CARMELINA® is specifically designed to evaluate both

CV and kidney safety

Primary and secondary endpoints in recent CVOTs with DPP-4 inhibitors

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. Cardiovasc Diabetol 2018;17:39 1
 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 2
 CARMELINA® includes a population of patients frequently seen
in clinical practice

Rosenstock J et al. Cardiovasc Diabetol 2018;17:39 3

CARMELINA® showed a reassuring long-term kidney safety profile
with Linagliptin.

HR (95% CI) HR (95% CI) p-value

Prespecified adjudicated kidney composite
outcome
1-3
Other DPP-4i CVOTs Not studied ?
4
ESKD, renal death or ≥40% eGFR decrease 1.04 (0.89, 1.22) 0.6164

ESKD or renal death 0.87 (0.69, 1.10) 0.2371

†
Prespecified microvascular composite outcome 0.86 (0.78, 0.95) 0.0032

Albuminuria progression 0.86 (0.78, 0.95) 0.0034

0.5 1.0 2.0

Favours linagliptin Favours placebo

CV, cardiovascular; CVOT, cardiovascular outcomes trial; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease;
VEGF, vascular endothelial growth factor
†ESKD, renal death, ≥50% decrease in eGFR, albuminuria progression, use of retinal photocoagulation or intravitreal injections of an anti-VEGF therapy for diabetic retinopathy, or vitreous haemorrhage or
diabetes-related-blindness
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. Boehringer Ingelheim. Data on file. 2018 4
 DPP-4 inhibitor CVOTs: Baseline characteristics

SAVOR-TIMI 53*1 TECOS*2 CARMELINA3 CAROLINA4

Mean age, years 65.1 65.4 65.8 64.0

% with prior MI 38.0 42.7 26.5 -

% with prior HF 12.8 17.8 27 5

% with prior CVD 78.4 100 57 41.8

Diabetes
10.3 11.6 14.7 6.3
duration, y
HbA1c, % 8.0 7.2 7.9 7.15

Naive 4.1 Naive – Naive - Naive 9

Metformin 69.9 Metformin 81.0 Metformin 54.8 Metformin 83.2
T2D therapy, % SU 40.5 SU 45.6 SU 34.9 SU 28.4
TZD 6.2 TZD 2.7 TZD 1.3 TZD -
Insulin 41.6 Insulin 23.5 Insulin 59.9 Insulin 0

*Data are provided for the DPP-4 inhibitor treatment arm

1. Scirica BM et al. N Engl J Med 2013;369:1317; 2. Green JB et al. N Engl J Med 2015;373:232 (Supplementary data); 3. Rosenstock et al. Cardiovasc Diabetol (2018) 17:39; 4.
Diabetes & Vascular Disease Research 2015, Vol. 12(3) 164–174 5
 Saxagliptin, Alogliptin, Sitagliptin & Linagliptin shows a reassuring
cardiovascular safety profile vs placebo

Primary
DPP-4
Placebo
cardiovascular inhibitor HR (95% CI) HR (95% CI) p-value
outcome Patients with event (%)

SAVOR-TIMI 531
7.3 7.2 1.00 (0.89, 1.12) 0.99
(saxagliptin)

EXAMINE2
11.3 11.8 0.96 (n/a, 1.16) 0.32
(alogliptin)

TECOS3
11.4 11.6 0.98 (0.89, 1.08) 0.65
(sitagliptin)

CARMELINA®4
12.4 12.1 1.02 (0.89, 1.17) 0.74
(linagliptin)

0.5 1 2
Direct comparison of trials should be interpreted with caution due to differences in study design,
populations and methodology Favours DPP-4 inhibitor Favours placebo
DPP-4, dipeptidyl-peptidase 4
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
6
 Robust evidence of heart failure safety with Linagliptin

DPP-4
Hospitalisation Placebo
inhibitor HR (95% CI) HR (95% CI) p-value
for heart failure1,2
Patients with event (%)

SAVOR-TIMI 53
3.5 2.8 1.27 (1.07, 1.51) 0.007
(saxagliptin)

EXAMINE
3.1 2.9 1.19 (0.89, 1.59) 0.24
(alogliptin)

