Early Management of Glycaemic

Control with Insulin Therapy

Prof. Dr. dr. AAG Budiarta, SpPD-KEMD, FINASIM
Overview
Epidemiology of T2DM
Complications of T2DM
Guidelines of management of T2DM
Insulin needs earlier in management of T2DM
Insulin therapy barriers
Estimated number of people with diabetes worldwide and per
region in 2015 and 2040 (20-79 years)

Prevalence of diabetes
IDF Diabetes Atlas Seventh Edition 2015
IDF Atlas 2015
Prevalence of Obesity and Diabetes in Indonesia:
Health Basic Research, 2013

IFG IGT UD-DM D-DM Total DM

2007 - 10.2 4.2 1.5 5.7

2013 36.6 29.9 4.5 2.4 6.9

Health Basic Research, 2007 and 2013

Only less than 30% of Indonesians with diabetes
are already diagnosed

Only less than 30% already diagnozed

26.3% diagnosed Mostly in the productive of ages
It can be predicted that mostly patients
will come to the health centers with
complication and need high cost
intensive care
73.7% undiagnosed

Indonesia Health Survey, 2007

The worldwide challenge of glycaemic control
HbA1c in T1D and T2D
T1D1* T2D24
Sweden: 8.7%2
Sweden: 8.0%
Poland: 9.0%2 Russia: 7.7%3
Norway: 7.9%
Netherlands: 7.5% Canada: 7.9%3
UK: 8.4%3 Turkey: 8.910.6%2,3
Denmark: 7.9%
UK: 8.38.5% Romania: 9.9%2
Ukraine: 7.4% Portugal: 9.7%2
France: 8.0%
Greece: 7.6% South Korea: 8.0%3
USA: 8.0%3 Greece: 9.0%2
USA: 7.5% Italy: 7.5%
China: 7.6%3
India: 8.6%3
Latin America: 8.5%4

New Zealand: 8.3%

*Data are median and in adults (25+ years)

T1D, type 1 diabetes; T2D, type 2 diabetes
1. McKnight et al. Diabet Med 2015;32:103650; 2. Oguz et al. Curr Med Res Opin 2013;29:91120; 3. Polinski et al. BMC Endocr Disord 2015;15:46; 4.
Mendivil et al. Curr Med Res Opin 2014;30:176976
Poor glycaemic control (HbA1c) is a global
problem
Patients
achieving
targets (%)
60 <7% <7%
50
53
40 51 <7%
<6.5%
30
36
20 31
10

0
USA Canada EUROPE Emerging countries*
(NHANES)1 (DICE)2 (CODE-2)3 (IDPMS)4
*Asia, Eastern Europe, Latin America and the Middle East and Africa

In the real world, 50% of patients do not achieve their glycaemic goals1

1. Casagrande S, et al. Diabetes Care 2013;36:2271-9; 2. Harris SB, et al. Diabetes Res Clin Pract 2005;70:90-7;
3. Liebl A, et al. Diabetologia 2002;45:S23-8; 4. Chan JC, et al. Diabetes Care 2009;32:227-33.
Diabcare 2008

Soewondo, P, et al. The DiabCare Asia 2008 Study Outcomes on control and complications of type 2 Diabetets
patients in Indonesia. Med J Indones 2010; 19:235-44)
Overview
Epidemiology of T2DM
Complications of T2DM
Guidelines of management of T2DM
Insulin needs earlier in management of T2DM
Insulin therapy barriers
T2D is a major and independent risk factor for both
microvascular and macrovascular complications

Macrovascular

Microvascular

1. World Health Organization. http://www.who.int/diabetes/action_online/basics/en/index3.html

DiabCare Indonesia 2008
Diabetes Complications
80%

70%

60%

50%

40%

30%

20%

10%

0%
Neuropathy Cataract Angina Pectoris Non Prol. Diab. Stroke Healed ulcer Serum Creatinine >
Retinopathy 2 mg/dL

Soewondo, P, et al. The DiabCare Asia 2008 Study Outcomes on control and complications of type 2 Diabetets
patients in Indonesia. Med J Indones 2010; 19:235-44)
Risk of complications increases as HbA1c increases

80
1000 patient-years
Incidence per

60

40
Myocardial infarction
20

0
5 6 7 8 9 10 11
Updated mean HbA1c (%)

Stratton et al. BMJ 2000;321:40512

UKPDS: Better glucose control means fewer
complications
EVERY 1% reduction RISK*

Myocardial infarctions 14%

21%
A1C

Deaths from diabetes

Microvascular 37%
complications
Peripheral vascular
disorders 43%

*P < 0.0001.
Adapted from Stratton IM et al. UKPDS 35. BMJ 2000; 321:405-12.
The benefits of early tight control: UKPDS 10-year
post-trial follow-up

