Linagliptin is a DPP-4 inhibitor indicated for type 2 diabetes. It has a unique xanthine-based structure that allows for tight binding to DPP-4 and full 24-hour inhibition. Clinical trials involving over 6,000 patients across many countries demonstrated linagliptin's ability to significantly reduce HbA1c levels when used as monotherapy, in combination with metformin, or metformin and sulfonylurea, with a safety profile similar to placebo. Linagliptin's structure contributes to its sustained glycemic control and safety advantages over other DPP-4 inhibitors.

1. Role in T2DM management
Expert panel on Linagliptin Incretin-based Treatment Evolution (ELITE)
Linagliptin

2. Diabetes: challenges to management
Adherence to
therapy
Coexisting risk of
declining
hepatic/renal/CV
function
Co morbidities
Hypertension
Need for Early and
Aggressive Care for
Sustained glucose
control
Treating to goal without
hypoglycemia & glycemic
variability

3. Gliptins: Addressing the unmet needs in T2DM
 Correct a core defect:
Stabilize deterioration of beta cell function
 Overcome risks:
Low risk of hypoglycemia and weight neutral
 Have acceptable safety profile:
No serious adverse events were noted during the
clinical trials
A Ramachandran, AK Das, SR Joshi, CS Yajnik, S Shah, KM Prasanna Kumar.
JAPI • JUNE 2010

4. Conducted between 2004 and 2010
More than 40 countries worldwide
More than 600 investigational sites
More than 6,000 patients participated
In total 4687 patients with type 2 diabetes &
453 healthy volunteers
3692 patients were treated for at least 24 wks,
2474 patients for at least 52 wks &
536 patients for more than 78 wks
Europe - 44.3% patients
Asia - 40.2% patients
North America - 9.3% patients
South America.- 6.2% patients
Linagliptin: the first DPP-4th inhibitor gliptin?
624 829
5,002
0
2,000
4,000
6,000
Phas
e I
Phase
II
Phase
III
Currently approved in > 7 major countries
US, EU, Brazil, Canada, Japan, Australia,
Mexico, Taiwan, India
Gliptin with largest clinical program before launch

5. 5
First in T2DM
First in men
Phase II
1st horizon
2nd horizon
3rd horizon
Phase IV
PK/PD studies
PK studies in
specific
populations
Phase IIIb
Phase IIIa
.50
.20
.23
.35
.16
.17
.18
.43
.63
.64
.61
.75
.36
.46
.6
.2
1218.1
.37
.27
.55
.34
.32
.84
.85
…
.88
.86
…
…
…
…
…
…
…
…
.15
Overview on phase I-IV trials according to clinical evolvement
DDI
.60
CAROLINA
.74
CV metaanalysis
DARLINA .89
Add. CV-
studies
.3
.11
.26
.58
.5
.52
.78
.65
.66
Specific
countries
.83
.87
.40
Pivotal
.62
.7
.7

6. Linagliptin: Indications
Linagliptin in monotherapy
Linagliptin as add-on to metformin and as initial combination
Linagliptin as add-on to SU
Linagliptin + pioglitazone in initial combination
Linagliptin as add-on to metformin + sulfonylurea
Linagliptin head-to-head study vs. sulfonylurea (in combination with metformin)
Linagliptin as monotherapy vs. -glucosidase inhibitor (voglibose)
Linagliptin in patients with severe renal impairment
Linagliptin as add-on to basal insulin (just completed)
Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and
exercise to improve glycemic control in adults with type 2 diabetes mellitus
• Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis
• Has not been studied in combination with insulin

7. Unique Structure
and related
benefits
Glycemic control
Safety and
tolerability
Special populations
Beyond glycemic
control – emerging
data
Linagliptin: not just a fourth gliptin

8. Unique Structure
and related
benefits
Glycemic control
Safety and
tolerability
Special populations
Beyond glycemic
control – emerging
data
Linagliptin: not just a fourth gliptin

9. Linagliptin: Xanthine based structure
Directly binds to the active site of the enzyme
Saxagliptin
Sitagliptin
Vildagliptin
Adapted from Deacon CF. Diabetes Obes Metab. 2011; 13: 7–18; 1 Davis JA. Indian J Pharmacol 2010;42:229-33, 2 Kirby M. Clinical Science (2010) 118, 31–41
Peptidomimetic DPP-4 inhibitors
Linagliptin
N
N
N
N
O
O
N
N
N
NH2
DPP-4 inhibitors directly binding to the
active site of the enzyme
Non-peptidomimetic DPP-4 inhibitors
N
N
N
N
O
F
F
F
F
F
F
NH2
NH2
O
HO
N
N OH
N
H
N
O
N
Non Covalent – fast binding/fast dissociation1
Covalent – slow binding/slow dissociation2 Non Covalent – Fast binding/slow dissociation

10. 0 5000 10000 15000 20000
0.0
0.2
0.4
0.6
0.8
1.0
Linagliptin
koff = 0.00003 s-1
Vildagliptin
koff = 0.00021 s-1
Time [s]
(v
control
-
v
inhibitor
)/v
control
mean
+
SEM
Linagliptin: Xanthine based structure
Tight, fast binding to and slow dissociation from DPP-4 Enzyme
Linagliptin (light-blue carbon
atoms) bound to DPP-4
Eckhardt et al., J Med Chem. 2007;50(26):6450–3.
Thomas et al., J Pharmacol Exp Ther. 2008;325(1):175–82.
The calculated koff rate for linagliptin
was ~10-fold slower than the off-rate
for vildagliptin

