The Unmet Need in Diabetes:

Present and Future from Clinical

Perspective

T2D is already a major healthcare burden

4.6
million

The number of deaths annually from

diabetes*1

510
years

The average reduction in life expectancy of a

person with T2D2

23
million

Life-years lost due to disability and reduced

quality of life caused by diabetes-related
complications1

US
$465
billion

The global healthcare expenditure attributed

to diabetes*1

*Estimated for 2011.

1. International Diabetes Federation. Diabetes Atlas, Fifth Edition: www.diabetesatlas.org. Accessed 25 June 2012.
2. International Diabetes Federation. Fact Sheet: Diabetes and Cardiovascular Disease: http://www.idf.org/fact-sheets/diabetes-cvd.
Accessed 25 June 2012.

Risk of complications decreases as HbA1c

decreases

Incidence per
1,000 patient-years

80

Microvascular
complications

Normal
HbA1c
levels

60

40
Myocardial
infarction

20

0
0

10

11

Updated mean HbA1c (%)

Stratton IM, et al. BMJ. 2000; 321:405412.

Lowering HbA1c reduces the risk of

complications
21%

Deaths related
to diabetes

37%

Microvascular
complications

14%

Myocardial
infarction

HbA1c
1%

Stratton IM, et al. BMJ . 2000; 321:405412

Stratton IM, et al. BMJ 2000; 321:405412.

Majority of type 2 DM patients in Asia Pacific fail

to achieve glycemic control (HbA1c < 7.0%)
Australia

Thailand

Singapore

India

Indonesia

(St Vincents1)

(Diab Registry2)

(Diabcare3)

(DEDICOM4)

(Diabcare5)

30.0%

30.2%

70.0%

69.8%

Hong Kong

China

(Diab Registry )

(Diabcare )

39.7%
60.3%

33.0%

41.1%

37.8%

67.0%

S. Korea
(KNHANES )
8

43.5%
58.9%

56.5%

37.8

32.1%

62.2%62.2

67.9%

Malaysia
(DiabCare9)
22.0%

HbA1c at or below
target
HbA1c above target

78.0%

DM, diabetes mellitus; HbA1c, glycated hemoglobin.

1. Bryant W, et al. MJA 2006;185:3059. 2. Kosachunhanun N, et al. J Med Assoc Thai 2006;89:S6671. 3. Lee
WRW, et al. Singapore Med J 2001;42:5017. 4. Nagpal J & Bhartia A. Diabetes Care 2006;29:2341

8. 5.

Soewondo P, et al. Med J Indoes 2010;19:23544. 6. Tong PCY, et al. Diab Res Clin Pract 2008;82:346
52. 7. Pan C, et al. Curr Med Res Opin 2009;25:3945. 8. Choi YJ, et al. Diabetes Care 2009;32:2016

-cell function continues to decline regardless of

intervention in T2DM
Progressive Loss of -cell Function
Occurs prior to Diagnosis

100

Sulfonylurea (n=511)
Diet (n=110)

-cell Function (%)*

Metformin (n=159)

80
60
40
20
0
5

Years since Diagnosis

T2DM=type 2 diabetes mellitus.

*-cell function measured by homeostasis model assessment (HOMA).
Adapted from UKPDS Group. Diabetes. 1995; 44: 12491258.

Glycaemic Control along using SU Based:

No sustainability of Glycemic Control with Sulfonylureas

DeFronzo (Diabetes 2009; 58:773-795)

ADA/EASD Algorithm:

As the progressive decline in beta cell function is a key factor

limiting long-term glycaemic control, more consideration should be
given to drugs with beta cell-preserving properties
Schernthaner G et al Diabetologia (2010) 53:12581269

Unmet Needs
Type 2 DM Control is Not Durable

12

15

18

21

24

27

30

Time (months)

omgarden, ZT. Diabtes Care. 2007;30(1):174-180.

33

36

39

42

45

Traditional stepwise approach provides only

conservative glycaemic control

Diet and
exercise

OAD
OAD*
monotherapy
monotherapy up-titration

OAD
dual
therapy

OAD
triple
therapy

OAD +
OAD +
multiple daily
basal insulin insulin injections

HbA1c (%)

10
9
8
HbA1c 7% ADA1

HbA1c 6.5% AACE2

6
Duration of diabetes
*OAD = oral anti-hyperglycaemia drugs

Adapted from Campbell IW. Br J Cardiol 2000;7:625-31

1. American Diabetes Association Clinical Practice Recommendations: Diabetes Care 2010;33(suppl.1):S4-10
2. AACE/ACE. Endocr Prac 2009;15:540-59

Algoritma Pengelolaan DM tipe 2 tanpa Dekompensasi

Kadar HbA1c
<7%

7-8%

GHS

GHS
+
Monoterapi

Gaya
Hidup
Sehat
- Penurunan
berat badan
- Mengatur
diit
- Latihan
Jasmani
teratur
Catatan:

Met, SU, AGI,

Glinid, TZD, DPPIV

8-9%

GHS
+
Kombinasi
2 obat
Met, SU, AGI,
Glinid, TZD, DPPIV

>9%

9-10%

>10%

Konsensus PERKENI
2011
GHS
+
Kombinasi
3 obat

GHS
+
Kombinasi
2 obat

Met, SU, AGI,

1. Dinyatakan gagal bila
Glinid, TZD, DPPdengan terapi 2-3 bulan
IV
tidak mencapai target
Met, SU, AGI,
HbA1c <7%
Glinid, TZD
3. Bila tidak ada
pemeriksaan HbA1c
dapat digunakan
+
pemeriksaan glukosa
Basal Insulin
darah.
Rata-rata glukosa darah
sehari dikonversikan ke
HbA1c menurut kriteria
ADA, 2010
* Insulin intensif : penggunaan insulin basal bersamaan dengan insulin

GHS
+
Insulin
Intensif*

Unmet Needs With Conventional

Antihyperglycemic Therapies
Many therapies are associated with weight gain
Insulin and non incretin oral insulin secretagogue
therapies are associated with significant risk for
hypoglycemia
Other AEs with some therapies include GI side effects
and edema
Many therapies fail to adequately control
postprandial hyperglycemia
Therapies often fail to maintain long-term glycemic
control
Blonde L. Am J Manag Care. 2007;13:S36-S40.
Blonde L, et al. J Manag Care Pharm. 2006;12(suppl):S2-S12.

