A Simple Approach to Achieve

Comprehensive Glycemic
Control in T2DM Management
Dr. Santi Syafril, SpPD-KEMD
Division of Endocrine Metabolic and Diabetes
Internal Medicine Department
Adam Malik Hospital Medan
Diabetes is a huge and growing
problem, and the costs to society are
high and escalating
382 million people
have diabetes

By 2035, this number
will rise to 592
million
IDF Diabetes Atlas 2013
6
th
Edition
IDF Diabetes Atlas 2013
6
th
Edition
4
Diabetic
Retinopathy
Leading cause
of blindness
in adults

Diabetic
Nephropathy
Leading cause of
end-stage renal disease

Cardiovascular
Disease
Stroke
2- to 4-fold increase in
cardiovascular mortality
and stroke

Diabetic
Neuropathy
Leading cause of
non-traumatic lower
extremity amputations

8/10 individuals with
diabetes die from CV
events

UK Prospective Diabetes Study Group. Diab Res 1990; 13: 111.
Fong DS, et al. Diab Care 2003; 26 (Suppl. 1): S99S102.
Molitch ME, et al. Diab Care 2003; 26 (Suppl. 1): S94S98.
Type 2 Diabetes is Associated With
Serious Complications
13
Impact of bad glycaemic legacy
Del Prato S. Diabetologia 2009; 52:12191226.
Time since diagnosis (years)
H
b
A
1
c

(
%
)

1 2 3 8 9 12 13 6 4 5 10 11 14 15 7 16 17
9.0
8.5
8.0
7.5
7.0
6.5
6.0
9.5 Drives risk of
complications
Before entering intensive treatment arm
After entering intensive
treatment arm
Generation of a
bad glycemic
legacy
Impact of bad glycaemic legacy
Del Prato S. Diabetologia 2009; 52:12191226.
Time since diagnosis (years)
H
b
A
1
c

(
%
)

1 2 3 8 9 12 13 6 4 5 10 11 14 15 7 16 17
9.0
8.5
8.0
7.5
7.0
6.5
6.0
9.5
Before entering intensive treatment arm
After entering intensive
treatment arm
Intensive
therapy early
Legacy Effect of Earlier Glucose Control
After median 8.5 years post-trial follow-up

Aggregate Endpoint 1997 2007
Any diabetes related endpoint RRR: 12% 9%
P: 0.029 0.040
Microvascular disease RRR: 25% 24%
P: 0.0099 0.001
Myocardial infarction RRR: 16% 15%
P: 0.052 0.014
All-cause mortality RRR: 6% 13%
P: 0.44 0.007
RRR = Relative Risk Reduction, P = Log Rank
UKPDS 80. N Eng J Med. 2008; 359
Benefits of tight glycaemic control
Comprehensive Glycemic
Control
THE GLUCOSE TRIAD
Postprandial
Glucose
+
FPG influenced by:
Hepatic glucose
production
Hepatic sensitivity
to insulin

PPG influenced by:
Pre-prandial glucose
Glucose load from meal
Incretin level
Insulin secretion
Insulin sensitivity in
peripheral tissues

1. DeFronzo RA. Ann Intern Med. 1999;131;281-303.
2. IDF. Guideline for Management of Postmeal Glucose. Available at: http://www.idf.org/webdata/docs/Guideline_PMG_final.pdf. Accessed
Jul 26, 2010.
3. Woerle HJ et al. Diabetes Res Clin Pract. 2007;77:280-285.
4. Drucker DJ. Cell Metab. 2006;3:153-165.