11. 11
DPP-4
enzyme
activity
[%
control]
Log dose [M]
0
20
40
60
80
100
120
- 12 - 10 - 8 - 6
IC501 [nM]
mean
1
19
Sitagliptin
24
Alogliptin
50
Saxagliptin
62
Vildagliptin
Thomas et al., J Pharmacol Exp Ther. 2008;325(1):175–82
1 Concentration of compound needed to inhibit 50% of DPP-4 activity, i.e. the lower the IC50,
the higher the potency to inhibit DPP-4 activity
Linagliptin concentration in
clinical use is 6-8 nmol/L,
resulting in >80% DPP-4
inhibition over 24 hours
Linagliptin
Linagliptin: Xanthine based structure
Highest potency inhibition in direct comparison to other DPP-4 inhibitors
Sitagliptin
Linagliptin
Saxagliptin
Alogliptin
Vildagliptin
Highest potency of
linagliptin in
inhibiting DPP-4
enzyme activity

12. Linagliptin: Full 24 h Duration of DPP-4 Inhibition, Not Observed
with Other DPP-4 Inhibitors (Preclinical data)
Thomas et al, J Pharmacol Exp Ther. 2008;325(1):175–82.
HanWistar rats were administered the respective compounds in single dose at 1 or 10 mg/kg.
Blood was taken for DPP-4 activity 7 and 24 h after dosing. Data are means ± SEM (n=5-10/group)
Thomas et al., J Pharmacol Exp Ther. 2008;325(1):175–82.
(linagliptin > sitagliptin, saxagliptin > vildagliptin)

13. Linagliptin: Good tissue distribution, mainly bound to
protein, long terminal half life, and does not accumulate
Retlich et al. 2010 J Clin Pharm. J Clin Pharmacol. 50:873-85;
Scheen et al. 2010, DOM 12: 648-658
1 In healthy subjects; distribution at steady state following a single 5 mg i.v. dose of linagliptin
2 US prescribing information
Linagliptin
Volume distribution, L
Fraction bound to
protein, %
70-80
11101
Terminal half life,
hours
Sitagliptin
198
38
12.4
Vildagliptin
71
9.3
2-3
Saxagliptin
151
very low
2.5
3.1 (active metabolite)
>100

14. Unique Structure
and related
benefits
Glycemic control
Safety and
tolerability
Special populations
Beyond glycemic
control – emerging
data
Linagliptin: not just a fourth gliptin

15. 1
21
41
61
81
101
0 4 8 12 16 20 24
Time (h)
% DPP-4 Inhibition
Linagliptin provides long-lasting DPP-4 inhibition
in patients with T2DM
Peak in 1.5 hours > 91% DPP-4 inhibition achieved
1. Steady state Achieved by 3rd dose
2. Linagliptin trough  6-8 nmol/L, resulting in >80% DPP-4 inhibition over 24 hours
3. GLP rise 3.2 fold rise in post-prandial active GLP-1 levels
Forst T, et al. Diabetes Obes Metab. 2011;13: 542–550
Source: Adapted from Heise et al., Diabetes Obes Metab. 2009;11(8):786–94
5 mg tablet, in type 2 diabetes patients

16. Linagliptin: Sustained HbA1c reductions over 2 years1
0
-0.4
-0.8
-1.2
Change from baseline HbA1c
Mean over time ± SE, percent; mean baseline HbA1c: 8.1%
24
Treatment duration in weeks
0 102
1429
1531 903
n
Open-label extension
Coefficient of durability2 of 0.14% meaning no relevant increase in
HbA1c from week 24 to week 102 (p-value < 0.0001)
Source: Gallwitz et al. EASD 2011
Placebo-controlled
double-blind
-0.8% HbA1c
reduction at
102 weeks
1 Open-label extension of 4 double-blind randomized controlled trials over 24 weeks. Patients randomized to linagliptin
treatment for the first 24 weeks continued on linagliptin for an extension of 78 weeks. The analysis shown is
restricted to this arm of the trial. Analysis of secondary endpoint in full analysis set, observed cases
2 Coefficient of durability (COD) is defined as HbA1c at week 102 visit subtracted by HbA1c at week 24 visit

17. Linagliptin: meaningful HbA1c reductions independent of
time since diagnosis of type 2 diabetes
Footnote: Pre-specified sub-group analysis on pooled data from 4 pivotal phase III randomized placebo-controlled trials
including treatment in monotherapy, as add-on to metformin, as add-on to metformin + SU, or in initial combination with
pioglitazone. Full Analysis Set (FAS), Last Observation Carried Forward (LOCF)
≤ 1 year
p< 0.0001
p< 0.0001
p< 0.0001
n
Mean baseline
HbA1c, percent
120
8.2
1,045
8.2
381
8.2
570
8.1
227
8.0
261
8.1
> 1 to ≤ 5 years > 5 years
Source: Data on file
0.5
0
-0.5
-1.0
0.7
-0.01
0.6
0.03
0.7
-0.17
Linagliptin
Placebo
Adjusted
mean
change in
HbA1c (%)
from
baseline at
week 24
Time since
diagnosis

