1. A New Easy DPP-4
Inhibitor Linagliptin

2. 織巢鳥，原產於非洲。
織布鳥吸引異性的媒介是鳥巢。
公鳥築巢，讓母鳥選巢，被母鳥選上的巢，就
表示築巢的公鳥，雀屏中選。
就像很多女性擇偶的條件之一是對方須是「有
殼蝸牛」一樣。

3. Content
Clinical background
• Rationale for early intervention
• Kidney in diabetes: Prevalence, implications and treatment limitations
Linagliptin
• Overview of Linagliptin
• What makes Linagliptin different
1.Efficacy
2.Tolerability
3.Safety

4. Early intensive glycemic control provides
lasting protection : The legacy effect
Microvascular Myocardial Any diabetes- Death from
disease Infraction related endpoint any cause
0
-5
Relative Risk Reduction (%)
-10
*
*
-15 **
**
*
Trial end (1997)
-20
Post-trial follow up (2007)
† Data from sulfonylurea–insulin group shown
-25 *** * P≤0.05; ** P≤0.01; *** P≤0.001;
***
10-year post-trial monitoring from 1997 to 2007 of UKPDS Study†
• Randomized intervention to achieve either intensive or conventional targets - stopped at the trial end (1997)
• Differences in mean HbA1c between the two groups were lost by year 1 of post-trial follow-up.
• Relative reductions in risk in patients who had been treated to intensive goals, compared with conventional targets, persisted after 10 years
1. UKPDS 33 Study Group. Lancet. 1998;352:837-853; 2. Holman RR, et al. N Engl J Med. 2008;359:1577-1589.
3. Chalmers J and Cooper ME. N Engl J Med. 2008; 359: 1618–1620.

5. DCCT/EDIC: long-term follow-up and
legacy effect
9 Glucose
Conventional treatment similar
BUT CV
8
events
HbA1C (%)
Intensive treatment still
7 higher
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Years
DCCT (intervention period) EDIC (observational follow-up)
Cumulative incidence of
0.06
non-fatal MI, stroke or
57% risk reduction in non-fatal MI, stroke or CVD death* Conventional
death from CVD
0.04
treatment
0.02 Intensive
treatment
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years
DCCT (intervention period) EDIC (observational follow-up)
*Intensive vs conventional
treatment. DCCT Research Group. N Engl J Med 1993; 329:977–986.
Nathan DM, et al. N Engl J Med 2005; 353:2643–2653.

6. Legacy Effect: milder complication
1997 2007
傳統
等量
1997 2007 P< 0.05
積極
傳統
P< 0.05 等比例
積極
Complications go at the
same time point.
Complication But they make different
Playground under different genetic
base.
1
2
3 Lin

7. The Action to Control Cardiovascular risk
in Diabetes study group ( ACCOD trial )

8. ACCORD Results

10. Why was mortality increased in
intensive treatment group in ACCORD?
• Not certain
• Speed of HbA1c reduction ( 1.4 % vs. 0.6% in 4 months)
• Drug combinations
• Unidentified hypoglycemia
• Weight gain
• Hypoglycemia unawareness (associated cardiac autonomic
neuropathy)
Analysis proves that the increased mortality rates are not related to
1. Specific OAD ( Rosiiglitazone, SU , Insulin etc)
2. Changes in other medications( Statins, Aspirin etc)
Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD,
ADVANCE, and VA Diabetes Trials Diabetes Care January 2009 vol. 32 no. 1 187-192

11. Increased Mortality, Myocardial Infarction, and
Hypoglycemia With Intensive Therapy:
ACCORD Trial
Mortality (% per year)
≥1 severe hypoglycemia
(n = 705)
3.1
No hypoglycemia
1.2
(n = 9,546)
a
Defined by requirement for medical or paramedical intervention, with
documented glucose <50 mg/dL and relief by parenteral or oral glucose
or by glucagon.
1 Bloomgarden ZT. Diabetes Care. 2008;31(9):1913–1919. 2. Dluhy RG, McMahon GT. N Engl J Med. 2008;358:2630–2633.

12. Summary
• Intensive glycemic control slows down progress of diabetic
complications, microvascular and probably macrovascular.
• Intensive glycemic control has patient risk hypoglycemia, and risk
higher CV mortality.
• Severe hypoglycemia increased CV mortality 3.1X than otherwise.
• Safety ( less hypoglycemia, no fear of hypoglycemia ) is a
dominant issue in the following era.

