Realizing the Potential of

Incretin Based Therapies

Linagliptin:
A Novel Unique DPP-4 Inhibitor
Diabetic
Retinopathy
Leading cause
of blindness
in adults
1,2
Diabetic
Nephropathy
Leading cause of
end-stage renal disease
3,4
Cardiovascular
Disease
Stroke
2- to 4-fold increase in
cardiovascular
mortality and stroke
5
Diabetic
Neuropathy
Leading cause of
non-traumatic lower
extremity amputations
7,8
8/10 individuals with
diabetes die from CV
events
6
Type 2 diabetes is associated with
serious complications
1
UK Prospective Diabetes Study Group. Diabetes Res 1990; 13:111.
2
Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99S102.
3
The Hypertension in Diabetes Study
Group. J Hypertens 1993; 11:309317.
4
Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94S98.
5
Kannel WB, et al. Am Heart J 1990; 120:672676.
6
Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences.
7
Kings Fund. Counting the cost. The real
impact of non-insulin dependent diabetes. London: British Diabetic Association, 1996.
8
Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78S79.
Microvascular
complications
Myocardial
infarction
HbA
1c

37%
14%
Lowering HbA
1c
reduces the risk of
complications
Deaths related
to diabetes
21%
1%


Stratton IM, et al. BMJ 2000; 321:405412.
Stratton IM, et al. BMJ . 2000; 321:405412
Two thirds of individuals do not
achieve target HbA
1c

Saydah SH, et al. JAMA 2004; 291:335342., Liebl A, et al. Diabetologia
2002; 45:S23S28.
PERKENI
Consensus 2011
<7% 7-8% 8-9% >9% 9-10% >10%
HbA1c Level
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)

Linagliptin:
A Novel Unique DPP-4 inhibitor
Pancreas
Linagliptin Mechanism of action
Active
GLP-1 (7-36)
Intestine
Inactive
GLP-1 (9-36)
amide
Linagliptin
Increases glucose utilisation
by muscle and adipose
Decreases hepatic glucose
release Improving overall glucose
control
DPP-4
Adapted from Drucker DJ. Expert Opin Invest Drugs. 2003;12(1):87100
Ahrn B. Curr Diab Rep. 2003;3:365372
His-Ala
cleaved from
amino terminus
Food intake
Linagliptin a DPP-4 inhibitor with a unique xanthine-based structure
Saxagliptin
Sitagliptin
Vildagliptin
Adapted from Deacon CF. Diabetes Obes, Metab. 2011; 13: 718.
Peptidomimetic DPP-4 inhibitors
DPP-4 inhibitors mimicking dipeptides
N
N
N
N
O
F
F
F
F
F
F
NH
2
NH
2
O
HO
N
N
OH
N
H
N
O
N
Linagliptin
N
N
N
N
O
O
N
N
N
NH
2
Xanthine-based structure
DPP-4 inhibitors directly binding to the
active site of the enzyme
Non-peptidomimetic DPP-4 inhibitors
Meaningful efficacy across complete range of
oral treatment algorithms
Linagliptin treatment effect across treatment lines
Add-on
to met*
Add-on
to SU**
Add-on to
met + SU*
With metformin
(Low dose)*
p <0.0001 for all studies vs. baseline, for initial
combination vs. respective monotherapy
With metformin
(High dose)*

Diet and exercise
-1.7%

-1.3%
-0.9%
-1.7%

Placebo-corrected, adjusted mean change from baseline HbA
1c
* 24 weeks treatment duration
**
18 weeks treatment duration
12 weeks treatment duration
Dual
Combination
Triple
Combinati
on
Initial
Combination
-0.6%
-0.5%
-0.6%
Barnett, et al. Diab, Obes, Metab. 2012; 14: 1145 1154 (Metformin ineligible); Kawamori et al. Diab, Obes, Metab. 2012; 14: 348 - 357 (Japan); Taskinen, et al.
Diabetes Obes Metab. 2011;13: 65-74 (Add-on to metformin); Lewin et al. Clin Ther . 2012; 34(9) : 1909 19 (Add-on to SU); 3. Owens DR, et al. Diabet Med.
2011; 28:1352-61 (Add-on to metformin + SU); Haak T, et al. Diab Obes Metab. 2012; 14(6):565-74 (Initial combi with met).
Linagliptin achieves HbA
1c
decrease of up to
1.2% in poorly controlled patients
Significant HbA
1c
reductions in type 2 diabetes patients with baseline
HbA
1c
9%

A
d
j
u
s
t
e
d

m
e
a
n

c
h
a
n
g
e

i
n

H
b
A
1
c

(
%
)

f
r
o
m

b
a
s
e
l
i
n
e

a
t

w
e
e
k

2
4

-1.5
-1
-0.5
0
-0.72
-0.80
Add-on to
metformin
1

Add-on to
metformin + SU
2

n =
29 96
Mean baseline HbA
1c
(%)