*p<0.05, **p=0.052 intensive vs. conventional treatment

UKPDS, United Kingdom Prospective Diabetes Study
Holman et al. N Engl J Med 2008;359:157789; UKPDS Study Group. Lancet 1998;352:83753
Overview
Epidemiology of T2DM
Complications of T2DM
Guidelines of management of T2DM
Insulin needs earlier in management of T2DM
Insulin therapy barriers
Antihyperglycemic therapy in type 2 diabetes:
general recommendations

American Diabetes Association. Diabetes Care Volume 40, Supplement 1, January 2017
Treatment algorithm for people with T2DM

IDF Clinical Guidelines Task Force. Global Guideline for Type 2 Diabetes, 2012. www.idf.org/sites/default/files/IDF-Guideline-for-Type-2-
Diabetes.pdf
Insulin can be initiated at any time
Traditionally, insulin has been reserved as the last line of therapy
However, considering the benefits of normal glycemic status, Insulin can be
initiated earlier and as soon as possible

Inadequate
+ 1 OAD + 2 OADs + 3 OADs
Lifestyle
A1C > 9.5%
FPG > 250 mg/dL
RBG > 300 mg/dL

INITIATE INSULIN

ADA, 2015
Skyler, 2005
Overview
Epidemiology of T2DM
Complications of T2DM
Guidelines of management of T2DM
Insulin needs earlier in management of T2DM
Insulin therapy barriers
Diabetes is a progressive disease
Type 2 diabetes (T2DM) progression is characterised by declining in beta-cell function
and worsening insulin resistance1
Getting to, or maintaining, target HbA1c levels in T2DM requires intensified treatment
over time2

1. Fonseca VA. Br J Diab Vasc Dis 2008;8:S3

2. Nathan DM, et al. Diabetes Care 2009;32:193-203
Type 2 diabetes is a progressive disease and in UKPDS
glycaemic control deteriorates across time
UKPDS 34 Study
9 Conventional* (n = 411)
Glibenclamide (n = 277)
Metformin (n = 342)
8.5 Insulin (n = 409)
Median HbA1c (%)

7.5 Recommended
treatment target < 7.0%
7

6.5

0 2 4 6 8 10
Years from randomisation
FPG = fasting plasma glucose; UKPDS = United Kingdom Prospective Diabetes Study
* Diet initially then sulphonylureas, insulin and/or metformin if FPG > 15 mmol/L.
ADA clinical practice recommendations. UKPDS 34, n = 1704.
UKPDS 34 Study. Lancet. 1998:352:854865.
Patients remain on multiple OAD therapy too long
8.9%
18.0

16.0
Clinical inertia exists despite:
14.0 41% had HbA1c 9.0%
The benefits of timely
Patients (%)

glycaemic control
12.0
Guidelines encouraging
10.0 earlier use of insulin

8.0 22% had HbA1c 10.0% At insulin initiation in SOLVE:

Average HbA1c was 8.9%
6.0

4.0

2.0

0.0
4 5 6 7 8 9 10 11 12 13 14 15 16
HbA1c (%) at insulin initiation

OAD, oral antidiabetic drug

Khunti et al. Diabetes Obes Metab 2012;14:65461
Reduction in HbA1c with OADs
1.3%*

10.0
+0.2%
0.5%*
1.0%*

9.0 Pre-treatment
Mean HbA1c (%)

Post-treatment

8.0

7.0

6.0
2 OADs 3 OADs 4 OADs Insulin

*p<0.001
OADs, oral antidiabetic drugs
Calvert et al. Br J Gen Pract 2007;57:45560
 Insulin remains the most efficacious glucose
lowering agent
Decrease in HbA1c: Potency of monotherapy

GLP-1 analogue
Pramlintide

Metformin
DPPIV inh

Exenatide

SU/GLIN

Insulin
AGIs

TZD
0

-0.5
HbA1c %

-1

-1.5

-2

-2.5 CHOOSING INSULIN EARLIER

-3
FOR BETTER EFFICACY

Nathan et al., Diabetes Care 2009;32:193-203.