13. Ominous Octet
Beta cell, fat, muscle, liver, gut, alfa cell, kidney, brain
Ralph A. DeFronzo Diabetes, Vol. 58, April 2009

14. Cerebral insulin resistance
After glucose ingestion, two hypothalamic areas with consistent
inhibition were noted: the lower posterior hypothalamus, which
contains the ventromedial nuclei, and the upper posterior
hypothalamus, which contains the paraventricular nuclei. In both
of these hypothalamic areas, which are key centers for appetite
regulation, the magnitude of the inhibitory response following
glucose ingestion was reduced in obese, insulin-
resistant, normal glucose tolerant subjects, and there was a
delay in the time taken to reach the maximum inhibitory
response, even though the plasma insulin response was markedly
increased in the obese group.
Ralph A. DeFronzo Diabetes, Vol. 58, April 2009

15. Increased Renal Glucose Reabsorption
 In animal models of both type 1 and type 2 diabetes, the maximal renal
tubular reabsorptive capacity, or Tm, for glucose is increased. In humans
with type 1 diabetes, Mogensen et al. have shown that the Tm for
glucose is increased.
 Cultured human proximal renal tubular cells from type 2 diabetic
patients demonstrate markedly increased levels of SGLT2 mRNA and
protein and a fourfold increase in the uptake of -methyl-D-
glucopyranoside (AMG), a nonmetabolizeable glucose analog
 Thus, an adaptive response by the kidney to conserve glucose, which is
essential to meet the energy demands of the body, especially the brain
and other neural tissues, which have an obligate need for
glucose, becomes maladaptive in the diabetic patient.
Ralph A. DeFronzo Diabetes

16. Pathogenesis of type 2 DM:
Implication for Therapy
 Effective treatment of type 2 diabetes requires multiple
drugs used in combination to correct multiple
pathophysiological defects.
 Treatment should be based on known pathogenic
abnormalities and not simply on reduction of A1C.
 Therapy must be started early in the natural history of
type 2 diabetes to prevent progressive beta-cell failure.

17. In Clinical Aspects
“Ideal oral drug”
• Targeting underlying pathogenesis, including lowering insulin
resistance ( BG, TZD ), recovering beta-cell function ( SU, glinide,
DPP-4i ) and reducing hepatic glucose production ( BG, DPP4i ).
• Safe, minimal hypoglycemia ( BG, ?TZD, AGI, DPP-4i, SGLT-2i )
• No weight gain ( BG, AGI, DPP-4i, SGLT-2i)
• Satiety promotion ( ? AGI, DPP-4i, BG; MC4R )
• Increased beta-cell mass ( ? TZD, DPP 4i )
• Reduced CV risk ( BG, AGI, DPP 4i )

18. Metformin & DPP-4 inhibitors: Combinations of oral glucose-
lowering agents with complementary mechanisms of action
DPP-4
Target site Action Metformin
inhibitors
Pancreatic β -cell Enhances glucose-dependent insulin
secretion 
Pancreatic α -cell Suppresses glucagon secretion

Lowers hepatic glucose production
 
Improves insulin resistance

Safety and
Low risk of hypoglycemia
 
Tolerability
No additional weight gain
 
Drucker DJ, Nauck MA. Lancet. 2006;368:1696–1705
Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.
Inzucchi SE. JAMA. 2002;287:360–372.

19. Kidney in diabetes:
Prevalence, implications and treatment
limitations

20. Approximately 40% of type 2 diabetes patients have renal
complications†
CKD prevalence was greater among people with diabetes than
among those without diabetes (40.2% versus 15.4%)
2.3
Data missing
9.5 no CKD
CKD stage 1
17.7
CKD stage 2
50.8
CKD stage 3
CKD stage 4/5
11.1
CKD Stage eGFR (mL/min)
8.6
No CKD ≥90*
1 ≥90**
* Normal kidney function, no sign of kidney damage 2 60–89
** Albuminuria – kidney damage
3 30–59
†Based on data from 1462 patients aged ≥20 years with T2DM who participated
in the Fourth National Health and Nutrition Examination Survey (NHANES IV) 4 15–29
from 1999 to 2004.
5 <15 or dialysis
1. Koro CE, et al. Clin Ther. 2009;31:2608–17; 2. Coresh J, et al. JAMA. 2007;298(17) 2038-2047