Achieving A1C Target Requires Action on
Both FPG and PPG
Fasting
Glucose

A1C
=
Treatment decisions to control hyperglycaemia
should consider guidelines on PPG and FPG
1-3

Glycaemic targets for the management of patients with
type 2 diabetes as recommended by various organisations
2-4
Targeting both postmeal plasma glucose and fasting plasma glucose
is an important strategy for achieving optimal glycaemic control
3
1. Monnier L, et al. Diabetes Metab. 2006;32:2S11-16. 2. Nathan DM, et al. Diabetologia. 2009;52:17-30. 3. IDF. International Diabetes
Foundation. Guidelines for Postmeal Glucose. Available at: http://www.idf.org/webdata/docs/Guideline_PMG_final.pdf. Accessed 26 Jan 2009. 4.
AACE. American College of Endocrinology. Endocr Pract. 2007; 13 (Suppl. 1):3-68. 5. PERKENI Konsesus Pengelolaan dan Pencegahan Diabetes
Mellitus Tipe 2 di Indonesia 2006.
Organisasi
HbA1c
(%)
PPG
(mg/dL)
FPG
(mg/dL)
ADA-EASD
2
<7,0 - -
IDF-Europe
3
<6,5 <140 <100
AACE
4
6,5 <140 <110
PERKENI
5
7,0 <140 <110
Appropriate A1C Management Should Consider
Both FPG and PPG Levels

FPG and PPG contributions to
A1C differ as A1C levels change
PPG is the major contributor
to A1C in patients with A1C
<7.3%
FPG is the major contributor
to A1C in patients with A1C
9.3%
Approximate Contribution
to A1C

(%)

>10.2
9.310.2
8.59.2
7.38.4
<7.3
A1C (%) FPG PPG
70%
*
30%

53%

47%

45% 55%
40%
*
60%
30%
*
70%
Monnier L et al. Diabetes Care. 2003;26:881-885.
Postprandial glycemic excursion is a major contributor to A1C,
particularly in patients with mild or moderate hyperglycemia
(A1C <8.5%)
Achieving A1C Goal Requires PPG Control
Woerle HJ et al. Diabetes Res Clin Pract. 2007;77:280-285.
PPG <140 mg/dL
FPG <100 mg/dL
P
a
t
i
e
n
t
s

A
c
h
i
e
v
i
n
g


A
1
C

<
7
%
,

%

Comprehensive glycaemic management
depends on all three components of the
glucose triad
1

The glucose triad
1. Monnier L, et al. JAMA. 2006;295:1681-7.
Comprehensive Glycaemic Control
. n=at baseline; Kahn et al (ADOPT).
N Engl J Med. 2006;355(23):2427-2443.
Weight gain associated with DM therapy
Years from randomization
C
h
a
n
g
e

i
n

w
e
i
g
h
t

(
k
g
)

0
1
5
8
7
6
4
3
2
UKPDS: up to 8 kg in 12 years
Glibenclamide (n=277)
Insulin (n=409)
Metformin (n=342)
0 3 6 9 12
Conventional treatment (n=411);
diet initially then sulphonylureas,
insulin, and/or metformin if FPG
> 15 mmol/L
ADOPT: up to 4.8 kg in 5 years
W
e
i
g
h
t

(
k
g
)

Annualized slope (95% CI)
Rosiglitazone, 0.7 (0.6 to 0.8)
Metformin, -0.3 (-0.4 to -0.2)
Glibenclamide, -0.2 (-0.3 to 0.0)
Years
0 1 2 3 4 5
96
92
88
0
100
Treatment difference (95% CI)
Rosiglitazone vs metformin 6.9 (6.3 tp 7.4);
P<0.001
Rosiglitazone vs glibenclamide, 2.5 (2.0 to 3.1);
P<0.001
Glibenclamide (n=1,441)
Rosiglitazone (n=1,456)
Metformin (n=1,454)
Hypoglycaemia in the UKPDS
Years of follow up
P
r
o
p
o
r
t
i
o
n

o
f

p
a
t
i
e
n
t
s

(
%
)

Conventional
Insulin
Chlorpropamide
Glibenclamide
Metformin
0
1 0
2 0
3 0
4 0
5 0
0 2 4 6 8 1 0
UKPDS 33. Lancet 1998; 352: 837-853
Therapeutic challenges in glycaemic
control in T2DM




