Unmet Needs in Diabetes:

Present and Future from

Clinical Practice
Sarwono Waspadji
Diabetes and Lipid Center,
Div. of Endocrinology and Metabolism, Dept. of Medicine,
School of Medicine Univ. of Indonesia / Cipto Hospital
Jakarta

Diabetes and Cardiovascular Disease

Intensive Glycemic Control vs. Conventional,
Lessons from Landmark Studies
Patients Compliance
Glycemic Control Achievement in Indonesia
Armamentarium for Achieving Glycemic Control
Conclusion

Diabetes in SEA and the Western Pacific

Region

Prevalence of Diabetes*
2000
2030

% Increase

Southeast Asia

47

120

255 %

Western Pacific

36

71

199 %

India
China
USA
Indonesia
Pakistan
Brazil
Bangladesh
Japan
Philippines
Egypt

By 2030
Most Diabetic
Patients Will Be in Asia
Adapted from: World Health Organization. Retrieved March 14, 2007:
http://www.who.int/diabetes/facts/world_figures/en/index5.html
http://www.who.int/diabetes/facts/world_figures/en/index6.html

DM Prevalence in Indonesia
1980-1990 1.4 2.3 %
Manado
Toraja

1980-s

6.1%
0.9 % (Rural)

Prevalence of T2DM increase in line with

lifestyle changes
Koja Utara Tanjungpriok 1982
1.7 %
Kayuputih Jak-Tim
1992
5.7 %
Abadijaya, Depok
2001
12.8%
Jakarta (5 wilayah)
2005
11.8%
Ujung Pandang
2004/5
11 %
National Health Survey 2008
5.8 %
Nangapanda Ende
2010 (Rural)
DM (with OGTT)
1.55 %
IGT
2.22 %

Type 2 Diabetes is NOT a Mild Disease

Microvascular

Macrovascular
Stroke

Diabetic
retinopathy

1.2- to 1.8-fold
increase in stroke3

Leading cause
of blindness
in working-age
adults1

Cardiovascular
disease
75% diabetic patients
die from CV events4

Diabetic
nephropathy
Leading cause of
end-stage renal disease2

Diabetic
neuropathy

Erectile Dysfunction
The most secretive
Complication of DM

Diabetic Foot

Leading cause of
non-traumatic lower
extremity amputations5

ong DS, et al. Diabetes Care 2003;e 26 (Suppl. 1):S99S102. 2Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94
S98.
3
Kannel WB, et al. Am Heart J 1990; 120:672676. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997.
5
Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78S79.

Natural History of Disease Progression

Aggressive treatment of established cardiovascular risk factors

Macrovascular
complications
Microvascular
complications

Aggressive glycemic control

-cell function

Insulin
resistance
Blood
glucose

10

Prevention
IGT/IF
G of IGT
Prevention

0
Diagnosis

Treatment

10

Years

Type 2
diabetes

Prevention of progression of IGT to Type 2 DM

Adapted from Bergenstal RM, et al. Diabetes mellitus, carbohydrate metabolism and lipid disorders. In

HbA1c and
the multivariable adjusted hazard of
various chronic
consequences of diabetes
7

Amputation or
death for PAD

6
Retinal or renal
disease

Hazard Ratio

5
4

Cataract extraction
Heart failure
Myocardial infarction
Stroke

3
2
1
0
5.5

6.5

Gerstein HC. Circulation. 2009;119:773-5

7.5

8.5

9.5

10.5 HbA1c (%)

Early and Intensive Glycemic Control

Delays Diabetes Complication

Adjusted Incidence per 1000

Person Years (%)

The Lower the Glycemia, the Lower the

Risk of Complications
UKPDS 35 (n=3642)
160
140
120
100
80
60
40
20
0

10

Updated Mean HbA1c Concentration (%)

From Stratton et al. BMJ. 2000;321:405-12.

