DMCombos JDM2014

Finding the Right Combination Therapy
of Anti Diabetic Drugs
Sarwono Waspadji
Diabetes and Lipid Center,
Div. of Endocrinology and Metabolism, Dept. of Medicine,
School of Medicine Univ. of Indonesia / Cipto Hospital
Jakarta
Diabetes Mellitus and Its Management in General

Glycemic Control Achievement and Related Factors
Pathophysiology of Hyperglycemia and Treatment of T2DM
Combinations of Hypoglycemic agents
Finding the Right Combination Oral-Oral
Finding the Right Combination Insulin-Oral
Conclusion
Global Burden of Diabetes

80% of people with diabetes live in
low- and middle-income countries
The greatest number of people with
diabetes are between 40 to 59 years
of age
183 million people (50%) with
diabetes are undiagnosed
Diabetes caused 4.8 million deaths
in 2012
Diabetes caused at least USD 471
billion dollars in healthcare
http://www.idf.org/diabetesatlas/5e/Update2012 Accessed 15 Dec 2012
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 %
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 (%)
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
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.
Early and Intensive Glycemic Control

Delays Diabetes Complication
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
AACE Comprehensive Diabetes Management Algorithm. Endocrine Practice. 2013;10(2):331
Individualized Treatment based on several criteria to control

blood glucose
Diabetes Care. 2012;35(6):1364-79
Slide 13
Inzucci SE, et al. Diabetologia. 2012

Conclusion
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%
33.0%
69.8%
Hong Kong
China
(Diab Registry )
(Diabcare )
39.7%
60.3%
15
41.1%
58.9%
37.8%
67.0%
S. Korea
(KNHANES )
8
43.5%
56.5%
37.8
32.1%
62.2%62.2
67.9%
Malaysia
(DiabCare9)
22.0%
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;29:23418.
5. Soewondo P, et al. Med J Indoes 2010;19:23544. 6. Tong PCY, et al. Diab Res Clin Pract 2008;82:34652.
7. Pan C, et al. Curr Med Res Opin 2009;25:3945. 8. Choi YJ, et al. Diabetes Care 2009;32:201620.
9. Mafauzy M, et al. Med J Malaysia 2011;66:17581.
HbA1c at or below
target
HbA1c above target
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
Complications of T2 DM Present at
Diagnosis
Complication
Prevalence (%)*
Any complication 50
Retinopathy 21
Abnormal ECG 18
Absent foot pulses ( 2) and/or ischaemic feet
14
Impaired reflexes and/or
decreased vibration sense
7
MI / angina / claudication ~2-3
Stroke / transient ischaemic attack ~1
* Some patients had more than one complication at time of
diagnosis
Adapted from UKPDS VIII. Diabetologia. 1991; 34: 87790.
-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.
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
Cheng AY, Fantus IG. CMAJ . 2005; 172: 213
How to Get Closer to Near-Normalization

of Glycemic Control
Approach each patient individually
Consider main defects ( Insulin resistance,
Hepatic glucose production, B cell defficiency
Use different drug with different mechanism
Target postprandial glucose control
21
Meta-analyses of RCTs on macrovascular outcomes with

intensive glycaemic control: summary and recommendations
Two meta-analyses show consistent CV benefit with intensive glucose

lowering:1,2
HbA1c reduction with ~5 years of follow-up was 0.9%
1517% RRR for MI
9% and 15% RR for CV and CHD events, respectively
No increased risk of stroke or all-cause mortality
Practical clinical implications
Initiate therapy early, before any micro- or

macrovascular disease
Reduce HbA1c steadily with care taken to avoid
hypoglycaemia
A combination of glucose-lowering
agents may be needed to achieve lower
CHD, coronary heart disease; CV, cardiovascular; HbA1c, glycated haemoglobin; MI,
glycaemic
targets
myocardial infarction; RCT,
randomised controlled
trial; RR, relative risk; RRR, relative risk
reduction
1. Ray KK, et al. Lancet. 2009;373:176572. 2. Turnbull FM, et al. Diabetologia. 2009;52:2288
98.

Pathophysiology of Hyperglycemia and

Treatment of T2DM
Conclusion
Pathogenesis of T2DM: the Ominous Octet

TZD
S
GLP1
DPP
4i
GLP1
DPP4i
TZDs
SGLT
2i
GLP
1DP
P4iG
TZDs,
MET
GLP1,DPP
4i
eFronzo RA. Diabetes. 2009;58:773-795.
GLP1
TZDs,GLP
1
INSULIN RESISTANCE
DEFECTIVE
INSULIN SECRETION
HYPERGLYCEMIA
Nutrient absorption
CHO absorption
Pathophysiological Basis
of Conventional Diabetes Therapies
HbA1c Level
7-8%
Lifestyle
Modification
Lifestyle
Modification
PERKENI Guideline 2011
<7%
+
Monotherapy
Met, SU, AGI,
Glinid, TZD,
DPP-IV
8-9%
>9%
9-10%
>10%
Lifestyle
Modification
+
2 OADs
Combination
Met, SU, AGI,
Glinid, TZD,
DPP-IV
Notes :
Fail : not achieving A1c target <7% after 23 months of treatment.
(A1c = average blood glucose conversion,
ADA 2010)
Lifestyle
Modification
+
3 OADs
Combination
Met, SU, AGI,
Glinid, TZD,
DPP-IV
Lifestyle
Modification
+
2 OADs
Combination
Met, SU, AGI,
Glinid, TZD
+
Lifestyle
Modification
Basal Insulin
+
Intensive
Insulin
ADA-EASD
Guideline
Initial
Drug
Combinat
ion
Advance
Combination
AACE Comprehensive Diabetes Management Algorithm. Endocrine Practice. 2013;10(2):332

Finding the Right Dose Combination Oral-Oral
Finding the Right Dose Combination Insulin-Oral
Conclusion
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
Need for an early and intensive approach

to type 2 diabetes management
At diagnosis of type 2
diabetes:
50% of patients already have complications1
up to 50% of -cell function has
already been lost2
Current management:
two-thirds of patients do not
achieve target HbA1c3,4
majority require polypharmacy
UKPDS Group. Diabetologia. 1991; 34:87790.