Glycaemic control
Hypoglycaemia
Weight effect
Extra glycaemic
effects


Diabetes Care2012;35:13641379
Diabetologia 2012;55:15771596

Initial drug
monotherapy
Efficacy (! HbA1c)
Hypoglycemia
Weight
Side effects
Costs
Healthy eating, weight control, increased physical activity
Metformin
high
low risk
neutral/loss
GI / lactic acidosis
low
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Efficacy (! HbA1c)
Hypoglycemia
Weight
Major side effect(s)
Costs
high
low risk
gain
edema, HF, fxs

high
Thiazolidine-
dione
intermediate
low risk
neutral
rare

high
DPP-4
Inhibitor
highest
high risk
gain
hypoglycemia

variable
Insulin (usually
basal)
Two drug
combinations*
Sulfonylurea

+
Thiazolidine-
dione
+
DPP-4
Inhibitor
+
GLP-1 receptor
agonist
+
Insulin (usually
basal)
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
TZD
DPP-4-i
GLP-1-RA
Insulin

SU


DPP-4-i
GLP-1-RA
Insulin

SU

SU


TZD TZD
TZD
DPP-4-i
Insulin

Insulin

Insulin
#

(multiple daily doses)
Three drug
combinations
More complex
insulin strategies
or
or
or
or
or
or
or
or
or
or
or
or GLP-1-RA
high
low risk
loss
GI

high
GLP-1 receptor
agonist
Sulfonylurea


high
moderate risk
gain
hypoglycemia

low
If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination
(order not meant to denote any specific preference):
Adapted Recommendations: When Goal is to Avoid Weight Gain
Diabetes Care2012;35:13641379
Diabetologia 2012;55:15771596

Initial drug
monotherapy
Efficacy (! HbA1c)
Hypoglycemia
Weight
Side effects
Costs
Healthy eating, weight control, increased physical activity
Metformin
high
low risk
neutral/loss
GI / lactic acidosis
low
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Efficacy (! HbA1c)
Hypoglycemia
Weight
Major side effect(s)
Costs
high
low risk
gain
edema, HF, fxs

high
Thiazolidine-
dione
intermediate
low risk
neutral
rare

high
DPP-4
Inhibitor
highest
high risk
gain
hypoglycemia

variable
Insulin (usually
basal)
Two drug
combinations*
Sulfonylurea

+
Thiazolidine-
dione
+
DPP-4
Inhibitor
+
GLP-1 receptor
agonist
+
Insulin (usually
basal)
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
TZD
DPP-4-i
GLP-1-RA
Insulin

SU


DPP-4-i
GLP-1-RA
Insulin

SU

SU


TZD TZD
TZD
DPP-4-i
Insulin

Insulin

Insulin
#

(multiple daily doses)
Three drug
combinations
More complex
insulin strategies
or
or
or
or
or
or
or
or
or
or
or
or GLP-1-RA
high
low risk
loss
GI

high
GLP-1 receptor
agonist
Sulfonylurea


high
moderate risk
gain
hypoglycemia

low
If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination
(order not meant to denote any specific preference):
If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination
(order not meant to denote any specific preference):
Adapted Recommendations: When Goal is to Avoid Hypoglycemia
Diabetes Care 2012;35:13641379
Diabetologia 2012;55:15771596

