Drive success from the start in

diabetes management: focus on

Linagliptin

TRA-TRD/034/FEB17/FY

Diabetes related facts: huge and growing

problem
The prevalence of
diabetes

2015

One
One

in

11

two adults with

Diabetes is undiagnoses

adults has diabetes

in

One

2040

in

10

Diabetes Atlas 7th edition 2015. International Diabetes Federation

adults will have diabetes

Diabetes is one of the major healthcare

burden in Indonesia

Diabetes Atlas 7th edition 2015. International Diabetes Federation

Every 10 seconds a person dies from diabetes related complications

Diabetes significantly increases the risk of

heart disease
by 24x*

In 2005 2008:
655,000 patients had
advance diabetic
retinopathy that
could lead severe
loss of vision

stroke
to more than 24x
the general population*

In 2008:
202,290 people with
end stage kidney
disease living on
chronic dialysis*

CDC 2011 National Diabetes Fact Sheet. http://www.cdc.gov/diabetes/pubs/estimates11.htm#12

In 2006:
65,700 patients will
have an amputation*

Approximately 40% of T2DM patients

have renal complications

Typical progression of CKD1

CKD
1

CKD
2

CKD
stage

CKD
3
CKD
45

No
CKD

eGFR
(mL/min)

% of T2DM
pts

Missing data

~9.5%

No CKD

90*

~50.8%

90**

~9%

6089

~11%

3059

~18%

45

<29

~2%

* No signs of kidney damage

** Albuminuria kidney damage

Based on data from 1462 patients aged 20 years with T2DM who participated in the Fourth
National Health and Nutrition Examination Survey . (NHANES IV) in the years 1999 through 2004
1. Koro CE, et al. Clin Ther 2009;31:260817.

Incidence per 100 patient-years

Risk for CV events are greater when

both diabetes and nephropathy are
present
75%
60%
45%
30%
15%
0%
CHF

AMI*

Non-diabetes/non-CKD
Diabetes/CKD

CVA/TIA*
Diabetes/non CKD

PVD*

ASVD*

Non-diabetes/CKD

* CHF=congestive heart failure; AMI=acute myocardial infarction; CVA/TIA=cerebrovascular accident/transient

ischemic attack;
PVD=peripheral vascular disease; ASVD=atherosclerotic vascular disease. aASVD was defined as the first occurrence
of AMI, CVD/TIA, or PVD.
Foley RN, et al. J Am Soc Nephrol 2005;16:48995.

Effective control of T2D reduces risk of

complications
1% decrease in HbA1c correlates with reduction in risk of
Microvascular Peripheral Myocardial
vascular
disease
infarction
disorders

Stroke

Heart
failure

12%

16%

p = 0.035

p = 0.016

Cataract
Death
extraction related to
diabetes

0
Relative Risk (%)

37%

43%

14%

19%

21%

15
30

p < 0.0001 p < 0.0001

45
p < 0.0001

Prospective observational analysis of UKPDS35 patients (n=4585, incidence analysis; n=3642, relative risk
analysis).
Median 10.0 years of follow-up.
Adapted from Stratton IM, et al. BMJ. 2000;321:405412.

Southeast Asia has one of the highest rates

of end stage renal disease (ESRD) in the
world
Consequently, CKD in diabetes patient is associated with considerable
morbidity and cardiovascular related mortality

Chow F Cc, et all. J Diabetes Invest Doi:10.1111/jdi.12006, 2012.

Type 2 diabetes is a progressive

disease
Progression of Type 2 Diabetes
Insulin resistance
Hepatic glucose
production
Insulin level
Beta-cell function

47 years

Postprandial
glucose
Fasting plasma
glucose

Development of Microvascular Complications

Development of Macrovascular Complications
Impaired Glucose Tolerance

Diabetes

Diabetes Diagnosis
Conceptual representation adapted from Ramlo-Halsted BA, Edelman SV. Prim Care 1999;26(4):771789. 1999 Elsevier

Hypoglycaemia - Why is this important?