Holman RR. Diabetes Res Clin Prac. 1998; 40 (Suppl.):S215.
5
3
Saydah SH, et al. JAMA. 2004; 291:33542.
4
Liebl A, et al. Diabetologia. 2002; 45:S238.
5
Turner RC, et al. JAMA. 1999; 281:200512.
to meet glycemic goals over time
UKPDS: Loss of Glycaemic Control

over Time with Traditional Agents
HbA1C (%)
Cohort, median
values
8
Conventional
Glyburide
Chlorpropamide
Metformin
Insulin
ULN =
6.2%
6
0
2
4
6
8
Years from randomisation
10
UK Prospective Diabetes Study (UKPDS) Group. UKPDS 33. Lancet 1998;

352: 83753.
Limited duration of glucoselowering efficacy of

antidiabetic
monotherapy
Data from overweight
patients
Duration of follow-up
Turner RC et al. JAMA . 1999;281:20
Rationale for Combination Therapy

In the UKPDS, 50% patients at 3 years and 75%
patients at 9 years needed combination therapy.
Up-titrating monotherapy to the maximum

recommended dose may not provide benefit.
Delays often occur between stepping up from
monotherapy to combination therapy.
HbA1c 7%
HbA1c <
7.5%
CHINA
(CODIC-2)1,2
CANADA
(DICE)
HbA1c < 7%
(NHANES)4
HbA1c <
6.5%
EUROPE
(CODE-2)5
37%
63%
31%
69%
USA
49% 51%
32%
68%
1. Xingbao C. Chinese Health Economics 2003; 2. Ling T. China Diabetic Journal 2003;
3. Harris SB et al. Diabetes Res Clin Pract 2005; 70: 907; 4. Saydah SH et al. JAMA
2004; 291: 33542;
5. Liebl A et al. Diabetologia 2002; 45: S23S28.
Change in HbA1c from placebo

(%)
Up-titrating monotherapy to the

maximum recommended dose
may not provide benefit
HbA1c
10
Patients stopping
treatment (%)
-0.5
8
6
-1
-1.5
4
2
-2
-2.5
Gastrointestinal side
effects
500 1000 1500 2000 2500

Metformin dosage (mg)
500 1000 1500 2000 2500

Metformin dosage (mg)
Optimal Dose = 1500 - 2000
Garber AJ, et al. Am J Med 1997; 103:491497.
Alogliptin + Pioglitazone
Change from Baseline in A1c (%) at Wk 26
Baseline A1c
8.5
8.5
Placebo background
Alogliptin
Pioglitazone
PLC 12.5 25
15
30
45
8.5
Alogliptin 12.5 +
pioglitazone
15 30
45
8.5
Alogliptin 25 +
pioglitazone
15 30 45
HbA1c Change
From Baseline (%)
-0.13
-0.5
-0.64
-0.75
-1.0
-0.9
-0.92
-1.27
-1.34
-1.5
-2.0
-1.0
***
***p < 0.001, compared to alogliptin and pioglitazone
DeFronzo RA. el al J Clin Endocrinol Metab. 2012 May;97(5):1615-22
***
-1.39
***
-1.55
***
-1.39
***
-1.6
***
Optimal Dose
DeFronzo R, et al. Presented at: 45th Annual Meeting of the European Association for the Study of
Diabetes.September 30-October 2, 2009. Vienna, Austria. Abstract 752 and poster.
MOVING FROM
MONOTHERAPY TO
COMBINATION THERAPY
EARLIER- optimal dose

WHY?
More effective
Smaller doses, Less side
effects
Better compliance
Stepwise Strategy Can Delay Patients Achieving Goals and

Increase Complications
10
Diet and
exercise
OAD
monotherapy
OAD
uptitration
monotherapy
OAD +
OAD
combination basal insulin
OAD +
multiple daily
insulin injections
9
Mean
HbA1c
(%)1 8
7
6
Duration of diabetes
Complications2
OAD = oral anti-diabetic
1. Adapted from Campbell IW. Br J Cardiol 2000; 7: 62531;

2. Stratton IM et al. BMJ 2000; 321: 40512.
The Case for Early Combination Therapy: Reaching and

Maintaining Glycaemic Goals
10
9
HbA1c
(%)1 8
Diet and
exercise
OAD
uptitrati
on
OAD
monotherapy
OAD +
basal insulin
OAD + multiple
daily insulin
injections
OAD
combination
Mean
7
6
Complications2
OAD = oral anti-diabetic
1. Adapted from Del Prato S et al. Int J Clin Pract 2005; 59: 134555;
2. Stratton IM et al. BMJ 2000; 321: 40512.
Combination Therapy
of Type 2 Diabetes

Finding the Right Dose Combination Oral-Oral

Finding the Right Dose Combination Insulin-Oral
Conclusion
Combination Therapy for T2DM

Megiglitinide Sulphonylurea
Biguanide
Alpha Glucosidase
Inhibitor
Incretin Based
Th/
Thiazolidinedione
Insulin
SGLT-2 Inhibitor
INSULIN RESISTANCE
DEFECTIVE
INSULIN SECRETION
HYPERGLYCEMIA
Nutrient absorption
CHO absorption
Pathophysiological Basis
of Conventional Diabetes Therapies
Insulin-resistance In Type 2
Diabetes
The insulin
Pharmacological Interventions
Anti-diabetic agents which

stimulate insulin
1. Sulfonylureas/Glinides
2. DPP4-inhibitors
3. GLP1r-agonists
Other
mechanisms
sensitizers
2 anti-diabetic agents
reduce insulin-resistance
1. Metformin
2. Pioglitazone
1. -glucosidaseinhibitors
2. SGLT2-inhibitors
Improved compliance with

Glucovance vs. metformin and
glibenclamide co-administered
Adherence rate (%)
p<0.001
Glucovance
(n=105)
Met + glib
co-administered
(n=1815)
Melikian C et al. Clin Ther 2002;24:46
Combination of sulfonylurea and metformin

is safe.
Diabetes Care. 2002;25(12):2244-8
Cardiovascular Safety: Myocardial Infarction

Anti-diabetic treatment is associated with a better postMI prognosis than no treatment
28-day mortality according to antidiabetic treatment before
hospitalization for acute MI
20
Mortality at day 28 (%)
19.9%
15
10
13.3%
11.7%
10.0%
5.1%
Odds ratio
p
Glimepiride
alone
Metformin
alone
Insulin
alone
0.50
0.026
0.46
0.060
0.59
0.185
Any
combination
No antidiabetic
drug
Vaur L et al. Diabetes Metab. 2003;29:241-49
. Is the Combination of Sulfonylureas and Metformin Associated With an

Increased Risk of Cardiovascular Disease or All-Cause Mortality?
A meta-analysis of observational studies
Ajay D. Rao, MD,1 Nitesh Kuhadiya, MBBS,2 Kristi Reynolds, PHD, MPH,2,3 and
Vivian A. Fonseca, MD1
Diabetes Care. 2008 August; 31(8): 16728

RESULTS
The pooled RRs (95% CIs) of outcomes for individuals with type 2 diabetes
prescribed combination therapy of sulfonylureas and metformin were 1.19 (0.88
1.62) for all-cause mortality, 1.29 (0.732.27) for CVD mortality, and 1.43
(1.10 1.85) for a composite end point of CVD hospitalizations or mortality
(fatal or nonfatal events).
CONCLUSIONS
significantly
increased the RR of the composite end point of cardiovascular
hospitalization or mortality (fatal and nonfatal events) irrespective of the
The combination therapy of metformin and sulfonylurea
reference group (diet therapy, metformin monotherapy, or sulfonylurea

monotherapy); however, there were no significant effects of this combination
therapy on either CVD mortality or all-cause mortality alone.
Negatif
Data Terapi Pasien Baru