11

Diabetes and Cardiovascular Disease

Intensive Glycemic Control vs. Conventional
Lessons from Landmark Studies
Patients Compliance
Glycemic Control Achievement
Armamentarium for Achieving Glycemic Control
Conclusion

Lessons from the large trials

ACCORD, ADVANCE and VADT
ACCORD
Number (N)
Length of Study
% with major CVD
Diff. of HbA1c

ADVANCE

10. 251
10 yrs

11. 140
8 yrs

35 %
6.4 vs. 7.5

32 %
6.5 vs. 7.3

Renal end-point Red. 21 % (p=0.005)

32 % (p=0.0013)
Primary CV outcome - 10 % ns
Mortality (overall)

+ 22 % (p=0.04)

CV mortality

+ 39 % (p=0.02)

21 % (p=0.006)

VADT
1. 791
11.5 yrs
40 %
6.9 vs. 8.4
33 % (p=0.001)

ns

-13% ns

- 12 %

+ 6.5 % ns
+ 25 % ns

Riddle MC, Karl DM. Practical lessons from ACCORD etc. Diabetes Care. 2012:35;2100-7

The Nice-Sugar Study

ICU setting 3 or more consecutive days
Intensive (81-108 mg/dL)
Conventional (<180 mg/dL)
Outcome mortality at 90 days
3054 intensive control vs. 3050 conventional
Similar characteristic baseline
Primary outcome available for 3010 and 3012 respectively
829 (27.5 %) mortality in intensive control, OR 1.14
751 (24.9%) mortality in conventional group
Severe hypoglycemia (< 40 mg/dL)
206 (6.8%) in intensive control
15 (0.5 %) in conventional group

Hypoglycaemia in T2DM: a possible link to

increased CV risk/events
Possible mechanisms1,2

Hypoglycaemia as link to tissue ischaemia3

Haemodynamic changes:

activation of autonomic nervous system

10-50 fold increased secretion of
adrenaline & noradrenaline

ECG changes:

longer QT interval
hypokalaemia

Haemorheological changes:

*P <0.01

Episodes accompanied by
cardiac symptoms (%)

20

platelet activation
increased viscosity

vs episodes during hyperglycaemia and normoglycaemia

Desouza CV et al. Diabetes Care 2010;33:13891394;
2
Robert TC et al. Diabetes 2003;52:146974;
3
Desouza C et al. Diabetes Care 2003; 26:14851489
1

15

10
5

0
Study of 72-h continuous glucose monitoring and
simultaneous cardiac Holter monitoring in patients with
T2DM treated with insulin and history of frequent
hypoglycaemia and coronary artery disease (n=19)
54 episodes of hypoglycaemia reported (BGL <70 mg/dl)
59 episodes of hyperglycaemia reported (BGL >200 mg/dl)

13

Fear of hypoglycaemia is a major

concern for patients
Male Female

Severe hypoglycaemia
Male Female

Mild hypoglycaemia
Male

Female

Kidney problems
Male Female

Blindness
Not worried

Very worried

Visual analogue scale showing patients worries about mild and severe
hypoglycaemic events, ranging from not worried to very worried
Pramming S, et al. Diabet Med .1991;8:21722

14

Weight gain in T2DM: a common

side effect post treatment

Weight gain is a common side

The vicious circle of type 2 diabetes
effect
OAD of
agents
Weight treatments
change (kg)
diabetes

Obesi
ty

Metformin13
SUs14

Insulin
resistan
ce

Treatme
nt
Type 2
Diabet
es

3.80.5
0.41.7
0.94.6

TZDs46
Meglitinides4,7,8
Metformin +
SU13
Metformin +
TZD5,6,9

0.33.0
0.31.9
0.82.1

5 4 3 2 1 0 1
Weight
Weight
loss
neutral

OAD=oral antidiabetic drug; SU=sulfonylurea; TZD=thiazolidinedione

Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb Company, 2004. 2Glucovance [package
insert]. Princeton, NJ: Bristol-Myers Squibb Company, 2004. 3Metaglip [package insert]. Princeton, NJ: BristolMyers Squibb Company, 2002. 4Malone M. Ann Pharmacother 2005; 39: 20462055. 5Actos [package insert].
Indianapolis, Ind: Eli Lilly and Company, 2004. 6Avandia [package insert]. Research Triangle Park, NC:
GlaxoSmithKline, 2005
7
Starlix [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2004
8
Prandin [package insert]. Princeton, NJ: Novo Nordisk, Inc, 2004
9
Avandamet [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2005
1

4 5
Weight
gain

Side Effects Negatively Impact

Patient Compliance
Linear Regression Analysis (n=445)
Variable

P Value

Age

<0.05

Comorbidity
Duration of disease
Depression symptom
score

<0.001

Multitherapy
Race
Income

Perceived side effect(s) of

0.2
medication
Less

0
0.
0.
0.1
1
2
compliant More compliant

<0.01

Chao J, et al. Clin Ther. 2007;29:177-80.