18. 1Poorly controlled = Baseline HbA1c ≥ 9%
2Del Prato S et al. 2011 DOM 13: 258-267
3Taskinen M R et al. 2011 DOM 13: 65-74
4Owens DR et al. Diabetes Obesity and Metabolism (in press) 2011
* Versus baseline
0.5
0
-0.5
-1.0
-1.5 -1.20
-0.40
-0.95
-0.23
-0.86
0.15
Linagliptin
Placebo
Add-on to metformin3
p <0.0001*
Linagliptin monotherapy2
p <0.0001*
Add-on to metformin + SU4
p <0.0001*
Adjusted
mean change
in HbA1c (%)
from baseline
at week 24
n 24 96
29
55
Mean baseline
HbA1c, percent
9.5 9.4
9.5
9.5
9.4
136
48
9.4
Source: Del Prato et al. American Diabetes Association, 71th Scientific Sessions,
San Diego, CA, June 24-28, 2011; 1067-LB
Meaningful HbA1c reduction in patients with baseline ≥9%1-4
Linagliptin achieves HbA1c decrease
up to -1.2% 1 T2DM patients with >9% baseline A1c

19. Initial combination of linagliptin and metformin achieves
significant reductions in HbA1c
19
Combination regimens were superior to metformin monotherapy
*** p<0.0001, combination therapy versus respective monotherapy
1 Randomized arm: mean (SE); full analysis set, last observation carried forward
2 Open-label arm in patients with poor glycemic control: mean (SE); full analysis set, observed cases (n = 48) BID = twice daily; FPG
= fasting plasma glucose; LIN = linagliptin; MET = metformin; OAD = oral antidiabetic drug; QD = once daily; T2DM = type 2
diabetes mellitus
Source: Haak, et al. American Diabetes Association,
71th Scientific Sessions, San Diego, CA, June 24-28, 2011; 279-OR
-1.0
-1.5
-2.0
-3.5
-4.0
-1.7
-3.7
0
-1.3
-0.5
8.7
140
11.8
66
LIN 2.5 +
MET 1000 mg
BID
LIN 2.5 +
MET 1000 mg
BID
Randomized arm1 (placebo-corrected) High baseline HbA1c Open-label arm2
Baseline HbA1c, %
Patients, n
Change
in
HbA1c
from
baseline,
%
8.7
137
LIN 2.5 +
MET 500 mg
BID
Initial combination of linagliptin 2.5 mg and metformin 500 mg
BID is as effective as metformin 1000 mg BID

20. 1 Adapted from Del Prato S et al. 2011 DOM 13: 258-267
2 Taskinen M R et al. 2011 DOM 13: 65-74
3 Owens DR et al. Diabetes Obesity and Metabolism (in press) 2011
4 Model includes continuous baseline HbA1c and treatment
5 Versus baseline
0.5
0
-0.5
-1.0
-1.5
-0.62
-0.64
-0.69
Linagliptin Placebo corrected
Add-on to metformin2
p <0.00017
Monotherapy1
p <0.00015
Add-on to metformin + SU3
p <0.00017
Adjusted4
mean change
in HbA1c (%)
from baseline
at week 24
n 513
333
Mean baseline
HbA1c, percent
8.1
8.0
778
8.2
Linagliptin achieves meaningful HbA1c decrease in T2DM
patients with 8.0 baseline A1c

21. Placebo-corrected, adjusted mean change in FPG and PPG in mg/dl
Monotherapy
Linagliptin1
5 mg OD
HbA1c baseline 8.0%
1Del Prato S, et al. Diabetes Obes Metab. 2011;13: 258–267;
2 Taskinen M R et al. 2011 DOM 13: 65-74
Linagliptin: achieves strong FPG and PPG decrease in type 2
diabetes patients
Add on to Metformin
Linagliptin2
5 mg OD
Baseline HbA1c 8.1%

22. Rate of patients achieving HbA1c
target <7%
75.6 76.4
0
20
40
60
80
100
Linagliptin Glimepiride
2 year study: Linagliptin was non-inferior to
glimepiride in treatment effect1
0.5
0
-0.5
-1.0
-1.5
Linagliptin vs glimepiride2 p <0.0001*
Adjusted
mean change
in HbA1c (%)
from baseline
at week 104
n
Mean baseline
HbA1c, percent
-0.60 -0.60
7.7
7.7
Rate of patients achieving HbA1c
target <7%
271 233
Gallwitz B., et al. ADA 2011 Late Breaker 39-LB

23. Unique Structure
and related
benefits
Glycemic control
Safety and
tolerability
Special populations
Beyond glycemic
control – emerging
data
Linagliptin: not just a fourth gliptin

24. Linagliptin: Xanthine based structure:
Lowest risk of "Off-target" DPP inhibition (i.e., inhibition of DPP-8/-9)
Source: Deacon CF. 2011 DOM;13:7-18
1 Quiescent cell proline dipeptidase
2 Drucker, DJ. Diabetes Care June 2007 30 (6): 1335-1343
3 Demuth et al. Biochim. Biophys. Acta 2005, 1751, 33
▪ "Off-target" DPP inhibition (i.e., inhibition of
DPP-8/-9) has shown severe toxicity in
preclinical studies3
QPP/DPP-21 DPP-8 DPP-9
Linagliptin
Sitagliptin
Vildagliptin
Saxagliptin
Alogliptin
> 100,000
> 5,500
> 100,000
> 50,000
> 14,000
40,000
> 2,660
270
390
> 14,000
> 10,000
> 5,500
32
77
> 14,000
Leading Selectivity for DPP-42 compared to