21. At least 67% of all patients with type 2 diabetes have cardiovascular
risk factors that also affect the kidneys
Prevalence of risk factors for declining renal function:
Prevalence in T2DM
Risk factor
patients
1 Arterial 67%1
Hypertension
2 Poor glycemic 63%2
control*
3 Microalbuminuria** 30%3
4 Dyslipidemia† 24%** 4,5
Risk range is likely to be significantly higher than 67% due to overlap of risk factors in individuals
*Defined as not reaching the target HbA1c of 7.0%2. **Defined as defined as a urinary albumin-to-creatinine ratio ≥ 30 ug/mg
† defined as hypertriglyceridemia in male subjects
1. CDC National Diabetes Fact Sheet 2011. http://www.cdc.gov/diabetes/pubs/factsheet11.htm (Accessed Sept 2011)
2. Saydah SH, et al. JAMA. 2004;291:335–342; 3. Cheung BMY, et al. Am J Med. 2009;122:443–53.
4. Mooradian A, Nat Clin Pract Endocrinol Metab. 2009:5;150–15; 5. Kannel WB. Am Heart J. 1985;110;1100–7.

22. Declining renal function increases risk of severe
hypoglycaemia
Decline in renal function dramatically increases the risk of hypoglycaemia in
patients with type 2 diabetes
Risk for severe hypoglycaemia
9
8
(incidence rate ratio)
7
6
5
4
3
2
1
0
+ CKD
+CKD / + ––CKD / +
CKD + CKD / –
+ CKD – CKD
– CKD / –
+ Diabetes
Diabetes +Diabetes
Diabetes Diabetes
– Diabetes Diabetes
– Diabetes
Around 74% of sulphonylurea-induced severe hypoglycaemic events
(loss of consciousness) occur in patients with reduced renal function
Moen MF, et al. Clin J Am Soc Nephrol. 2009 Jun;4(6):1121–1127

23. Linagliptin is the first only DPP-4 inhibitor that does not require dose
adjustment: Easy use
Linagliptin Sitagliptin Vildagliptin Saxagliptin
(Trajenta®) (Januvia®) (Galvus®) (Onglyza®)
No renal
100 mg
50 mg BID
5 mg
issues
At risk
of renal
5 mg
impairment
Mild
5mg5mg
renal
impairment
50 mg 25 mg
50 mg QD
2.5 mg
Moderate
renal
impairment
Severe
renal
impairment

24. Linagliptin Overview
Efficacy Safety & Tolerability
Overall safety profile similar to placebo:
Meaningful and reliable efficacy across • No clinically relevant weight gain
complete range of oral diabetes therapies • Very low risk of hypoglycemia
Most common adverse
Durable efficacy in longer reaction1: nasopharyngitis
term treatment up to 2
years Not associated with
an increase in CV risk
Linagliptin
Primarily excreted
One dose fits all*
via bile & gut
Once-daily Renal excretion = 5%
With or without food
No dose adjustment in
Convenience renal or hepatic impairment
* Please consult the prescribing information before prescribing
1 In placebo controlled clinical trials adverse reactions that occurred in ≥5% of patients receiving linagliptin
US prescribing information

25. Linagliptin – a DPP-4 inhibitor with a unique xanthine-based structure
DPP-4 inhibitors mimicking dipeptides DPP-4 inhibitors directly binding to
the active site of the enzyme
O
N
N
N
N
N
Sitagliptin N
O N
NH2
Linagliptin
Xanthine-based structure
Saxagliptin
Vildagliptin
Peptidomimetic DPP-4 inhibitors Non-peptidomimetic DPP-4 inhibitors
Adapted from Deacon CF. Diabetes Obes Metab. 2011; 13: 7–18.

26. Linagliptin provides long-lasting DPP-4 inhibition in patients
with type 2 diabetes
Steady-state plasma levels are already reached after the third dosing interval providing >91% of
DPP-4 inhibition at peak levels
100
80
DPP-4 Inhibition [%]
60
40
20
0
0 4 8 12 16 20 24
Time after administration (h)
Steady State linagliptin 5mg once daily – oral application
Tablet taken Tablet taken
linagliptin 5 mg linagliptin 5 mg
Adapted from Heise T et al. Diabetes Obes Metab. 2009;11(8):786–94

27. Linagliptin increases post-prandial* active GLP-1 levels in patients with
type 2 diabetes
16
14
13.9
12
GLP-1 (pmol/L)
10 3.2 fold
increase
8
6
4
4.4
2
0
Day 0 Day 29 n=15
Linagliptin 5 mg
* Mean plasma levels of active GLP-1 measured 30 min after a meal tolerance test.
Forst T, et al. Diabetes Obes Metab. 2011;13: 542–550.