Weight gain is associated with lower

treatment satisfaction
Treatment
satisfaction score side efects*

100

p<0.0001 throughout vs. no

weight gain

94.4
92.4
91

89.1

90

82.3

81.2

80

No

Yes

Reported
weight gain

<4.5
(<10)

4.59.1 9.513.6
(1020) (2130)

>13.6
(>30)

Weight gain kgs (lbs)

*Treatment Satisfaction Questionnaire for Medication v.1; TSQM score range: 0100
(greatest satisfaction)
Adapted from Marret E, et al. Diabetes, Obesity and Metabolism. 2009;11:113844.

Diabetes and Cardiovascular Disease

Intensive Glycemic Control vs. Conventional
Lessons from Landmark Studies
Patients Compliance
Glycemic Control Achievement
Armamentarium for Achieving Glycemic Control
Conclusion

Poor compliance:
an important medical problem
Poor or erratic compliance is most common when:

The treatment is preventive

The patient is frequently asymptomatic
Therapy is long-term
Therapy is associated with significant
side effects

Rand C. Am J Cardiol. 1993; 72: 68-74D.

Compliance:
influenced by several factors
Compliance is frequently compromised by
more than one barrier
Social and economic factors
Healthcare team/system
Condition-related factors
Therapy-related factors
Patient-related factors
WHO. Compliance to long-term therapies: evidence for action. Geneva: WHO, 2003.

Consequences of poor compliance

Lack of compliance leads to:1
Reduction in effectiveness of treatment
Poor health outcomes and increased health care costs
Reduced quality of life
Increasing the effectiveness of adherence interventions
may have a far greater impact on the health of the
population than any improvement in specific medical
treatments2
1. WHO. Compliance to long-term therapies: evidence for action. Geneva: WHO, 2003;
2. Haynes RB et al. The Cochrane Database of Systematic Reviews 2002, Issue 2.

Patients need support, not blame

Patient-related factors not necessarily
the biggest barrier to compliance
focus on provider/health system-related
determinants (e.g. feedback, short consultations etc.)
Support patients in their efforts at self-management
More effective interventions are essential
WHO. Compliance to long-term therapies: evidence for action.
Geneva: WHO, 2003.

New Era In treating

Type 2 DM
Therapies

Addressing underlying
pathophysiology

Weight neutral/weight reducing

Reduced Hypoglycaemia risk

Individualised therapies
complex co-morbidities interactions

Early Therapeutic intervention

Improved compliance

g Improved RiskCheng
Factor
control
AY, Fantus
IG. CMAJ . 2005; 172: 213

Diabetes and Cardiovascular Disease

Intensive Glycemic Control vs. Conventional
Lessons from Landmark Studies
Patients Compliance
Glycemic Control Achievement in Indonesia
Armamentarium for Achieving Glycemic Control
Conclusion

Majority of type 2 diabetes patients in US

and EU have inadequate glycemic control
US1
80

80

64%

60
40

36%

20
0

69%

60
40

31%

20
0

< 7%

7%

HbA1c (%)
1

Subjects (%)

100

Subjects (%)

100

EU2

6.5%

> 6.5%

HbA1c (%)

Koro CE, et al. Diabetes Care. 2004; 27:1720. 2Liebl A. Diabetologia. 2002;
45:S238.

26

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

% Target Achievement
70

58

60
50

44

40

40

37.4

34.45

30

16

20
10
0

China

South Korea

Panama

Egypt

Indonesia DIabCare-Indonesia

40.6

HbA1c
Measurement

59.4
A1c Measurements
No A1cMeasurements

OGLD
HbA1c
OGLD Insulin
+
Group
Insulin
<7%
14.3
32.9
15.8
HbA1c
8.49
8.12
8.58
Mean (SD) (1.42) (2.12)
(2.61)

Diet +
Exerci Total
se
44.4
30.5
7.04
8.27
(1.18) (2.19)
IDMPS Indonesia

Comorbidities and
Complications
Variable
Type 2 DM
Hypertension
Yes with treatment
Yes but no treatment
No hypertension
Dislipidemia
Yes with treatment
Yes but no treatment
No dislipidemia
Late complication
At least one
No complication