<7% 7-8% 8-9% >9% 9-10% >10%
Treatment based on HbA1c Level
PERKENI Guidelines 2011
Lifestyle
Modification
Lifestyle
Modification
+
Monotherapy
Met, SU, AGI,
Glinid, TZD,
DPP-IV
Lifestyle
Modification
+
2 OADs
Combination
Met, SU, AGI,
Glinid, TZD,
DPP-IV
Lifestyle
Modification
+
3 OADs
Combination
Met, SU, AGI,
Glinid, TZD,
DPP-IV
Lifestyle
Modification
+
2 OADs
Combination
Met, SU, AGI,
Glinid, TZD
+
Basal Insulin
Lifestyle
Modification
+
Intensive
Insulin
Notes :
Fail : not achieving A1c target
<7% after 2-3 months of
treatment.
(A1c = average blood glucose
conversion, ADA 2010)
Comprehensive Glycemic
Control
DPP-4 Inhibitor
Place In Therapy
Ominous Octet of Type 2 Diabetes
DeFronzo RA. Diabetes. 2009;58:773-795.
Role of the Incretin System
in Glucose Homeostasis
DPP=dipeptidyl peptidase; GLP=glucagon-like
peptide; GIP=gastric inhibitory peptide.
Adapted with permission from Drucker DJ et al. Cell Metab. 2006;3:153-165.
Beta
cells
Alpha
cells
Enhanced incretin release
+ -
Blood
glucose
homeostasis
Incretins (GLP-1 and GIP)
released throughout the
day
Effect of incretins
Increased
insulin
Decreased
glucagon
Pancreas
GI tract
Liver
Muscle
Decreased
glucose output
by liver
Increased
glucose
uptake by
muscles
DPP4 enzymes
rapidly degrade
incretins
Caloric intake
24
Mechanism of action
of Dipeptydilpeptidase-4 enzyme Inhibitor
(DPP-4 inhibitor)
1. Adapted from Deacon CF et al Diabetes 1995;44:11261131; 4. Kieffer TJ et al Endocrinology 1995;136:35853596;
2. Ahrn B Curr Diab Rep 2003;3:365372; 5. Deacon CF et al J Clin Endocrinol Metab 1995;80:952957;
3. Weber AE J Med Chem 2004;47:41354141.
Intestinal
GIP and GLP-1
release
GIP and GLP-1 actions

GIP (142)
GLP-1 (736)


GIP (1-42)
GLP-1 (7-36)


Rapid degradation
(minutes)
Meal
DPP-4
enzyme
DPP-4 inhibitor
Adapted from Unger RH. Metabolism. 1974; 23: 581593. Ahrn B. Curr Enzyme Inhib. 2005; 1: 6573.
Insulin
Glucagon
Improved
glycemic control
Incretin
activity
prolonged
Improved islet
function
DPP-4 inhibitor
Insulin
Glucagon
Hyperglycemia
Incretin
response
diminished
Further impaired
islet function
T2DM
DPP-4 Inhibitor decrease
glucagon secretion in type 2DM
DPP-4=dipeptidyl peptidase-4
T2DM=type 2 diabetes mellitus

DPP-4 Inhibitors for Glycemic Control
Rationale
Targets FPG and PPG via a glucose-dependant
mechanism of action
1,2
May be more effective than traditional agents in
patients with mild or moderate hyperglycemia (A1C
<8.5%)
1

Ideal candidates for combination therapy
No increased risk of hypoglycemia and weight
neutral
3
Complementary mechanisms of action
1
1. Bode BW. Postgrad Med. 2009;121:82-93.
2. Rodbard HW et al. Endocr Pract. 2009;15:540-559.
3. Phung OJ et al. JAMA. 2010;303:1410-1418.
Considering DPP-IV therapy in
glycaemic control as a simple
approach in T2DM
management
ROLE OF SAXAGLIPTIN
Saxagliptin: Provide Early, Strong,
Sustained Control of HbA1c
DeFronzo RA et al. Poster presented at ADA 69
th
scientific session 2009, USA, (547-P)
Saxagliptin is associated with significant glycaemic improvements during
the short-term and sustained benefits in a long-term extension period

Saxagliptin associated with low
incidence of hypoglycaemia

Reported hypoglycemia events
were a combination of reports
of either signs or symptoms
consistent with hypoglycemia
with or without documented
glucose levels or reported low
glucose levels without any
symptoms. Therefore, it is not
possible to conclusively
determine that all these
reports reflected true
hypoglycemia.