28. Linagliptin restores ß-cell survival in isolated human islets
With linagliptin, less apoptosis is seen under stress conditions. The study provides evidence
of a direct protective effect of linagliptin on ß-cell survival and insulin secretion
5 Vehicle Linagliptin
*
Example of TUNEL Staining
* Insulin (ß-cell marker)
4 **
% TUNEL +β-cells
TUNEL (marker for apoptosis)
3 *
*
* Vehicle
2
** ** **
**
1 Linagliptin
(100 nM)
0
Oxidative
Physiological Glucotoxicity Glucotoxicity Lipotoxicity Inflammatory
stress
condition stress
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

29. Meaningful efficacy across complete range of
oral treatment algorithms
Linagliptin treatment effect across treatment lines
Placebo-corrected, adjusted mean change from baseline HbA1c
Mono Dual combi Triple Initial combi
combi
Diet and exercise Diet and exercise
With With
Metformin Add-on Add-on Add-on to metformin metformin
International* ineligible** Japan† to met* to SU** met + SU* (Low dose)* (High dose)*
-0.5%
-0.6% -0.6% -0.6%
-0.7%
-0.9%
-1.3%
p <0.0001 for all studies vs. baseline, for initial
combination vs. respective monotherapy
* 24 weeks treatment duration -1.7%
** 18 weeks treatment duration
† 12 weeks treatment duration
Del Prato, et al. Diabetes Obes Metab. 2011;13:258-267 (International); Barnett, et al. EASD 2010, Poster 823-P (Metformin ineligible); Kawamori et al. EASD
2010 , Poster 696-P (Japan); Taskinen et al. Diabetes Obes Metab. 2011;13: 65-74 (Add-on to metformin); Lewin et al. EASD 2010, Poster 821-P (Add-on to
SU); 3. Owens DR, et al. ADA 2010, Poster 548-P (Add-on to metformin + SU); Haak T., et al. ADA 2011 oral presentation 279-OR (Initial combi with met).

30. Linagliptin achieves HbA1c decrease of up to 1.2% in poorly
controlled patients
Significant HbA1c reductions in type 2 diabetes patients with baseline HbA1c ≥ 9%
Linagliptin Add-on to Add-on to
monotherapy 1 metformin 2 metformin + SU3
0.5
p <0.0001 p <0.0001 p <0.0001
Adjusted mean change in HbA1c
0.15
(%) from baseline at week 24
0
-0.23
-0.5 -0.40
-0.72
-0.80
-1 -0.86
-0.95
-1.01
-1.20
-1.5
n= 24 55 29 96 48 136
Mean baseline HbA1c (%) 9.5 9.4 9.5 9.5 9.4 9.4
Placebo
p-values for between group difference (versus placebo) Linagliptin
1. Del Prato S, et al. Diabetes Obesity and Metabolism 2011;13(3):258–267.
2. Taskinen M-R, et al. Diabetes Obesity and Metabolism 2011;13(1):65–74. Linagliptin placebo-corrected
3. Owens DR, et al. Diabetic Medicine 2011;28,1352-1361

31. HbA1c change over 2 years
Adjusted1 mean over time ± SE, percent
Mean (± SE) of HbA1c Percent Linagliptin Glimepiride
7.5
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 95 100 104
Treatment duration Weeks
Linagliptin, has similar efficacy as a SU over 104 weeks1,2
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 et al. American Diabetes Association, 71th Scientific Sessions, San Diego, CA, June 24-
28, 2011; 39-LB

32. Linagliptin provides reliable HbA1C reductions independent
of patient age
Change from baseline HbA1c by age1
Adjusted mean change from baseline at 24 weeks of treatment
0.5
≤50 years 51 to 64 years 65 to 74 years ≥75 years
Adjusted mean change in HbA1c
p =0.0002
(%) from baseline at week 24
p <0.0001 p <0.0001 p <0.0001
0.02 0.03
0
-0.02
-0.09
-0.5
-0.54 -0.56
-0.60
-0.66 -0.64 -0.69
-0.80
-0.83
-1 194 442 363 970 152 398 19 66
n=
Mean baseline HbA1c (%) 8.2 8.2 8.2 8.2 8.1 8.1 8.1 8.0
Pre-specified sub-group analysis on pooled data from 4 pivotal phase III randomized Placebo
placebo-controlled trials: treatment in monotherapy, add-on to metformin, add-on to
metformin + SU, initial combination with pioglitazone. Linagliptin
p-values for between group difference (versus placebo) Linagliptin placebo-corrected
Source: Patel S, et al. 2011 EASD Poster P-832