25. Linagliptin shows favorable tolerability and safety
1 Categories of organ-specific adverse events described
if mentioned in the labels of currently marketed DPP-4
inhibitors in the US
2 Linagliptin US prescribing information
Placebo
Linagliptin
2,523 1,049
Upper respiratory tract
infection
3.3% 4.9%
Nasopharyngitis 5.9% 5.1%
Cough 1.7% 1.0%
Blood and lymphatic
system disorders
1.0% 1.2%
Hypersensitivity 0.1% 0.1%
Urinary tract infection 2.2% 2.7%
Hepatic enzyme increase 0.1% 0.1%
Headache 2.9% 3.1%
Pancreatitis 1/538 0 /433
(in person years) 2
Serum creatinine increase 0.0% 0.1%
Number of patients
Source: Scherntharner et al. American Diabetes Association, 71th Scientific Sessions, San Diego, CA, June 24-28, 2011 Abstract 2327-PO
Organ-specific adverse
event (AE) rate for AE
previously associated
with the DPP-4
inhibitor class1 in a
pooled analysis of 8
randomized, placebo-
controlled, phase III
trials

26. Linagliptin (2523) Placebo (1049)
Hypoglycemia 8.2% 5.1%
Severe hypoglycemia 0.2% 0.2%
Receiving SU 20.7% 13.3%*
Not receiving SU 0.6% 1.0%
Linagliptin shows lower incidence of hypoglycemia
*Notably, 38% of patients on sulphonylurea background therapy accounted for
96% of all hypoglycaemic events in the linagliptin-treated group
The somewhat higher incidence of hypoglycaemia associated with linagliptin was
almost exclusively attributable to the combination with sulphonylurea
Source: Scherntharner et al. American Diabetes Association, 71th Scientific Sessions, San Diego, CA, June 24-28, 2011 Abstract 2327-PO

27. 0
10
20
30
40
50
Linagliptin
7.5
Glimepiride
36.1
Incidence of hypoglycemia1
Percent of patients over 104 weeks
Adjusted2 weight change from baseline
kg, over 104 weeks
2.0
1.5
0.5
0
-0.5
-1.5
-2.0
Significantly lower incidence of
hypoglycemia with linagliptin as
compared to glimepiride
(p-value < 0.0001)
Significant relative weight loss
with linagliptin as compared to
glimepiride
(p-value < 0.0001)
12 28 52 104
weeks
78
80%
lower
-2.9
kg
Linagliptin has significantly lower incidence of hypoglycemia and
relative weight loss as compared to glimepiride
Key secondary endpoints: Incidence of hypoglycemia: Treated set, n = 775 for glimepiride and n = 776 for linagliptin; Weight change: Full Analysis Set (FAS), Observed
cases (OC), n=755 for glimepiride and n=764 for linagliptin
1 Hypoglycemic episode defined by a blood glucose ≤70 mg/dl
2 Model includes baseline HbA1c, baseline weight, number of prior OADs, treatment, week repeated within patients and week by treatment interaction
Glimepiride Linagliptin
Source: Gallwitz et al. American Diabetes Association,
71th Scientific Sessions, San Diego, CA, June 24-28, 2011; 39-LB

28. Potential CV safety profile: First gliptin with a prospective, pre-specified meta-
analysis with independent adjudication of CV endpoints
Incidence rate of CV events1
Number and percentage of patients
Years of
exposure
1,372
2,060
1 CV events as defined as primary endpoint
2 977 patients receiving placebo, 781 glimepiride, 162 voglibose
11
23
Comparator2
Linagliptin
Source: Johansen et al. American Diabetes Association
71st Scientific Sessions, San Diego, CA,
June 24-28, 2011; 30-LB
Out of
3,319
patients
= 0.3%
Out of
1,920
patients
= 1.2%
Risk ratio 0.34
95% CI (0.15/0.74)
p<0.05

29. Note: CV death, non-fatal MI, non-fatal stroke, hospitalization due to unstable angina pectoris
1. Johansen et al. American Diabetes Association 71st Scientific Sessions, San Diego, CA, June 24-28, 2011; 30-LB;
2. Sitagliptin Williams-Herman et al. 2010, BMC Endocrine disorders;
3. Vildagliptin; Schweizer et al. 2010, DOM;
4. Saxagliptin: Frederich et al. 2010, Postgraduate Medicines;
5. Alogliptin White et al 2010, ADA Scientific sessions 2010 Abstract 391-pp
Total
patients in
analysis
DPP-4 inhibitor better Comparator better
1
1/2
1/4
1/8 2 4 8
x
Primary
endpoint Comments
5,239 CV death, MI,
stroke, hospitali-
zation due to angina
Prespecified/in-
dependent
adjudication
Linagliptin1
0.34
0.15 0.74
10,246 Med DRA terms for
MACE
No formal
adjudication
Sitagliptin2 x
0.68
0.41 1.12
10,988 Acute coronary
syndrome, transient
ischaemic attack,
stroke, CV death
Prespecified/
independent
adjudication
Vildagliptin3 x
0.84
0.62 1.14
4,607 MI, stroke, CV death Prespecified/
independent
adjudication
Saxagliptin4 x
0.42
0.23 0.80
3,489 Non-fatal MI, non-
fatal stroke, CV
death
Prespecified/
independent
adjudication
Alogliptin5 x
0.63
0.21 1.91
▪ No increased risk of CV events was observed in patients randomly treated with DPP-4 inhibitors
▪ There are no clinical studies so far that conclusive establish macrovascular risk reduction with
any anti-diabetic drug
Potential CV safety profile: Risk ratios for major CV events for
different DPP-4 inhibitors1-5