TECOS
3.1 3.1 1.00 (0.83, 1.20) 0.98
(sitagliptin)

CARMELINA®
6.0 6.5 0.90 (0.74, 1.08) 0.2635
(linagliptin)

0.5 1 2
Favours DPP-4 inhibitor Favours placebo
Direct comparison of trials should be interpreted with caution due to differences in study design, populations and methodology
DPP-4, dipeptidyl-peptidase 4 Rosenstock J et al. JAMA 2018; doi: 10.1001/jama.2018.18269
1. McGuire D et al, JAMA Cardiol 2016;1:126; 2. [PLACEHOLDER for manuscript]
CAROLINA Trial and Real World
Evidence; Understanding the
right clinical implications

Name of the speaker

 CAROLINA® evaluated the long-term CV safety of linagliptin vs. an active
comparator (glimepiride) in patients with early T2D at increased CV risk

CAROLINA® is the only DPP-4 inhibitor, active-comparator CV outcomes trial

to assess the CV safety profile of linagliptin versus glimepiride in patients with
early T2D at increased CV risk or established CV complications

CAROLINA® adds evidence to the long-term safety profile

of linagliptin in a broad range of patients, and provides insights
into the relative safety profiles of linagliptin and glimepiride

CV, cardiovascular; DPP-4, dipeptidyl peptidase-4; T2D, type 2 diabetes

Marx N et al. Diab Vasc Dis Res 2015;12:164 9
 CAROLINA® is an active-comparator CVOT

Patients with T2D were randomised to daily oral treatment with

linagliptin or glimepiride

N=6042

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) 10
 CAROLINA: Longest CVOT till date

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 randomized Last participant
Last participant completed
(6042) randomized

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, inter quartile range
Rosenstock J et al. ADA 2019 11
 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 established
On metformin 83% 42% CV disease

Displayed ≥2 defined
On insulin 0%* 37% CV risk factors

Treatment naïve 9% 40% Had T2D for ≤5 years

Receiving
standard of care
*Exclusion criteria for CV risk
CV, cardiovascular; T2D, type 2 diabetes
Rosenstock J et al. ADA 2019 12
 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
89%

80 Mean dose throughout study:

2.9±1.1 mg 66.3%
Patients (%)

60

40

20
4.6%
0
0 4 8 12 16 32 48 64 80 96 112 128 144 160 176 192 208 224 240 256 272 288 304 320 336 352

Uptitration Phase Weeks

Treated set without duplicates.
Rosenstock J et al. ADA 2019 13
 No difference in HbA1c levels in both arms- Linagliptin
demonstrated similar glycemic efficacy compared to glimepiride
MMRM analysis Linagliptin Glimepiride
Adjusted* mean (SE) change

0.2
from baseline in HbA1c (%)

0.1
BL 7.16
0.0
BL 7.15
-0.1
-0.2
-0.3
-0.4
-0.5
0 16 32 48 64 80 96 112 128 144 160 176 192 208 224 240 256
Weeks
Linagliptin (n) 3013 2924 2806 2719 2653 2593 2518 2467 2426 2393 2382 2333 2288 2247 2235 2190 2184
Glimepiride (n) 3000 2920 2808 2731 2668 2600 2541 2498 2467 2401 2361 2300 2271 2223 2196 2165 2146
Treated set without duplicates (observed cases - ALL). *Based on MMRM including treatment, week, week by treatment interaction, continuous baseline HbA1c
and baseline HbA1c by week interaction. BL, baseline; HbA1c, glycated haemoglobin; MMRM, mixed-model repeated measures.
Rosenstock J et al. ADA 2019 14
 Occurrence of any hypoglycaemic AE* was lower with linagliptin
versus glimepiride

50 Rate:
HR 0.23 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
No. of patients Years
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
AE, adverse event; PY, patient-years.
Rosenstock J et al. ADA 2019 15
 The incidence of hypoglycaemic events was consistently reduced 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
2.2 0.9
0.3 0.1
0
Any Moderate/severe* Severe* Hospitalisation due
to hypoglycaemia
TS_D+7 (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
Rosenstock J et al. ADA 2019 16
 Linagliptin was associated with reduced weight compared
with glimepiride
MMRM analysis Linagliptin Glimepiride
Weighted average mean difference up to Week 256: –1.5 kg (95% CI –1.8, –1.3)
1.0
change from baseline
Adjusted* mean (SE)