Most current therapies for T2DM promote

weight gain

Glibenclamide (n=277

Change in weight (kg)

UKPDS 34 Study

Conventional*
(n=411)
Metformin (n=342)

6
5

Insulin (n=409)

4
3
2
1
0

12

Years from randomization

Up to 5 kg is already gained within just 3 years

with a sulphonylurea or insulin
*Diet initially then sulphonylureas, insulin and/or metformin if FPG>15
mmol/L
UKPDS 34 Study. Lancet 1998:352:85465

Hypoglycaemia - Why is this important?

Hypoglycaemia is linked to cardiac arrythmias1

Up to 38% of people with type 2 diabetes experience
symptomatic hypoglycaemia2
o

It is believed that many incidences of hypoglycaemia go unreported

to healthcare professionals3

Hypoglycaemia results in reduced quality of life, treatment

satisfaction and therapy adherence2,4
Hypoglycaemia is a barrier to optimal insulin dose titration and
the achievement of glycaemic control5

Hypoglycaemia is associated with cognitive dysfunction and

delayed recovery in the elderly6

Hypoglycaemia is associated with increased anxiety7

1. Nordin C. Diabetologia.2010; 53: 155261. 2. Alvarez Guisasola F, et al. Diab Obes Metab. 2008; 10 Suppl 1: 2532.
3. Leiter LA, et al. Can J Diab. 2005; 29: 18692. 4. Jermendy G, et al. Health Qual Life Outcomes. 2008; 6: 88. 5.
Briscoe VJ, et al. Clin Diab. 2006; 24: 11521. 6. Zammitt N, et al. Diabetes. 2008; 57: 7326. 7. Labad J, et al.

Challenge in treating patients with

T2DM
Improve glycemic control without compromising
safety i.e hypoglycemia
Preserve beta-cells function
Provide clinically meaningful weight loss
Address cardiovascular risk factors accompanying
diabetes
Offer a simple and flexible regimen
De Fronzo Ra et al.Diabetes care 2013, 36 (Suppl2) : S127-S138

Ominous Octet
TZDS
GLP1
DPP4i

GLP1
DPP4i

TZDs

SGLT2
i
GLP1
DPP4
iG

TZDs,GLP1
TZDs,
MET
GLP1,DPP4i

eFronzo RA. Diabetes. 2009;58:773-795.

GLP1

Based on the pathophysiology

background
Effective treatment will require multiple drugs
combination to correct the multiple
pathophysiological defects
Treatment should be based upon establish
pathogenic abnormalities and not simply on
HbA1c reduction
Therapy must be started early in the natural
history of T2DM to prevent progressive beta-cell
failure
De Fronzo Ra et al.Diabetes care 2013, 36 (Suppl2) : S127-S138

AACE Guidelines 2013:

When Metformin/1st OAD is not enough, we can directly move to start with
combination 2 OAD directly

18
AACE Guidelines 2013. Endo Prac 2013;19:327-36

Summary
Therapy should have the ability to achieve the
desired level of glycemic control, based upon
starting HbA1c
In most newly diagnosed diabetic patients, mono
therapy will not reduce HbA1c< 6.5-7% or most
optimally < 6% and combination therapy will be
required
Medications used in combination therapy should
have an additive effect
Progressive beta-cells failure is responsible for
progressive HbA1c rise inT2DM

Summary
Insulin resistance is a core defect in T2DM and
exacerbates the decline in -cells function,
medication should ameliorate IR in muscle/liver
That drugs exert beneficial effects on
cardiovascular risk factors and decrease
cardiovascular events
Combination therapy should be weight neutral
and if possible promote weight loss
Combination therapy should be safe and not
exacerbate underlying medical conditions

thank you

Limits to getting patients to

target
Limited efficacy on glycaemic control
Hypoglycaemia
Weight gain
Side effects other than weight gain or
hypoglycaemia

22

AACE Guidelines 2013. Endo Prac 2013;19:327-36

New Classes Presently in Development

Long-acting GLP-1 receptor agonists

Ranolazine
Dual & Pan PPAR agonists
11 Hydroxysteroid Dehydrogenase (HSD)- 1 inhibitors
Fructose 1,6-bisphosphatase inhibitors
Glucokinase activators
G protein-coupled Receptor (GPR)- 40 & -119 agonists
Protein Tyrosine Phosphatase (PTB)- 1b inhibitors
Camitine- Palmitoyltransferase (CPT)- 1 inhibitors
Acetyl COA Carboxylase (ACC)- 1 & -2 inhibitors
Glucagon receptor antagonists
Salicylate derivatives
Immunomodulatory drugs
Sodium- Glucose Cotransporter (SGLT) {-1} & -2 inhibitors

New Era In treating Type 2

Diabetes
Therapies
Addressing underlying pathophysiology
Weight neutral/weight reducing
Reduced Hypoglycaemia risk

Individualised therapies complex comorbidities interactions

Early Therapeutic intervention
Improved compliance
g Improved Risk Factor control
g Improved outcomes

Cheng AY, Fantus IG. CMAJ . 2005; 172: 2132