SC PH 00389 - TRAJENTA Module 2020 1Q

Simplifying T2D
management with
Linagliptin
Name
Date
DISCLOSURE
Most systems work
best in the long term
if they are kept simple
rather than made
complicated.
KISS PRINCIPLE
Usability
Broad utility
Less can go wrong
Reduced costs
Long-term view
Understandable
KISS PRINCIPLE
DPP4 INHIBITORS - MECHANISM OF ACTION
Meal ingested
DPP-4
inhibitor Islet
Stomach Slows gastric enteric-brain vagal

DPP-4 emptying pancreas axis
afferent neurons
within the liver, Pancreas
L K Active GLP-1 portal vein and
L Active GIP
intestine
> 90% of secreted GLP-1 Amplify glucose-dependent

is metabolized by DPP-4 before insulin secretion
reaching the central venous
Suppresses postprandial
circulation
glucagon secretion
5
DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1
Adapted from: Drucker DJ. Expert Opin Invest Drugs 2003;12:87; Ahrén B. Curr Diab Rep 2003;3:365; Robinson LE et al. BMJ Open 2013;3:pii e001986
LINAGLIPTIN - MECHANISM OF ACTION
DPP4 inhibition increases post-prandial* active
GLP-1 levels in patients with type 2 diabetes
GLP-1 (pmol/L)
16
14
12
3.2 fold 13.9
10
increase
8 Linagliptin 5 mg
n=15
6
4
4.4
2
0
Day 0 Day 29
* 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.
DPP4 inhibitors - MECHANISM OF ACTION
High concentration of free drug
Sitagliptin (216nM)
Mostly free of DPP4
F
F
P4
NH2 O
N N
P
N
F
D
N
GLP-1 F F
Short On/Off Kinetics Peptido-mimetic F
s1 GLP-1 N
s2 O
HO N
Low protein binding
NH2
Saxagliptin
1. Wright et al. Int J Phrmacol Ther (2012); 2. Scherntharner, et al. Diabetes Obes Metab. 2012;14:470–478 .
DPP4 inhibitors - MECHANISM OF ACTION
High concentration of free drug
Vildagliptin (267nM)
Mostly free of DPP4
OH
P4
N
P
N
D
H O
GLP-1 N
s1 GLP-1
s2
Low protein binding
Linagliptin - MECHANISM OF ACTION1
Lowest concentration of free drug (~ 0.4nM)2
O
N N
N
P4
N N
O N N
P
NH2
s’ 2
D s1
s‘ 1
s2
Fast on,
slow off (>130h) GLP-1
High affinity (1nM)
GLP-1
Linagliptin has advantageous pharmacokinetics
High affinity
High selectivity
Tight binding
Linagliptin High potency
Long duration of action
Limited renal clearance
Boehringer Ingelheim and Eli Lilly. Trajenta®(linagliptin) Prescribing Information. 2017

Linagliptin has the highest DPP-4 inhibition potency
DPP-4 enzyme activity [% control]
120
100 Linagliptin
Mean IC50* [nM]
Alogliptin
80 Sitagliptin Linagliptin 1
Saxagliptin Alogliptin 24
60 Vildagliptin
Sitagliptin 19
40
Saxagliptin 50
20 Vildagliptin 62
0
- 12 - 10 -8 -6
Log dose [M]
Highest potency of linagliptin in

inhibiting DPP-4 enzyme activity
*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.
DPP-4, dipeptidylpeptidase-4; IC50, half maximal inhibitory concentration. Adapted from Thomas L et al. J Pharmacol Exp Ther. 2008;325:175 11
RENAL EXCRETION AND DOSING IN CKD
Dosing according to eGFR
5 mg qd
100 mg qd 50 mg qd 25 mg qd
50 mg bd 50 mg qd
5 mg qd 2.5 mg qd
25 mg 12.5 mg qd 6.75 mg qd
70 65 60 55 50 45 40 35 30 25 20
DPP-4, dipeptidyl peptidase-4; CKD, Chronic Kidney Disease; *Including metabolites and unchanged drug; excretion after single-dose administration of C14-labelled drug.
1. Trajenta® (linagliptin) summary of product characteristics. July 2018; 2. Januvia ® (sitagliptin). Summary of product characteristics. Merck Sharp & Dohme B.V. (August 2018); 3. Galvus ® (vildagliptin). Summary of product
characteristics. Novartis Europharm Limited (April 2018); 4. Onglyza (saxagliptin). Summary of product characteristics. AstraZeneca AB (August 2018); 5. Vipidia ® (alogliptin). Summary of product characteristics. Takeda
Pharma A/S (May 2018); 6. Boehringer Ingelheim. Data on File. 2018.
EFFICACY IN A BROAD RANGE OF SETTINGS
Age
Independent of:
Linagliptin
Liver
mg Disease
5 once
daily
function
duration
Background
Ethnicity T2D therapy
BMI Kidney
function
BMI, body-mass index

Boehringer Ingelheim and Eli Lilly. Trajenta®(linagliptin) Prescribing Information. 2017 13
Age
Independent of:
Linagliptin
Liver
mg Disease
5 once
daily
function
duration
Background
BMI Kidney
function

LINAGLIPTIN IS EFFECTIVE INDEPENDENT OF AGE
≤50 years 51–64 years 65–74 years ≥75 years†
p<0.0001 p<0.0001 p<0.0001 p=0.0013
-0.59 -0.68 -0.60 -0.77
0.0
Adjusted* mean change
in HbA1c from baseline
at Week 24 (%)
Change from baseline HbA1c (%) by age at Week 24
Del Prato S et al. Nutr Metab Cardiovasc Dis 2016;26:886

Age
Independent of:
Linagliptin
Liver
mg Disease
5 once
daily
function
duration
Background
BMI Kidney
function

LINAGLIPTIN IS EFFECTIVE INDEPENDENT OF
DISEASE DURATION
Adjusted mean HbA1c change from baseline at week 24 by time since diagnosis, placebo-corrected *,†
(Mean baseline HbA1c: 8.1%, n=2,224 )
0 -0.54 -0.61 -0.68

in HbA1c (%) vs placebo at week 24
-0.2
Adjusted mean change
≤1 >1 to ≤5 >5
-0.4 years years years
-0.6
p<0.0001
-0.8 p<0.0001
p<0.0001
Del Prato et al. . Nutrition, Metabolism and Cardiovascular Diseases 2016 26, 886-892DOI: (10.1016/j.numecd.2016.06.015)
Age
Independent of:
Linagliptin
Liver
mg Disease
5 once
daily
function
duration
Background
BMI Kidney
function

LINAGLIPTIN IS EFFECTIVE REGARDLESS OF
BACKGROUND THERAPY
m e a n d i ff e r e n c e ( 9 5 % C I )
Standardised mean difference in HbA1c: meta-analysis on 301 clinical trials (N=118,094)
Monotherapy Add to metformin* Add to MET + SU†

H b A 1 c s t a n d a r d is e d
3.5 3.5
3 3
2.5 2.5
2 2
3.5
3 1.5 1.5
2.5 Ref Ref Ref
2
1 1
1.5 0.5 0.5
1
0.5 0 0
4i i I 4i i GI
0 SU TZ
D - T2 RA -G TZ
D
P- LT
2 RA α-
D PP S GL
P - 1 α
DP S G P -1
GL GL
*Add-on to metformin; †Add-on to metformin + SU αGI, α-glucosidase inhibitor; DPP-4i, dipeptidyl peptidase-4 inhibitor; HbA1c, glycated haemoglobin; GLP-1 RA, glucagon-like peptide-1 receptor agonist;
Met, metformin; Ref, reference; SGLT2i, sodium-glucose co-transporter-2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedione Palmer SC et al. JAMA 2016;316:313
Age
Independent of:
Linagliptin
Liver
mg Disease
5 once
daily
function
duration
Background
BMI Kidney
function

LINAGLIPTIN IS EFFECTIVE INDEPENDENT OF RENAL
IMPAIRMENT1-3
Adjusted mean HbA1c change vs placebo from baseline by degree of renal impairment (RI)*
Normal Mild RI Moderate RI Severe RI
eGFR
≥90 ≥69 to <89 ≥45 to <59 <30
5 mg OD
Adjusted mean change in HbA1C (%)
Pooled analysis of three Phase III trials: 1† RCT2,3‡

At 24 weeks At 52 weeks
0
-0.5
-0.63 -0.53
p<0.0001 -0.67
p<0.0001
p<0.01
-0.72
p<0.0001
-1.0
n 1,212 838 93 128
Mean baseline 8.1 8.0 8.2 8.2
HbA1c (%)
Scr: Serum creatinine; RCT: Randomised controlled trial. LOCF: Last observation carried forward. A small proportion of patients in these studies were receiving treatment combinations that fall outside of the licensed indications for TRAJENTA® (linagliptin).
Prespecified subgroup analysis on pooled data from three pivotal Phase III, randomised placebo-controlled trials: treatment in monotherapy, add-on to metformin
and add-on to metformin plus sulphonylurea. P values for between-group difference (versus placebo). Model includes continuous baseline HbA1c, baseline body mass index (category), washout period, treatment, study, age group, gender, time since diagnosis of diabetes, race, renal
function (MDRD) and treatment × renal function (MDRD). 1-year, randomised, double-blind, placebo-controlled study: treatment added to existing background therapy. (LOCF).
GFR (mL/min/1.73m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if Black); 1. Groop PH, et al. Diabetes Obes Metab 2014;16(6):560-568. 2. McGill JB, et al. Diabetes Care 2013;36:237-244. 3. TRAJENTA® Summary of Product Characteristics. February 2016.
Age
Independent of:
Linagliptin
Liver
mg Disease
5 once
daily
function
duration
Background
BMI Kidney
function

LINAGLIPTIN IS EFFECTIVE INDEPENDENT OF BMI
OR HOMA-IR
Adjusted mean HbA1c change from baseline at week 24 by time since diagnosis, placebo-corrected *,†
(Mean baseline HbA1c: 8.1%, n=2,224 )
Body Mass Index (kg/m2) HOMA-IR (mIU/L*mmol/L)

25-30 30 <4.0 4-5.5 5.5-8.5 >8.5
<25
0
in HbA1c (%) vs placebo at week
-0.2
-0.4
24
-0.57 -0.42
-0.6 -0.63
-0.79 -0.65 -0.64
-0.8
-0.69
BMI: body mass index. * Pre-specified sub-group analysis on pooled data from 3 pivotal Phase III, randomised, placebo-controlled trials: treatment in monotherapy, add-on to metformin and add-on to metformin plus sulphonylurea. p-values for
between-group differences (vs placebo). † ANCOVA adjusted for continuous HbA 1c, BMI group, washout phase, treatment group, study, age group, sex, time since diagnosis of diabetes, race and age × treatment or type 2 diabetes × treatment
interactions. Del Prato et al. . Nutrition, Metabolism and Cardiovascular Diseases 2016 26, 886-892DOI: (10.1016/j.numecd.2016.06.015)
23
Age
Independent of:
Linagliptin
Liver
mg Disease
5 once
daily
function
duration
Background
BMI Kidney
function