Hypoglycaemia is associated with increased risk of death,

especially in patients with coronary artery disease or
acute myocardial infarction1
Up to 38% of people with type 2 diabetes experience
symptomatic hypoglycaemia2
o

It is believed that many incidences of hypoglycemia go

unreported to healthcare professionals3

Hypoglycaemia results in reduced quality of life,

treatment satisfaction and therapy adherence2,4

Hypoglycaemia is associated with cognitive

dysfunction and delayed recovery in the elderly5

Hypoglycaemia is associated with increased anxiety6

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. Zammitt N, et al. Diabetes. 2008; 57: 7326 ; 6. Labad J, et al. Diabetologia. 2010; 53: 46771

Risk of hypoglycaemia increases as

therapy intensifies

Wright et al. J Diabetes Complicat 2006;20:395401 (UKPDS 73)

Burden of weight gain

Weight gain can be a barrier to intensifying treatment1, 2
Approximately 50% of patients are very anxious about
their weight3
Weight gain results in increased cardiovascular risk
factors
weight gain/obesity is associated with
hyperlipidaemia, hypertension, heart disease and
stroke4
Increased body mass index (BMI) has been associated
with an increased risk of morbidity and mortality from
coronary heart disease (CHD)5
1. Davis. Int J Obesity 2004;28(Suppl. 2):S14S22. 2. Korytkowski. Int J Obesity 2002;26(Suppl. 3):1824. 3. Alberti. Pract Diab Int 2002;19:22
24. 4. WHO obesity fact sheet. www.who.int. 5.Fava SL, et al. Arteriosclerosis, Thrombosis and Vascular Biology. 1996

Most current therapies for T2DM

promote weight gain

Change in weight (kg)

8
7

Conventional* (n =
411)
Glibenclamide
(n = 277)
Metformin (n = 342)
Insulin (n = 409)

UKPDS 34 Study

6
5
4
3
2
1
0
0

Years from randomization

* Diet initially then sulphonylureas, insulin and/or metformin if FPG > 15

mmol/L.
UKPDS 34
Study. Lancet. 1998:352:854865.

12

Relative Risk of Death

Relationship between BMI and

cardiovascular disease mortality

Men
Women

Lean
<18.5

18.5

20.4

20.5

21.9

Overweight
22.0

23.4

23.5

24.9

25.0

26.4

26.5

27.9

28.0

29.9

Body Mass index

Calle et al. N Engl J Med 1999;341:1097.

30.0

31.9

Obese
32.0

34.9

35.0 >40.0

39.9

Expectations for new agents

and/or new strategies
Consistent efficacy across broad range of Type 2

Diabetes Mellitus
Lowering HbA1c to targets as close to normal as

possible without unacceptable hypoglycaemia

in selected populations
Not increasing cardiovascular event
Lowering HbA1c without weight gain
Not increasing risk of target organ damage (eg.

kidney)

DPP-4 Inhibitors and incretin mimetics

address a core defect in a unique way
Glucose
absorption

Inadequate
glucagon
suppression

Insulin
resistance

-glucosidase
inhibitors1

Acute
Chronic
-cell
-cell
dysfunction insufficiency

DPP-4
DPP-4
inhibitors
inhibitors
and incretin
and incretin
1
sulphonylurea
3
mimetics
mimetics4

TZDs2
Metformin1

Glinide1

Blood glucose

1. Inzucchi SE. JAMA. 2002;287-360372; 2. DeFronzo RA. Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24S40;
3. Nauck MA. Am J Med. 2011;124(1 Suppl):S3S18; 4. Garber AJ. Diabetes Care. 2011;34(Suppl 2):S258S263.

Benefits and limitations of T2DM treatment

options

DPP-4
inhibitor

Sulfonilurea

Biguanide

Glinide

TZD

AGI

GLP-1
agonist

Insulin

FPG

++

++

++

Neutral

+++

PPG

++

++

++

++

+++

+++

Level of Risk

Hypoglycem
Neutral
ia

Moderate

Neutral

Mild

Neutral

Neutral Neutral

Moderate to
severe

Weight gain Neutral

Mild

Benefit

Mild

Moderate

Neutral Benefit

Mild to
Moderate

CV event

Neutral

Neutral

Drug-drug
interaction

Neutral

Moderate

Contraindicat
Contraindicat
Neutral
Neutral Neutral
ed in CHF
ed in CHF
Neutral

Adapted from: Rodbard HW, et al. Endocr Pract. 2009;15:540-559.