Early insulin treatment prolongs beta-cell function and
promotes metabolic control

Alvarsson et al. Diabetes Care 2003;26:22317

Early insulin therapy improves beta-cell function and
glycaemic control

CSII, continuous subcutaneous insulin infusion; MDI, multiple daily injection; OHA, oral hypoglycaemic agent
Weng et al. Lancet 2008;371:175360
Overview
Epidemiology of T2DM
Complications of T2DM
Guidelines of management of T2DM
Insulin needs earlier in management of T2DM
Insulin therapy barriers
Non-adherence
Prevalence (%)

Fig. Non-adherence in common conditions

DiMatteo MR. Med Care 2004; 42: 200-9.
Non-adherence

Outcome Adherent patients Non-adherent p value

(n=9076) patients (n=2456)

All cause mortality, % 4.0 5.9 <0.001

All cause hospitalisation, % 19.2 23.2 <0.001

Mean BP, mmHg

Systolic 131.4 132.1 0.09
Diastolic 74.2 75.8 <0.001

Mean LDL-C, mmol/L 2.21 2.34 <0.001

Mean HbA1c 7.7 8.1 <0.001

Table. Association between medication adherence and outcomes

Ho PM et al. Arch Intern Med 2006; 166: 1836-41

 Patient adherence: Multidrug treatment
Adherence rate can decrease by 5-25%
with the addition of one to three
Mean adherence rate SD

medication dose
Mean adherence rates for a drug taken
once daily are approximately 80%, and
for every increase in dosage frequency,
up to 4 doses/day, adherence decreases
(%)

by between 4 and 14%

'White-coat adherence' is commonly
observed when patients improve their
adherence to medication 5 days before
and after their physician visit, compared
with 30 days after a visit
Adherence rates significantly improve
with a single-pill, fixed dose combination
compared with two-pill combination
Medication dosing schedule per day (dose) therapy

Fig. Rate of dose-taking adherence by frequency of regimen

Adopted from Brown MT and LeRoith D. Expet Rev Endocrinol Metab 2010; 5: 741-751
Clinical inertia
Adherence to therapy is not just a problem of the patients, but it involves the
physician as well.
Too often, physicians are slow in making changes of suboptimal medical regimens in
diabetic patients not at target
P=0.009

P=0.7 P=0.2

P=0.001

Fig. Proportion of patients in specialist care and in exclusively primary care with
drug regimen intensification in response to poor glycemic control (HbA1c .8%)

Shah BR et al. Diabetes Care 2005; 28: 600-606

Clinical inertia: patient and physician barriers
Lack of appropriate Complex regimens
education

Head in the sand Hypoglycaemia

I can do it with lifestyle Barriers

Excess weight gain

Patient perceptions of
worsening disease
Health service delivery
Patient perceptions of
insulin treatment and
outcomes
Resource issues Financial restrictions

Peyrot et al. Diabetes Care 2005;28:26739; Elgrably et al. Diabet Med 1991;8:7737; Wallace & Matthews. QJM
2000;93:36974; Kunt & Snoek. Int J Clin Pract 2009;63(Suppl. 164):610
Barriers to the initiation of insulin therapy in patients with type 2
diabetes at Sanglah Hospital, Bali, Indonesia

Descriptive, a survey at Diabetes Outpatient Clinic, Sanglah Hospital, Denpasar, Indonesia

120 diabetic patients, >40 years, primary adherent patients newly prescribed insulin
Questionnaire related barriers to the initiation of insulin therapy
Barriers to the initiation of insulin therapy Frequency (N=120) Percentage

Fear of needle 19 15.8

Fear of pain 16 13.3
Fear of weight gain 7 5.8
Confusing in using insulin 6 5.0
High cost (insulin is too expensive) 5 4.2
Fear of hypoglycemia 4 3.3
Afraid of negative effect of insulin (information from the 4 3.3
others)
Others 1 0.8

Kresnasari NLP, et al. Data on file, 2011

Practical approaches to reducing clinical inertia

Monitoring and providing

Financial incentives feedback on quality of care

Cognitive interventions
Visit resolution Reducing targeting specific decision
and accountability clinical inertia pathologies
tools

Patient initiative
Physician initiative
Healthcare system
More frequent clinic initiative
Clinical decision support visits

OConnor PJ, et al. Agency for Healthcare Research and Quality 2005. Available at:
www.ahrq.gov/downloads/pub/advances/vol2/OConnor.pdf (accessed June 2012).
Triggers to initiate insulin in primary care

Patients uncontrolled on triple therapy

Patients with long-standing diabetes that is poorly
controlled
Any patient not at HbA1c target despite intensive
treatment
Summary
The majority of patients with Type 2 diabetes worldwide fail to control HbA1c
Good glycemic control, including early intervention, remains the cornerstone of
diabetes care
Challenges in increasing patients adherence to therapy
Type 2 diabetes is a progressive disease in which -cell function continually declines
and eventually fails, ultimately requiring nearly all patients to be placed on insulin
therapy.
Insulin therapy should be started at appropriate time; and can be used at initially or
after OAD failed