RSUPN CiptoMangunkusumo
Macam Terapi
N(%)
Diet Saja
Sulfonilurea
Biguanide
Acarbose
Glinid
Tiazolidindion
2003
N(%)
582(57,7)
310(30,8)
222(22,0)
3(0,3)
2(0,2)
0
2004
510(57,4)
282(31,8)
233(26,2)
11(1,2)
0
0
Data Poli Met-End 2005
Data Terapi Kombinasi Pasien Baru

RSUPN CiptoMangunkusumo
Macam Terapi Kombi 2003
Sulfo- Biguanid
Sulfo-Acarbose
Sulfo-Insulin
Biguanid- Acarbose
Biguanide-Insulin
Sulfo-Biguanid-Acarbose
Sulfo-Biguanide-Glinid
Sulfo-Biguanid- Insulin
Sulfo-Acarbose-Insulin
84
2004
78
8
3
4
2
0
0
0
4
1
Data Poli Met-End 2005
Combinations of Hypoglycemic Agents

Sulphonyl urea and-
Biguanide - Rational combination for T2DM
Acarbose
TZD
- Rational combination for T2DM
Insulin (Bed-time Insulin Daytime SU)
DPP-4 Inhibitor GLP 1 agonist
Biguanide and
- Sulphonylurea
Acarbose - GIT side effects
TZD - Rational combination for Obese T2DM
Insulin
DPP-4 Inhibitor - GLP-1 agonist
Acarbose and
- SU, Biguanide, Acarbose, Insulin,

DPP-4 Inhibitor- GLP1 A
TZD and
- SU, Biguanide, Acarbose, Insulin, DPP-4 Inhibitor GLP-1 agonist

DPP-4 Inhibitor - SU, Biguanide, Acarbose, TZD, Insulin
Insulin and
Biguanide, Acarbose, TZD, SU (not for T1DM),

DPP-4 Inhibitor GLP-1 agonist
Rational: sensible,
that can be tested by reasoning,
having logical basis
What is Rational, changes
with time,
with the current accepted concept,
with evidence based
Rational diabetes diet

No carbohydrate, high fat diet
Moderate carbohydrate (30- 40- 50 %)
High carbohydrate (50 - 60- 70%), high fibre diet
High CHO, monounsaturated fatty acid diet
Dual
Endocrine Defect of Type 2
Diabetes
Insulinresist -cell
ance 1
Metformin + insulin secretagogue
deficiency
Metformin + AGI
Metformin + DPP-4 inhibitors
Sulfonylurea + TZD
*
Sulfonylurea + AGI
Sulfonylurea + DPP-4 inhibitors
TZDs + AGI
SGLT-2 Inhibitor
Insulin Independent
Metformin + TZD
Sulfonylurea or meglitinide
TZD: thiazolidinedione
AGI: -glucosidase inhibitor
1
DPP-4
Nonglycemic Effects of Diabetes Medications
Anti-Diabetes Medications with

Their Reductions in A1c and Effects on Weight
Choosing antidiabetic agents:

efficacy
ANTIDIABETIC AGENTS
Insulin
Metformin-glucosidase TZDs*
secretagogues
inhibitors
EFFICACY
Insulin
Effect on FPG/HbA1c1
Effect on plasma
insulin1,2
Effect on insulin
resistance3
Effect on insulin
secretion4
= reduced levels
= increased levels
= no significant effect
*TZDs = thiazolidinediones
DeFronzo RA. Ann Intern Med. 1999; 131:281303. 2Lebovitz HE. Endocrinol Metab Clin North
Am. 2001; 30:90933.
3
4
Matthaei S, et al. Endocrine Reviews. 2000; 21:585618. Raptis SA & Dimitriadis GD. J Exp
Choosing antidiabetic agents:

safety and tolerability
ANTIDIABETIC AGENTS
SAFETY AND
TOLERABILITY
Insulin
Metformin-glucosidase TZDs*
secretagogues
inhibitors
Insulin
Risk of
hypoglycemia1,2
Weight gain1,2
Gastrointestinal
side effects1
Lactic acidosis1
Edema3
= treatment-related adverse
event
= not commonly seen in monotherapy

*TZDs = thiazolidinediones
DeFronzo RA. Ann Intern Med. 1999; 131:281303. 2UKPDS. Lancet. 1998;
352:83753
Special Conditions
Elderly:
Beware hypoglycemia
Multipharmacy
Drug interaction
Renal Failure: Hypoglycemia

Lactic Acidosis
Liver Failure: Hypoglycemia

Lactic Acidosis
Congested Heart Failure: Fluid accumulation /

edema
Pregnancy:
Sulphonylureas pass
placenta barrier
AACE Guidelines 2013. Endo Prac 2013;19:327-36
End-Point Studies with different 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


Conclusion
Combination Therapy in T2DM:

Insulin Plus Oral Hypoglycemic Agents
Insulin Plus Sulphonylurea - BIDS
Some insulin is endogenous, with natural secretory pattern
Biguanide Plus Insulin

Reduces hepatic resistance
May achieve better control with less insulin
Can reduce weight gain
Alpha Glucosidase Inhibitor Plus Insulin

Reduces postprandial glucose level
Thiazolidinedione Plus Insulin

Reduces peripheral insulin resistance
Reduces insulin requirement
Must balance TZD and insulin carefully to minimize weight gain
Insulin is needed whenever there is

Insufficient Endogenous Insulin Production
Insulinopenia : suggested by clinical findings
Thinner patient
Weight loss
Marked hyperglycemia
Ketonuria
Unstable glucose pattern
Insulin combination with OHA:

Meta-analysis
Comparison between Insulin and
Combination Insulin and OHA
Weight gain : Less in combination with Metformin
No difference with Sulphonylurea
More with Thiazolidinedione
Hypoglycemia: Less in combination with Metformin
No difference with Sulphonylurea
No difference with Acarbose
More with Thiazolidinedione
Jarvinen HK. Diabetes care, 2001; 24(4):758-67
Combination Therapy OHA with Insulin

Meta-analysis
Glycemic control
Insulin Nave Patients: 15 comparisons
Most (11 of 15 studies) similar,
4 studies: combination was better
Previously insulin treated : 25 comparisons
Most (19 of 25) studies: combination was better
Insulin needs
Combination OHA+Insulin : less insulin needed

Insulin nave patients: Mean insulin sparing: Metformin 32 %
Sulphonylurea 42 %
Thiazolidinedione 53 %
Metformin and Sulphonylurea 62 %
Previously insulin treated :
Mean insulin sparing: metformin 19 %
S.U
21 %
More than 63 different configurations of

Combination OHA + Intermediate Insulin
Even more if the insulin varied:
Long acting
Short acting
Mixed short and long acting ,
different composition of mixture
Treating T2DM to achieve optimal

blood glucose control is real medicine,
the ART of treatment is paramount
Fixed-dose combinations
. Metformin + glibenclamide (Glucovance

. Metformin + glimepiride (Amaryl-M)
. Metformin + glipizide (Metaglip)
. Metformin + rosiglitazone (Avandamet
. Metformin + pioglitazone (ActoplusMet)
. Metformin + DPP-4 inhibitors
Janumet
Galvusmet
Trajenta Duo
Combiglyze
Dailey GE. Expert Opin Pharmacother 2003;4:14
Bailey CJ, Day C. Int J Clin Pract 2004;58:8