Confirmed hypoglycemia was
defined as a fingerstick
glucose 50 mg/dL with
associated symptoms.


Reported Hypoglycemia:
13 patients in the saxagliptin 5
mg + MET IR group reported
19 hypoglycemic events
156 patients in the up-titrated
GLIP + MET IR group reported
750 hypoglycemic events
Hypoglycemia During 52-Week Treatment Period*
P
r
o
p
o
r
t
i
o
n

o
f

P
a
t
i
e
n
t
s

(
%
)


0
10
20
30
50
40
Saxagliptin 5 mg +
MET IR
(n=428)
3.0

Reported

Up-titrated
GLIP + MET IR
(n=430)
8.1

Confirmed

36.3

Reported

Up-titrated
GLIP + MET IR
(n=430)
0.0

Confirmed

Saxagliptin 5 mg +
MET IR
(n=428)
* Safety analysis set.

P<0.0001 vs up-titrated GLIP + MET IR group.

MET IR=metformin immediate release; GLIP=glipizide.

Gke B et al. Int J Clin Pract. 2010;64(12):1619-1631.
Adjusted mean change in body weight: baseline to Week 52
(safety analysis set)
*p<0.0001.
GPZ: glipizide; MET: metformin; SAXA: saxagliptin,
1.1
GPZ + MET
(n=426)
-1.1*

SAXA + MET
(n=424)
-1.5
0
1.5
A
d
j
u
s
t
e
d

m
e
a
n

c
h
a
n
g
e

i
n

b
o
d
y

w
e
i
g
h
t

(
k
g
)

S
E

0.5
-
-
-
1.0 -
-0.5 -
-1.0 -
Saxagliptin provides a weight
neutral/ negative effect
Gke B, et al. Int J Clin Prac 2010;doi:10.1111/j.1742-1241.2010.02510.x.
Ongoing trials examining CV risk
reduction using DPP-IV
b
Raz I, et al. Eur Heart J 2012; 14 (SupplB): B22-B29

DPP-IV- Inhibitor





Glycaemic control
Hypoglycaemia
Weight effect
Extra glycaemic effects





Combination therapy
Why do we use combination therapy?
As an escalation of therapy in the
treatment of type 2 diabetes mellitus
Maximise therapeutic effects
Complimentary physiological action
More convenience. Better compliance



Progressively declining cell function in T2DM
The Need of Escalation Therapy
Adapted from: Heine RJ et al. BMJ. 2006;333:1200-1204.
100
0
0
HbA1c
-cell function
Lifestyle Monotherapy
Dual
therapy
Insulin oral
drugs for
lowering
blood glucose
Time
(years)

-
c
e
l
l

f
u
n
c
t
i
o
n

(
%
)

H
b
A
1
c

(
%
)

8
>15
5
6
7
9
0
10

Limitation of Monotherapy in DM
Maximise therapeutic effects



Multiple Pathophysiology of T2DM
Complimentary physiological action

H Y P E R G L Y C E M I A
Decreased
Incretin
Effect
Decreased
Glucose
Uptake
Islet -cells
Neurotransmitter
Dysfunction
Increased
Lipolysis
Decreased
Insulin
Secretion
Increased
Glucagon
Secretion
Increased
HGP
Increased
Glucose
Reabsorption
DeFronzo Ralph A Diabetes 2009; 58:773
Islet -cell
Three-times-daily
*
P<0.05;
**
P<0.01
vs once-daily
administration
20
40
60
80
P
a
t
i
e
n
t
s

(
%
)

w
i
t
h

o
p
t
i
m
a
l

c
o
n
c
o
r
d
a
n
c
e

**
*

Twice-daily Once-daily
The lower the dosing frequency, the higher the concordance