LINAGLIPTIN IS EFFECTIVE IN DIFFERENT ETHNIC
GROUPS
Monotherapy Add on to MET Add on to MET + SU Pooled

Global1* Chinese2* Japanese3† Global4* Chinese5* Global6* Chinese7* Global8‡ Asian9*
BL HbA1c 8.00 7.95 8.07 8.09 7.99 8.15 8.14 NC 8.2
-0.50
0.0
-0.2
-0.4
-0.6 -0.52
-0.64 -0.62 -0.63
-0.8 -0.69 -0.68 -0.73
-1.0 -0.87
-1.2
BL, baseline; HbA1c, glycosylated haemoglobin; MET, metformin; NC, not calculated; SU, sulphonylurea. *24 weeks’ treatment duration. †12 weeks’ treatment duration. ‡18 weeks’ treatment duration.
. Del Prato S et al. Diabetes Obes Metab. 2011;13:258; 2. Chen Y et al. J Diabetes Invest J 2015;6:692; 3. Kawamori R et al. Diabetes Obes Metab 2012;14:348; 4.Taskinen MR et al. Diabetes Obes Metab 2011;13:65;
5. Wang W et al. J Diabetes 2016;8:229; 6. Owens DR et al. Diabetic Med 2011;28:1352; 7. Zeng Z et al. Curr Med Res Opin 2013;29:921; 8. Singh-Franco D et al. Diabetes Obes Metab 2012;14:694; 9. Ning G et al. IDF 2013. Poster P-
1046
EFFICACY IN DIFFERENT ETHNIC GROUPS
Elderly patients (≥ 65 years) – a pooled analysis of Asian subgroup
-0.90 -0.08
from baseline in HbA1c,
0.0
-0.2 Placebo
(n = 108)
% (SE)
Linagliptin
-0.4 (n = 239) Between-group difference:
-0.6 -0.82 (0.10); 95% CI: -1.02, -0.62;
-0.8 p < 0.0001
-1.0
Baseline HbA1c Baseline HbA1c

8.21 (0.83) 8.22 (0.85)
• Sheu WH, et al. AASD 2013. Oral 170.

Age
Independent of:
Linagliptin
Liver
mg Disease
5 once
daily
function
duration
Background
BMI Kidney
function

LINAGLIPTIN IS EFFECTIVE INDEPENDENT OF
HEPATOBILLIARY DISEASE1
Adjusted mean HbA1c change from baseline at week 24*,†
Hepatobiliary No hepatobiliary
0
disorders
-0.19 -0.72
‡ -0.16 -0.78
disorders ‡
Placebo
in HbA1c (%) vs placebo over 24
-0.2 TRAJENTA®
-0.4 Between group Between group

weeks
difference: difference:
-0.6 -0.52% -0.62%

p<0.001 p<0.001
[95% CI -0.70, -0.35] [95% CI -0.68, -0.57]
-0.8
-1.0
n 154 301 1,772 3,219
Mean baseline 8.3 8.2 8.2 8.2
HbA1c (%)
* Because of its chiefly hepatic metabolism, vildagliptin (Galvus) is not recommended for patients with hepatic
impairment including patients with aminotransferases more than 2.5X times the upper limit of normal.
†
* Pooled analysis of 17 trials with study duration ≥24 weeks; FAS (LOCF), all participants who had a baseline and at least one on-treatment HbA1c measurement.
† ANCOVA model includes treatment, study, baseline HbA1c, prior OADs, hepatobiliary disorders, and hepatobiliary disorders x treatment interaction. P value of interaction between treatment and hepatobiliary disorder is >0.05.
‡ Hepatobiliary disorders included: hepatic steatosis, cholelithiasis, cholecystitis, liver disorder, hepatomegaly, gallbladder polyp and chronic hepatitis.
1. Inagaki N, et al. 2013 International Conference on Diabetes and Metabolism & 5th Scientific Meeting of the Asian Association for the Study of Diabetes, 6−9 November 2013, Seoul, Korea; P13-16145.
MAKING A BALANCED CHOICE
EFFICACY
SAFETY SIMPLICITY
YES
Overall Safety of Linagliptin
• Low risk for hypoglycemia
• Reduced risk of weight gain
• Cardiovascular safety
• No increase in HHF risk
• Renal safety
H y p o g l y c a e m i a , r e l a ti v e r i s
Overall hypoglycaemia for medications added-on metformin
12
10.36
10
2 1.15 1.18
0.71 0.51 0.80
0
DPP-4i Acarbose SU TZD SGLT2i GLP-1 RA
DPP-4i, dipeptidyl-peptidase 4 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SGLT2i,
sodium-glucose transported 2 inhibitor; TZD, thiazolidinedione Mearns ES et al. PLoS One 2015;10:e0125879
Hypoglycaemia during Ramadan: DPP4i vs SU
Favours DPP4 SU
Loh et al. Primary Care Diabetes (2015)

• No increase in HHF risk
• Renal safety
Overall weight gain for medications added-on metformin
C h a n g e in b o d y w e ig h t ( k g )
2.5 2.11
1.98
2.0
1.5
1.0
0.5
0.07
0.0
-0.5 -0.10
-1.0
-1.5
-2.0 -1.67
-2.5 -2.13
DPP-4i Acarbose SU TZD SGLT2i GLP-1 RA
DPP-4i, dipeptidyl-peptidase 4 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SGLT2i,
sodium-glucose transported 2 inhibitor; TZD, thiazolidinedione Mearns ES et al. PLoS One 2015;10:e0125879
• Renal safety
Cardiovascular Outcome Trials (CVOT)
DECLARE-TIMI
DECLARE-TIMI 58
15
5815
SAVOR-TIMI 5311 FREEDOM-CVO6,7
6,7 EXSCEL10
10 Dapagliflozin
Dapagliflozin VERTIS CV2020
Saxagliptin ITCA 650 Exenatide N=17,160 Ertugliflozin

N=16,492
N=16,492 N=4156
N=4156 N=14,752
N=14,752 3P-MACE N=8000
N=8000
1222
1222 3P-MACE
3P-MACE 4P-MACE 1744 3P-MACE CV death or HHF 3P-MACE
EXAMINE22 TECOS44 LEADER88 CARMELINA®12®12 CAROLINA®16,17

®16,17
Alogliptin
Alogliptin Sitagliptin
Sitagliptin Liraglutide
Liraglutide Linagliptin
Linagliptin Linagliptin vs
Linagliptin vs SU
SU
N=5380
N=5380 N=14,671
N=14,671 N=9340
N=9340 N=6979
N=6979 N=6041
N=6041
621
621 3P-MACE
3P-MACE 1690
1690 4P-MACE
4P-MACE 1302
1302 3P-MACE
3P-MACE 3P-MACE
3P-MACE ++ kidney
kidney ≥631
≥631 3P-MACE
3P-MACE
2013 2014 2015 2016 2017 2018 2019 2020
ELIXA33 CANVAS Program1111 HARMONY13 13 CREDENCE1919
Lixisenatide
Lixisenatide Canagliflozin
Canagliflozin Albiglutide
Albiglutide Canagliflozin
Canagliflozin
N=6068
N=6068 N=10,142
N=10,142 N=9463
N=9463 N=4402
N=4402
805
805 4P-MACE
4P-MACE 1011
1011 3P-MACE
3P-MACE 3P-MACE
3P-MACE CV/kidney
CV/kidney composite
composite
EMPA-REG
EMPA-REG OUTCOME
OUTCOME®5
®5 SUSTAIN-6
SUSTAIN-699 REWIND
REWIND1414 PIONEER-6
PIONEER-61818
Empagliflozin Semaglutide (inj) Dulaglutide

Dulaglutide Semaglutide (oral)
Semaglutide (oral)
N=7020 N=3297 N=9901 N=3183
772
772 3P-MACE
3P-MACE 254
254 3P-MACE
3P-MACE 3P-MACE 3P-MACE
GLP-1 receptor agonist SGLT2 inhibitor DPP-4 inhibitor
3P-MACE, 3-point major adverse cardiovascular events; 4P-MACE, 4-point major adverse cardiovascular events; 5P-MACE, 5-point major adverse cardiovascular events; CV, cardiovascular; 36
CVOT, cardiovascular outcomes trial; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; HHF, hospitalisation for heart failure; SGLT2, sodium-glucose co-transporter-2; SU, sulphonylurea
Adapted from: Johansen OE. World J Diabetes 2015;6:1092. See notes for full list of references
CARMELINA®: a unique trial investigating the long-term CV and
kidney safety of linagliptin versus placebo
Patients with T2D were randomised to oral treatment with linagliptin or placebo on top of standard of care*
N=6,979 LINAGLIPTIN 5 MG/DAY + STANDARD OF CARE*

STOP
1:1
AFTER ≥611
CV EVENTS
RANDOMISED MATCHING PLACEBO + STANDARD OF CARE*
+ TREATED
• Additional glucose-lowering therapy may be given on top of study medication if HbA1c >7.5%
• Investigators were encouraged to treat all other CV risk factors in accordance with local or regional
standards of care
*Patients received additional glucose-lowering therapy and were treated for CV risk factors in accordance with local or regional standards of care
CV, cardiovascular; HbA1c, glycated haemoglobin; T2D, type 2 diabetes
Boehringer Ingelheim. Data on file. 2018 3
7
Key inclusion criteria
Documented T2D diagnosis, on stable doses of glucose-lowering drugs

Age ≥18 years
HbA1c 6.5%–10.0%
BMI ≤45 kg/m2
High risk of CV events
Macrovascular disease Impaired kidney function

and albuminuria (UACR ≥30 mg/g) and/or albuminuria
≥1 of the following: • eGFR: 15−<45 ml/min/1.73 m2
• Confirmed history of MI
• Advanced CAD • eGFR: ≥45−75 ml/min/1.73 m2 + UACR
• High-risk single-vessel CAD >200mg/g*
• History of ischaemic or haemorrhagic stroke
• Presence of CAD
• Presence of PAD
*200 mg/g or >200 mg/l or >200 μg/min or >200 mg/24 h/\. BMI, body-mass index; CV, cardiovascular; CAD, coronary artery disease; eGFR, estimated glomerular
filtration rate; HbA1c, glycated haemoglobin; MI, myocardial infarction; PAD, peripheral artery disease; T2D, type 2 diabetes; UACR, urinary albumin-to-creatinine
ratio
Rosenstock J et al. Cardiovasc Diabetol 2018;17:39
Baseline characteristics
N=6,979
3
9
Prior CVD
Elevated risk
60% for CVD
CVD Cardiovascular disease 4

Rosenstock J et al. Cardiovasc Diabetol 2018;17:39 0
eGFR >60
Elevated risk
for renal
impairment eGFR<60
62.3%
CKD, Chronic Kidney disease, eGFR, estimated GFR 4