33. Linagliptin provides reliable HbA1c reductions independent of
time since diagnosis of type 2 diabetes
Change from baseline HbA1c by time since diagnosis of type 2 diabetes
Adjusted mean at 24 weeks of treatment, percent
0.5 ≤ 1 year > 1 to ≤ 5 years > 5 years
Adjusted mean change in HbA1c
p <0.0001 p <0.0001 p <0.0001
(%) from baseline at week 24
0.03
0
-0.01
-0.17
-0.5
-0.49
-0.59 -0.62
-0.66 -0.67 -0.66
-1
n= 120 261 227 570 381 1045
Mean baseline HbA1c (%) 8.2 8.1 8.0 8.1 8.2 8.2
Pre-specified sub-group analysis on pooled data from 4 pivotal phase III randomized Placebo
placebo-controlled trials: treatment in monotherapy, add-on to metformin, add-on to
metformin + SU, initial combination with pioglitazone. Linagliptin
p-values for between group difference (versus placebo) Linagliptin placebo-corrected
Source: Patel S, et al. 2011 EASD Poster P-832

34. Linagliptin significantly improves ß-cell function in monotherapy
Effect of linagliptin monotherapy Effect of linagliptin monotherapy
on HOMA-%B on proinsulin/insulin ratio
proinsulin/insulin ratio from baseline at wk 24
Placebo-corrected adjusted mean change in
40 0
Placebo-corrected adjusted mean change in
(HOMA-%B [(mU/l) × (mmol/l)] from baseline
35 * -0.01
30
-0.02
25
at wk 24
-0.03
20 + 22.2 - 0.04
-0.04
15
-0.05
10
-0.06
5
†
0 -0.07
+35% change from baseline - 21% change from baseline
relative to placebo relative to placebo
at 24 weeks at 24 weeks
The mean change from baseline in HOMA-%B for The mean change from baseline in
linagliptin at 24 weeks was an increase of 5.0 proinsulin/insulin for linagliptin at 24 weeks was
(mU/l)/(mmol/l) versus a decrease of 17.2 an decrease of 0.02 versus an increase of 0.02
(mU/l)/(mmol/l) with placebo (*p<0.049) with placebo (†p<0.025)
Note: Baseline HOMA-%B: 66.9 (mU/l)/mmol/l) linagliptin-treated group; 62.3 (mU/l)/mmol/l) placebo group
Baseline proinsulin:insulin: 0.20 linagliptin-treated group; 0.18 placebo group
Del Prato S, et al. Diabetes Obes Metab. 2011;13: 258–267.

35. First in man study - Linagliptin Phase I: Single rising dose study
During controlled clinical trials in healthy subjects, with single doses of up
to 600 mg of linagliptin (equivalent to 120 times the recommended daily
dose) there were no dose related clinical adverse drug reactions. There is
no experience with doses above 600 mg in humans.
600 mg dose well tolerated
(therapeutic dose is 5 mg)
>100-fold therapeutic window
Recommended
dose: 5mg QD
Source: Hüttner et al. 2008 J. Clin. Pharmacol. 48: 1171-8

36. DPP-4 Inhibitors:
Selectivity for DPP-4 compared to QPP*/DPP-2, DPP-8 and DPP-9
Selectivity for DPP-4 compared to the DPP gene family (QPP/DPP-2, DPP-8 and DPP-9)
QPP*/DPP-2 DPP-8 DPP-9
Linagliptin > 100,000 40,000 > 10,000
Sitagliptin > 5,500 > 2,660 > 5,500
Vildagliptin > 100,000 270 32
Saxagliptin > 50,000 390 77
Alogliptin > 14,000 > 14,000 > 14,000
* Quiescent cell proline dipeptidase
Deacon CF. Diabetes, Obes Metab. 2011;13(1):7–18.