0.5
BL 83.6
in weight (kg)

0.0
BL 84.3
-0.5
-1.0
-1.5
-2.0
-2.5
0 16 32 48 64 80 96 112 128 144 160 176 192 208 224 240 256
Weeks
Linagliptin (n) 3014 2936 2822 2741 2674 2620 2546 2522 2466 2433 2426 2378 2326 2280 2280 2236 2221
Glimepiride (n) 2998 2931 2812 2738 2680 2619 2570 2532 2496 2432 2396 2339 2289 2255 2227 2191 2176
Treated set without duplicates (observed cases - ALL). *Based on MMRM including treatment, week, week by treatment interaction, continuous baseline weight
and baseline weight by week interaction. BL, baseline; MMRM, mixed-model repeated measures
Rosenstock J et al. ADA 2019 17
 Summary of key secondary metabolic efficacy endpoints
Linagliptin Glimepiride
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%

0.25 0.50 1.00 2.00 4.00

Favours glimepiride Favours linagliptin

*The proportion of participants that are on study treatment at study end, that at final visit maintain glycaemic control (glycated haemoglobin ≤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
Rosenstock J et al. ADA 2019 18
Cardiovascular outcomes:
CAROLINA
 Linagliptin was non-inferior to glimepiride for 3P-MACE, the primary
outcome

Rate:
16
HR 0.98 2.1/100 PY
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
No. of patients Years
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
Rosenstock J et al. ADA 2019 20
 Linagliptin did not have increased risk for the individual components
of MACE compared with glimepiride
Linagliptin Glimepiride p-value
HR (95% CI) HR (95% CI)
n with event / N analysed (%) (2-sided)

3P-MACE 356/3023 (11.8) 362/3010 (12.0) 0.98 (0.84, 1.14)* 0.7625

CV death 169/3023 (5.6) 168/3010 (5.6) 1.00 (0.81, 1.24) 0.9863
Non-fatal MI 145/3023 (4.8) 142/3010 (4.7) 1.01 (0.80, 1.28) 0.9060
Non-fatal stroke 91/3023 (3.0) 104/3010 (3.5) 0.87 (0.66, 1.15) 0.3352
4P-MACE 398/3023 (13.2) 401/3010 (13.3) 0.99 (0.86, 1.14)* 0.8668

0.25 0.50 1.00 2.00 4.00

Favours linagliptin Favours glimepiride

*95.47 CI. Treated set; hazard ratio and CI based on Cox regression model
3P-MACE, 3-point MACE; 4P-MACE, 4-point MACE; CV, cardiovascular; HUA, hospitalisation for unstable angina;
MACE, major adverse CV events; MI, myocardial infarction; PY, patient years
Rosenstock J et al. ADA 2019 21
 Linagliptin did not increase the risk for all-cause mortality compared
with glimepiride, although the curves separated at ~5 years

Rate:
1.8/100 PY
14 HR 0.91 Linagliptin Glimepiride
336 patients
12 (95% CI 0.78, 1.06)
308 patients
p=0.2263
Patients (%)

10
Rate:
8 1.7/100 PY

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
No. of patients Years
Linagliptin (n) 3023 3009 2991 2976 2951 2934 2908 2873 2838 2808 2780 2706 2045 1164 236
Glimepiride (n) 3010 2999 2982 2955 2937 2916 2885 2857 2823 2797 2751 2656 2068 1144 237

Treated set; Kaplan-Meier estimate; hazard ratio and 95% CI derived from Cox regression with factor treatment; 2-sided p value; PY, patient years
Rosenstock J et al. ADA 2019 22
Clinical implications of CAROLINA
 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

Had established On insulin Prevalent kidney

On metformin 83% 42% CV disease
58% 74% disease

Displayed ≥2 Had established

On insulin 0% 37% defined CV risk
On metformin 55% 57% 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