Lifestyle

OGLD

Insulin +

Total

8 (38.1)
0
13 (61.9)

230 (44.2)
17 (3.3)
273 (52.5)

59 (45.4)
5 (3.8)
66 (50.8)

297 (44.3)
22 (3.3)
352 (52.5)

8 (40.0)
4 (20.0)
8 (40.0)

179 (42.6)
36 (8.6)
205 (48.8)

53 (50.0)
12 (11.3)
41 (38.7)

240 (44.0)
52 (9.5)
254 (46.5)

9 (69.2)
4 (30.8)

290 (70.6)
121 (29.4)

97 (85.8)
16 (14.2)

396 (73.7)
141 (26.3)

Most diabetic patients have at least one late diabetic complication

Diabetic Complications
60

Microangiopathy >>
Macroangiopathy

54

50

Re nopathy
Neuropathy
Proteinuria

40
30

Dialysis

33.4

Foot Ulcer
26.5

Amputa on
Angina
MCI

20
10.9

8.7
10
0.5
0

7.4
1.3

5.3

2.7

5.3

Heart Failure
Stroke
PAD
IDMPS Indonesia

Resource Use
Variable
Specialty
GPs/ internists
Endocrinologists
Follow up in the last 3
months
By GPs/ internists
Followed up
None
By endocrinologists
Followed up
None

Type 2 DM

Lifestyle

OGLD

Insulin +

Total

13 (61.9)
8 (38.1)

387 (74.0)
136 (26.0)

71 (54.6)
59 (45.4)

471 (69.9)
203 (30.1)

1 (33.3)
2 (66.7)

105 (60.7)
68 (39.3)

23 (47.9)
25 (52.1)

129 (57.6)
95 (42.4)

13 (100.0)
0

332 (95.4)
16 (4.6)

96 (98.0)
2 (2.0)

446 (96.1)
18 (3.9)

Education Session
Variable
Lifestyle
Diabetes education
Given
None
Mean (SD)
Median

8 (40.0)
12 (60.0)
6.8 (4.7)
3.0

Type 2 DM
OGLD
Insulin +
168 (34.6)
317 (65.4)
4.1 (3.3)
3.0

49 (41.2)
70 (58.8)
4.3 (3.9)
7.0

Total
225 (36.1)
399 (63.9)
4.2 (3.5)
3.0

Only 36.1% of diabetic patients had

formal diabetic education session

Awareness, agreement and adherence of

physicians to
Indah S. Widyahening,
Geert JMG
van der Heijden,
Pradana
type 2 diabetes
guideline
in Indonesia
Soewondo, Yolanda van der Graaf

Characteristics
Participation in DM training
(n=367)
Yes
Number of DM patients seen in
a week (n=343)
Proportion of DM patients
among all patients seen
(n=381)
<10%
10-30%
>30%

n (%)

Minmax

1-120

234 (64)

243 (64)
117 (31)
21 (5)

Awareness to DM consensus
(n=383)
Never know
Heard but never had
Had but never read

Media
n

43 (11)
138 (36)
78 (20)

GPs' awareness of, agreement with, adoption of, and

adherence to selected recommendations of the Indonesian
T2DM guidelines

Indah S. Widyahening, Geert JMG van der Heijden, Pradana

Diabetes and Cardiovascular Disease

Intensive Glycemic Control vs. Conventional
Lessons from Landmark Studies
Patients Compliance
Glycemic Control Achievement
Armamentarium for Achieving Glycemic Control
Conclusion

New Era In treating

Type 2 DM
Therapies

Addressing underlying
pathophysiology

Weight neutral/weight reducing

Reduced Hypoglycaemia risk

Individualised therapies
complex co-morbidities interactions

Early Therapeutic intervention

Improved compliance

g Improved RiskCheng
Factor
control
AY, Fantus
IG. CMAJ . 2005; 172: 213

Pathogenesis of T2DM: the 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

Current Available Treatments:

Unmet Needs in T2DM Management

Insulin Resistance
(Impaired insulin action)

Pancreatic Islet Dysfunction

Inadequate
glucagon
suppression
(-cell
dysfunction)

Metformin

TZDs

Insufficient
Insulin
secretion
(-cell
dysfunction)