Rosenstock J et al. Cardiovasc Diabetol 2018;17:39 1
CARMELINA® fills a data gap as it included patients across the full range of
kidney function
Pati ents, %
100
80 To date CVOTs in T2D* 100
Baseline eGFR
80
60 CARMELINA ®
60
40 37.7
40 27.8
20 15.2 19.3
20
0 0
0 20 40 60 80 100 <30 30-45 45-60 ≥60
Proportion of patients with severely eGFR (MDRD) (ml/min/1.73 m2)
increased albuminuria (%)
*SAVOR-TIMI 53, TECOS, ELIXA, LEADER, EMPA-REG OUTCOME®,
CANVAS, CAROLINA®, DECLARE-TIMI 58, REWIND, VERTIS
42
CVOT, cardiovascular outcomes trial; eGFR; estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease study equation; T2D, type 2 diabetes
Rosenstock J et al. JAMA 2019;321:69
Higher prevalence of renal impairment CARMELINA than recent
P r o p o r tio n o f p a r tic ip a n ts w ith
r e d u c e d k id n e y fu n c tio n ( % )
CVOTs
100
90 eGFR at baseline:
80
≥30 to <60
70 ml/min/1.73 m²
60 2.9/26.2
0.1/23.1 25.9† <30 ml/min/1.73 m²
50 22.7† 2.4/20.7 0.1/21.5
47.1 19.8†
40 2.1/13.6
30 *
20
10 15.7
SAVOR-TIMI EXAMINE2 ELIXA3 CARMELINA TECOS4 EMPA-REG CANVAS LEADER7 EXSCEL8
0
531 (alogliptin) (lixisenatide) (linagliptin) (sitagliptin) OUTCOME®5 Program6 (liraglutide) (exenatide)
(saxagliptin) N=5380 N=6068 N-6980 N=14,671 (empagliflozin) (canagliflozin) N=9340 N=14,752
N=16,492 N=7020 N=10,142
*eGFR ≥30 to <50 ml/min/1.73 m2; †Trial excluded patients with eGFR <30 ml/min/1.73 m2 CVOT, cardiovascular outcomes trial; eGFR, estimated
glomerular filtration rate
1. Scirica BM et al. N Engl J Med 2013;369:1317; 2. White WB et al. N Engl J Med 2013;369:1327 (supplementary appendix); 3. Pfeffer MA et al. N Engl
J Med 2015;373:2247 (supplementary appendix); 4. Green JB et al. N Engl J Med 2015;373:232 (supplementary appendix); 5. Zinman B et al. N Engl J
Med 2015;373:2117 6. Neal B et al. Diabetes Obes Metabol 2017;19:926; 7. Marso SP et al. N Engl J Med 2016;375:311; 8. Holman RR et al. N Engl J
Med 2017;377:1228
CARMELINA® was designed to evaluate the CV and kidney
safety of linagliptin in patients with T2D
• CV death • Sustained* eGFR decrease by

• Non-fatal MI 3P-MACE ≥40%
• Non-fatal stroke • Progression to sustained* ESKD
• Death due to kidney disease
All events included in the primary and key secondary endpoints were confirmed by central
adjudication
CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; HHF, hospitalization for heart failure; MI,
myocardial infarction; T2D, type 2 diabetes
* Sustained defined as two or more consecutive assessments performed at least 28 days apart.
1. Rosenstock J et al. Cardiovasc Diabetol 2018;17:39; 2. Boehringer Ingelheim. Data on file. 2018 4
4
A small difference in HbA1c was observed
HbA1c over time
8.5 Mean difference (95% CI) throughout study:

–0.36 (–0.42, –0.29), p<0.0001
Adjusted* mean (SE)
8.0 Placebo
HbA1c (%)
–0.03 (0.02) Linagliptin

7.5
–0.53 (0.02)
7.0
6.5
0 12 24 36 48 60 72 84 96 108120132144156168180
Weeks
Placebo (n) 3,387 3,331 3,151 2,968 2,395 1,725 1,156 732 358
Linagliptin (n) 3,419 3,373 3,173 3,015 2,455 1,811 1,237 777 379
Treated set (observed cases). *Baseline values are descriptive; post-baseline data from MMRM adjusting for treatment, region, baseline HbA1c value, week, treatment-by-week interaction and
baseline HbA1c value-by-week interaction. HbA1c, glycated haemoglobin; MMRM, mixed-model repeated measures
Rosenstock J, et al. JAMA. 2018 Nov 9. doi: 10.1001/jama.2018.18269
Overall linagliptin did not increase the risk of hypoglycemia
Hypoglycemia: rates per 100 patient-years overall
30 Linagliptin Placebo
Rate per 100 patient-years
19.9 20.2
20
9.3 9.8
10
1.6 1.7
0
Any Plasma glucose Severe*
hypoglycemia <54 mg/dl
or severe*
Treated set. MedDRA version used for reporting: 20.1. AEs occurring between first study drug intake until 7 days after last permanent study drug stop
*Requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions
Hypoglycaemia: rate per 100 patient years in subgroups
40 Linagliptin Placebo
SU-treated Insulin-treated
30
Rate per 100 patient-years
20
10
0
Any Plasma glucose Any Plasma glucose Severe
<54 mg/dl Severe
<54 mg/dl
or severe* or severe*
*Requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions
Treated set. MedDRA version used for reporting: 20.1. AEs occurring between first study drug intake until 7 days after the last intake of study medication
eGFR, estimated glomerular filtration rate; SU, sulphonylurea
Rosenstock J et al. JAMA 2018; doi: 10.1001/jama.2018.18269 (supplementary appendix)
Cardiac Safety
The long-term CV safety profile of linagliptin was confirmed
Time to first occurrence of 3P-MACE

Placebo Linagliptin
30 HR 1.02
Patients with event (%)
(95% CI 0.89, 1.17)

p=0.0002 for non-inferiority Median
20 p=0.7398* for superiority time in 434 patients
study 420 patients
10
0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
No. of patients Years
Placebo (n) 3,485 3,353 3,243 2,625 1,931 1,285 758 251
Linagliptin (n) 3,494 3,373 3,254 2,634 1,972 1,306 778 269
Linagliptin event rate 5.77/100 PY Placebo event rate 5.63/100 PY
Treated set, Kaplan-Meier estimate. Hazard ratio and 95% CI based on Cox regression model with terms for treatment group (p=0.7398) and region (p=0.7878); *Two-sided
3P-MACE, 3-point major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke)
CARMELINA® shows Linagliptin’s consistent CV safety in challenging
setting
• DPP-4 inhibitor CVOTs reported to date met the FDA-mandated criteria for demonstrating CV
safety (i.e. non-inferiority versus placebo) on the 3P-MACE Outcome
FDA-mandated
n with event/N analysed (%) upper 95% CI for
CV safety
Trial Trial drug Placebo HR (95% CI) p-value*
SAVOR-TIMI 531
613/8280 (7.3) 609/8212 (7.2) 1.00 (0.89, 1.12) 0.99
(saxagliptin)
EXAMINE2
305/2701 (11.3) 316/2679 (11.8) 0.96 (≤1.16*) † 0.32
(alogliptin)
TECOS3
695/7257 (9.6) 695/7266 (9.6) 0.98 (0.88, 1.09) 0.65
(sitagliptin)
CARMELINA®4
434/3494 (12.4) 420/3485 (12.1) 1.02 (0.89, 1.17) 0.74
(linagliptin)
0.5 1.3
Direct comparison of trials should be interpreted with caution due to differences in study design, populations and methodology
*p-value for superiority; †Upper boundary of 1-sided repeated CI Favours trial drug Favours placebo
Refer to slide notes for abbreviations 52
1. Scirica BM et al. N Engl J Med 2013;369:1317; 2. White WB et al. N Engl J Med 2013;369:1327; 3. Green JB et al. N Engl J Med 2015;373;232;
4. Rosenstock J et al. JAMA 2018; doi: 10.1001/jama.2018.18269
There was no increased risk of hospitalization for HF with Linagliptin
Time to first occurrence of adjudication-confirmed hospitalization for HF

15
HR 0.90
(95% CI 0.74, 1.08)
10 p=0.2635* Placebo
Linagliptin
0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Placebo (n) 3,485 3,336 3,222 2,621 1,923 1,285 767 258
Linagliptin (n) 3,494 3,361 3,243 2,647 1,979 1,317 787 280
Linagliptin event rate 2.77/100 PY Placebo event rate 3.04/100 PY

Treated set, Kaplan-Meier estimate. Hazard ratio and 95% CI based on Cox regression model with terms for treatment group (p=0.2635), region (p=0.0012),
history of heart failure (p≤0.0001); *Two-sided
HF, heart failure
CARMELINA® provided an opportunity to robustly establish
heart failure safety in a very high-risk population
HHF event rates in DPP-4 inhibitor CVOTs
HHF, hospitalization for heart failure 5

1. Filion KB and Suissa S. Diabetes Care 2016;39:735-737; 2. Rosenstock J, et al. JAMA. 2018 Nov 9. doi: 10.1001/jama.2018.18269 4
Hospitalisation for heart failure in completed
DPP-4 inhibitor CVOTs
• Saxagliptin was associated with a significant increased risk of hospitalisation for heart failure compared
with placebo
n with event/N analysed (%)
Trial Trial drug Placebo HR (95% CI) p-value
SAVOR-TIMI 53*1
289/8280 (3.5) 228/8212 (2.8) 1.27 (1.07, 1.51) 0.007
(saxagliptin)
EXAMINE*2
106/2701 (3.9) 89/2679 (3.3) 1.19 (0.90, 1.58) 0.22
(alogliptin)
TECOS†3
228/7332 (3.1) 229/7339 (3.1) 1.00 (0.83, 1.20) 0.98
(sitagliptin)
CARMELINA®4
209/3494 (6.0) 226/3485 (6.5) 0.90 (0.74, 1.08) 0.26
(linagliptin)
Direct comparison of trials should be interpreted with caution due to differences in study design, populations and methodology 0.5
*According to an FDA safety review, saxagliptin and alogliptin may increase the risk of HF, particularly in patients who already have heart
or kidney disease. A warning has been added to the labels of these drugs 5; †Not evaluated for assessment of HF risk at time of trial Favours trial drug Favours placebo
CVOT, cardiovascular outcomes trial; DPP-4, dipeptidyl peptidase-4; HF, heart failure
1. Scirica BM et al. N Engl J Med 2013;369:1317; 2. Zannad F et al. Lancet 2015;385:2067;
3. Green JB et al. N Engl J Med 2015;73:232; 4. Rosenstock J et al. JAMA 2018; doi: 10.1001/jama.2018.18269 55
No increased risk of HHF was consistent across high risk subgroups
CARMELINA® showed
that linagliptin did not
History of HF Renal impairment ASCVD
increase HHF risk…
…regardless of baseline
characteristics such as
Insulin use World region Age ≥65
Treated set. 2-sided p value for HR (not p-value for interaction)