Modera
-te

Neutral

Neutral Neutral

Neutral
Neutral

Algoritme pengelolaan DM Tipe 2 di Indonesia KONSENSUS

PERKENI 2015
Modifikasi pola hidup sehat

Kombinasi 2 obat*
dengan mekanisme
kerja yang berbeda

Metformin

Agonis GLP-1

Penghambat DPP-IV

Penghambat
Glukosidase Alfa

Agonis GLP-1

Penghambat DPP-IV

Tiazolidindion

Penghambat SGLT-2

Insulin Basal

SU/Glinid

Kolsevelam**

Penghambat SGLT-2**

Tiazolidindion

Sulfonilurea

Bromokriptin-QR

Glinid
Jika HbAc1 > 6.4%

Penghambat

dalam 3 bulan tambahan

obat ke 2 (kombinasi 2
obat)

Kombinasi 3 obat

Kombinasi 2 obat

Kombinasi 3 obat

Insulin obat jenis lain

Agonis GLP-1

Penghambat DPP-IV

Tiazolidindion

Penghambat SGLT-2

Insulin Basal

Keterangan

Kolsevelam**

*Obat yang terdaftar, pemilihan dan

Bromokriptin-QR

Penghambat
Glukosidase Alfa

Jika belum memenuhi

Glukosidase Alfa

Jika belum memenuhi sasaran

sasaran dalam 3 bulan,

dalam 3 bulan, mulai terapi

masuk ke kombinasi 3

insulin atau intensifikasi terapi

obat

insulin

Konsensus Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 di

Gejala
(+)

Gejala
(-)

Obat lini kedua +

Monoterapi* dengan
salah satu obat di
bawah ini

HbA1c 9.0%

Metformin atau obat lini pertama yang

lain +

HbA1c 7.5%

Metformin atau obat lini pertama yang lain +

HbA1c < 7.5%

Mulai atau intensifikasi

Insulin

penggunaannya disarankan
mempertimbangkan faktor
keuntungan, kerugian biaya, dan
ketersediaan sesuai tabel 11
** Kolsevelam belum tersedia di
Indonesia
Bromokriptin QR umumnya
digunakan pada terapi tumor

abcd

hipofisis

ADA/EASD 2015 guidelines for managing hyperglycaemia

Metformin

Monotherapy

High
Low risk
Neutral/loss
GI/lactic acidosis
Low

Efficacy (HbA1c)
Hypo risk
Weight
Side effects
Cost

If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not
meant to denote any specific preference choice dependent on variety of patients- and disease-specific
factors

Metformin +
SU
Dual Therapy
Efficacy (HbA1c)
Hypo risk
Weight
Side effects
Cost

High
Moderate risk
Gain
Hypoglycaemia
Low

Metformin +
TZD
High
Low risk
Gain
Edema.HF,FXs
High

Metformin +
DPP-4i
Intermediate
Low risk
Neutral
Rare
High

Metformin +
SGLT2i
Intermediate
Low risk
Loss
GU, dehydration
High

Metformin +
GLP-1 RA
High
Low risk
Loss
GI
High

Metformin +
Insulin(basal)
Highest
High risk
Gain
Hypoglycaemia
Variable

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any
specific preference choice dependent on variety of patients- and disease-specific factors

Metformin +

Metformin +

SU +

TZD +

TZD
OR

Triple Therapy

Combination
injectable
therapy

DPP-4i

Metformin +
DPP-4i++
DPP-4i

SU
OR

DPP-4i

OR SGLT2-i

OR SGLT2i

OR GLP-1 RA

OR

OR Insulin

OR Insulin

GLP-1 RA

Metformin + Metformin +
SGLT2i +

SU

GLP-1 RA + +

TZD

OR

TZD

OR

SGLT2i

OR

DPP4i

OR

Insulin

OR

Insulin

Insulin +
TZD

SU

SU

OR

Metformin +

OR

TZD

OR Insulin

OR

DPP-4i

OR SGLT2i
OR GLP-1 RA

If HbA1c target not achieved after ~3 months of triple therap and patients (1) on oral combination, move to injectable; (2) on GLP-1
RA, add basal insulin; or (3) on optimally treated basal insulin, add GLP-1 RA or mealtime insulin. In refractory patients consider
adding TZD or SGLT2i

