2. Endocrinologist faculty of Mazandaran university
Dr.Ozra.Akha
Endocrinologist faculty of Mazandaran university 2

3. Natural History of Type 2 Diabetes Progression
Years from
diagnosis
-10 -5 5 10 15
Insulin resistance
Insulin secretion
Microvascular complications
Macrovascular complications
Pre-diabetes
Type 2 diabetes (T2DM)
Onset
Diagnosis 3

4. T2DM is a progressive disease with β-cell function decrease over time
Insulin secretion (%) in T2DM patients
100
Diagnosis
IGT 75
Insulin initiation 50
PPBG 25
OADs*
Basal initiation / titration
Basal + prandial -8 -2 +2 +8
+14
Years
Insulin-naive
Insulin intensification
Lebovitz. Diab Rev 1999;7:139. 4

5. Lessons from UKPDS: Better control in T2DM means fewer complications
1% reduction in HbA1c
Risk reduction*
-21% 1%
Deaths from diabetes
The UKPDS has proven that intensive glycemic control is strongly associated with significant clinical benefits for patients with T2DM. In an epidemiological analysis of the UKPDS cohort (n=3,642) every 1% decrease in HbA1C was associated with clinically important reductions in the incidence of:1
Diabetes-related death (-21%)
Myocardial infarction (-14%)
Microvascular complications (-37%)
Peripheral vascular disease (-43%).
Reference
Stratton IM, Adler AI, Neil AW et al. Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405–412.
-14%
Myocardial Infarction
-37%
Microvascular complications
-43%
Peripheral vascular disorders
*p< n=3,642 type 2 diabetes patients
1. Stratton IM et al. BMJ 2000;321:405–412 5

6. Risk of Microvascular Complications vs. A1C in Type 1 Diabetes
Results From the DCCT 20
Retinopathy progression
Neuropathy progression 15
Relative risk
Microalbuminuria progression 10 5 1 5 6 7 8 9 10 11 12
A1C (%)
Skyler JS. Endocrinol Metab Clin North Am. 1996;25:

7. The benefits of early tight control: UKPDS 10-year post-trial follow-up

8. Early Insulinization Prevents the Progressive β-cell Dysfunction
Early intensive insulin therapy has favorable outcomes on recovery and maintenance of β-cell function compared with oral hypoglycemic agents
Insulin provides a type of β-cell rest and reduce excessive secretory demands on damaged
β-cell
recovery
and maintenance of
β-cell function
Weng JP et al. Lancet, 2008, 301:

9. HbA1c targets in current guidelines
ADA/EASD
<7
IDF
NICE
<6.5
AACE
≤6.5
France
Canada ≤7
Australia
Latin America 9

10. Only around one-third of patients
Only around one-third of patients* in developing countries achieve HbA1c <7%
The International Diabetes Management Practice Study (IDMPS)
Patients* with HbA1c <7% (%)
*Patients with HbA1c test (36% of overall population)
Chan JC, et al. Diabetes Care 2009;32:227–33. 10 10

11. Fewer than 5% of patients in developing countries achieve glycaemic and CV goals
The International Diabetes Management Practice Study (IDMPS)
Patients achieving goals (%)*
*HbA1c <7%, blood pressure 130/80 mmHg, LDL-C <100 mg/dL
Chan JC, et al. Diabetes Care 2009;32:227–33. 11 11

12. Clinical inertia: ‘Failure to advance therapy when recommended’10
9.6%
Combination oral agents
8.9% 9
8.6%
Mean HbA1c at last visit (%)
SU or metformin
Diet & exercise 8
ADA goal 7
2.5 years
2.9 years
2.8 years
Years since initial diagnosis
8.2 years
Initiation of
insulin therapy
Brown JB, et al. Diabetes Care 2004;27:1535–40. 12

13. Delaying insulinization results in increased A1C10
Combination therapy
Sulfonylurea or metformin monotherapy
Insulin
Diet/exercise 9
Mean A1C at last visit (%) 8
ADA/ EASD goal
<7% 7 6 2 3 4 5 6 7 8 9 10
Diagnosis
Years
Brown JB, et al. Diabetes Care 2004;27:1535−40