HF heart failure; ASCVD atherosclerotic cardiovascular disease
Time to first occurrence of adjudication-confirmed hospitalisation for
HF by selected baseline characteristics
Linagliptin Placebo
p-value for
HR (95% CI)
n with event / N analysed interaction
All patients 209/3,494 226/3,485

Age 0.8504
<65 years 67/1,467 77/1,501
≥65 years 142/2,027 149/1,984
Region 0.0368
North America 42/593 61/587
Latin America 54/1,156 54/1,154
Europe (incl. S. Africa) 101/1,473 88/1,461
Asia 12/272 23/283
Insulin 0.0360
Yes 169/2,007 163/1,943
No 40/1,487 63/1,542
History of HF 0.8104
Yes 113/952 122/921
No 96/2,542 104/2,564
eGFR (MDRD), ml/min/1.73 m2 0.9339
<60 173/2,200 185/2,148
≥60 36/1,294 41/1,337
UACR, mg/g 0.6157
<30 26/696 32/696
30–300 72/1,463 80/1,431
>300 111/1,333 113/1,357
Treated set. 2-sided p value for HR 0.25 2.50

eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Kidney Disease study equation;
UACR, urinary albumin-to-creatinine ratio Favours linagliptin Favours placebo
McGuire DK et al. Circulation 2018;doi: 10.1161/CIRCULATIONAHA.118.038352 5
7
HHF in Asian patients with T2D in the CARMELINA trial
Treated set. 2-sided p value for HR

McGuire DK et al. Circulation 2018;doi: 10.1161/CIRCULATIONAHA.118.038352
Time to first occurrence of adjudication-confirmed hospitalisation for
HF by selected baseline characteristics
Linagliptin Placebo
p-value for
HR (95% CI)
n with event / N analysed interaction
All patients 209/3,494 226/3,485

Age 0.8504
<65 years 67/1,467 77/1,501
≥65 years 142/2,027 149/1,984
Region 0.0368
North America 42/593 61/587
Latin America 54/1,156 54/1,154
Europe (incl. S. Africa) 101/1,473 88/1,461
Asia 12/272 23/283
Insulin 0.0360
Yes 169/2,007 163/1,943
No 40/1,487 63/1,542
History of HF 0.8104
Yes 113/952 122/921
No 96/2,542 104/2,564
eGFR (MDRD), ml/min/1.73 m2 0.9339
<60 173/2,200 185/2,148
≥60 36/1,294 41/1,337
UACR, mg/g 0.6157
<30 26/696 32/696
30–300 72/1,463 80/1,431
>300 111/1,333 113/1,357
Treated set. 2-sided p value for HR 0.25 2.50

eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Kidney Disease study equation;
UACR, urinary albumin-to-creatinine ratio Favours linagliptin Favours placebo
McGuire DK et al. Circulation 2018;doi: 10.1161/CIRCULATIONAHA.118.038352 6
0
CARMELINA Asian sub-analysis
Key result 1: No increased risk of CV events with linagliptin in Asian
participants, consistent with overall trial population (1)
Linagliptin Placebo
p-value for treatment by
HR (95% CI) HR (95% CI)
n with event / N analysed (%) region interaction
3-point MACE 0.3349

Overall 434/3494 (12.4) 420/3485 (12.1) 1.02 (0.89–1.17)
Asian 29/272 (10.7) 33/283 (11.7) 0.90 (0.55–1.48)
4-point MACE 0.2789
Overall 463/3494 (13.3) 459/3485 (13.2) 1.00 (0.88–1.13)
Asian 30/272 (11.0) 36/283 (12.7) 0.84 (0.52–1.37)
Fatal or non-fatal MI 0.2723
Overall 165/3494 (4.7) 146/3485 (4.2) 1.12 (0.90–1.40)
Asian 16/272 (5.9) 19/283 (6.7) 0.87 (0.45–1.69)
Non-fatal MI 0.3314
Overall 156/3494 (4.5) 135/3485 (3.9) 1.15 (0.91–1.45)
Asian 16/272 (5.9) 19/283 (6.7) 0.87 (0.45–1.69)
Fatal or non-fatal stroke 0.3251
Overall 81/3494 (2.3) 88/3485 (2.5) 0.91 (0.67–1.23)
Asian 6/272 (2.2) 10/283 (3.5) 0.60 (0.22–1.66)
Non-fatal stroke 0.6857
Overall 65/3494 (1.9) 73/3485 (2.1) 0.88 (0.63–1.23)
Asian 6/272 (2.2) 10/283 (3.5) 0.60 (0.22–1.66)
CV death 0.8026
Overall 255/3494 (7.3) 264/3485 (7.6) 0.96 (0.81–1.14)
Asian 9/272 (3.3) 13/283 (4.6) 0.70 (0.30–1.64)
0.25 2.5
Favours linagliptin Favours placebo
3-point MACE, 3-point major adverse CV events (CV death, non-fatal MI or non-fatal stroke);
4-point MACE, 4-point major adverse CV events (CV death, non-fatal MI, non-fatal stroke or hospitalisation for unstable angina);
CV, cardiovascular; MI, myocardial infarction. Source: Inagaki N et al. Diabetol Int 2019; Oct 22. doi: 10.1007/s13340-019-00412-x [Epub ahead of print]
Key result 1: No increased risk of CV events with linagliptin in Asian
participants, consistent with overall trial population (2)
Linagliptin Placebo
p-value for treatment by
HR (95% CI) HR (95% CI)
n with event / N analysed (%) region interaction
Non-CV death 0.4443

Overall 112/3494 (3.2) 109/3485 (3.1) 1.02 (0.78–1.33)
Asian 3/272 (1.1) 7/283 (2.5) 0.44 (0.11–1.68)
All-cause mortality 0.4077
Overall 367/3494 (10.5) 373/3485 (10.7) 0.98 (0.84–1.13)
Asian 12/272 (4.4) 20/283 (7.1) 0.61 (0.30–1.25)
HHF 0.0368
Overall 209/3494 (6.0) 226/3485 (6.5) 0.90 (0.74–1.08)
Asian 12/272 (4.4) 23/283 (8.1) 0.47 (0.24–0.95)
HHF or CV death 0.3224
Overall 406/3494 (11.6) 422/3485 (12.1) 0.94 (0.82–1.08)
Asian 19/272 (7.0) 30/283 (10.6) 0.60 (0.34–1.06)
HHF or all-cause mortality 0.2191
Overall 499/3494 (14.3) 518/3485 (14.9) 0.95 (0.84–1.07)
Asian 20/272 (7.4) 35/283 (12.4) 0.55 (0.32–0.95)
Hospitalisation for unstable angina 0.7888
Overall 42/3494 (1.2) 48/3485 (1.4) 0.87 (0.57–1.31)
Asian 2/272 (0.7) 3/283 (1.1) 0.68 (0.11–4.07)
All-cause hospitalisation 0.2182
Overall 1157/3494 (33.1) 1213/3485 (34.8) 0.93 (0.85–1.00)
Asian 98/272 (36.0) 130/283 (45.9) 0.74 (0.57–0.96)
0.25 2.5
CV, cardiovascular; HHF, hospitalisation for heart failure
Source: Inagaki N et al. Diabetol Int 2019; Oct 22. doi: 10.1007/s13340-019-00412-x [Epub ahead of print]
CAROLINA® is an active-comparator CVOT
Patients with T2D were randomised to daily oral treatment with

linagliptin or glimepiride
N=6033
RANDOMISATION *
Titration-phase: Weeks 1–16
Event-driven
• Study medication given on top of stable background glucose-lowering therapy (N=6033)

• Investigators encouraged to treat all other CV risk factors in accordance with local guidelines
CV, cardiovascular; CVOT, CV outcomes trial; T2D, type 2 diabetes

Marx N et al. Diab Vasc Dis Res 2015;12:164. ClinicalTrials.gov NCT01243424 (accessed August 2018) 6
3
CAROLINA® was designed to evaluate the long-term CV safety
profile of linagliptin versus glimepiride
5-step hierarchical testing strategy with a subsequent confirmatory test
only performed in the event of a significant prior result
1. Non-inferiority test (margin 1.3) of the primary outcome 3P-MACE for CV safety
2. Superiority test of the primary outcome 3P-MACE for CV benefit
3. Superiority test for the secondary outcome 4P-MACE for CV benefit
4. Superiority test for the 1st key secondary metabolic efficacy outcome*
5. Superiority test of the 2nd key secondary metabolic efficacy outcome†
*HbA1c ≤7.0% without rescue medication, moderate or severe hypoglycaemic episodes and >2% weight gain at final visit; †HbA1c ≤7.0% without rescue
medication, and without >2% weight gain at final visit
3P-/4P-MACE, 3-point/4-point major adverse cardiovascular events; CV, cardiovascular; HbA1c, glycated haemoglobin
Marx N et al. Diab Vasc Dis Res 2015;12:164 6
4
Patients with relatively early T2D were eligible for inclusion if they
met both glycaemic and CV risk criteria
Adult patients with T2D, HbA1c 6.5–8.5%,
BMI ≤45 kg/m2 and elevated CV risk
Early T2D or suboptimal glycaemic control Increased CV risk or established CV disease

• HbA1c 6.5–8.5% if treatment naïve or treated with • Previous vascular disease
metformin and/or ɑ-glucosidase inhibitor – MI†
• HbA1c 6.5–7.5% if receiving: – Documented CAD‡
– SU/glinide monotherapy – Percutaneous coronary intervention †
– Metformin + SU* – CABG§ or with recurrent angina after surgery
– Metformin + glinide* – Ischaemic or haemorrhagic stroke ¶
– SU + ɑ-glucosidase* – PAD
– Glinide + ɑ-glucosidase* • Evidence of vascular-related end-organ damage**
• Age ≥70 years
No patients requiring insulin therapy for glucose control were
allowed in the trial • ≥2 CV risk factors††
*For patients with T2D duration ≤5 years; †>6 weeks prior to IC; ‡ 50% luminal diameter narrowing of the left main coronary artery or in at least 2 major
coronary arteries in angiogram; § >4 years prior to IC; ¶>3 months prior to IC; **eGFR 30–59 ml/min/1.73 m2, UACR ≥30 µg/mg in 2 out of 3 specimens in the
previous 12 months, proliferative retinopathy; ††T2D duration >10 years, SBP >140 mmHg or ≥1 blood pressure-lowering treatment, current smoker, LDL-
cholesterol ≥135 mg/dl, BMI, body mass index; CABG, coronary artery bypass grafting; CAD, coronary artery disease; eGFR, estimated glomerular filtration
rate; HbA1c, glycated haemoglobin; IC, informed consent; LDL, low-density lipoprotein; MI, myocardial infarction; PAD, peripheral arterial disease; SBP,
systolic blood pressure; SU, sulphonylurea. Marx N et al. Diab Vasc Dis Res 2015;12:164; ClinicalTrials.gov NCT01243424 (accessed August 2018) 6
5
Study/treatment exposure
Nov 11th 2010:

First participant
screened (10606
screened)
2010 2011 2012 2013 2014 2015 2016 2017 2018
Dec 2nd 2010:

Dec 4th 2012: Aug 21st 2018:
First participant
Last participant Last participant
randomised
randomised completed
(6042)
Assessed for primary analysis
Linagliptin Glimepiride
(N=3023) (N=3010)
Median (IQR) time in study (years) 6.3 (5.9, 6.6) 6.3 (5.9, 6.6)
Median (IQR) treatment exposure (years) 5.9 (3.5, 6.4) 5.9 (3.4, 6.4)
IQR, interquartile range
Rosenstock J et al. ADA 2019 6
6
Baseline demographics and clinical characteristics
Linagliptin
(N=3023) Glimepiride
(N=3010)
Men, n (%) (N=3023)
1838 (60.8) (N=3010)
1781 (59.2)
Men, n (%) mean ± SD
Age, years, 1838 (60.8)
63.9±9.5 1781 (59.2)
64.2±9.5
Age, years,
Weight, mean ±± SD*
kg, mean SD 63.9±9.5
84.3±18.0 64.2±9.5
83.6±17.9
Weight,
BMI, kg/m kg,2, mean
mean ±± SD*
SD† 84.3±18.0
30.2±5.2 83.6±17.9
30.0±5.1
BMI, kg/m22, mean ± SD‡ †† 30.2±5.2 30.0±5.1
HbA1c, %, mean ± SD 7.2±0.6 7.2±0.6
HbA1c, %, mean ± SD‡ 7.2±0.6 7.2±0.6
T2D duration, years, median
T2D 6.3 (3.0, 11.1) 6.2 (2.9, 10.9)
(IQR)duration,
§ years, median
6.3 (3.0, 11.1) 6.2 (2.9, 10.9)
(IQR) §
T2D duration ≤5 years, n (%) 1224 (40.5) 1212 (40.3)
T2D duration ≤5 years, n (%) 1224 (40.5) 1212 (40.3)
Glucose-lowering drug, n (%)¶
None 274 (9.1) 272 (9.0)
1 1984 (65.6) 1982 (65.8)
2 736 (24.3) 725 (24.1)
3 20 (0.7) 21 (0.7)
Treated set. Data missing for *21 (0.3%) (linagliptin: n=9 [0.3%]; glimepiride: n=12 [0.4%]); †24 (0.4%) (linagliptin: n=11 [0.4%]; glimepiride: n=13 [0.4%]);
‡20 (0.3%) (linagliptin: n=10 [0.3%]; glimepiride: n=10 [0.3%]); §50 (linagliptin: n=22 [0.7%]; glimepiride: n=28 [0.9%]); ¶19 (0.3%) (linagliptin: n=9 [0.3%]; 6
7
glimepiride: n=10 [0.3%]) participants. BMI, body-mass index; HbA1c, glycated haemoglobin; T2D, type 2 diabetes. Rosenstock J et al. ADA 2019
Glucose-lowering therapies at baseline
100 SU/glinide were discontinued at randomisation
80 n=1765 n=1774
Linagliptin
Patients (%)
58.4 58.9 Glimepiride

60
40 n=650 n=645
n=274 n=272
n=189 n=171 21.5 21.4 n=97 n=92 n=28 n=38
20 9.1 9
6.4 5.7 3.2 3.1 0.9 1.3
0
Metformin SU Metformin AGI Glinide None
monoth...
Information was not available for 19 patients
monoth... + SU
AGI, alpha glucosidase inhibitor; SU, sulphonylurea
8
(N=3023) (N=3010)
SBP, mmHg, mean ± SD* 136.1±16.1 135.9±16.2
DBP, mmHg, mean ± SD* 79.2±9.5 79.0±9.5
Hypertension, n (%)* 2720 (90.0) 2698 (89.6)
Macrovascular disease, n (%) 1272 (42.1) 1250 (41.5)
Coronary artery disease* 968 (32.0) 937 (31.1)
Cerebrovascular disease* 371 (12.3) 356 (11.8)
Peripheral artery disease* 207 (6.8) 200 (6.6)
Heart failure† 122 (4.0) 149 (5.0)
Microvascular disease, n (%) 847 (28.0) 881 (29.3)
Diabetic neuropathy* 515 (17.0) 495 (16.4)
Diabetic nephropathy* 352 (11.6) 372 (12.4)
Diabetic retinopathy* 212 (7.0) 236 (7.8)
Treated set. *Data missing for 19 (0.3%) (linagliptin: n=9 [0.3%]; glimepiride: n=10 [0.3%]); †Based on cardiac failure narrow Standardised MedDRA Query (SMQ) at
baseline; New York Heart Association (NYHA) class III and IV excluded. DBP, diastolic blood pressure; SBP, systolic blood pressure. Rosenstock J et al. ADA 2019 6
9
(N=3023) (N=3010)
eGFR (MDRD), ml/min/1.73 m2,
mean ± SD* 76.5±19.7 77.0±19.8
eGFR (MDRD), ml/min/1.73 m2, n (%)*
≥90 693 (22.9) 722 (24.0)
≥60−<90 1726 (57.1) 1740 (57.8)
<60 592 (19.6) 538 (17.8)
UACR, n (%)†
<30 mg/g 2228 (73.7) 2234 (74.2)
30−300 mg/g 645 (21.3) 630 (20.9)
>300 mg/g 134 (4.4) 124 (4.1)
Treated set
**Data missing for 22 (0.4%) patients (linagliptin: n=12 [0.4%]; glimepiride: n=10 [0.3%])
†
Data missing for 38 (0.6%) patients (linagliptin: n=16 [0.5%]; glimepiride: n=22 [0.7%])
eGFR, estimated glomerular filtration rate; UACR, urinary albumin-to-creatinine ratio
0
CAROLINA® included participants with relatively early T2D at
increased CV risk
Participants reflect those typically seen in clinical practice
Median T2D
duration
6.3 years
Had
On metformin 83% 42% established CV
disease
Displayed ≥2
On insulin 0%* 37% defined CV risk
factors
Treatment naïve 9% 40% Had T2D for ≤5

years
Receiving
standard of
*Exclusion criteria care for CV risk
CV, cardiovascular; T2D, type 2 diabetes
1
Glimepiride was appropriately and adequately uptitrated
• Glimepiride was titrated from Week 1−16, guided by self-monitored glucose level
• Starting dose of 1 mg/day uptitrated at 4-week intervals to a maximum of 4 mg/day
100 1 mg 2 mg 3 mg 4 mg
80 Mean dose throughout study:
2.9±1.1 mg 66.3%
Patients (%)
60 49.1%
40
20 4.6%
0
0 4 8 12 16 64 112 160 208 256 304 352
Uptitration Phase Weeks
Treated set without duplicates
2
New introduction of glucose-lowering medication post baseline
Any glucose- 41.0 (n=1237)

lowering therapy
39.7 (n=1192)
Non-insulin 30.6 (n=922)

therapies
29.0 (n=869)
18.6 (n=561)
Insulin
19.2 (n=577)
0 10 20 30 40 50
Patients (%)
Numbers show patients with at least 1 new medication introduced post-baseline. Takes into account new onset of insulin regardless of duration, but does not
take into consideration dose increase of background therapy
3
Linagliptin was non-inferior to glimepiride for 3P-MACE, the primary
outcome
Rate:
HR 0.98 2.1/100 PY
16 Linagliptin Glimepiride
(95.47% CI 0.84, 1.14)*
14 362 patients
p<0.0001 for non-inferiority 356 patients
12
Patients (%)
p=0.7625 for superiority

10 Rate:
2.1/100 PY
8
6
4
2
0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
Linagliptin (n) 3023 2957 2901 2846 2803 2762 2725 2679 2627 2582 2534 2451 1830 1040 213
Glimepiride (n) 3010 2940 2890 2833 2797 2757 2710 2662 2618 2569 2509 2414 1865 1020 207
*The 95.47% bound for the CI reflects an O’Brien & Fleming alpha-spending adjustment for the two interim analyses of the primary outcome, in addition to
Bonferroni adjustment for change from 4P-MACE to 3P-MACE. Treated set; Kaplan-Meier estimate; hazard ratio and CI derived from Cox regression with
factor treatment; 1-sided p value for non-inferiority and 2-sided p value for superiority. 3P-MACE, 3-point major adverse cardiovascular events (cardiovascular
death, non-fatal myocardial infarction, non-fatal stroke); PY, patient-years
4
The overall findings for 3P-MACE were consistent across subgroups
p-value
for
n with event / N analysed HR (95% CI) HR (95% CI)
interactio
(%) n
All patients 356/3023 (11.8) 362/3010 (12.0) 0.98 (0.84, 1.13)*
History of vascular disease 0.5416
No 166/1963 (8.5) 162/1962 (8.3) 1.03 (0.83, 1.27)
Yes 190/1051 (18.1) 199/1038 (19.2) 0.94 (0.77, 1.14)
Age 0.2110
<70 years 196/2009 (9.8) 180/1975 (9.1) 1.08 (0.88, 1.32)
≥70 years 160/1005 (15.9) 181/1025 (17.7) 0.89 (0.72, 1.10)
Gender 0.2571
Male 250/1838 (13.6) 263/1781 (14.8) 0.92 (0.77, 1.09)
Female 106/1185 (8.9) 99/1229 (8.1) 1.11 (0.84, 1.46)
Prior anti-diabetic treatment 0.2912
No prior use of sulphonylurea or glinide 234/2117 (11.1) 225/2116 (10.6) 1.04 (0.87, 1.25)
Prior use of sulphonylurea or glinide 122/897 (13.6) 136/884 (15.4) 0.88 (0.69, 1.13)
Background metformin 0.4010
No 69/510 (13.5) 77/499 (15.4) 0.86 (0.62, 1.20)
Yes 287/2504 (11.5) 284/2501 (11.4) 1.01 (0.86, 1.19)
Baseline HbA1c 0.8099
<7.0% 133/1255 (10.6) 135/1228 (11.0) 0.96 (0.76, 1.22)
≥7.0% 223/1758 (12.7) 226/1772 (12.8) 1.00 (0.83, 1.20)
Baseline eGFR, ml/min/1.73 m 2 0.9036
≥60 248/2419 (10.3) 260/2462 (10.6) 0.97 (0.82, 1.15)
<60 107/592 (18.1) 101/538 (18.8) 0.95 (0.72, 1.25)
Favours linagliptin Favours glimepiride

*95.47 CI; Treated set; p-value for subgroup-by-treatment interaction and HR for each subgroup based on Cox regression model with factors for treatment, subgroup and subgroup-by-treatment interaction. 3P-MACE, 3-point major adverse 7
cardiovascular events; eGFR, estimated glomerular filtration rate; HbA1c, glycated haemoglobin 5
Rosenstock J et al. ADA 2019
Summary of key secondary sustainability endpoints*
OR (95.47% CI) OR (95.47% CI) p-value
n (%)
HbA1c ≤7.0%,
Without need for rescue medication,
Without weight gain >2%, 481 (16.0) 305 (10.2) 1.68 (1.43, 1.96) <0.0001
Without moderate/severe
hypoglycaemia
HbA1c ≤7.0%,
Without need for rescue medication,
524 (17.4) 422 (14.1) 1.29 (1.11, 1.48) 0.0004
Without weight gain >2%
Favours glimepiride Favours linagliptin
(This data is exploratory)