Adapted from Inzucchi S, et al. Diabetes Care 2015

Basal insulin + mealtime insulin or GLP-1 RA

Linagliptin Mechanism of action

Linaglipti
n

http://cdn.intechweb.org/pdfs/21462.pdf access on 05.03.2015

DPP IV inhibitors Excretion Route*

Share of renal excretion
Linagliptin 5 %
1

Sitagliptin2,3

87

Vildagliptin4,5

87%
%

No dose adjustment
and/or no additional
drug monitoring
required1
All other DPP-4
inhibitors are
primarily excreted via
the kidneys

They all require doseadjustment, or are not

%
Saxagliptin6
recommended in
patients
with renal impairment.
75
Drug-related kidney
* of currently globally approved DPP-4 inhibitors
monitoring
may
also
Data from multiple trials, includes metabolites and unchanged drug; excretion after single dose
administration
of [14C]
labeled drug
be required
85

1.
2.
3.
4.
5.

Trajenta Local Product Information 2014.

Vincent SH, et al. Drug Metab Dispos. 2007;35(4): 533538
Sitagliptin Prescribing Information 2015
He H, et al. Drug Metab. Dispos.2009 37(3):545554
Vildagliptin Prescribing Information 2014

7
6
5
4
3
2
1

(n=6)
Creatinine clearance*>80
(mL/min)

Linagliptin
Fold increase
increase in
in
Fold
exposure relative
relative to
to
exposure
normal renal
renal
normal
function
function

Fold increase
increase in
in
Fold
exposure
relative
to
exposure relative to
normal
renal
normal
function
function

No dose adjustment: Linagliptin is the only DPP-4 inhibitor that can be given in
full dose even in patients with renal impairment

(n=6)
(n=6)
(n=6)
(n=6)
30 <30 on HD
>50 to
>30 to
80 Saxagliptin
Renal50
impairment status

7
6
5
4
3
2
1

(n=6)
Creatinine clearance*>80
(mL/min)

7
6
5
4
3
2
1

(n=8)
Creatinine clearance*>80
(mL/min)

(n=6)
(n=6)
(n=6)
(n=6)
30
on HD
>50 to
>30 to
80 Renal50
impairment status

Vildagliptin
(LAY151 metabolite)3
Fold increase
increase in
in
Fold
exposure relative
relative to
to
exposure
normal renal
renal
normal
function
function

Fold increase
increase in
in
Fold
exposure relative
relative to
to
exposure
normal renal
renal
normal
function
function

(5-hydroxy saxagliptin metabolite)2

Sitagliptin

(n=8)
(n=8)
(n=7)
(n=8)
30 <30 on HD
>50 to
>30 to
80 Renal50
impairment status

Renal impairment status

ESRD = end-stage renal disease; HD = Haemodialysis; * Estimated creatinine clearance values were calculated using the Cockcroft-Gault
formula
Source: Graefe-Mody U, et al. Diabetes, Obes Metab. 2011; 13(10): 939 - 946
2 Geometric mean ratios fet al.or saxagliptin were calculated from the geometric mean data reported by Boulton et al; 90% confidence intervals are not available from that publications.
3 Numbers of patients, 90% confidence intervals and definitions of renal impairment status according to creatinine clearance are not available for the vildagliptin study.