CV, cardiovascular; T2D, type 2 diabetes

1. Rosenstock J et al. ADA 2019; 2. Rosenstock J et al. JAMA 2019;321:69 24
 Together, CARMELINA® and CAROLINA® demonstrate the long-term CV
safety profile of linagliptin
CARMELINA® Linagliptin, n/N (%) Placebo, n/N (%) HR (95% CI) p-value

3P-MACE 434/3494 (12.4) 420/3485 (12.1) 1.02 (0.89, 1.17) 0.7398

HHF or CV death 406/3494 (11.6) 422/3485 (12.1) 0.94 (0.82, 1.08) 0.3881

All-cause mortality 367/3494 (10.5) 373/3485 (10.7) 0.98 (0.84, 1.13) 0.7402

CAROLINA® Linagliptin, n/N (%) Glimepiride, n/N (%) HR (95% CI) p-value

3P-MACE 356/3023 (11.8) 362/3010 (12.0) 0.98 (0.84, 1.14)* 0.7625

HHF or CV death 236/3023 (7.8) 234/3010 (7.8) 1.00 (0.84, 1.20) 0.9671

All-cause mortality 308/3023 (10.2) 336/3010 (11.2) 0.91 (0.78, 1.06) 0.2263

*95.47 CI. 3P-MACE, 3-point MACE; 4P-MACE, 4-point MACE; CV, cardiovascular; HF, heart failure;
HHF, hospitalisation for HF; MACE, major adverse CV events; MI, myocardial infarction
Rosenstock J et al. JAMA 2019;321:69; Rosenstock J et al. ADA 2019 25
 CARMELINA® and CAROLINA® constitute a unique and comprehensive
CVOT programme demonstrating linagliptin’s long-term safety profile
CARMELINA®1 A robust CVOT programme demonstrating
N=6979 the LONG-TERM SAFETY OF LINAGLIPTIN
PLACEBO controlled in two independent CVOTs
Patients with established
CVD and/or CKD
2.2 years duration

CAROLINA®2
N=6033
Unique ACTIVE comparator
(glimepiride)
Patients with early T2D at
increased CV risk for a BROAD RANGE of T2D patients
6.3 years duration
CKD, chronic kidney disease; CV, cardiovascular; CVD, CV disease; CVOT, CV outcomes trial; HbA1c, glycated haemoglobin; T2D, type 2 diabetes
1. Rosenstock J et al. Cardiovasc Diabetol 2018;17:39; 2. Marx N et al. Diab Vasc Dis Res 2015;12:164 26
Questions from an expert’s perspective

• We documented markedly reduced rates of hypoglycemia with linagliptin

compared with glimepiride: Should we care?

• Weight gain differences: Are they important?

• Durability of glycemic control: Are there real differences?

 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
hypoglycemia 1-7
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 SE et al. Br J
Clin Pharmacol 2016;82:1291; 7. Canadian Clinical Practice Guidelines 2018, Chapter 14. Hypoglycaemia. 28
 Hypoglycemia is indeed a real concern for people with T2D

Why?

• Falls1

• Need for hospitalization or care2

• Costs3

• Fear of hypoglycemia4

• Quality of life5

• Uncertainty about CV risk

CV, cardiovascular; T2D, type 2 diabetes

1. Lu CL et al. Medicine (Baltimore) 2015;94:e13392; 2. Budnitz DS et al. N Engl J Med 2011;365:2002; 3. Wong C et al. Diabetes Obes Metab 2019;21:1330;
4. Hajos T et al. Diabetes Care 2014;37:102; 5. International Hypoglycemia Study Group. Lancet Diabetes Endocrinol 2019;7;385
 Sulfonylurea use is associated with increased hospitalization

Percentage of emergency hospitalizations Readmission rates after initial hospitalization2

for drug-related AEs in elderly adults*
in the US caused by OADs1
23.2% 16.1%

10.7%

SU monotherapy VS. Other oral AHA monotherapy

From 1999-2010, the estimated hazard ratio for risk of

hospital readmission was 1.29 (95% CI 1.01, 1.65; p=0.04)
for SU monotherapy2

*2007–2009 data in 5077 participants ≥65 years of age, independent of diabetes status
AE, adverse event; AHA, anti-hyperglycemic agent; CI, confidence interval; OAD, oral anti-diabetes drug
1. Budnitz DS et al. N Engl J Med 2011;365:2002; 2. Heaton PC et al. BMC Endocr Disord 2016;16:4
 Number needed to treat to prevent 1 hypoglycaemic event over 6 years