37. Linagliptin is well tolerated
Organ-specific adverse event (AE) rate for AE previously associated with the DPP-4
inhibitor class1
Linagliptin Placebo
n 2,523 1,049
Headache 2.9% 3.1%
Upper respiratory tract
3.3% 4.9%
infection
Pancreatitis:
Pancreatitis was reported Nasopharyngitis 5.9% 5.1%
more often in patients Cough 1.7% 1.0%
randomized to linagliptin
(1 per 538 person years Hepatic enzyme increase 0.1% 0.1%
versus zero in 433 person
years for comparator)*
Serum creatinine increase 0.0% 0.1%
Urinary tract infection 2.2% 2.7%
Blood and lymphatic
1.0% 1.2%
system disorders
Hypersensitivity 0.1% 0.1%
1. Organ-specific adverse events taken from label of currently marketed DPP-4 inhibitor in the US; * Linagliptin US PI
Schernthaner G., et al. ADA 2011 Abstract 2327-PO. Pooled data from 8 studies

38. Linagliptin brings patients to target (HbA1c <7%) with significantly less
hypoglycemia and relative weight loss compared to glimepiride
Incidence of hypoglycemia Adjusted2 means for body weight change
Percent of patients - Treated set1 from baseline ± SE
Kg - FAS (OC)
50 Linagliptin
p<0.0001
Glimepiride
40
2.0
30 1.5 +1.4
79%
20 1.0
reduction
0.5
10 7.5 Rate of patients achieving
0
HbA1c target <7% 12 28 52 78 104
0 -0.5 weeks
Linagliptin Glimepiride Percent of patients at week
104 completers cohort3 -1.0
-1.5
100 -1.5
-2.0 p<0.0001 -2.9
80
75.6 76.4
60
40
20
0
Linagliptin Glimepiride
1 Treated Set: Linagliptin n=776, glimepiride n=775
2 Model includes baseline HbA1c, baseline weight, no. prior OADs, treatment, week repeated within patients and week by treatment interaction
3 Completers cohort: linagliptin n=233, glimepiride n=271
Gallwitz B., et al. ADA 2011 Late Breaker 39-LB

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

40. Linagliptin is the only DPP-4 inhibitor which is primarily excreted
by bile and gut*
Share of renal excretion
% No dose adjustment
Linagliptin1 5 and/or no additional drug
monitoring required1
87%
Sitagliptin2 All other DPP-4 inhibitors
are primarily excreted via
the kidneys
%
Vildagliptin3 85
They all require dose-
adjustment, or are not
Saxagliptin4 75% recommended in patients
with renal impairment.
Drug-related kidney
60-71 monitoring may also be
required
* 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
1. Linagliptin US prescribing information
2. Vincent SH et al. Drug Metab Dispos. 2007;35(4): 533–538
3. He H, et al. Drug Metab. Dispos.2009 37(3):536–544
4. Saxagliptin US prescribing information
5. Christopher R et al. Clin Ther. 2008;30(3):513–527.

41. No dose adjustment: Linagliptin is the only DPP-4 inhibitor that can be
given in full dose even in patients with renal impairment
7 7 Sitagliptin
normal renal function
Linagliptin
normal renal function
exposure relative to
exposure relative to
6 6
Fold increase in
Fold increase in
5 5
4 4
3 3
2 2
1 1
Normal Mild Moderate Severe ESRD Normal1 Mild Moderate Severe ESRD
(n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6)
Creatinine clearance* >80 >50 to ≤80 >30 to ≤50 ≤30 <30 on HD Creatinine clearance* >80 >50 to ≤80 >30 to ≤50 ≤30 on HD
(mL/min) (mL/min)
Renal impairment status Renal impairment status
normal renal function
normal renal function
7 7
exposure relative to
exposure relative to
Saxagliptin Vildagliptin
Fold increase in
Fold increase in
6 6
(5-hydroxy saxagliptin metabolite)
2 (LAY151 metabolite)3
5 5
4 4
3 3
2 2
1 1
Normal Mild Moderate Severe ESRD Normal Mild Moderate Severe ESRD
(n=8) (n=8) (n=8) (n=7) (n=8) (n=8) (n=8) (n=8) (n=7) (n=8)
Creatinine clearance* >80 >50 to ≤80 >30 to ≤50 ≤30 <30 on HD Creatinine clearance* >80 >50 to ≤80 >30 to ≤50 ≤30 <30 on HD
(mL/min) (mL/min)
Renal 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. 2011 Diabetes, Obes Metab. (in press)