Progressive
decline of -cell
function

Sulfonylureas
Glinides

DPP-4 Inhibitor
Weight of red arrows reflects the degree to which DPP-4 inhibitors influence the disease mechanisms.
DPP-4=dipeptidyl peptidase-4; TZD=thiazolidinedione; T2DM=type 2 diabetes mellitus.
Adapted from DeFronzo RA. Br J Diabetes Vasc Dis 2003;3(Suppl1):S24S40

Traditional oral glucose-lowering agents do not

cover the entire pathophysiology of T2DM
Glucose
absorption

Insulin
resistance

-glucosidase
inhibitors1

TZDs2
Metformin1

Inadequate
glucagon
suppression

Incretin
Based
Therapy

Acute
-cell
dysfunction

sulphonylurea1
Glinide1

Blood glucose / A1c

Chronic
-cell
insufficiency

Incretin
Based
Therapy

CV
Outcomes
??

TZDs = thiazolidinediones
1. Inzucchi SE. JAMA. 2002;287:360372; 2. DeFronzo RA. Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24S40.

End-Point Studies with diferent Classes of

Antidiabetic Drugs for the Treatment of Patients
with Type 2 Diabetes Mellitus

c Drug Class

Positive End-Point Studies: Reduction of

Death, Myocardial Infarction or Stroke

Biguanides (Metformin, Buformin, Phenformin)

Metformin: yes
Sulfonylureas (Glibenclamide, Glimepiride, Gliclazide)
no
Glinides (Repaglinide, Nateglinide)
no
-Glucosidase Inhibitors (Acarbose, 7500,Feb 2009Oct 2014) On going
Glitazones (Troglitazon, Pioglitazone, Rosiglitazone) Pioglitazone: yes
Glitazares (Muraglitazar)
negative
Insulins
no
Insulin-Analogues
no
Proinsulin
negative
GLP-1 Analogues (Exenatide, Liraglutide, Exenatide LAR)
?
Saxagliptin (Savor TIMI Sept 2013- 16,500, 900 days )
non inferior
Linagliptin (Carolina June 2013, 9500, 12 104 wks) vs. Glim. On going
Alogliptin (Examine White et al. NEJM 369(2013)1327-35)
non inferior

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

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

Obat Baru ??
SGLT-2 inhibitor
May be YES, May be NO

Conclusion

Type 2 diabetes is characterized by an initially

metabolically
induced insulin resistance and a genetically
determined -cell
dysfunction as well as Alpha cells impairment

Many patients do not meet treatment goals

causing escalating
chronic complications
problems

Polypharmacy is often required to achieve

adequate glycaemic
control with an increased risk of adverse effects
as a result of
age-related changes in drug metabolism
There are unmet medical needs with the current
T2DM
treatment.

Personal Healthcare Service Flow *

*Diambil dari alur pelayanan kesehatan PT. Askes

Health Care Services Flow

Members

Captiation

Primary Care
Provider

Referral

BPJS Center

Drug Prescription

Hospital

Emergency

Claim Ina
CBG

Apotek

BPJS
Branch Office

Primary Care Provider as a Gate Keeper

Disease Management Program (DM Type2)

Why DM Type 2:
big trigger for other
chronic
Hospital
Start from June 2010
(Medical Specialist)
- Members Database
- Reminder activity
- Health Promote
(Media)
- Club Chronic for
Members

PT Askes
(Persero)

Members
Chronic Disease
DM Tipe2
(individual
treatment)

Referral
- Comprehensive & Continued Care
control
(Guidelines Evidence Based) Mentor &
- Referral to the advanced level consultant for
- Health Education
GPs
- Health Status Monitoring
- Prescription chronic
drugs

- Health status evaluation and

feedback
- Health care cost
- Workshop for family Physician (DM
Family Physician
Type2)
by endokrin specialist

DM Guidelines
MEDICAL PROFESIONAL ORGANIZATION
PERHIMPUNAN ENDOKRINOLOGI INDONESIA (PERKENI)

7 PILAR PPDM 2
KONSU
L-TASI
MEDIS
REMINDE
R

KLUB
RISTI
PENYULU
HAN
OLAHRAGA

7
PILA
R
PPD
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PEMANTAUAN STATUS
KESEHATAN

CLINICA
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GUIDELI
NE

PELAYAN
AN OBAT
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