NNT 3 4 45 99
Any Moderate/severe* Severe* Hospitalisation due
to hypoglycaemia
40 37.7

30.9
30
Patients (%)

Linagliptin
Glimepiride
20

10.6
10 6.5
2.2 0.9
0.3 0.1
0 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

TS_D+7 (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
NNT, number needed to treat. PY, patient years. Data on file 31
 Number needed to harm to cause 1 hypoglycaemic event over 6 years

NNH

1 in 4 patients treated with Glimepiride will suffer

from moderate or severe hypoglycemia

TS_D+7 (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 32
NNh, number needed to harm. PY, patient years. Data on file
 Body weight is also an important patient-centric consideration

Linagliptin Glimepiride
Weighted average between-group difference of –1.5 kg (95% CI –1.8, –1.3)
from baseline in weight (kg)
Adjusted mean (SE) change

1.0
0.5
BL 83.6
0.0
BL 84.3
-0.5
-1.0
-1.5 -1.5kg
-2.0
-2.5
0 16 32 48 64 80 96 112 128 144 160 176 192 208 224 240 256
Weeks

Rosenstock J et al. ADA 2019 33

 Comparable long term efficacy of Linagliptin and Glimepiride (Better
durability with linagliptin)
MMRM analysis Linagliptin Glimepiride
Adjusted* mean (SE) change

0.2
from baseline in HbA1c (%)

Weighted average of the treatment difference in adjusted means until Week 256:
0.00% (95% CI –0.05%, 0.05%)
0.1
BL 7.16
0.0
BL 7.15
-0.1
-0.2
-0.3
-0.4
-0.5
0 16 32 48 64 80 96 112 128 144 160 176 192 208 224 240 256
Weeks
Linagliptin (n) 3013 2924 2806 2719 2653 2593 2518 2467 2426 2393 2382 2333 2288 2247 2235 2190 2184
Glimepiride (n) 3000 2920 2808 2731 2668 2600 2541 2498 2467 2401 2361 2300 2271 2223 2196 2165 2146

Treated set without duplicate participants

*Based on MMRM including treatment, week repeated within participants, week by treatment interaction, continuous baseline HbA1c and baseline HbA1c by week
interaction. BL, baseline; HbA1c, glycated hemoglobin; MMRM, mixed-model repeated measures
 Overall conclusions and implications

• Linagliptin was superior to glimepiride in the context of hypoglycemia

• Over a third of glimepiride-treated patients had hypoglycemia, which was greatly

reduced by linagliptin despite similar HbA1c reductions

• Linagliptin was associated with a modestly greater mean weight loss relative
to glimepiride

• Other than cost considerations, CAROLINA supports the use of a DPP-4 inhibitor
(linagliptin) before sulfonylureas (glimepiride)

DPP-4, dipeptidyl peptidase-4; HbA1c, glycated hemoglobin

 Bridging the gap between a
controlled environment setting and
routine clinical practice
Rationale

• The use of antidiabetic agents(including SUs &

Linagliptin) in routine care settings outside a highly
controlled research environment may differ, however, with
respect to patient characteristics and adherence patterns.
Real world • Large healthcare database studies containing longitudinal
Evidence recordings of routine clinical practice of tens of thousands
of patients

• RWE represent an important complementary tool to

compare and contrast effectiveness and safety findings
with results from clinical trials.
*Measure of an intervention under real-world conditions
CV, cardiovascular; HHF, hospitalisation for heart failure; T2D, type 2 diabetes; SU: Sulphonylureas; RWE: Real world evidence
ClinicalTrials.gov. NCT03363464 (accessed Jul 2018) 37
 Objectives