48 136
9.5 9.5 9.4 9.4
-0.23
-0.40
-0.95
-1.20
Placebo
Linagliptin
Linagliptin placebo-corrected
p <0.0001
p <0.0001
p-values for between group difference (versus placebo)
1. Taskinen MR, et al. Diab Obes Metab. 2011;13(1):6574.
2. Owens DR, et al. Diabet Med. 2011; 28:1352-61
-0.17
0.03
-0.01
-0.66
-0.59
-0.67
-0.49
-0.62
-0.66
-1
-0.5
0
0.5
Linagliptin provides reliable HbA
1c
reductions independent
of time since diagnosis of type 2 diabetes
1 year
Change from baseline HbA
1c
by time since diagnosis of type 2 diabetes
Adjusted mean at 24 weeks of treatment, percent
p <0.0001 p <0.0001 p <0.0001
> 1 to 5 years > 5 years
A
d
j
u
s
t
e
d

m
e
a
n

c
h
a
n
g
e

i
n

H
b
A
1
c

(
%
)

f
r
o
m

b
a
s
e
l
i
n
e

a
t

w
e
e
k

2
4

n =
227 570
Mean baseline HbA
1c
(%)

8.2 8.1
381 1045 120 261
8.0 8.1 8.2 8.2
p-values for between group difference (versus placebo)
Placebo
Linagliptin
Linagliptin placebo-corrected
Pre-specified sub-group analysis on pooled data from 4 pivotal phase III randomized
placebo-controlled trials: treatment in monotherapy, add-on to metformin, add-on to
metformin + SU, initial combination with pioglitazone.
Source: Barnett A, et al. Diabetes. 61(Suppl 1):A260(Abstr 1017-P
-1
-0.5
0
0.5
Linagliptin provides reliable HbA
1C
reductions
independent of patient age
50 years
Change from baseline HbA
1c
by age
1

Adjusted mean change from baseline at 24 weeks of treatment
p <0.0001
p <0.0001
p <0.0001
51 to 64 years 65 to 74 years 75 years
p =0.0002
n =
363 970
Mean baseline HbA
1c
(%)

8.2 8.2
194 442
A
d
j
u
s
t
e
d

m
e
a
n

c
h
a
n
g
e

i
n

H
b
A
1
c

(
%
)

f
r
o
m

b
a
s
e
l
i
n
e

a
t

w
e
e
k

2
4

8.2 8.2
152 398
8.1 8.1
19 66
8.1 8.0
-0.56
0.02
-0.54
-0.64
-0.02
-0.66
-0.60
-0.09
-0.69
0.03
-0.80
-0.83
p-values for between group difference (versus placebo)
Placebo
Linagliptin
Linagliptin placebo-corrected
Pre-specified sub-group analysis on pooled data from 4 pivotal phase III randomized
placebo-controlled trials: treatment in monotherapy, add-on to metformin, add-on to
metformin + SU, initial combination with pioglitazone.
Source: Barnett A, et al. Diabetes. 61(Suppl 1):A260(Abstr 1017-P
-0.6
-0.6
Both linagliptin and glimepiride show better efficacy in
those patients who respond to the trial medication
Completers cohort: Linagliptin n = 233, glimepiride n = 271
Mean baseline HbA1c: 7.2% (linagliptin), 7.3% (glimepiride)
Linagliptin
Glimepirid
e
Mean ( SE) of HbA1c in Percent
7.5
7.0
6.5
6.0
Treatment duration Weeks
105 100 95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0
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
previously
2
. 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
Significant relative weight loss and lower incidence of
hypoglycemia with linagliptin compared to glimepiride
1 Hypoglycemic episode defined by a blood glucose 70 mg/dl
2 Treated Set: Linagliptin n=776, glimepiride n=775
3 Model includes baseline HbA
1c
, baseline weight, no. prior OADs, treatment, week repeated within patients and week by treatment interaction
7.5
Incidence of hypoglycemia
1

Percent of patients - Treated set
2
Adjusted
3
means for body weight change
from baseline SE
Kg - Full analysis set (OC)
2.0
1.5
1.0
0.5
0
-0.5
-1.0
-1.5
-2.0
Glimepiride
Linagliptin
p<0.0001
28 104
weeks
52 78 12
-2.9
0
10
20
30
40
50
Linagliptin Glimepiride
p<0.0001
+1.4
-1.5
4.8x
reduction
Gallwitz B, et al. Lancet. 2012; 380 (9840): 475-83
In a prospective, pre-specified meta-analysis, Linagliptin
was not associated with an increased CV risk
Incidence rate of CV events
1
Number and percentage of patients
Out of
3,319 patients
= 0.3%
1. CV events as defined as primary endpoint; 2. 977 patients receiving placebo, 781 glimepiride, 162 voglibose
Comparator
2
Linagliptin
Out of
1,920 patients
= 1.2%
Risk ratio
0.34
95% CI
(0.15/0.74)
p<0.05
Years of exposure
2,060 1,372
Johansen OE, et al. Cardiovascular Diabetology. 2012; 11: 3-10
Share of renal excretion
All other DPP-4 inhibitors are
primarily excreted via the
kidneys