Goldstein BJ et al. Clin Ther 2003;25:89
Combination Therapy with Oral Antidiabetic Agents

*Sulfonylurea not specified; **The dose used was 30 mg; The dose used was 8 mg
Combination
Additional Reduction in
FPG (mg/dl)
Additional Reduction in
Hemoglobin A1c (%)
Glyburide/Acarbose
-34 compared to
glyburide alone
-0.6 compared to
glyburide alone
Sulfonylurea*/Pioglitazone**
-58 compared to
sulfonylurea alone
-1.3 compared to
sulfonylurea alone
Sulfonylurea*/Rosiglitazone
-48 compared to
sulfonylurea alone
-0.8 compared to
sulfonylurea alone
Glyburide/Metformin
-63 compared to
glyburide alone
-1.7 compared to
glyburide alone
Metformin/Acarbose
-34 compared to
metformin alone
-0.6 compared to
metformin alone
-38 compared to
-0.8 compared to
metformin alone
metformin alone
-56 compared to
metformin alone
-0.8 compared to
metformin alone
Metformin/Pioglitazone**
Metformin/Rosiglitazone
Alogliptin + Pioglitazone
Clinical Value of
Combination Therapy

Conclusion
nclusion
oosing the right combination of

glycemic agents we have to conside
y aspects:
Effectiveness in lowering blood glucose
Extraglycemic effect that may reduce
long-term complications outcomes
Safety profile
Tolerability
Ease of use
Cost
Nathan DM et al. Clinical Diabetes. 2009; 27
(1): 4-16
Are All the FDC the same ?

Of Course Not
Depends on - Ingredients of the FDCs
- Doses of each ingredients
- Cost
Individualization - with FDCs means
less flexibility for physicians
Which One(s) ?
e Choice is You
Thank You
Thank You
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.
76
The risk of overall mortality in patients with Type 2 diabetes receiving

different combinations of sulfonylureas and metformin: a retrospective
analysis
1.K. M. Pantalone1, M. W. Kattan2, C. Yu2, B. J. Wells2, S. Arrigain2, B. Nutter2, A. Jain3,
8.A. Atreja4, R. S. Zimmerman5
Diabetic Medicine
Volume 29, Issue 8, pages 10291035, August 2012
Results
No statistically significant difference in overall mortality risk was observed
among the different combinations of sulfonylureas and metformin: glimepiride
and metformin vs. glipizide and metformin (HR 1.03; 95% CI 0.891.20),
glimepiride and metformin vs. glyburide (glibenclamide) and metformin (HR
1.08; 95% CI 0.901.30), or with glipizide and metformin vs. glyburide
(glibenclamide) and metformin (HR 1.05; 95% CI 0.951.15).
Conclusions
Our results did not identify an increased mortality risk among the different
combinations of sulfonylureas and metformin, suggesting that overall mortality
is not substantially influenced by the choice of sulfonylurea.
Positif ? , semua SU =
Three-year mortality in diabetic patients treated with different

combinations of insulin secretagogues and metformin
Matteo Monami, Chiara Luzzi, Caterina Lamanna, Veronica Chiasserini, Filomena Addante, Carla Maria Desideri,
Giulio Masotti, Niccol Marchionni, Edoardo Mannucci *
Diabetes/Metabolism Research and Reviews

Volume 22, Issue 6, pages 477482, November/December 2006
Conclusions
In the present study, sulphonylureas with greater selectivity for cell receptors, such as glimepiride and gliclazide, were associated
with a lower mortality when used in combination with metformin in
comparison with glibenclamide. Safety of such combinations
deserves further investigation.
SU tidak semua sama
Oral hypoglycaemic agents and the development of non-fatal

cardiovascular events in patients with type 2 diabetes mellitus
1.Yi-Chih Hung1,2, Che-Chen Lin3,4, Tzu-Yuan Wang1,5, Man-Ping Chang6,
2.Fung-Chang Sung3,4, Ching-Chu Chen1,5,*
Volume 29, Issue 8, pages 673679, November 2013
Conclusions
T2DM patients taking metformin and glimepiride are at lower risk
of non-fatal cardiovascular events than those taking glyburide.
Positif ??
SU tidak semua sama

Fixed Dose Combination
Indications for Insulin Therapy

in Type 2 DM
Glucose toxicity
Insufficient endogenous insulin
production
Contraindication to oral therapy
Diabetes Is a Serious and

Not Well-Controlled Disease
Diabetes
Is the leading
cause of
retinopathy,
nephropathy,
and amputations
Accelerates
atherosclerosis,
increasing the
incidence of heart
disease and stroke
by 2-4 times
Controlled
(HbA1c <7%)
45% 55%
From American Diabetes Association, 2000; Harris et al. Diabetes Care.

1999;22:403-408; American Diabetes Association, 2000.
Uncontrolled
or Poorly
Controlled
Conservative management of glycemia:

traditional stepwise approach
OAD
OAD +
monotherapy OAD
Diet and
OAD*
OAD +
multiple daily
exercise monotherapyup-titration
combination
basal insulininsulin injections
HbA1c (%)
10
9
8
HbA1c = 7%
HbA1c =
6.5%
6
*OAD = oral
antidiabetic
Campbell IW. Br J Cardiol 2000; 7:625
Efficacy of Combination
Therapies
Metformin +
antidiabetic agent
Glibenclamide (10-20 mg)a
Repaglinide (1.5-12 mg)b
Glimepiride (2-6 mg)c
Rosiglitazone (8 mg)d
Acarbose (300 mg)e
Net change
in HbA1C
-1.8% (1-2 %)
-1.1%
-0.8%
-1.2%
-0.8% (0.5-1%)
DeFronzo RA et al. N Engl J Med 1995;333:541-9; bMoses R et al,

Diabetes Care 1999;22:119-24; cCharpentier G et al, Diabet Med
2001;16:828-34; dFonseca V et al, JAMA 2000;283:1695-702;
Adherence to prescribed
medication
atients meeting medication goals

Days of drug exposure
Adherence Index > 90%
40
30
20
31
p<0.01
365
34
13
10
0
Su
Met Met + Su
alone
alone co-admin.
(n=1329)(n=531)(n=1060)
No. of days
% Adherence
p<0.01
310
300
302
266
255
200
Su
Met Met + Su
alone
alone co-admin.
(n=1329)(n=531)(n=1060)
Morris AD et al. Diabetes. 2000;49 (Suppl 1): A
Insulin
resistance
Diet
Exercise
Glitazone
Metformin
Incretin based
Type 2
Diabetes
Impaired
insulin
secretion
Insulin secretagogues:
Sulphonylureas
Benzoic acid derivates
Phenilalanin derivates
Incretin Based
Insulin
Algoritma Pengelolaan DM tipe 2 tanpa disertai Dekompensasi Metabolik
PB PERKENI. Konsensus Penegelolaan DM tipe 2, 2010
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.
Changing Therapies to Address