• To assess the comparative CV safety of

Linagliptin versus DPP-4i, TZD, and SUs in
patients with T2D
• 5 years of Linagliptin use: 2011−2016
• Over 150,000 patients included in the study 2 large USA databases
completion
– 19,731 Linagliptin : 19,371 Sulphonylureas
– 23,316 Linagliptin: 23,316 Pioglitazone
– 31,492 Linagliptin: 31,492 Other DPP-4i

Academic collaboration between Brigham and Women's Hospital/ Harvard

Medical School and Boehringer Ingelheim
38
Patorno E et al. Diabetes Obes Metab.2019;1-13
 Largest possible combination of databases in the US

Optum MarketScan

150 million patient

65 million patient lives
lives

Patorno E et al. Diabetes Obes Metab.2019;1-13

39
Robust Study design

1 Patients with T2D Patients with T2D in routine clinical care were enrolled.

Makes patients more similar. Reduces confounding by use of

2 New users design
new-user comparative cohorts. Minimises the potential for bias
Represent common therapeutic strategies used at comparable
DPP-4i, TZD, & SU stages of diabetes progression. Improves clinical equipoise
3
comparator across treatment groups, reduced confounding.

Reduces confounding by improving comparisons between

1:1 propensity score (PS)
4 patients matched by measured baseline variables to achieve
matching (>100 covariates) similar characteristics.

5 As-treated analyses As-treated analyses aim to avoid bias due to non-adherence

CV, cardiovascular; DPP-4i, dipeptidyl peptidase-4 inhibitor; T2D, type 2 diabetes

Patorno E et al. Diabetes Obes Metab.2019;1-13 40

Eligibility criteria

Key inclusion criteria1

• Adults aged ≥18 years
• Initiation* of any comparator or Linagliptin between May 2011 and December 2016
• Patients with T2D (defined as an outpatient or inpatient diagnosis)

Key exclusion criteria1,2

• Use of either Linagliptin or any comparator class in the 6 months preceding cohort
entry (switchers).
• Diagnosis of T1D, h/o secondary or gestational diabetes, malignancy, ESRD, HIV
• Patients with nursing home admission 6 months prior to drug initiation
Further criteria also apply

*No use of DPP-4i in the previous 12 months

DPP-4i, dipeptidyl peptidase-4 inhibitor; ; T2D, type 2 diabetes;T1D: Type 1 Diabetes; ESRD: End-stage renal disease, HIV: Human Immunodeficiency Virus
41
Patorno E et al. Diabetes Obes Metab.2019;1-13
 This RWE will provide a comprehensive picture of CV
safety of Linagliptin in routine clinical practice
Primary outcome was defined as a composite CV outcome comprising:

Hospitalization for
Hospitalization for Hospitalization for
Unstable Angina or
Acute myocardial Ischaemic or
Coronary
infarction Haemorrhagic stroke
Revascularization

Secondary outcomes included the individual components of the primary CV composite outcomes.

42
Patorno E et al. Diabetes Obes Metab.2019;1-13
 Well Matched Baseline characteristics
Linagliptin Sulphonylureas Standardised
(n=19,731) (n=19,731) differences
Age, years, mean (SD) 54.65 (11.65) 54.63 (11.67) 0.00
Female 8,162 (41.4%) 8,123 (41.2%) 0.00
Coronary Atherosclerosis 1662 (8.4%) 1657 (8.4%) 0.00
Old MI 157 (0.8%) 156 (0.8%) 0.00
Haemorrhagic stroke 145 (0.7%) 146 (0.7%) 0.00
Coronary procedure (CABG or PTCA) 407 (2.1%) 405 (2.1%) 0.00
Unstable Angina 175 (5.3%) 162 (5.2%) 0.00
HF 879 (0.9%) 868 (0.9%) 0.00
Hypertension 7484 (37.9%) 7457 (37.8%) 0.00
Hyperlipidemia* 6479 (32.8%) 6502 (32.9%) 0.00
Renal dysfunction 2088 (10.6%) 2071 (10.5%) 0.00

