/public/awareness/stateofdiabetes/ DiabetesAmericaReport.pdf. Accessed January 6, 2006.

A1c 6.5%

AACE survey 2003 -2004 2

N=157 ,000 type 2 patients 39 US states included

33%

A1c

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

0

20

40

60

80

100

% o

f S

ub

jects

Percentage of subjects advancing when A1C >7% < 8%

Clinical Inertia:

Failure to Advance Therapy When Required

Diet

66.6%

Sulfonylurea Metformin

35.3%

44.6%

Combination

18.6%

At insulin initiation, the average patient had:

5 years with A1C > 8%

10 years with A1C > 7%

Slide Source:

Lipids Online Slide Library www.lipidsonline.org

Initial drug monotherapy

ADA/EASD Position Statement

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

Combination therapy: 2 drugs

Efficacy ( A1C) Hypoglycemia Weight Side effects Costs

More -complex insulin strategies

Combination therapy: 3 drugs

Efficacy ( A1C) Hypoglycemia Weight Side effects Costs

Efficacy (A1C)

Hypoglycemia

Weight

Side effects

Costs

INSULIN THERAPY !!!!

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

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 (T 2DM)

Addition of GLP-1 RA (T 2DM)

Timely initiation of insulin(T 2DM)

Basal insulin analogs

Premixed analogs

NPH (pregnancy)

Slide 21

To normalise blood glucose both FPG and PPG

Adapted from Monnier L et al. Diabetes Care 2003 ; 26 : 881 5

PPG

FPG

50 % 55 % 60 %

70 %

50 % 45 % 40 %

30 %

30 %

70 %

< 7.3 7.3 8.4 8.5 9.2 9.3 10.2 > 10.2

0

20

40

60

80

100

HbA 1 c range (%)

% c

on

trib

uti

on

to

Hb

A1

c

Most insulin is initiated when HbA 1 c > 8.5 %

Treatment options in type 2 diabetes

Basal insulin therapy

long-acting insulin

+/- OAD

Prandial/Intensified

Insulin Therapy

Short acting insulin or

insulin analog prandially

+

long-acting insulin ad lib

Conventional

Insulin Therapy

Usually 2 injections

of a mixture of regular

insulin/short-acting insulin

analog and long-acting

insulin

Targets:

- HbA1c

- Fasting glucose

- Postprandial glucose

Targets:

- HbA1c

- Fasting glucose

Normal Secretory Pattern of Insulin

in Eating Patients

Breakfast Lunch Dinner S L E E P

Insulin

Level

Prandial Insulin

Basal Insulin

0

(mmol)

3

6

9

7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 AM PM

time

Can lower HbA1clevel, but can not improve PPG

Basal Insulin

0

(mmol)

3

6

9

7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 AM PM

time

Can lower HbA1clevel, but can not improve glucose spike?

Basal Insulin

Fasting Hypos

FIX THE FASTING FIRST !!!

Options for basal insulin

Pre mix insulin

Levemir insulin

Glargine

NPH

Pre meal control

Basal Insulin

Glargine

Cover that ONE meal

with rapid acting

If the A1c remains >7%, despite

control of fasting glucose (90-120

the problem is post prandial

Find the meal associated

the highest

2 hour PP

Basal Insulin

Makan

Pagi

Makan

Siang

Makan

Malam

Sebelum tidur

Rapid Insulin

Insulin endogen

----

----

Regimen Basal Bolus REGIMEN BASAL-BOLUS

Kelebihan :

1. Sangat ideal, dapat menghasilkan terapi yang

menyerupai profil insulin endogen

2. Sangat mudah mengatur dosis insulin basal

maupun bolusnya

Kelemahannya :

1. Pasien tidak menyukainya karena 4 x suntik

2. Pasien harus menggunakan 2 jenis insulin (berisiko

pasien salah suntik) dan biaya terapi lebih mahal

+

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 TID-QID dosing, based on BG & sensitivity

In-Hospital Basal-Bolus Insulin Therapy