Diabetes Progression
Lifestyle
Change
Combination
Monotherapy Oral Agents
Insulin with
or without
Oral Agents
Benefits of Combination
Insulin and Oral Agents
Improved glycemic control
Treats multiple physiologic abnormalities
Less insulin is needed to achieve good glycemic
control
Reduces potensial for weight gain
Patients: more practical and less frightening
improved psychological acceptance, patients
continue the oral drugs
less / minimal education is needed
treatment can be started in an outpatients-setting
better compliance, and cost may be less
Choice of Insulin Regimen

Intermediate acting insulin at 21.00 p.m.
maximal glucose lowering between 4.00 8.00 a.m
no more effect by 3.00 p.m. (18 hours)
Long acting insulin analog Gargline vs. NPH

in combination therapy
423 insulin nave patients- T2DM, for 1 year
Insulin Gargline
overall hypoglycemia less 35 %
nocturnal hypoglycemia less 56 %
dinner- time glucose levels were lower
Short acting insulin vs. NPH

No difference in glycemic control
Greater weight gain in multiple injection with
short acting insulin
Timing of Intermediate Insulin Injection

Morning vs. Bed-time
2 studies: Bed-time insulin injection yielded
less hypoglycemia and less weight gain
1 study no difference were found
Glucose Control Among Diabetics Attending

Diabetic Clinic CiptoMangunkusumo Hospital
August, September and October 2001
Patients attending the diabetic clinic First Time in 1999
Total amount of newly registered patients in 1999 = 1119
Total amount of attendees (3 months)
98
Total amount of visit (3 months)
172
GOOD AND SUSTAINABLE COMPLIANCE
8.8 %
Patients attending the diabetic clinic First Time in 2000
Total amount of newly registered patients in 2000 = 1050
Total amount of attendees (3 months)
138
Total amount of visit (3 months)
172
GOOD AND SUSTAINABLE COMPLIANCE
13.1 %
Body Mass Index and Methods of R/

(Registered Cases 1999 and 2000, Last 3 Months 2001)
Body Mass Index
Methods of R/
<27 kg/M2
Diet Only
Sulphonylurea
Biguanide
Acarbose
28
65
30
33
6
20
71
50
Comb. 2 OHA
52
Comb. 3 OHA
1
Comb. OHA + Ins. 5
Insulin
Total
> 27 kg/M2
60
0
1
15
196
40
1
6
15
236
Degree of Glucose Control and Methods of R/
(Cipto
Hospital, Registered Cases 1999 and 2000)

Mean 2 hrs PP Blood Glucose Last 3 Visits
Methods of R/
<160 mg/dL
Diet Only
Sulphonylurea
Biguanide
Acarbose
-
13
15
10
Susilowati & Waspadji 2001
17
33
24
Comb. 2 OHA
5
Comb. 3 OHA
0
Comb. OHA + Ins. 1
Insulin
Total
> 160 mg/dL
48
34
-
29
34
1
1
3
46
101
4
9
147
Conclusion
Knowledge on current basic concepts of etiology and
pathophysiology of diabetes mellitus as well as the
treatment of diabetes mellitus are important as bases
for minimizing irrational treatment in diabetes mellitus
Some examples of irrational treatment in diabetes mellitus have been discussed
Daily practice in the management of diabetes mellitus

in Ciptomangunkusumo hospital has been reviewed.
Many improvements should be implemented toward better management and
toward better results of treatment of diabetes mellitus

Mean Fasting Blood Glucose Last 3 Visits
Methods of R/
<120 mg/dL
Diet Only
Sulphonylurea
Biguanide
Acarbose
22
18
17
62
47
Comb. 2 OHA
9
Comb. 3 OHA
0
Comb. OHA + Ins. 1
Insulin
29
44
30
44
53
1
4
11
71
141
Total
> 120 mg/dL
1
5
15
212
(Cipto
(Cipto

Mean 2 hrs PP Blood Glucose Last 3 Visits
Methods of R/
<160 mg/dL
Diet Only
Sulphonylurea
Biguanide
Acarbose
13
15
10
48
34
Comb. 2 OHA
5
Comb. 3 OHA
0
Comb. OHA + Ins. 1
Insulin
17
33
24
29
34
1
1
3
46
101
Total
> 160 mg/dL
4
9
147
Irrational Treatment in DM,
Before we embark into

we have to summarize some current, basic concepts
in the classification and pathophysiology of DM, and also
discuss drugs available for the treatment of DM, treatment
goals etc. as
bases for the rational thinking
Changing Therapies to Address

Diabetes Progression
Lifestyle Monotherapy Combination

Changes
Oral Agents
Insulin with
or without
Oral Agents
Management of Diabetes Mellitus

The Earlier the Better
(prevention of Complications)
Early Diagnosis
Early Treatment
Early Combination
Early Insulin Therapy
Managing Diabetics is an Art,
Have to be Very Delicate
Start Low Go Slow(avoid side effects)
Some Examples
of Irrational Treatment in DM
Try to treat T1DM with Sulphonylurea(s)
Start treatment directly with pharmacological
therapy
Use patients symptoms only, not monitoring BG
Not using BG 2 hrs PP as a parameter of BG
monitoring
Not using A1c as a parameter of monitoring DM
Some Examples
Start treating obese diabetics with
insulin secretagoque(s)
Start treating longstanding lean DM with
biguanide / TZD
Start TZD as monotherapy (?)
Some Examples
Ignoring hypoglycemic reaction
long-acting S.U.
in the elderly
In renal failure pts
Reluctant to use combined oral HA although BG are

still high
Combining 2 kinds of insulin secretagogues
SU with SU
SU with Glinid(?)
Reluctant to use insulin therapy in longstanding

uncontrolled T2DM
Some Examples
Ignoring the pharmacokinetic and side effect(s) of
drug(s) used
Longacting SU, 3 times a day
Combination of Biguanide and Acarbose
(possible combined GI Side Effects)
Non Holistic Treatment Approach

Herbal Medicine ??
Urine Therapy ??? , Alternative Therapy ???
Type of Oral Hypoglycemic Agent(s)

Ciptomangunkusumo Hospital
60
50
40
30
20
10
S(ulfonilurea)
B(iguanide)
S+B
S + A(carbose)
B+A
S+B+A
1992+1993
1997+1998
Most commonly used OHA: Combination of S + B
Sulfonilurea
Type of Oral Hypoglycemic Agent(s)

Ciptomangunkusumo Hospital
S
S+B
S+A
B+A
S+B+A
N % N
1992
13
23.6
5.5
31
56.4
5.5
1993
14
22.6
12.9
30
48.4
3.2
1.6
3.2
1997
18
29.0
11
17.7
26
41.9
1998
31
40.3
10.4
26
33.8
5.2
2.6
Total
76
32.6
30
12.9
113
48.5
4.1
0.47
3.0
Yrs
The most commonly used OHA(s):