*The proportion of participants that are on study treatment at study end, that at final visit maintain glycaemic control (HbA1c ≤7.0%) without need for rescue
medication (between end of titration [Visit 6: Week 16] and final visit) and participants without any moderate/severe hypoglycaemic episodes (between Visit 6
and final visit) and without >2% weight gain at final visit (between Visit 6 and final visit). Treated set; odds ratio for composite sustainability endpoint at study end
HbA1c, glycated haemoglobin
6
Occurrence of any hypoglycaemic AE* was lower with linagliptin
versus glimepiride
50 HR 0.23 Rate:
Linagliptin Glimepiride 11.1/100 PY
(95% CI 0.21, 0.26) 1132 patients
40 p<0.0001
Patients (%)
30
20 Rate:
2.3/100 PY
320 patients
10
0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
Linagliptin (n) 3014 2708 2531 2430 2315 2223 2152 2054 1982 1912 1843 1761 1274 498 163
Glimepiride (n) 3000 2278 2018 1866 1752 1652 1565 1481 1407 1337 1274 1187 847 297 88
*Investigator-defined hypoglycaemic AE
Treated set without duplicates (AEs occurring between first study drug intake until 7 days after last permanent study drug stop); Kaplan-Meier estimate; hazard
ratio and 95% CI derived from Cox regression with factor treatment; 2-sided p-value
PY, patient-years
7
Hypoglycaemia remains an everyday challenge and limits optimal
glucose control in many patients in clinical practice
Headache
Dizziness Blurred vision
Patient-relevant
consequences of Increased hospitalisations
Confusion Sweating
hypoglycemia1-7
Patient-relevant Increased cost
consequences of
hypoglycaemia1-7 Decreased quality of
life
Anxiety/irritability Trembling/seizures
Palpitations/fast pulse
Suboptimal outcome
1. Schernthaner et al. Diabetologia 2018;61:1503; 2. Wild D et al. Patient Educ Couns 2007;68:10; 3. Schwartz SS et al. Mayo Clin Proc 2010;85:S15;
4. Zoungas S et al. N Engl J Med 2010;363:1410. 5. Cryer PE. N Engl J Med 2013;369:362; 6. Cryer PE Diabetes Care 2017;40:1641;
6. Andersen
78 SE et al. Br J Clin Pharmacol 2016;82:1291; 7. Canadian Clinical Practice Guidelines 2018, Chapter 14. Hypoglycaemia.
A consistently lower risk of hypoglycaemia* was observed with
linagliptin across all subgroups analysed
p-value
for
n with event / N analysed HR (95% CI) HR (95% CI)
interactio
(%) n
All patients 320/3014 (10.6) 1132/3000 (37.7) 0.23 (0.21, 0.26)
History of vascular disease 0.07
No 197/1963 (10.0) 751/1962 (38.3) 0.21 (0.18, 0.25)
Yes 123/1051 (11.7) 381/1038 (36.7) 0.27 (0.22, 0.33)
Age 0.41
<70 years 223/2009 (11.1) 749/1975 (37.9) 0.24 (0.21, 0.28)
≥70 years 97/1005 (9.7) 383/1025 (37.4) 0.22 (0.17, 0.27)
Sex 0.47
Male 193/1833 (10.5) 650/1776 (36.6) 0.24 (0.21, 0.28)
Female 127/1181 (10.8) 482/1224 (39.4) 0.22 (0.18, 0.27)
Prior anti-diabetic treatment <0.0001
No prior use of sulphonylurea or glinide 189/2117 (8.9) 805/2116 (38.0) 0.19 (0.16, 0.22)
Prior use of sulphonylurea or glinide 131/897 (14.6) 327/884 (37.0) 0.35 (0.29, 0.43)
Background metformin 0.23
No 39/510 (7.6) 167/499 (33.5) 0.19 (0.14, 0.27)
Yes 281/2504 (11.2) 965/2501 (38.6) 0.24 (0.21, 0.27)
Baseline HbA1c 0.72
<7.0% 149/1255 (11.9) 512/1228 (41.7) 0.23 (0.19, 0.27)
≥7.0% 171/1758 (9.7) 620/1772 (35.0) 0.24 (0.20, 0.28)
Baseline eGFR, ml/min/1.73 m 2 0.56
≥60 246/2419 (10.2) 906/2462 (36.8) 0.23 (0.20, 0.26)
<60 74/592 (12.5) 226/538 (42.0) 0.25 (0.19, 0.32)
*Investigator-defined hypoglycaemic AE
Treated set without duplicates. HR and p-value for subgroup-by-treatment interaction based on Cox regression model with
factors for treatment, subgroup and subgroup-by-treatment interaction
eGFR, estimated glomerular filtration rate; HbA1c, glycated haemoglobin
Favours linagliptin Favours glimepiride 7
9
The incidence of hypoglycaemic events was consistently lower with linagliptin
compared with glimepiride across all categories of hypoglycaemia
HR 0.23 HR 0.18 HR 0.15 HR 0.07
(95% CI 0.21, 0.26) (95% CI 0.15, 0.21) (95% CI 0.08, 0.29) (95% CI 0.02, 0.31)
p<0.0001 p<0.0001 p<0.0001 p=0.0004
2.34/100 PY 11.1/100 PY 1.4/100 PY 8.4/100 PY 0.07/100 PY 0.45/100 PY 0.01/100 PY 0.18/100 PY
40 37.7
Linagliptin
30.9 Glimepiride
30
Patients (%)
20
10.6
10 6.5
0.3 2.2 0.1 0.9
0
Any Moderate/severe Severe* Hospitalisation due
* to hypoglycaemia
Treated set without duplicates (AEs occurring between first study drug intake until 7 days after last permanent study drug stop); MedDRA version used for
reporting: 21.0. *Hypoglycaemic event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions
PY, patient-years
0
Classification of hypoglycaemia adverse events
Any hypoglycaemia:
• Includes all of the following
Moderate hypoglycaemia:
• Documented symptomatic hypoglycaemia with plasma glucose ≤70 mg/dl (≤3.9 mmol/l),
without the need for external assistance
Severe hypoglycaemia:
• A hypoglycaemic event requiring the assistance of another person to administer carbohydrate, glucagon or
other resuscitative actions
Moderate or severe hypoglycaemia:
• As defined above
Hospitalisation due to hypoglycaemia:
• Investigator reported hypoglycaemic AE concomitantly fulfilling serious AE criterion “requiring hospitalisation”

1
Safety topics of particular interest: Overview
Linagliptin (N=3014) Glimepiride (N=3000)

Rate/100 Rate/100
n (%) n (%)
patient-years patient-years
Hypersensitivity reactions, all AEs* 404 (13.4) 3.00 346 (11.5) 2.55
Serious hypersensitivity AEs 26 (0.9) 0.18 32 (1.1) 0.22
Angioedema events, all AEs † 54 (1.8) 0.37 50 (1.7) 0.34
Angioedema events with ACEi/ARB at baseline 42 (1.9‡) 0.39 41 (1.9‡) 0.39
Hepatobiliary AEs§ 233 (7.7) 1.65 261 (8.7) 1.88
Renal AEs¶ 178 (5.9) 1.23 156 (5.2) 1.09
Skin lesions** 9 (0.3) 0.06 4 (0.1) 0.03
Arthralgia-related events†† 721 (23.9) 5.84 727 (24.2) 5.96
Serious arthralgia-related events 87 (2.9) 0.60 90 (3.0) 0.62
Pemphigoid‡‡ 5 (0.2) 0.03 0 (0.0) 0.00
Treated set without duplicates, except serious hypersensitivity and serious arthralgia related AEs (treated set: linagliptin, n=3023; glimepiride, n=3010);
AEs occurring between first study drug intake until 7 days after last permanent study drug stop; MedDRA version used for reporting: 21.0
*narrow SMQ Hypersensitivity; †narrow SMQ Angioedema; ‡percentages based on 2216 and 2195 participants in the linagliptin and glimepiride groups, respectively,
with ACE inhibitor/ARB use at baseline; §narrow sub−SMQs Hepatitis, non−infectious, Hepatic failure, fibrosis and cirrhosis and other liver damage-related
conditions, liver related investigations, signs and symptoms and Cholestasis and jaundice of hepatic origin; ¶narrow SMQ Acute renal failure; **narrow SMQ Severe
cutaneous adverse reactions; ††high-level group term Joint disorder; ‡‡preferred term. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor 8
3
blocker; SMQ, Standardised MedDRA Query. Rosenstock J et al. ADA 2019
Safety topic of interest: Pancreatitis

Rate/100 Rate/100
n (%) n (%)
Investigator-reported*
Acute pancreatitis 24 (0.8) 0.13 21 (0.7) 0.12
Chronic pancreatitis† 7 (0.2) 0.04 2 (0.1) 0.01
Adjudicated
Acute pancreatitis 15 (0.5) 0.08 16 (0.5)‡ 0.09
Chronic pancreatitis 3 (0.1) 0.02 0 (0.0) 0.00
Treated set; AEs occurring between first study drug intake until study end; MedDRA version used for reporting: 21.0
*Treated set without duplicates for investigator-reported events (linagliptin: n=3014; glimepiride: n=3000)
†
Preferred term Pancreatitis chronic
‡
One patient with adjudicated acute pancreatitis with fatal outcome
4
Safety topic of interest: Malignancies

Rate/100 Rate/100
n (%) n (%)
All malignancies* 280 (9.3) 1.59 303 (10.1) 1.74
Specific malignancies†
Pancreatic cancer‡ 16 (0.5) 0.09 24 (0.8) 0.14
Prostate cancer 32 (1.1) 0.18 37 (1.2) 0.20
Colorectal cancer 32 (1.1) 0.18 30 (1.0) 0.17
Breast cancer 19 (0.6) 0.10 18 (0.6) 0.10
Bladder cancer 8 (0.3) 0.04 18 (0.6) 0.10
Gastric cancer 9 (0.3) 0.05 5 (0.2) 0.03
Thyroid cancer 1 (0.0) 0.01 3 (0.1) 0.02
Treated set (AEs occurring between first study drug intake until study end)
*Broad BIcMQ Malignancy (defined by narrow sub−SMQ Malignant tumors and sub−SMQ tumors of unspecified malignancy); †Selected high-level terms from
MedDRA version 21.0 (not a comprehensive list of all high-level terms occurring under broad BIcMQ Malignancy in CAROLINA®); ‡adjudication-confirmed
pancreatic malignancy. BIcMQ, BI-customised MedDRA query; SMQ, Standardised MedDRA Query Rosenstock J et al. ADA 2019 8
5
• Renal safety
Time to first occurrence of key secondary outcome: sustained ESKD, sustained
decrease of ≥40% in eGFR from baseline, or death due to kidney disease
The kidney safety profile of linagliptin was confirmed
30 HR 1.04 Placebo Linagliptin Rate:

(95% CI 0.89, 1.22) 4.66/100 PY

p=0.62*
20 306 patients
327 patients
Rate:
10
4.89/100 PY
0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
No. at risk Years
Placebo 3485 3213 2995 2298 1608 1005 496 103
Linagliptin 3494 3227 3018 2345 1675 1040 518 109
Treated set, Kaplan–Meier estimate. HR based on Cox regression analyses in patients treated with ≥1 dose of study drug, with treatment and region as factors. *Two-sided
eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; PY, patient-years
Rosenstock J et al. JAMA 2018; doi: 10.1001/jama.2018.18269 8
7
Linagliptin was associated with a significant reduction in
albuminuria progression
Time to first occurrence of albuminuria progression*
80
HR 0.86 Placebo Linagliptin

(95% CI 0.78, 0.95) 819 patients
60 763
p=0.0034†
patients
40
20
0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Placebo (n) 2,129 1,972 1,434 1,139 667 430 200 35
Linagliptin (n) 2,162 2,004 1,554 1,263 756 487 213 39
(This data is exploratory)
Linagliptin event rate 21.36/100 PY Placebo event rate 2.4.54/100 PY
Treated set, Kaplan-Meier estimate. Hazard ratio and 95% CI based on Cox regression model with terms for treatment group (p=0.0034) and region
(p<0.0001)
*change from normo- to micro- or macroalbuminuria, or from micro- to macroalbuminuria; †two-sided
Boehringer Ingelheim. Data on file. 2018
Key result 2: No increased risk of kidney events with linagliptin in Asian
participants, consistent with overall trial population
Linagliptin Placebo
p-value for treatment
HR (95% CI) HR (95% CI)
n with event / N analysed (%) by region interaction
Death due to renal failure, progression to ESKD, or sustained decrease of ≥40% in eGFR 0.8215
Overall 327/3494 (9.4) 306/3485 (8.8) 1.04 (0.89–1.22)
Asian 29/272 (10.7) 31/283 (11.0) 0.96 (0.58–1.59)
Death due to renal failure or progression to ESKD 0.7487
Overall 136/3494 (3.9) 154/3485 (4.4) 0.87 (0.69–1.10)
Asian 8/272 (2.9) 14/283 (4.9) 0.58 (0.24–1.39)
Death due to renal failure, progression to ESKD, or eGFR <10 ml/min/1.73 m 2 0.6150
Overall 149/3494 (4.3) 172/3485 (4.9) 0.84 (0.67–1.05)
Asian 9/272 (3.3) 18/283 (6.4) 0.52 (0.24–1.17)
Doubling of serum creatinine with eGFR <60 ml/min/1.73 m 2 0.1922
Overall 155/3494 (4.4) 153/3485 (4.4) 0.97 (0.78–1.21)
Asian 10/272 (3.7) 20/283 (7.1) 0.51 (0.24–1.10)
Albuminuria progression* 0.1685
Overall 763/2162 (35.3) 819/2129 (38.5) 0.86 (0.78–0.95)
Asian 55/137 (40.1) 63/149 (42.3) 0.95 (0.66–1.36)
Composite microvascular endpoint† 0.1706
Overall 785/2160 (36.3) 843/2129 (39.6) 0.86 (0.78–0.95)
Asian 57/137 (41.6) 64/149 (43.0) 0.94 (0.66–1.34)
Composite ocular endpoint‡ 0.7901
Overall 36/3489 (1.0) 49/3484 (1.4) 0.73 (0.47–1.12)
Asian 3/272 (1.1) 7/283 (2.5) 0.43 (0.11–1.68)
*Change from normoalbuminuria (UACR <30 mg/g) to microalbuminuria (UACR 30–300 mg/g) or macroalbuminuria (UACR >300
mg/g), or from microalbuminuria to macroalbuminuria; †Death due to renal failure, sustained ESKD, sustained decrease of ≥50% in 0.25 2.5
eGFR, albuminuria progression, use of retinal photocoagulation or intravitreal injections of an anti-VEGF therapy for diabetic
retinopathy, vitreous haemorrhage, or diabetes-related blindness; ‡Retinal laser coagulation therapy or intravitreal injection(s) of an
anti-VEGF therapy for diabetic retinopathy, vitreous haemorrhage, or diabetes-related blindness. eGFR, estimated glomerular
filtration rate; ESKD, end-stage kidney disease; UACR, urinary albumin-to-creatinine ratio; VEGF, vascular endothelial growth factor
Source: Inagaki N et al. Diabetol Int 2019; Oct 22. doi: 10.1007/s13340-019-00412-x [Epub ahead of print]
CAROLINA® and CARMELINA® provide evidence across
a broad spectrum of T2D disease duration, CV and kidney risk
Median T2D Mean T2D
CAROLINA®1 duration duration CARMELINA®2
6.3 years 14.75 years
83% 42% Had On insulin 58% 74% Prevalent

On metformin
established CV kidney disease
disease
0% 37% Displayed ≥2 On metformin 55% 57% Had established

On insulin
defined CV risk CV disease
factors
Treatment 9% 40% Had T2D for Treatment naïve <3% 33% Had established
naïve ≤5 years CV disease and
Active- Placebo- prevalent kidney
comparator controlled disease
Target-organ damage
Early Advanced
Chronic kidney disease
disease disease
Atherosclerosis
Risk Asymptomatic Symptomatic

CVD, cardiovascular disease; HbA1c, glycated haemoglobin
Rosenstock J et al. JAMA 2019;321:69 9
0
Clinical evidence from CVOTs in the
DPP-4 inhibitor class
Increasing comorbidities and disease burden
Monotherapy + MET + MET + SU MRF CVD HHF CKD
  
* Proven CV safety up
Saxagliptin 1,2 Proven safety Proven safety Safety signal to severe RI
  
†
Proven CV safety up
Alogliptin 3,4 No CVOT data§ Proven safety Uncertain‡ to severe RI
Sitagliptin5–7
   No CVOT data§ Proven safety Proven safety
Proven CV safety up
to moderate RI
Linagliptin8,10-11
   Proven safety Proven safety Proven safety
Proven CV/Renal
safety up to severe RI
  
*
Vildagliptin 9 No CVOT data§ No CVOT data§ No CVOT data§ No CVOT data§
*Not studied in combination with metformin and thiazolidinedione(s); †Not studied in combination with metformin and sulphonylurea(s); ‡Numerical, non-significant increase in hospitalisation for heart
failure; §No CVOT has been conducted CV, cardiovascular; CVOT, cardiovascular outcomes trial; DPP-4, dipeptidyl peptidase-4
1. Scirica B et al. N Engl J Med 2013;369:1317; 2. AstraZeneca. Onglyza® (saxagliptin) summary of product characteristics. 2017; 3. White W et al. N Engl J Med 2013;369:1327; 4. Takeda. Vipidia®
(alogliptin) summary of product characteristics. 2015; 5. Green J et al. N Engl J Med 2015;373:232; 6. Engel SE et al. Diabetes Obes Metab 2017;19:1587; 7. Merck. Januvia® (sitagliptin) summary of
product characteristics. 2016; 8. Rosenstock J et al. JAMA 2018; doi: 10.1001/jama.2018.18269 ; 9. Novartis. Galvus® (vildagliptin) summary of product characteristics. 2016 10. Trajenta Local Product 9
Insert, 18 August 2017; 11. Rosenstock J.et al.JAMA 2019.doi:10.1001/jama.2019.13772 1
VIVIDD®: Vildagliptin in Ventricular Dysfunction Trial
Patients with T2D and NYHA Class I-III (LVEF < 0.40) were randomized to vildagliptin 50
mg bid (50 mg od if on SU)
McMurray et al JACC Heart Failure 2018

VIVIDD ® Timeline: Study and Publication

LV Function in VIVIDD ®

Implications of ↑ LVEDV

Summary of Benefits: Linagliptin
Safety, Efficacy and Simplicity of Linagliptin across a broad range of T2D patients:
• Linagliptin has proven efficacy in a single 5mg dose
• Linagliptin demonstrated long-term CV and Kidney Safety:
 In CARMELINA®, linagliptin demonstrated a long-term CV safety profile in patients
with T2D, CV and/or kidney disease
 Linagliptin showed no increase in risk of hospitalization for heart failure, even in
patients at high‑risk of heart failure
 CARMELINA® established the long-term CV and kidney safety profile of linagliptin vs.
placebo and demonstrated no increased risk for HF, even in patients at very high HF
risk
 Linagliptin demonstrated a reassuring long-term kidney safety profile, with a reduction
in progression of albuminuria
Summary of Benefits: Linagliptin
 CAROLINA® confirmed the long-term CV safety profile of linagliptin relative to
glimepiride in patients with early T2D and increased CV risk in the longest DPP-4i
CVOT to date
• At similar overall glycaemic levels, the risk of hypoglycaemia was significantly lower
with linagliptin compared with glimepiride
 CAROLINA® and CARMELINA® constitute a comprehensive CV outcomes trial
programme demonstrating the long-term safety profile of linagliptin in a broad range
of patients
• Linagliptin is simple to use
• Linagliptin can be used for a broad range of T2D patients
Linagliptin +
Metformin FDC
98
Metformin + DPP-4 inhibitors: Combinations of oral glucose lowering
agents with complementary mechanisms of action
DPP-4
Target site Action Metformin
inhibitors
• Metformin chiefly works by
Pancreatic β-cell
Enhances glucose-
dependent insulin secretion  reducing hepatic gluconeogenesis
due to mitochondrial inhibition1
Pancreatic α-cell
Suppresses glucagon
secretion  • Metformin stimulates GLP-1
Lowers hepatic glucose
production   • Metformin increases expression
of GLP-R2-4
Improves insulin resistance  • Metformin increases sensitivity to
GLP-1
Safety and
Low risk of hypoglycaemia   • Via PPARα dependent pathway
tolerability (independent AMPK)2
No additional weight gain  
Drucker DJ, Nauck MA. Lancet. 2006;368:1696–1705. 9

Del Prato S, et al. Int J Clin Pract. 2005; 59:1345–1355.
Inzucchi SE. JAMA. 2002;287:360–372.
9
DPP4 INHIBITION AND METFORMIN
· As initial therapy, combination is twice as likely to achieve HbA1c target than
with metformin alone1
· Additive effect on GLP-1 levels2
combined
Metformin
DPP4 inhibition
Placebo
Linagliptin + Metformin provides powerful HbA1c reductions for
high baseline metformin-uncontrolled patients
A d ju s t e d m e a n c h a n g e in H b A 1 C ( % )
Placebo-adjusted mean HbA1c change from baseline at 24 weeks*1
Metformin Linagliptin 2.5 mg BD +