Data are n (%) unless otherwise stated; *CVD defined as history of MI, unstable angina, coronary atherosclerosis and other forms of chronic ischemic heart disease,
coronary procedure, HF, ischemic or hemorrhagic stroke, TIA, PAD or surgery, lower extremity amputation;
CKD, chronic kidney disease; CVD, cardiovascular disease; DPP-4i, dipeptidyl peptidase-4 inhibitor; MI, myocardial infarction, HF, heart failure; TIA, transient
ischaemic attack; 44
Patorno E et al. Diabetes Obes Metab.2019;1-13
 Well Matched Baseline characteristics
Linagliptin Sulphonylureas Standardised
(n=19,731) (n=19,731) differences
Antihypertensive therapy
Loop diuretics 1382 (7.0%) 1340 (6.8%) 0.00
ACE inhibitors/ARBs 12,214 (61.0%) 12,198 (61.0%) 0.00
Beta-blockers 4695 (23.8%) 4608 (23.4%) 0.00
Lipid lowering therapy
Statins* 10,478 (53.1%) 10,481 (53.1%) 0.00
Glucose-lowering therapy
Metformin 10,606 (53.8%) 10,687 (54.2%) 0.00
Thiazolidinediones 1052 (5.3%) 1037 (5.3%) 0.00
GLP-1 RAs 336 (1.7%) 327 (1.7%) 0.00
Insulin 1700 (8.6%) 1639 (8.3%) 0.00

Data are all n (%). ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; GLP-1 RA, glucagon-like peptide-1 receptor agonist 45
Patorno E et al. Diabetes Obes Metab.2019;1-13
 Patients are reflective of those seen in routine practice

55 20% 10% 9%
*

Mean age of patients Patients aged > 65 Patients with CV Insulin use at
at baseline (in years) years disease baseline

46
Patorno E et al. Diabetes Obes Metab.2019;1-13
 Linagliptin was associated with a 23% reduced risk of
composite CV outcome vs SU

HR 0.77 23%
(95%CI 0.66-0.90) RRR

47
Patorno E et al. Diabetes Obes Metab.2019;1-13, Patorno et al ADA 2019
 Consistent CV risk reduction with Linagliptin vs SU

48
Patorno E et al. Diabetes Obes Metab.2019;1-13
 Linagliptin shows lower risk on individual CV outcomes
compared with SUs
Linagliptin Sulphonlyureas
Rate/ Rate/
Outcome n event 1000 PY n event 1000 PY HR (95% CI)
0.76
Composite CV outcome 213 14.58 286 18.74
(0.64, 0.92)
Myocardial Infarction 0.79
87 5.93 115 7.48
(0.60, 1.04)
0.71
Stroke 59 4.01 87 5.65
(0.51, 0.98)
0.57
Unstable Angina 47 3.20 85 5.53
(0.40, 0.82)
Coronary 0.81
105 7.16 136 8.86
Revascularization (0.62, 1.04)

0.125 0.25 0.5 1 2

Favours Favours
Linagliptin Sulphonylureas
CVD, cardiovascular disease;
DPP-4i, dipeptidyl peptidase-4 inhibitor; HHF, hospitalisation for heart failure; PY, patient-years.
49
Patorno E et al. Diabetes Obes Metab.2019;1-13
 Linagliptin showed a favorable trend in CV safety vs other
DPP-4i

HR 0.90
(95%CI 0.80-1.02)

50
Patorno E et al. Diabetes Obes Metab.2019;1-13, Patorno et al ADA 2019
Strengths and limitations of Linagliptin RWE results
Strengths Limitations
• Provide insights into broader patient • Residual unmeasured confounding cannot be
population in routine clinical care excluded

• Provide insights into treatment decision • USA only databases included

between initiating DPP-4i or Sulphonylureas

• The design reduces confounding and the

potential for bias with evidence of solid
confounding control on variables assessed

51
Real-world evidence from
Asia

A population-based cohort study from

Korea
 Objectives

• To assess the risk of Heart Failure & cardiovascular

outcomes of DPP-4i versus SUs in patients with
T2D
• Primary outcome: Hospitalization for Heart Failure
• Secondary outcomes: Hospital admission for
MI, UA, stroke, PCI or CABG
• Over 500,000 patients included in the study
completion

Largest Korean database

covering >99% of the South
Korean population

MI: Myocardial Infarction, UA:Unstable Angina; PCI: Percutaneous Coronary Intervention; CABG: Coronary Artery Bypass Graft
Circ Heart Fail. 2017;10:e003957. 53
26% relative risk reduction in Hospitalization for Heart
Failure with Linagliptin compared to SUs