Combination Sulphonylurea & Biguanide (48.5%)
Sulphonylurea (32.6%)
Biguanide (12.9%)
Combination Biguanide & Acarbose (0.47%)
Combination Sulphonylurea + Biguanide + Acarbose (3.0 %)
Conclusion
Knowledge on current basic concepts of etiology and
pathophysiology of diabetes mellitus as well as the
treatment of diabetes mellitus are important as bases
for maximizing rational treatment in diabetes mellitus
Some examples of rational hypoglycemic drugs combinations have been discussed
Daily practice in the management of diabetes mellitus

in Ciptomangunkusumo hospital has been reviewed.
Many improvements should be implemented toward better management and
toward better results of treatment of diabetes mellitus
Thank You
Early OAD Combination

In Type 2 Diabetes:
What is Rational
Sarwono Waspadji
Jakarta Diabetes and Lipid Center

Division of Endocrinology and Metabolism
epartment of Medicine, School of Medicine University of Indones
Jakarta
Mortality/1000 patient-years
IGT is associated with

adverse clinical outcomes
FPG <7.0 mmol/L
All-cause
Cardiovascular
50
40
50
46
39
40
29
30
14
13
6
33
30
22
21
20
10
FPG >7.0 mmol/L
16
10
0
<7.8 7.8-11.0 >11.0
IGT
20
DM
2-h plasma glucose
0
<7.8 7.8-11.0 >11.0
IGT
DM
2-h plasma glucose
Saydah et al. Diabetes Care. 2001;24:1397-40
chanism Underlying the Progressive Defe

n Insulin Action and Early Insulin Secretio
Hypothesis :
Prolonged hyperglycemia (Glucose-toxicity)
Elevated FFA concentration (Lipo-toxicity)
Hyperinsulinemia amyloid deposit
Small islet
Fibrous deposit
Amyloid deposits
Reduced -cell volume (60% of normal)
Loss of insulin secretory granules (degranulation)
1. Managing dysglycemia as early as possible

to prevent diabetes complications:
early diagnosis
early treatment
2. Current traditional management can not
achieve the desirable outcome
Factors affecting the unsuccesful
outcome:
Not aggressive enough?
Need drug combination?
Need earlier drug combination?
NEW STRATEGIES
FOR THE TREATMENT OF TYPE
2
DIABETES MELLITUS
Early detection Screening of diabetes
in clinical setting
Aggressive treatment
(UKPDS)
Current Guideline Goal Values for

Persons with Diabetes
IDF (2005)
ADA (2005)
Asian-Pacific
(2005)
Glycaemia
Pre-meal
glucose
<6.0 mmol/L
HbA1C <7.0%
FPG 5.07.2
mmol/L
Peak postprandial
glucose <10.0
mmol/L
HbA1C <6.5%
FPG 4.46.1
mmol/L
Non-fasting
glucose 4.48.0
mmol/L
BP
<130/80 mmHg
<130/80 mmHg
<130/80 mmHg
Lipids
(mmol/L)
LDL-C <2.5
TG <2.3
HDL-C >1.0
LDL-C <2.6
TG <1.7
HDL-C >1.03 a
>1.29 b
LDL-C <2.5
TG <1.5
HDL-C >1.1
Men; bwomen
International Diabetes Federation (2005); American Diabetes Association (20

Asian-Pacific Type 2 Diabetes Policy Group (2
ESC and EASD Recommendation for

Treatment Target for Patients with DM and
Variable CAD
Treatment Target
Glycemic control
A1c (%)
< 6.5
FBG
mmol/L
<6
(< 108 mg/dL)
PP
< 7.5 (< 135 mg/dL)
Blood Pressure
Systolic/Diastolic (mmHG) < 130 / 80
Renal Impairment or
proteinuria > 1 g / 24 h
< 125 / 75
Lipid Profile
Total-Chol (mg/dL)
<175
LDL-chol (mg/dL)
< 70
Triglyceride (mg/dL) < 150
HDL-chol Men
> 40
HDL-chol Women > 46
Total-chol / HDL-chol < 3
Lifestyle counselling Smoking cessation obligatory
Regular Phys. Activity
(min/day) > 30 -45
BMI (Kg /m2)
< 25
Weight Reduction
> 10 %
W.Circumference Men
< 94
Women < 80
Targets for Diabetes Control

Good
Fasting Blood Glukose (mg/dL)
Fair
80-109
Bad
110-125
>126
2 hr PP Blood Glukose (mg/dL) 80-144
145-179
>180
A1c (%)
<6,5
6,5-8
Total- Cholesterol (mg/dL)
>8
<200
200-239
> 240
LDL- Cholesterol
(mg/dL)
<100
(mg/dL)
>45
100-129
> 130
HDL- Cholesterol
Triglyseride (mg/dL)
<150
>200
BMI (Kg/M2)
18,5-22,9
150-199
Konsensus Pengelolaan DM
Di Indonesia PERKENI 2006
23-25
> 25

early diagnosis
early treatment
3. Target treatment available.
The lower, the better. Achieve blood
glucose as normal as possible (aggressive),
avoiding hypoglycemia
Etiology of Type 2 Diabetes

Mellitus:
Insulin Resistance and Diminished Insulin
Lifestyle and
Insulin
Genes
Secretion
Diet
Resistance
Normal
Beta Cell
Function
Abnormal
Beta Cell Function
Relative Insulin Deficiency

Compensatory
Hyperinsulinemia
Hyperglycemia
Normoglycemia
Type 2 Diabetes Mellitu

early diagnosis
early treatment
3. Target treatment available.
The lower, the better. Achieve blood
glucose as normal as possible (aggressive),
avoiding hypoglycemia
4. Addressing the pathophysiology of Type 2 DM,
both Insulin resistance
and defective insulin secretion
Combination therapy ?
TREATMENT ALGORITHM FOR TYPE 2 DIABETES
Aim
Diet, exercise, health education

Sulphonylurea, metformin
Glucosidase Inhibitors
Glitinides
Thiazolidinediones
Oral combinations
Insulin plus oral agents
Improved Control
Insulin
esetaraan Rerata Kadar Glukosa Darah dan A1

A1c%
Glukosa* (mg/dL)
Glukosa**(mg/dL)
135
70
170
131
205
194
240
257
10
275
319
11
310
381
12
345
444
Surrogate
for HBA1c
DCCT (Amerika Serikat dan Kanada) pada DM tipe 1

dasar hasil glukosa darah sebelum tidur, dengan persamaan regresi:
% = 0,016 X GDS + 4,891 (penelitian Dudy Mulyawan FKUI 2007), DM tip
New Treatment Paradigms for