1,000 mg BD metformin 1,000 mg BD
0
1.7%
-0.4 reduction
-0.8
-1.2
-1.6
-1.2
-2.0 -1.7
n 138 140
Mean baseline 8.5 8.7
HbA1c (%)
BD: Bi-daily.
* 24-week, double-blind, placebo-controlled, Phase III trial. Two arms received linagliptin 2.5 mg twice daily (BD) + either low (500 mg) or high (1,000 mg) dose metformin BD. Four arms received linagliptin 5 mg once daily, metformin 500 mg or
1,000 mg bid or placebo. Patients with HbA1c ≥11.0% were not eligible for randomisation and received open-label linagliptin + high-dose metformin. High baseline defined as HbA1c >8.5% to <11.0%.
1. Haak T, et al. Diabetes Obes Metab. 2012;14:565–74.
Linagliptin + Metformin provides powerful HbA1c reductions for newly diagnosed high
A d j u s t e d m e a n c h a n g e in H b A 1 C ( % )
baseline patients
Adjusted mean HbA1c change from baseline at 24 weeks*†1

Linagliptin 5 mg +
Linagliptin 5 mg metformin
0 2.8%
reduction
Treatment
-1.0 difference: -0.8%
p<0.0001
-2.0
-2.0
-3.0
-2.8
n 113 132
Mean
baseline 9.9 9.8
HbA1c (%)
* 24-week, randomised, double-blind, double-dummy, active-controlled, parallel-group trial. Patients were recently diagnosed (≤12 months) with uncontrolled type 2 diabetes, with no glucose-lowering therapy in the previous 12 weeks.
Patients received free-combination treatment with linagliptin 5 mg once daily and metformin twice daily (uptitrated to 2000 mg/day maximum) or linagliptin monotherapy.
† Adjusted mean change in glycated haemoglobin (HbA 1c) at week 24 in the per-protocol completers’ cohort (PPCC; observed cases).
1. Ross SA, et al. Diabetes Obes Metab 2015;17(2):136-144.
For high baseline patients Linagliptin + Metformin
provides up to 3.7% HbA1c reduction
Placebo-adjusted mean HbA1c change from baseline at 24 weeks*1
in H b A 1 C (% ) at 2 4 w eek s
A d ju sted m ean ch an ge
Open-label arm:
Linagliptin 2.5 mg BD + Linagliptin 2.5 mg + Linagliptin 2.5 mg BD +
metformin 500 mg BD metformin 1,000 mg BD metformin 1,000 mg BD
0 3.7%
reduction
in open-label arm
-1.0
-2.0
-1.3 -1.7
-3.0
-4.0
-3.7
n 137 140 66†

Mean baseline 8.7 8.7 11.8
HbA1c (%)
BD: Bi-daily.
* 24-week, double-blind, placebo-controlled, Phase III trial. Two arms received linagliptin 2.5 mg twice daily (BD) + either low (500 mg) or high (1,000 mg) dose
metformin BD. Four arms received linagliptin 5 mg once daily, metformin 500 mg or 1,000 mg BD or placebo. Patients with HbA1c ≥11.0% were not eligible for
randomisation and received open-label linagliptin + high-dose metformin.
High baseline defined as HbA1c >8.5% to <11.0%.
† 56 of the 66 patients randomised to open label treatment of linagliptin 2.5 mg BD + metformin 1,000 mg BD completed treatment.
Open-label arm: patients with poor glycaemic control: mean; full analysis set, observed cases (n = 48).
1. Haak T, et al. Diabetes Obes Metab 2012;14:565–574.
Higher reduction in HbA1c for Asian patients
Adjusted mean HbA1c change from baseline in Asian patients*
Additional parallel group 2
A d ju s ted m ea n ch a n g e
Main group1
24 weeks 12 weeks
Linagliptin 2.5 mg BD + Linagliptin 2.5 mg + Linagliptin 2.5 mg BD +

metformin 1,000 mg FDC
in H b A 1 C ( % )
0
metformin 500 mg BD metformin 1,000 mg BD
BD 4.7%
reduction
in patients with
baseline
-1.0 HbA1c 12.1%
-2.0
-2.2 -2.3
-3.0
-4.0
-4.7
n 142 141 68
Mean baseline 8.7 8.7 12.1
HbA1c (%)
BD: Bi-daily.
1. Pan C, et al. Poster 1247-P, American Diabetes Association 75th Scientific Sessions, 5-9 June 2015, Boston, MA, USA.
2. Mu Y, et al. Poster 1218-P, American Diabetes Association 75th Scientific Sessions, 5-9 June 2015, Boston, MA, USA.
*24-week, double-blind, placebo-controlled, Phase III study in drug naïve Asian patients: Main group (Pan et al,2015) 1. Patients with HbA1c ≥7.5% to HbA1c ≥11.0 % were randomised to either linagliptin 5 mg QD,
metformin 500 mg BID, metformin 1,000 mg BID, linagliptin 2.5 + metformin 500 mg BID or linagliptin 2.5 mg + metformin 1,000 mg BID. Parallel group (Mu et al, 2015)2: Patients with HbA1c ≥11.0% were
randomised to linagliptin 2.5 mg + metformin 1,000 mg FDC BID or linagliptin 5 mg for 12 weeks. At week 12, patients receiving linagliptin 5 mg with HbA1c ≥8.0% were switched to the FDC group. FAS: All
randomised patients with a baseline HbA1c value, treated with HbA1c ≥1 dose of the study drug, and who have ≥1 on-treatment HbA1c value; LOCF model includes continuous baseline HbA1c and treatment group.
BD: Bi-daily; FDC: Fixed dose combination: LOCF: Last observation carried forward; FAS: Full analysis set
The unique characteristics of Linagliptin is NOT LOST
in Linagliptin + Metformin FDC
Clinical Advantages
+ Very low likelihood of drug-related off
High affinity target effect
High selectivity
+ Small tablets
Linagliptin Tight binding + Suitable for combination tablets
High potency + Large therapeutic window

+ No relevant drug–drug interactions with
Long duration of commonly used co-medications
action
+ Very forgiving pharmacology
Convenience of Fixed Dose Combination
• FDCs might be considered to simplify treatment regime,
especially for polymedicated patients
Prof. J. Wilding
• Treatment of T2D may require the use of multiple daily

medications
– Negative impact on patient adherence
– Growing interest in FDC’s that reduce pill burden; many FDC’s contain metformin
– Multiple studies on efficacy of FDC’s in diabetes
Haak T. Adv Ther. 2012;29(12):1005-15.

Mu Y, et al. Diabetes Res Clin Pract. 2017;124:48-56.
Haak T. Clin Med Insights Endocrinol Diabetes. 2015;8:1-6.
Ross SA, et al. Postgrad Med. 2016;128(8):747-54.
Scheen AJ. Expert Opin Drug Saf. 2013;12(2):275-89.
Linagliptin + Metformin FDC combines linagliptin and metformin
in a convenient, single small pill1*
500 mg
metformin
2.5 mg 2.5 mg850 mg

metformin 2.5 mg
linagliptin linagliptin linagliptin
1,000 mg
metformin
Available in multiple strengths

for dosing flexibility
Summary of Benefits: Linagliptin+Metformin FDC
• Linagliptin + Metformin FDC provides proven efficacy

better than monotherapy
• Contains Linagliptin which demonstrated long-term CV
and Kidney safety
• Simple and convenient titration
Linagliptin & Linagliptin+Metformin FDC
• Efficacious across many settings

• Safe, even in high risk patients
• Simple to use and combine
Simplicity is the
ultimate sophistication
Leonardo Da Vinci
110
Thank you for
Your Attention
Please Review Product Information before Prescribing
Boehringer Ingelheim (Philippines) Inc.

23rd Floor Citibank Tower
8741 Paseo de Roxas,
Salcedo Village, Makati City 1227
Additional Information available upon request Production date: December 2019
Email us: BI.SKIES.ph@boehringer-ingelheim.com RIN NO. SC-PH-00389

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Simplifying T2D

Stomach Slows gastric enteric-brain vagal

> 90% of secreted GLP-1 Amplify glucose-dependent

Low protein binding

Linagliptin High potency

Long duration of action

Limited renal clearance

Boehringer Ingelheim and Eli Lilly. Trajenta®(linagliptin) Prescribing Information. 2017

Highest potency of linagliptin in

BMI, body-mass index

BMI, body-mass index

Change from baseline HbA1c (%) by age at Week 24

Del Prato S et al. Nutr Metab Cardiovasc Dis 2016;26:886

BMI, body-mass index

0 -0.54 -0.61 -0.68

BMI, body-mass index

Standardised mean difference in HbA1c: meta-analysis on 301 clinical trials (N=118,094)

Monotherapy Add to metformin* Add to MET + SU†

BMI, body-mass index

Pooled analysis of three Phase III trials: 1† RCT2,3‡

BMI, body-mass index

Body Mass Index (kg/m2) HOMA-IR (mIU/L*mmol/L)

BMI, body-mass index

Monotherapy Add on to MET Add on to MET + SU Pooled

-0.8 p < 0.0001

Baseline HbA1c Baseline HbA1c

• Sheu WH, et al. AASD 2013. Oral 170.

BMI, body-mass index

-0.4 Between group Between group

-0.6 -0.52% -0.62%

Loh et al. Primary Care Diabetes (2015)

Saxagliptin ITCA 650 Exenatide N=17,160 Ertugliflozin

EXAMINE22 TECOS44 LEADER88 CARMELINA®12®12 CAROLINA®16,17

2013 2014 2015 2016 2017 2018 2019 2020

ELIXA33 CANVAS Program1111 HARMONY13 13 CREDENCE1919

Empagliflozin Semaglutide (inj) Dulaglutide

GLP-1 receptor agonist SGLT2 inhibitor DPP-4 inhibitor

N=6,979 LINAGLIPTIN 5 MG/DAY + STANDARD OF CARE*

Documented T2D diagnosis, on stable doses of glucose-lowering drugs

High risk of CV events

Macrovascular disease Impaired kidney function

CVD Cardiovascular disease 4

CKD, Chronic Kidney disease, eGFR, estimated GFR 4

• CV death • Sustained* eGFR decrease by

8.5 Mean difference (95% CI) throughout study:

–0.03 (0.02) Linagliptin

Hypoglycemia: rates per 100 patient-years overall

Time to first occurrence of 3P-MACE

(95% CI 0.89, 1.17)

Time to first occurrence of adjudication-confirmed hospitalization for HF

Linagliptin event rate 2.77/100 PY Placebo event rate 3.04/100 PY

HHF, hospitalization for heart failure 5

n with event/N analysed (%)

Trial Trial drug Placebo HR (95% CI) p-value

Insulin use World region Age ≥65

Treated set. 2-sided p value for HR (not p-value for interaction)

All patients 209/3,494 226/3,485

Treated set. 2-sided p value for HR 0.25 2.50

Treated set. 2-sided p value for HR

All patients 209/3,494 226/3,485

Treated set. 2-sided p value for HR 0.25 2.50

3-point MACE 0.3349

Non-CV death 0.4443