Synergistic effects of Metformin and

Linagliptin
Metformin

AMPK
activation

Linagliptin

GLP-1
production

Gut

GLP-1
Inactivation

DPP4
inhibition
GIP

Liver

Pancreas
GLP-1

Insulin

Gluconeogensis
Hyperglycaemia
(fasting and post-prandial
AMPK: AMP activated protein kinase; DPP4: Dipeptidyl peptidase; GIP: Glucose-dependent insulinotropic
polypeptide; GLP-1: Glucagon-like peptide 1
Source: Scheen AJ. Expert Opin Drug Metab Toxicol. 2013;9:363377.

Glucagon

(Glucose dependent)

Metformin + DPP-4 inhibitors: combinations of oral glucose lowering agents with

complementary mechanisms of action

Target site
Pancreati
c -cell
Pancreati
c -cell

Action
Enhances glucose-dependent
insulin secretion1
Suppresses glucagon secretion1
Lowers hepatic glucose
production1,2
Improves insulin resistance3

Safety and
tolerability

Metformin

Low risk of hypoglycaemia1,3

No additional weight gain1,3

1.Drucker DJ, Nauck MA. Lancet. 2006;368:16961705.

2.Inzucchi SE. JAMA. 2002;287:360372.
3.Del Prato S, et al. Int J Clin Pract. 2005; 59:13451355.

DPP-4
inhibitors

Comparable efficacy vs. Glimepiride and sustain for 104 weeks

of treatment

Mean ( SE) of HbA1c in Percent

7.5

Linagliptin

Glimepiri
de

7.0

-0.6

6.5

-0.6

6.0
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95100105
Treatment duration Weeks
Completers cohort: Linagliptin n = 233, glimepiride n = 271
Mean baseline HbA1c: 7.2% (linagliptin), 7.3% (glimepiride)

Completers cohort (CC) post-hoc analysis: All patients who completed the full 104 weeks on treatment in the
FAS without important protocol violation that did not receive rescue medication and did achieve defined
HbA1c goals as described previously2. All observed cases were included.
1 Model includes treatment, baseline HbA1c and number of prior OADs
2 As described previously by Seck et al. Int J Clin Pract 2010; 64: 562-576
Source: Gallwitz B, et al. Lancet. 2012; 380 (9840): 475-83

Similar efficacy of Linagliptin

2,5 mg BID vs 5 mg QD in combination with
Metformin

ss SA et al. Curr Med Res Opin 2012; 28(9): 1-10

Linagliptin is well tolerated

(2)

Organ-specific
adverse event (AE)
rate for AE previously
associated with the
DPP-4 inhibitor class1

Pancreatitis:
1 per 538 person
years versus zero in
433 person years
for comparator1

Schernthaner G, et al. Diab, Obes, Metab. 2012; 14(5): 470- 478

LinagliptinPlacebo
n 2,523 1,049
Headache

2.9%

3.1%

Upper respiratory 3.3%

tract infection
Nasopharyngitis 5.9%

4.9%

Hepatic enzyme
increase
Serum creatinine
increase
Urinary tract
infection
Blood and lymphatic
system disorders
Hypersensitivity

5.1%

0.1%

0.1%

0.0%

0.1%

2.2%

2.7%

1.0%

1.2%

0.1%

0.1%

Linagliptin clinical profile

Efficacy
Meaningful and reliable efficacy
across complete range of oral
diabetes therapies

Durable efficacy in
longer term treatment
up to 2 years

One dose fits all

Once-daily
With or without food

Convenience

Safety & Tolerability

Overall safety profile similar to placebo:
No clinically relevant weight gain
low risk of hypoglycaemia
Most common adverse
reaction: nasopharyngitis
Not associated with
an increase in CV risk

Primarily excreted
via bile & gut
Renal excretion = 5%

No dose adjustment in
renal or hepatic impairment

Summary
Diabetes is difficult to control due to its barrier in disease
condition, patients, and provider.
As patient with type 2 diabetes develop complication
(including renal impairment), renal function should be
considered when choosing an antidiabetic therapy.
Linagliptin has an unique pharmacological profile that shows
good tolerability in renal and hepatic impaired type 2 DM
patient, similar efficacy to Sulfonilurea with low risk of
hypoglycemia and weight neutral.
Early combination of Linagliptin + Metformin result in
significant HbA1c reduction up to 3.7% in poorly controlled

Thank You