Type 2 Diabetes Mellitus
Stepwise Treatment
Diet/
Oral
Oral
Oral
exercise monotherapycombination +/- insulin
Insulin
Early Aggressive
Combination Therapy
Early Combination of 2 or more oral hypoglycemic
agent:
SU + Biguanide
SU + Thiazolidinedione
Biguanide + Thiazolidinedione
Combination Therapy
Delayed deterioration of cells
o Liver glucose production
(gluconeogenesis)
o Insulin action & insulin
resistance
o Insulin secretion
Smaller dose of OAD, Less side
effects
Combination Therapy in Type 2 DM
Metformin + Sulphonylurea
Resistensi
Insulin
Defisiensi
Sel
Metformin + TZD
Metformin + AGI
Sulphonylurea + TZD
Sulphonylurea + AGI
TZDs + AGI
Sulphonylurea or meglitinide
TZD: thiazolidinedione
AGI: -glucosidase inhibitor
1
Combination therapy:
Estimated Improvements in Glycemic Control
HbA1c
Regimen
Sulfonylurea + metformin
~1.7%
Sulfonylurea + troglitazone~0.9-1.8%
Sulfonylurea + pioglitazone ~1.2%
Sulfonylurea + acarbose
Repaglinide + metformin
Pioglitazone + metformin
Rosiglitazone + metformin
Insulin + oral agents
~1.3%
~1.4%
~0.7%
~0.8%
FBG
~65 mg/dL
~50-60 mg/dL
~50 mg/dL
~40
~40
~40
~50
mg/dL
mg/dL
mg/dL
mg/dL
Open to Target Open to Target
DeFronzo, et al. N Engl J Med 1995;333:541-549; Horton, et al. Diabetes Care.

1998;21:1462-1469; Coniff, et al. Diabetes Care.
1995;18:817-824; Moses, et al. Diabetes Care 1999;22:119-124; Schneider, et al. Diabetes
1999; 48 (Suppl 1): A106; Egan, et al. Diabetes 1999; 48 (Suppl 1):A117. Fonseca, et al.
Diabetes 1999:48 (Suppl 1):A100.
Factors Affecting
Compliance of Type 2 DM Patients
Difficult/Unmodifiable
Age
Complication
Modifiable
Disablility
Polipharmacy
Education
Fixed Combination
Multipel Regimen
Low income- cost
1. Donan-PT, Adherence to prescribed oral hypoglicemic medication in T2DM
patients, Diabetic.Med, 2002, 19 : 279 - 284
2. Paes-AHP et al, Impact of dose frequency on patients compliance, Diabetes
Care,
1997, 20 : 1512 - 1517
Once Daily Dosage :

Better Compliance
*p<0.5
**p<0.01
vs. once daily
Optimal Compliance
(%)
70
60
**
50
40
** **
30
20
10
0
Once
Twice
3 times
Frequency/day
11,896 cohort of T2 DM with self reported compliance
Guillausseau, Influence of Oral Antidiabetic drug compliance on

metabolic Control in T2 DM, Diabetes Metab. 2003, 29, 79 - 81
Once Daily Dosage :

Better Glucose Control
*p<0.5
**p<0.01
vs. once daily
**
11,896 cohort of T2 DM with self reported compliance

Guillausseau, Influence of Oral Antidiabetic drug compliance on
metabolic Control in T2 DM, Diabetes Metab. 2003, 29, 79 - 81
Compliance
p=0.1511
100
94.6
91.4
Compliance (%)
90
80
70
60
50
Fixed
Free
Change in HbA1c
From baseline to endpoint
Equivalence analysis for the change in HbA1c (%)
PP analysis set
Fixed
n=91
Free
n=85
Baseline (mean)
7.99
7.88
Endpoint (mean)
Adjusted means change
6.85
-1.09
6.84
-1.08
Hypoglycemia
Fixed
Free
Number of patients
n=110
n=99
Any hypoglycemia
50(45.5 41(41.4 0.6838

%)
%)
Symptomatic
40(36.4 37(37.4 0.9947

%)
%)
Asymptomatic
12(12.7 10(10.1 0.5765

%)
%)
Severe
Change in body weight (kg)
Body Weight
3
2
1
0.25
- 0.12
0
-1
-2
-3
Fixed
Free
The Choice ?
Arts of
treatment
Individual, person to
person,
Doctors clinical
judgement,
Cost,
Side effect(s), tolerability,
etc.
THANK YOU
A Rational Combinations
of Hypoglycemic Drugs
Sarwono Waspadji
Jakarta Diabetes and Lipid Centre,
Div. of Endocrinology and Metabolism, Dept. of Medicine,
School of Medicine, University of Indonesia,
Jalan Salemba 6, Jakarta Pusat 10430
Rational:
sensible,
that can be tested by reasoning,
having logical basis
What is Rational, changes
with time,
with the current accepted concept,
with evidence based
Rational diabetes diet

No carbohydrate, high fat diet
Moderate carbohydrate (30- 40- 50 %)
High carbohydrate (50 - 60- 70%), high fibre diet
High CHO, monounsaturated fatty acid diet
Bases for the Rational Thinking

Current, basic concepts
Classification
Pathophysiology of DM,
Drugs available for R/ of DM,
Treatment strategy
Treatment goals etc.
Strategy to Prevent the Deterioration

of Type 2 Diabetes
Life Style
Monotherapy
Oral Hypo(s)
Combination
Insulin with
or without
Oral Hypo
Glycemic agent
Beta Cell
Function
(%)
IGT
-12 10
T2DM phase III
Postprandial T2 DM
Hyperglycemia phase I
-6
-2
T2DM
phase II
2
Years from Diagnosis

Lebovitz H. Diabetes Review 1999;7:139-53
10
14
The UKPDS Demonstrated Progressive

Decline of -cell function over time
-cell function (% )
100
Start of treatment
80
60
40
Mean -cell function at diagnosis
20
P < 0.0001
0
10 9 8 7 6 5 4 3 2 1
Time (years)
HOMA, diet-treated
n = 376
Adapted from Holman RR. Diabetes Res Clin Pract 1998; 40 (Suppl): S215.
New Treatment Paradigms for

Type 2 Diabetes Mellitus
Stepwise Treatment
Diet/
exercise
Oral
monotherapy
Oral
combination
Oral
+/- insulin
Insulin
Early Aggressive
Combination Therapy
Early Combination of 2 or more oral hypoglycemic agent:
(SU + Biguanide + Thiazolidinedione)
Good Glycaemic Control Reduces

the Incidence of Complications
Risk Reduction by Decrease in A1c (%)
Complications
of Diabetes Mellitus
DCCT1,2 Kumamoto3 UKPDS4

(9%
7%)
(9%
7%)
(8%
7%)
Retinopathy
63%
69%
21%
Nephropathy
54%
70%
34%
Neuropathy
60%
Macrovascular
Disease
41%*
16%*
*Not statistically significant

DCCT Research Group. N Engl J Med 1993; 329: 97786. 2DCCT Research Group. Diabetes 1995; 44: 96883.
3
Ohkubo Y et al. Diabetes Res Clin Pract 1995; 28: 10317. 4UKPDS Group. Lancet 1998; 352: 83753.
Changes of Strategy to Prevent

The Deterioration of Type 2 Diabetes Mellitus
Insulin with
or without
Oral HypoGlycemic
agent
Monotherapy
Oral Hypo(s)
Life Style
Combination
Beta Cell
Function
(%)
IGT
-12 10
T2DM phase III
Postprandial T2 DM
Hyperglycemia phase I
-6
-2
T2DM
phase II
2
Years from Diagnosis