Frequency of daily dosing and concordance
More convenience. Better compliance

A major factor found to be associated with treatment concordance is the
frequency of daily dosing of oral glucose-lowering agents
Guillausseau PJ. Diabetes Metab. 2003;29:79-81.
Compliance = days supplied/total days.
Modified from Melikian C et al. Clin Ther. 2002;24:460-467.
Compliance decreases depending on
number of tablets
Monotherapy
(n=33,567)
Switched to
Combination single pill
(Glyburide/
Metformin)

Switched to
Non-FDC
(Glyburide
+ Metformin)
C
o
m
p
l
i
a
n
c
e

r
a
t
e

(
%
)

82
77
54
0
20
40
60
80
100
Muscle/Fat
in response to insulin release:
peripheral glucose uptake
Liver
in response to glucagon release:
hepatic glucose output
Pancreas
glucagon release
from cells
insulin release
from cells
in response to GLP-1 concentrations:

Muscle/Fat
Improves insulin sensitivity and
glucose uptake and utilization
Liver
glucose output by the liver
Pancreas
Insulin secretion remains unchanged
while fasting insulin levels and
day-long plasma insulin response
may decrease
Muscle/Fat
in response to insulin release:
peripheral glucose uptake
Liver
in response to glucagon release:
hepatic glucose output
Muscle/Fat
Improves insulin sensitivity and
glucose uptake and utilization
Liver
glucose output by the liver
Pancreas
Insulin secretion remains
unchanged while fasting insulin
levels and
day-long plasma insulin response
may decrease
Once-a-Day Saxagliptin+Metformin XR fixed-dose
combination: Has a Comprehensive Mechanism of Action
GLP=glucagon-like peptide; DPP=dipeptidyl peptidase.
1. Verspohl EJ. Pharmacol Ther. 2009;124:113-138.
Saxagliptin Metformin


Gut
Decreases () intestinal
glucose absorption


Gut
Decreases () intestinal
glucose absorption


Lower levels of the incretin hormone
GLP-1 are released from the gut
in patients with type 2 diabetes
Saxagliptin increases () incretin
concentrations in the bloodstream
Gut
Saxagliptin inhibits DPP-4 enzyme
activity
DPP-4
Enzymes
S


Lower levels of the incretin hormone
GLP-1 are released from the gut
in patients with type 2 diabetes
Saxagliptin increases () incretin
concentrations in the bloodstream
Gut
Saxagliptin inhibits DPP-4 enzyme
activity
DPP-4
Enzymes
S
Pancreas
glucagon release
from cells
insulin release
from cells
in response to GLP-1 concentrations:

Saxagliptin+Metformin XR fixed-dose
combination: Achieve Better Glycemic Control
than Increasing Metformin XR dose
Adjusted mean change from baseline HbA1c, was 0.88% for saxagliptin +
metformin XR and 0.35% for uptitrated metformin XR; the between-group
difference was0.52% (p < 0.0001)
Fonseca, V et al Diabetes, Obesity and Metabolism 14: 365371, 2012.
Saxagliptin+Metformin XR fixed-dose
combination is associated with fewer
gastrointestinal event

* DeFronzo RA et al. Diabetes Care. 2009;32(9):1649-1655.
Saxagliptin+Metformin XR Fixed-Dose
Combination Tablets
Outer layer :
color
Saxagliptin :
spray-coated layer
Inner layer :
seal coat
Metformin XR :
core tablet
Summary
Gradual deterioration in control occurs with time (UPKDS,1998).
Poor control leads to complications; good control can prevent
complications.
Benefit of combination therapy:
As an escalation of therapy in the treatment of type 2 diabetes
mellitus
Maximise therapeutic effects
Complimentary physiological action
More convenience. Better compliance
Summary
Advantages of Saxagliptin
Excellent glycaemic improvement profile
Neutral weight effect
Low hypoglycaemia risk
More convenient Once Daily dosing improves compliance for
both Saxagliptin and Fixed-Dose Saxagliptin+Metformin XR




Thank You