HR 0.74 26%
95% CI (0.59,0.92) RRR
P=0.007

54
Circ Heart Fail. 2017;10:e003957.
 Secondary outcomes: Linagliptin vs SUs
:
Hospitalization for Hospitalization for
Hospitalization for Hospitalization for
Ischaemic or Acute myocardial
Unstable Angina PCI
Haemorrhagic stroke infarction

HR 0.71 HR 0.62 HR 0.83 HR 0.86

95% CI (0.62,0.82) 95% CI (0.46,0.82) 95% CI (0.73,0.96) 95% CI (0.78,0.96)

29% 38% 17% 14%

RRR RRR RRR RRR

55
Circ Heart Fail. 2017;10:e003957.
Summary
• A well-designed non-interventional study excels in the ability to provide real-world
evidence on safety and effectiveness of treatments in routine clinical care settings,
thus complementing results from RCTs of interest
• Analyses from a large real-world study in routine care of patients with T2D,
showed that Linagliptin had a reduced CV risk compared to sulphonylureas
• Linagliptin showed protective effects on Heart Failure hospitalizations compared
with Sulphonylureas in routine clinical care
• Linagliptin also showed a relative risk reduction in hospitalizations for stroke,
acute myocardial infarction, unstable angina and percutaneous coronary
interventions as compared to Sulphonylureas in routine clinical practice.
• Findings were consistent in the real world evidence from United States as well as
Asia.
56
 Heart Failure outcomes in
regional and insulin subgroups

- Confidential - CARMELINA Working Introduction 23.07.18

 Time to first occurrence of hHF for North America
HR

Participants with event (%) 0.65

20 HR 0.65 Placebo Linagliptin
(95% CI 0.44, 0.97)
p=0.03*

10

0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
No. of participants Years
Placebo (n) 587 553 536 480 401 321 215 97
Linagliptin (n) 593 563 540 488 412 332 221 112
Treated set, Kaplan-Meier estimate. HR and 95% CI based on Cox regression model with terms for treatment group (p=0.0254),
hHF (p≤0.0001), region (p=0.0030), treatment group × region (p=0.0368).
hHF, hospitalization for HF.
*2-sided p-value.
Source: McGuire DK et al. Circulation 2018;139: Nov 11. doi: 10.1161/CIRCULATIONAHA.118.038352 [Epub ahead of print].
 Time to first occurrence of hHF for Asia HR

Participants with event (%)

0.47
20 HR 0.47 Placebo Linagliptin
(95% CI 0.24, 0.95)
p=0.04*

10

0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
No. of participants Years
Placebo (n) 283 270 264 201 149 110 66 23
Linagliptin (n) 272 266 260 192 150 109 77 25
Treated set, Kaplan-Meier estimate. HR and 95% CI based on Cox regression model with terms for treatment group (p=0.0254),
hHF (p≤0.0001), region (p=0.0030), treatment group × region (p=0.0368).
hHF, hospitalization for HF.
*2-sided p-value.
Source: McGuire DK et al. Circulation 2018;139: Nov 11. doi: 10.1161/CIRCULATIONAHA.118.038352 [Epub ahead of print].
 Time to first occurrence of hHF by no insulin use at
baseline HR

Participants with event (%) 0.62

20 HR 0.62 Placebo Linagliptin
(95% CI 0.42, 0.92)
p=0.02*

10

0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
No. of participants Years
Placebo (n) 1542 1485 1451 1170 850 554 324 100
Linagliptin (n) 1487 1448 1406 1155 860 592 363 110
Treated set, Kaplan-Meier estimate. HR and 95% CI based on Cox regression model with terms for treatment group (p=0.0386),
hHF (p≤0.0001), region (p=0.0031), insulin (p≤0.0001), treatment group × insulin (p=0.0360).
hHF, hospitalization for HF.
*2-sided p-value.
Source: McGuire DK et al. Circulation 2018;139: Nov 11. doi: 10.1161/CIRCULATIONAHA.118.038352 [Epub ahead of print].