They all require dose-
adjustment, or are not
recommended in patients
with renal impairment.
Drug-related kidney
monitoring may also be
required
No dose adjustment
and/or no additional drug
monitoring required
1
60-71 Alogliptin
5
Saxagliptin
4
Vildagliptin
3
Sitagliptin
2
87
Linagliptin
1
1. Approved Trajenta Local PI
2. Vincent SH, et al. Drug Metab Dispos. 2007;35(4): 533538
3. He H, et al. Drug Metab. Dispos.2009 37(3):545554
4. Dave DJ. J Pharmacol Pharmacother. 2011; 2(4): 230-235
5. Andukuri R, Drincic A, Rendell M. Diab, Metab Syndrom, Obes: Target and Ther. 2009; 2: 117-126
* of currently globally approved DPP-4 inhibitors
Data from multiple trials, includes metabolites and unchanged drug; excretion after single dose administration of [14C] labeled drug
Linagliptin is the only DPP-4 inhibitor which is primarily excreted by
bile and gut*
5
85
75
%
%
%
%
%
Prescribing characteristics of DPP-4 inhibitors
Renal Impairment* Hepatic Impairment
Inhibitor
Linagliptin
Sitagliptin
Not recommended (EU)
dose (US)
1
Not recommended (EU)
dose (US)
1


Not recommended
1

Vildagliptin
2

Not recommended
1
Not recommended
1
Not recommended Not recommended
Saxagliptin
3

dose (EU)
dose (US)
1

dose (use with caution)
not recommended in ESRD (EU)
dose (US)
1


(Moderate: use with
caution)
Not recommended
1

Alogliptin
dose dose

Not recommended
1

CrCl = Creatinine clearance; ESRD = end-stage renal disease
* Assessment of renal function recommended prior to initiation of treatment and periodically thereafter
1. Not studied/no clinical experience
2. Assessment of hepatic function recommended prior to initiation of vildagliptin and periodically thereafter
3. Dose reduction (2.5 mg) when saxagliptin co-administered with strong CYP450 3A4/5 inhibitors (e.g. ketoconazole)
Adapted from Deacon CF. Diabetes, Obes Metab. 2011;13(1):718.
Linagliptin is well tolerated
1. Organ-specific adverse events taken from label of currently marketed DPP-4 inhibitor in the US; * Trajenta Prescribing Information by
BPOM
Schernthaner G, et al. Diab, Obes, Metab. 2012; 14(5): 470- 478
Organ-specific adverse event (AE) rate for AE previously associated with the DPP-4
inhibitor class
1
Upper respiratory tract
infection
Nasopharyngitis
Cough
Blood and lymphatic
system disorders
Hypersensitivity
Urinary tract infection
Hepatic enzyme increase
Headache
Pancreatitis:
Pancreatitis was reported
more often in patients
randomized to linagliptin
(1 per 538 person years
versus zero in 433 person
years for comparator)*
Serum creatinine increase
n
Linagliptin
2,523
3.3%
5.9%
1.7%
1.0%
0.1%
2.2%
0.1%
2.9%
0.0%
Placebo
1,049
4.9%
5.1%
1.0%
1.2%
0.1%
2.7%
0.1%
3.1%
0.1%
Linagliptin 2,5 mg Bid Vs Linagliptin 5 mg QD

Ross SA et al. Curr Med Res Opin 2012; 28(9): 1-10
Efficacy of Linagliptin
2,5 mg Bid vs 5 mg QD

Ross SA et al. Curr Med Res Opin 2012; 28(9): 1-10
Start and stay with Linagliptin
27 October 2014 PLEASE INSERT Presentation title 21
Summary: Rationale for early combination therapy
The risk of type 2 diabetes complications can be reduced by an early improvement of glycaemic
control
1
DPP-4 inhibitors have a complementary mechanism of action to metformin
2
Combining metformin with a DPP-4 inhibitor provides the improved glycaemic control required,
along with
4
3

Low risk of hypoglycaemia
No additional weight gain
By addressing the core pathophysiological mechanisms of type 2 diabetes, the addition of a DPP-
4 inhibitor to metformin delivers comprehensive therapeutic advantages
1. Stratton IM, et al. BMJ. 2000;321:405412; 2. Migoya EM, et al. Clin Pharmacol Ther. 2010;88(6):801808; 3. Goldstein BJ, et al. 2007. Diabetes Care.
2007;30:19791987.
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