30. Linagliptin: CV risk modulation potential1
Increases GLP-1 positively thus
modulates lipid metabolism,
reduces infarct size and
improves cardiac function
Reduces inflammation,
stimulates endothelial
repair, and
blunts ischaemic injury
Improves glycaemic control,
including the lowering of
postprandial glucose
Possesses inherent anti-
oxidative properties, most
likely due to its xanthine-
based molecular structure
Johanssen OE et al. Cardiovascular Diabetology 2012, 11:3

31. 31
Linagliptin reduced infarct size in an acute model of
myocardial infarction
Source: Sharkovska et al. American Diabetes Association 71th, Scientific Sessions, San Diego, CA, June 24–28,
2011; 974-P; Sharkovska et al EASD 2011
Representative cardiac section.
Data are means ± SD. n=8-12 per group for the 7 day follow-up
and n=16-18 for the 8 week follow-up. *p<0.05, **p<0.001 vs.
respective vehicle group
Reduced infarct size under linagliptin in an acute model of myocardial infarction
Representative cardiac section
after staining with triphenyl-
tetrazolium-chloride. The
infarcted area was defined as
the area unstained by
triphenyl-tetrazolium-chloride

32. Linagliptin reduces oxidative stress and inflammatory cell
activation – indirect anti-oxidant effect
1 p<0.05 vs. control and #, p<0.05 vs. LPS.
Source: Schuff et al. American Diabetes Association 71th, Scientific Sessions, San Diego, CA, June 24–28, 2011; 981-P
Sharkovska et al. American Diabetes Association 71th, Scientific Sessions, San Diego, CA, June 24–28, 2011; 974-P ;EASD 2011
Effects of linagliptin (LG) on activation of white blood cells:
Quantification of oxidative burst in isolated neutrophils (PMNs)
Linagliptin
inhibits
oxidative burst
in stimulated
human
neutrophils

33. 33
Outcomes trial: CAROLINA
The CAROLINA trial aims to
investigate the long-term impact
of Linagliptin on maintenance of
glycemic control and on
cardiovascular morbidity and
mortality in patients with T2DM
CAROLINA has an innovative
design (only trial versus active
comparator) and is unique in
the diabetes environment,
advancing scientific knowledge
in this field
Sub-studies within the CAROLINA
protocol
1. Impact of linagliptin vs glimepiride
on glycemic durability, need for
rescue therapy, C-peptide etc in
LADA1 patients (Europe and North
America)
2. Impact of linagliptin vs glimepiride
on silent myocardial infarction
(incidence, outcomes)
3. Biomarker evaluation (outcome,
biomarker for risk, etc)
4. Health economics

34. Unique Structure
and related
benefits
Glycemic control
Safety and
tolerability
Special populations
Beyond glycemic
control – emerging
data
Linagliptin: not just a fourth gliptin

35. No signs or symptoms until >70% of
kidney function is lost1,2
CVD risk equivalent. 3
Serum creatinine rises only if
>50% of renal function
is already lost4
50% of beta cell function may be lost at
diagnoses in T2DM.
What about renal function at baseline?
PCPs screen only 20% of their
diabetic patients for kidney
disease, before prescribing
Hypoglycemia worsens in kidney
impairment
Kidney Disease in Diabetes: a silent killer ?
1. Keen and Viberti, J Clin Pathol. 1981;34:1261–6.
2. McLaughlin NG et al., Northeast Florida Medicine, 2005.
3. United States Renal Data System. Annual data reportt, 2009. http://www.usrds.org/atlas.htm
4. Jemel A et al., CA Cancer J Clin. 2007;57;43–66.

36. Liver Disease in Diabetes
1 Cusi K. Curr Opin Endocrinol Diabetes Obes 2009; 16: 141–9.
2 Nordenstedt H, White DL, El-Serag HB. Dig Liver Dis 2010; 42(Suppl 3): S206–14.
3 Garcia-Compean D, Jaquez-Quintana JO, Gonzalez-Gonzalez JA, Maldonado-Garza H. World J
Gastroenterol 2009; 15: 280–8.
70% of patients
with T2DM have
nonalcoholic fatty
liver disease1
Patients with
T2DM frequently
suffer from various
forms of liver
disease 30% of patients with
cirrhosis have diabetes,
potentially both a cause
and consequence of
diabetes2,3

37. ~ 5% of orally administered
linagliptin is excreted via the
kidneys
The majority of linagliptin is excreted unchanged via
non-renal route
Metabolism
~90%
transferred
unchanged
~10%
(inactive)
metabolite
~ 95% of orally administered
linagliptin is excreted via the
bile and gut
Excretion1:
~95% bound to plasma
proteins (in essence DPP-4)
Absolute bioavailability:
~30%, with or without food
Tablet intake: 5mg QD,
independent of food
Absorption
Source: US prescribing information
1 At steady state

38. Linagliptin undergoes limited metabolism and is
primarily excreted unchanged (about 90%)1
0
0.5
1
1.5
Fold
increase
in
exposure
relative
to
normal
hepatic
function
Fold
Increase
in
exposure
relative
to
normal
hepatic
function
Source: Graefe-Mody et al. 4th International Congress on
Prediabetes and the Metabolic Syndrome, Madrid, Spain,
April 6-9, 2011
Healthy Mild (Grade A) Moderate (Grade B) Severe (Grade C)
n=7
n=8 n=9 n=8
Patients with mild, moderate and severe hepatic impairment
(according to the Child-Pugh classification A-C)
Child-Pugh Grade Points
A Well-compensated disease 5-6
B Significant functional compromise 7-9
C Decompensated disease 10-15
No dosage adjustment for linagliptin is necessary for patients
with hepatic impairment