42. In clinical trials renal function was unaffected by treatment
with linagliptin
Renal/
function Diabetes
baseline1 treatment Renal function1
Normal renal
function2 120 ± 33 linagliptin 119 ± 34
(n=1,216 )
Mild renal
impairment2 67 ± 8 linagliptin 69 ± 13
(n=314)
Moderate renal
impairment2 45 ± 5 linagliptin 48 ± 8
(n=27)
Severe renal
impairment3 22 ± 6 linagliptin 22 ± 7
(n=68)
1.Mean GFR ± SEM according to Cockcroft-Gault in mL/min (for normal, mild and moderate renal impairment) and according to MDRD
(for severe renal impairment); 24 weeks trial duration for normal, mild, moderate, 12 weeks for severe
2. Pooled analysis of three PIII clinical trials (normal, mild and moderate renal impairment). Cooper M., et al. ADA 2011, Poster 1068-P
3. Individual analysis (severe renal impairment). Sloan L., et al. ADA 2011 Poster 413-PP

43. Influence of hepatic impairment on pharmacokinetics &
exposure of Linagliptin
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
1.5
Fold Increase in exposurerelative to
B Significant functional compromise 7-9
Fold increase in exposure relative
C Decompensated disease 10-15
normal hepatic function
to normal hepaticfunction
1
0.5
0
Healthy Mild (Grade A) Moderate (Grade B) Severe (Grade C)
Hepatic impairment (Child-Pugh classification)
n=8 n=7 n=9 n=8
No dosage adjustment for linagliptin is necessary for patients
with mild, moderate or severe hepatic impairment
Source: Data on file

44. Clinical characteristics of Linagliptin compared to other
DPP-4 inhibitors
Characteristics Linagliptin Sitagliptin Vildagliptin Saxagliptin
One dose fits all* 
No dose adjustment in renal impairment 
No dose adjustment in hepatic impairment   
No dose adjustment based on
drug-drug-interactions   
No drug-related monitoring of renal
function 
No skin toxicity in pre-clinical studies1  
No liver toxicity1   
No reports of decrease in renal function1   
* Without limitations in renal or hepatic impairment: please consult the label before prescribing
1. Linagliptin, Sitagliptin, Saxagliptin US prescribing informations. Other sources: Vildagliptin EU SmPC

45. In a prospective, pre-specified meta-analysis, Linagliptin
was not associated with an increased CV risk
Incidence rate of CV events1
Number and percentage of patients
Risk ratio
0.34
95% CI
(0.15/0.74)
p<0.05
Out of Out of
3,319 patients 1,920 patients
= 0.3% = 1.2%
Linagliptin Comparator2
Years of exposure 2,060 1,372
1. CV events as defined as primary endpoint; 2. 977 patients receiving placebo, 781 glimepiride, 162 voglibose
Johansen O-E., et al. ADA 2011 Late breaker 30-LB

46. Safety observations so far are promising, therefore all DPP-4
compounds are currently involved in outcome studies
No increased risk of CV events was observed in patients randomly treated with DPP-4 inhibitors
Total patients Primary
DPP-4 inhibitor better Comparator better in analysis endpoint Comments
Linagliptin1
CV death, MI, stroke, Pre-specified/
0.15 0.34 0.74 5,239 hospitalisation due to independent
angina pectoris adjudication
Sitagliptin2 1.12 10,246 Med DRA terms No formal
0.41 0.68 for MACE adjudication;
Post-hoc analysis
Vildagliptin3 0.62 0.84 1.14 10,988 Acute coronary syndrome, Pre-specified/
transient ischaemic attack, Independent
stroke, CV death adjudication
MI, stroke, CV death Pre-specified/
Saxagliptin4 0.23 0.42 0.80
4,607 Independent
adjudication
1/8 1/4 1/2 1 2 4 8
Risk ratio for major CV events1-5
1. Johansen O-E., et al. ADA 2011 Late breaker 30-LB; 2. Williams-Herman D, et al. BMC Endocr Disord. 2010;10:7.
3. Schweizer A, et al. Diabetes Obes Metab. 2010;12(6):485–494; 4. Frederich R, et al. Postgrad Med. 2010;122(3):16–27;
5. White et al. 2010, ADA Scientific Sessions. Abstract 391-PP

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

49. Thanks for your attention!!