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!!!