39. Linagliptin: No clinically relevant drug-drug interactions
There are no clinically relevant drug-drug interactions between linagliptin and...
Commonly used oral glucose-lowering medications
• Metformin
• Glyburide
• Pioglitazone
Commonly used cardiovascular medications
• Digoxin
• Warfarin
• Simvastatin
P-glycoprotein/CYP 3A4 inducer: The efficacy of linagliptin may be reduced when administered in combination (e.g., with
rifampin). Use of alternative treatments is strongly recommended. Source: Linagliptin US prescribing information

40. Linagliptin is the only DPP-4 inhibitor with no need for dose adjustment
even in patients with RI
40
1 Estimated creatinine clearance values were calculated using the Cockcroft-Gault formula
2 90% confidence intervals not available
3 n numbers, 90% confidence intervals and definitions of RI according to creatine clearance not available for vildagliptin
(n=6) (n=6) (n=6) (n=6) (n=6)
>80 50 to ≤80 30 to ≤50 <30 <30 on HD
Renal impairment status
Creatinine
clearance1
(mL/min)
Fold
increase
in
exposure
relative
to
normal
renal
function
Linagliptin
0
1
2
3
4
5
6
7
ESRD
Severe
Moderate
Mild
Normal
(n=8) (n=8) (n=8) (n=8) (n=8)
>80 >50 to ≤80 >30 to ≤50 <30 on HD
Renal impairment status
Creatinine
clearance1
(mL/min)
Fold
increase
in
exposure
relative
to
normal
renal
function
Saxagliptin
(5-hydroxy saxagliptin metabolite)2
0
1
2
3
4
5
6
7
ESRD
Severe
Moderate
Mild
Normal
(n=6) (n=6) (n=6) (n=6) (n=6)
>80 50 to ≤80 30 to ≤50 <30 on HD
Renal impairment status
Creatinine
clearance1
(mL/min)
Fold
increase
in
exposure
relative
to
normal
renal
function
Sitagliptin
0
1
2
3
4
5
6
7
ESRD
Severe
Moderate
Mild
Normal
Renal impairment status
Fold
increase
in
exposure
relative
to
normal
renal
function
Vildagliptin
(LAY151 metabolite)3
Source: Graefe-Mody et al. 1011 DOM in press, Bergman et al. Diabetes Care 2007, 30:1862-1864; Boulton et al. Clin Pharmacokinet
2011, 50:253-265; European Medicines Agency (EMEA). Galvus (vildagliptin). European Public Assessment Report (EPAR)
Two-fold safety margin
0
1
2
3
4
5
6
7
Normal Severe
Mild Moderate ESRD

41. -1
-0.5
0
0.5
Linagliptin provides reliable HbA1C reductions in elderly
Change from baseline HbA1c by age1
Adjusted mean change from baseline at 24 weeks of treatment
p<0.0001
65 to 74 years ≥75 years
p=0.0002
n =
Mean baseline HbA1c (%)
Adjusted
mean
change
in
HbA
1c
(%)
from
baseline
at
week
24
152 398
8.1 8.1
19 66
8.1 8.0
-0.09
-0.69
0.03
-0.80
p-values for between group difference (versus placebo)
Source: Linagliptin data on file
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.
Linagliptin
Placebo

42. -0.18
-0.28
-0.56
-1.18
-1.5
-1
-0.5
0
Severe renal
impairment
Severe renal
impairment
Adjusted
mean
change
in
HbA
1c
(%)
from
baseline
at
week
24
Linagliptin provides reliable HbA1c reductions in
severe renal function
<0.0001
p-value
between group difference
(versus placebo)
Mean baseline HbA1c (%) 8.3 8.2
62 66
n =
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.
13 11
>9 >9
0.8% reduction in HbA1c from baseline after 12 weeks of treatment
Sloan L et al. Poster: 413-PP, ADA, 2011

43. Long-term efficacy and safety of linagliptin in patients
with type 2 diabetes and severe renal impairment
Conclusion:
Rates for any AE/ SAE were similar
with linagliptin (94.1% and 36.8%,
respectively) and PBO (92.3% and
41.5%).
Renal function remained stable
throughout the study in both
treatment arms, and numbers of
cardiovascular deaths in this
high-risk population were similarly
low (linagliptin, n=2 [2.9%];
PBO, n=3 [4.6%]).
Authors: J. Newman1, J.B. McGill2, S. Patel3, C. Friedrich4, C. Sauce5, H.-J. Woerle6; EASD Poster 821
0.72% reduction in HbA1c from baseline after 52 weeks of treatment

44. DARLINA study: safety and efficacy in patients at risk of
renal impairment
44

45. Unique Structure
and related
benefits
Glycemic control
Safety and
tolerability
Special populations
Beyond glycemic
control – emerging
data
Linagliptin: not just a fourth gliptin

46. The progressive nature of established
Type 2 diabetes is well recognized,
and occurs despite attempts to
maintain glucose as near to normal as
possible
The major reason for the decline in
glucose tolerance seems to be a
progressive loss of beta-cell function,
based on the UKPDS and the
longitudinal assessment in Pima
Indians
Need to stabilize deteriorating beta cell function early
Hyperglycemia
(glucose toxicity)
Beta cell
Insulin resistance
Lipotoxicity
(elevated FFA, TG)
TG accumulation
Genetics
Amyloid plaque deposits
Insulin Resistance and Beta Cell dysfunction: both are typically
present very early in the natural history of the disease
Authors: Kahn SE J Clin Endocrinology 2001;88:4047-4058
Ludwig DS JAMA 2002; 287:2414-2423