14. Perceived burden of treating diabetes in experienced and inexperienced patients
Lower Greater
burden burden
Moderate diet
Self-monitoring of blood glucose once a day
Insulin once a day
Combination bedtime insulin and daytime oral
agents
Self-monitoring of blood glucose three times
a day
Insulin twice a day
Insulin twice a day+ self-monitoring of blood
glucose three times a day
Insulin 3- 4 times a day
n= Rating with experience Rating without experience
Inexperienced patients perceived a greater burden of treating diabetes than experienced patients
2.0
1.8
2.6
2.4
3.5
3.1
3.7
4.7
4.3
4.9
4.1
5.1
5.2
Vijan et al. J Gen Intern Med 2005;20:479–82.

16. §Usually a basal insulin (NPH, glargine, detemir, degludec)

17. Combination Injectable Therapy

19. Stepwise management of T2DM+
Diet &
exercise
Oral monotherapy
Oral combination
Oral plus insulin
Insulin
Biggest clinical hurdle???
Adapted from Williams G. Lancet 1994;343:95–100. 19 19 19

20. When is insulin initiated in T2DM
Data from retrospective or longitudinal surveys (initiation of insulin not protocol driven)
Before insulin initiation
After insulin initiation (1–4 yrs)
n = 272
n = 31
n = 735
n = 52
n = 883
Mean HbA1c (%HB)
These data show the level of control at which insulin is initiated in type 2 diabetes. They are taken from either retrospective or prospective longitudinal surveys of various cohorts i.e. where the decision to start insulin was not determined by study protocols but rather reflected the decision-making of the patients’ carers. Typically, HbA1c was above 9% before insulin was started.
Interestingly, many of the data are from the Netherlands where such surveys have been made to assess quality of life and treatment satisfaction changes.
Also of interest, though speculative, is the observation that there is no evidence of improvement between the earliest and most recent surveys in terms of point of intervention. 20 20

23. Multinational, observational study of T2DM (66,726) ACHIEVE study: Insulin therapy started in routine clinical care when HbA1c 9.3–9.8%:
China
S. Asia
E. Asia
N. Africa
Mid East
Lat. Am.
Russia n
9,493
21,107
9,062
3,623
11,971
1,032
2,954
Age (yrs)
55.7
51.7
56.5
58.3
52.8
59.6
59.2
T2DM (yrs)
7.9
6.7
12.5
11.4
10.2
15.5
9.6
Complications (%)
86.1
94.0
90.3
89.7
79.9
90.7
96.1
CV disease (%)
22.9
32.5
29.4
28.5
30.5
35.3
74.6
Renal disease (%)
26.1
28.7
34.6
36.5
43.6
41.8
41.7
Eye problems (%)
25.6
22.0
29.9
41.2
36.8
71.0
Foot ulcer (%)
2.5
6.5
5.8
3.5
8.7
7.7
5.1
Neuropathy (%)
33.7
40.1
38.9
56.0
47.6
84.4
Adjusted for age at diagnosis; Complications (%) predicted from a logistic model
Complications already present in people with T2DM when initiating insulin therapy
Zilov AV, et al. Diabetes 2011;60(Suppl.1):2485.

24. Clinical inertia: patient and physician barriers
Peyrot et al. Diabetes Care 2005;28:2673–9; Elgrably et al. Diabet Med 1991;8:773–7; Wallace & Matthews. QJM 2000;93:369–74; Kunt & Snoek. Int J Clin Pract 2009;63(Suppl. 164):6–10

26. Barriers to insulin initiation
Nakar et al. J Diabetes Complications 2007;21:220–6

27. Do not forget!
The beneficial effects of early insulin therapy in T2DM on beta-cell function, micro/macrovascular morbidity and mortality, and total mortality.

28. Conclusions
Achievement and maintenance of tight glycaemic control is of paramount importance
The ‘reality’ is that this is not being achieved in daily clinical practice
Regular monitoring of HbA1c and frequent assessment of treatment regimens are needed
For most patients on a 3-monthly basis
Failure to advance therapy when required, particularly insulin therapy, needs to be urgently addressed

29. Start Insulin At The Right Time!
So, why not to do!
Start Insulin At The Right Time!
Adjust
&
Follow!

30. Thank You!