Lebovitz H. Diabetes Review 1999;7:139-53
10
14
ADA Treatment Goals for Glycemic Control

Glycemia
Normal Goal
Required*
Average Preprandial
<110
Fasting Glucose (mg/dL)
Average Postprandial
Glucose (mg/dL)
HbA1C (%)
<140
<6
Further Action
80 to 120
<80
>140
<160
>180
<7
>8
*Further Action Required = Get off your rear and DO something

Adapted from the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus
Diabetes Care 1999;22:S32-S41
Diabetes Control Target

Good
Fasting Blood Glucose (mg/dL)
80-109
Post Prandial Glucose (mg/dL) 80-144

A1c (%)
<6,5
Fair
Total Cholesterol (mg/dL)
110-125
145-179
6,5-8
<100
HDL Cholesterol (mg/dL)
>45
Tryglyseride (mg/dL)
<150
BMI (Kg/M2)
18,5-22,9
Blood Pressure (mmHg)
<130/80
>126
>180
>8
<200
LDL Cholesterol (mg/dL)
Bad
200-239
> 240
100-129
> 130
150-199
>200
23-25
130-140/80-90
> 25
>140/90
Consensus Management of DM in Indonesia

Indonesian Society of Endocrinology (PERKENI) 2002
TZ
D
s
in glu
hi c
bi os
to id
rs a
s
In
se sul
cr in
et
ag
og
ue
M
s
et
fo
rm
in
Oral Antidiabetic Agents:

Physiological Effects
Effect on FPG/HbA1c
Effect on plasma insulin
Effect on LDL-cholesterol
Effect on HDL-cholesterol
Effect on triglycerides
Adapted from DeFronzo RA. Ann Int Med 1999; 131: 281303 .
in glu
hi c
bi os
to id
rs a
se
TZ
D
s
In
se sul
cr in
et
ag
og
ue
M
s
et
fo
rm
in
Oral Antidiabetic Agents:

Side Effects
Risk of hypoglycaemia
Weight gain
Gastrointestinal
side-effects
Lactic acidosis
Oedema
Anaemia
*Observed in patients with renal impairment
Adapted from DeFronzo RA. Ann Int Med 1999; 131: 281303.
Combinations of Hypoglycemic Agents

Sulphonyl urea and-
Biguanide - Rational combination for T2DM
Acarbose
TZD
- Rational combination for T2DM
Insulin (Bed-time Insulin Daytime SU)
Biguanide and
- Sulphonylurea
Acarbose - GIT side effects
TZD - rational combination for Obese T2DM
Insulin
Acarbose and
TZD and
- SU, Biguanide, Acarbose, Insulin
- SU, Biguanide, Acarbose, Insulin
Insulin and
Biguanide, Acarbose, TZD, SU (not for T1DM)
Management of Diabetes Mellitus

As Early and as Prompt as Possible
(to prevent diabetes complications)
Early Diagnosis
EarlyTreatment
Early Combination
Early Insulin Treatment
Should be meticulous to prevent side

effects - Hypoglycemia
Individualization, Start Low Go Slow
Treatment options for type 2

diabetes
Sulfonylureas
1st generation e.g.
chlorpropamide,
tolbutamide
2nd generation e.g. glyburide,
gliclazide, glipizide, gliquidone
3rd generation e.g. glimepiride
Modified release
Biguanides
e.g. metformin
-glucosidase inhibitors
e.g. acarbose
Insulin
regular
intermediate/long acting
pre-mixed
analogs
rapid acting
long acting
Fixed-dose oral antidiabetic

drug combinations
e.g. glyburide/metformin,
glipizide/metformin,
rosiglitazone/metformin
Glinides/meglitinides
Non-sulfonylureic e.g. repaglinide
Amino acid derivatives e.g.
nateglinide
Thiazolidinediones
e.g. rosiglitazone, pioglitazone
Thank You
Efficacy as a Combination Therapy
Research Article
All-cause mortality in diabetic patients treated with combinations of
sulfonylureas and biguanides
Edoardo Mannucci*, Matteo Monami, Giulio Masotti, Niccol Marchionni

Volume 20, Issue 1, pages 4447, January/February 2004
Conclusions
A higher mortality was observed in patients treated with
combinations of sulfonylureas and biguanides, even at low doses.
Safety of such combinations deserves further

investigation.
Negatif

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Finding the Right Combination Therapy

of Anti Diabetic Drugs

Diabetes Mellitus and Its Management in General

Global Burden of Diabetes

http://www.idf.org/diabetesatlas/5e/Update2012 Accessed 15 Dec 2012

Prevalence of T2DM increase in line with

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

10.5 HbA1c (%)

Natural History of Disease Progression

Aggressive treatment of established cardiovascular risk factors

Aggressive glycemic control

Prevention of progression of IGT to Type 2 DM

Risk of complications decreases

Updated mean HbA1c (%)

Early and Intensive Glycemic Control

Lessons from the large trials

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

The Nice-Sugar Study

AACE Comprehensive Diabetes Management Algorithm. Endocrine Practice. 2013;10(2):331

Individualized Treatment based on several criteria to control

Diabetes Care. 2012;35(6):1364-79

Inzucci SE, et al. Diabetologia. 2012

Diabetes Mellitus and Its Management in General

Glycemic Control Achievement and Related Factors

Majority of type 2 DM patients in Asia Pacific

DM, diabetes mellitus; HbA1c, glycated hemoglobin.

-cell function continues to decline

-cell Function (%)*

Years since Diagnosis

T2DM=type 2 diabetes mellitus.

New Era In treating

Weight neutral/weight reducing

Reduced Hypoglycaemia risk

Early Therapeutic intervention

Cheng AY, Fantus IG. CMAJ . 2005; 172: 213

How to Get Closer to Near-Normalization

Meta-analyses of RCTs on macrovascular outcomes with

Two meta-analyses show consistent CV benefit with intensive glucose

Practical clinical implications

Initiate therapy early, before any micro- or

Diabetes Mellitus and Its Management in General

Pathophysiology of Hyperglycemia and

Pathogenesis of T2DM: the Ominous Octet

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

PERKENI Guideline 2011

AACE Comprehensive Diabetes Management Algorithm. Endocrine Practice. 2013;10(2):332

Diabetes Mellitus and Its Management in General

Natural History of Disease Progression

Aggressive treatment of established cardiovascular risk factors

Aggressive glycemic control

Prevention of progression of IGT to Type 2 DM

Need for an early and intensive approach

majority require polypharmacy

UKPDS Group. Diabetologia. 1991; 34:87790.

to meet glycemic goals over time

UKPDS: Loss of Glycaemic Control

UK Prospective Diabetes Study (UKPDS) Group. UKPDS 33. Lancet 1998;

Limited duration of glucoselowering efficacy of

Turner RC et al. JAMA . 1999;281:20

Rationale for Combination Therapy

Up-titrating monotherapy to the maximum

Change in HbA1c from placebo

Up-titrating monotherapy to the