47. Beta cell function: Linagliptin Shows Significant Improvements in
β-cell Function Across Individual Pivotal Phase IIIa Trials
aIn this study, the placebo arm consisted of pioglitazone + placebo
ADA 70th Scientific Sessions 2010. Poster numbers: 1. Del Prato S et al., 695-P; 2. Taskinen M-R et al., 579-P; 3 Gallwitz B., et al. ADA 2011 Late Breaker 39-LB
• Monotherapy1 - 33%
• Add on to metformin2 - 24%
% improvement in HOMA
%B at 24 weeks
• Monotherapy1 - 20%
• Compared to Glimepiride3 - 21%
% reduction in Proinsulin:
Insulin ratio at 24 weeks
• Compared to Glimepiride3 –
16.5%
% reduction in HOMA IR
at 24 weeks
• Monotherapy2 -
• Combination with pioglitazone
Disposition Index

48. Beta cell function: Linagliptin restores ß-cell survival in
isolated human islets in T2DM
Lipotoxicity
Glucotoxicity Inflammatory
stress
Oxidative
stress
Physiological
condition
Glucotoxicity
With linagliptin, less apoptosis is seen under stress conditions
Vehicle
Linagliptin
(100 nM)
Insulin (ß-cell marker)
TUNEL (marker for apoptosis)
*
**
** ** **
**
*
*
*
*
%
TUNEL
+β-cells
0
1
2
3
4
5 Vehicle Linagliptin Example of TUNEL Staining
Note: Human isolated islets were exposed for 48 h. ß-cell apoptosis was analyzed by double labeling for the TUNEL assay and insulin. Results are means
from 3 independent experiments from 3 donors *P<0.05 to 5.5 mM glucose alone, **P<0.05 to vehicle
Source: Shah P, et al. ADA 2010, Poster 1742-P

49. Linagliptin: Improves Hepatic Steatosis in DIO Mice
A MRS and Histology Based Study
A: Red oil staining of liver specimen from DIO mice fed with a) HFD vehicle b) HFD + 30 mg/kg/d linagliptin c) HFD
+ linagliptin 3 mg/kg/d
d) chow diet control; HFD for 4 months, treatment for 21 days
B: Quantification of red oil staining by histological scoring, mean + SEM, n=9 animals per group (*P<0.05,
**P<0.01; ***P<0.001)
Klein et al., ADA 70th Scientific Sessions 2010. Poster number 577-P;
Date of preparation: March 2010
A B

50. 51
Linagliptin improves wound healing in the ob/ob mouse1
Source: Schurmann et al. American Diabetes Association 70th, Scientific Sessions, Orlando, Florida, June 25–29, 2010; -
P; Linke et al. American Diabetes Association 69th, Scientific Sessions, June 2009 -P
1 Obese mouse model for type 2 diabetes mellitus
Linagliptin improves
wound healing through
accelerated re-
epithelialization
Quantification of wound size in ob/ob
mice following 12 days treatment with
3 mg/kg linagliptin (n=10) or control
(n=9)
Decreased wound size
with linagliptin
treatment compared to
control

51. 52
Linagliptin decreases inflammation in wounds of ob/ob
mice
Source: Schurmann et al. American Diabetes Association 70th, Scientific Sessions, Orlando, Florida, June 25–29, 2010; -
P; Linke et al. American Diabetes Association 69th, Scientific Sessions, June 2009 –P
Note: Mock- (ctrl) and linagliptin-treated ob/ob mice
Immunoblot showing the presence of
GR1 protein, a marker for neutrophil
infiltrate, in 10 day wound tissue
Linagliptin decreases
neutrophil infiltration in
wounds of ob/ob mice
Stained for neutrophil infiltrate using
the anti-Ly6C (GR1) antibody.
Immunopositive signals (brown) are
indicated by arrows
Neutrophil (PMN) cell numbers from total 10
day wound sections * p<0.05 as compared to
control mice. Means ± SD from 3 wounds from
3 animals (n=3)

52. Linagliptin: place in therapy
Adherence to
therapy
Coexisting risk of
declining
hepatic/ renal/ CV
function
Co morbidities
Hypertension
Lack of early and
Aggressive Care for
Sustained glucose
control
Treating to goal without
hypoglycemia & glycemic
variability
Effective as monotherapy and initial
combination with metformin
Sustained Efficacy across treatment
populations
Well tolerated
Least off target
inhibition
Low discontinuation
due to AEs
No dose adjustment
required
One dose fits all
Proven CV safety profile
No clinically relevant drug
interactions

53. Thank you
54

54. Summary: Linagliptin
55
Unique xanthine based structure
Rapid and sustained action
Sustained Efficacy across treatment regimens
Independent of age, duration of disease,
insulin resistance, baseline A1c,
special populations
Acceptable Safety and tolerability
Least potential for off target inhibition
Low risk of hypoglycemia and weight gain
Proven CV safety profile
Special populations
No dose adjustment in any grade of on renal and hepatic dysfunction
Beyond glycemic control
Emerging data on preservation of beta cell function and immuno-
modulatory effects

55. Linagliptin clinical profile
56
1 Please consult the Trajenta prescribing information before prescribing
2 In placebo controlled clinical trials adverse reactions that occurred in ≥5% of patients receiving linagliptin
Convenience
▪ One dose fits all1
▪ Once-daily
▪ With or without food
▪ Primarily excreted via bile
and gut
▪ Share of renal excretion: 5%
No dose adjustment in renal
or hepatic impairment
▪ Overall safety profile similar to placebo:
– No clinically relevant weight gain
– Very low risk of hypoglycemia
Efficacy
▪ Meaningful and reliable efficacy across
complete range of oral
diabetes therapies
▪ Durable efficacy in longer
term treatment up to 2 years
Safety & Tolerability
▪ Most common adverse
reaction2: nasopharyngitis
▪ Not associated with increase
in CV risk
Source: US prescribing information

56. Summary on glycemic control
57
Age
Insulin
resistance
Renal
Elderly
CV risk
2 year data
Duration of
disease
Special
populations
A1c
baselines
Efficacy
across
disease
continuum
Source: US prescribing information

57. Linagliptin Significantly Lowers HbA1c in
Initial Combination Therapy with Pioglitazone
By Week 24, the linagliptin + pioglitazone group showed a significantly greater mean HbA1c reduction
compared with the pioglitazone + placebo group (P<0.0001)
Baseline HbA1c: 8.60% linagliptin-treated group; 8.58% placebo group;
Last observation carried forward (LOCF)
Gomis R et al., ADA 70th cientific Sessions 2010. Poster number 551-P
0.65%
Baseline HbA1c: 8.60% linagliptin-treated group; 8.58% placebo group;

58. Clinical characteristics of linagliptin compared to other
DPP-4 inhibitors
59
Source: US prescribing information; EMEA summary of product characteristics
1 Without limitations in renal or hepatic impairment: please consult the Trajenta prescribing information
before prescribing 2 As per US prescribing information
Characteristics
Vilda-
gliptin
Saxa-
gliptin
Sita-
gliptin
Lina-
gliptin
One dose fits all1 
No dose adjustment in renal impairment 
No dose adjustment based on drug-drug-interactions 
 
No drug-related monitoring of renal function 
No skin toxicity in preclinical studies2  
No liver toxicity (e.g. hepatic dysfunction)2  

No reports of acute renal failure2   
No dose adjustment in hepatic impairment   
Linagliptin is the first one dose, once
daily oral antidiabetic drug (OAD)

59. Linagliptin can be used with no dose adjustment in various
patient populations
60
Declining
renal function
Hepatic
insufficiency
Long disease
duration
Obese vs. lean
Cardiovascular
disease
Ethnicity
Any age group
including
geriatric
No
limitations
No dose
adjustment
Source: US prescribing information

60. Initial combo met
61

61. Del Prato S, et al. Diabetes Obes Metab. 2011;13: 258–267.
Del Prato S et al., ADA 70th Scientific Sessions 2010. Poster number 695-P
Monotherapy Linagliptin (336) Placebo (167)
Hypoglycemia (mild) 0.3% (n=1) 0.6% (n=1)
Weight Difference 0.28 kg
Waist circumference -0.6 cm 0.4 cm
Metformin Add On Linagliptin (336) Placebo (167)
Hypoglycemia 0.6% (n=3) 2.8% (n=5)
Weight -0.4 kg -0.5 kg
Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65–74.
Linagliptin shows lower incidence of hypoglycemia
Metformin + SU
Add On
Linagliptin (792) Placebo (263)
Hypoglycemia 14.8% (n=3) 22.7% (n=5)
Weight Difference 0.33 kg
Weight -0.2 kg 0.0 kg

62. Del Prato S, et al. Diabetes Obes Metab. 2011;13: 258–267.
Del Prato S et al., ADA 70th Scientific Sessions 2010. Poster number 695-P
Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65–74.
Linagliptin shows lower
incidence of hypoglycemia
*Notably, 38% of patients on
sulphonylurea background therapy
accounted for
96% of all hypoglycaemic events in
the linagliptin-treated group
The somewhat higher incidence of
hypoglycaemia associated with
linagliptin was almost exclusively
attributable to the combination
with sulphonylurea

63. DECODE: Importance of Post prandial glucose reduction
Compared with men with normal FPG (<110
mg/dL), men with newly diagnosed T2DM by the
ADA fasting criteria (>126 mg/dL) had a hazard
ratio for death of 1·81; for women it was 1·79.
For IFPG ( 110– 125 mg/dL), the hazard ratios
were 1·21 and 1·08.
For the WHO criteria (200 mg/dL), the ratios for
newly T2DM were 2·02 in men and 2·77 in
women, and for IGT (140-200 mg/dL) were 1·51
and 1·60.
Trial design: To assess mortality associated with the ADA fasting glucose criteria
compared with the WHO 2 h post-challenge glucose criteria. 18 048 men and 7316
women aged 30 years or older followed for a mean of 7·3 years for CV events
Results
Conclusions
•FPG alone do not identify individuals at
increased risk of death associated with
hyperglycaemia. The OGTprovides
additional prognostic information.
L a n c e t 1999; 3 5 4 : 6 1 7 – 2 1
Relative Risk of Mortality Increased with
Increasing 2-Hr Glucose Level

64. New Treatment Algorithm from IDF
PPG control deteriorates earlier (HbA1c ~6.5%) indicating that people with relatively
normal FPG values can exhibit abnormal elevations of PPG
No severe hypoglycaemia was observed in a study targeting PPG
The IDF sets of a target of 160 mg/dl for PPG
71

65. 72

66. 73

67. Glycemic variability at same A1c can be different for different
individuals
74
Graphic representations of glycemic control with a high mean glucose level and high (a) or low (b) variability.