Management of TYPE 2 DM

Overcoming The Challenges

Mesbah Sayed Kamel

MD

Trajenta (Linagliptin) has been Registered in Egypt

since June 2015

Disclosure

How an Ideal OADs therapy should be?

Factors for choice of OADs. Agents

Efficacy;

• ß-cell preservation, delay 2ry failure, consistent and sustained effect ..etc

Safety; • Risk of hypoglycemia

• Side effects

• Effect on body weight …etc)

Co morbidities;

• CV Safety & Impact

• Special populations e.g elderly, Hepatic & Renal impairment …etc

Patient preference;

• Convenience/Cost/Simplicity …etc

Strength Evidenced based & Guidelines recommendations

Healthy eating, weight control, increased physical activity & diabetes education

Metformin high low risk

neutral/loss

GI / lactic acidosis

low

If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione

intermediate low risk

neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

or

or

or

GLP-1-RA

high low risk

loss

GI

high

GLP-1 receptor agonist

Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate low risk

loss

GU, dehydration

high

SU

TZD

Insulin§

GLP-1 receptor agonist

+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:

Metformin +

Combination injectable therapy‡

GLP-1-RA Mealtime Insulin

Insulin (basal)

+

Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

DPP4 inhibitor: Mechanism of action

Source: Adapted from Drucker DJ. Exp Opin Invest Drugs. 2003;12:87–100;

Ahrén B. Curr Diab Rep. 2003;3:365–372.

Food intake

Glucose-dependent

insulin secretion

Increases glucose utilization

by muscle and adipose tissue

Decreases hepatic glucose release, improving overall

glucose control

Glucose-dependent

glucagon

suppression

β-cells

α-cells

DPP4

inhibitor

DPP4Active

GLP-1 (7–36)

Inactive

GLP-1 (9–36)

amide

2 amino acids

cleaved from

amino terminus

Intestine

Pancreas

DPP4 INHIBITORS :

A NOVEL APPROACH TO

OVERCOME CHALLENGES

Do all DPP4 inhibitors look similar…?

DPP4, dipeptidyl peptidase 4.

DPP4 inhibitors: Chemical structure

*Small protein-like chain designed to mimic a peptide.†Licensed in the US.

Source: Adapted from Deacon CF. Diabetes Obes Metab. 2011;13:7–18.

Saxagliptin

Sitagliptin

Vildagliptin

Peptidomimetic* DPP4 inhibitorsDPP4 inhibitors mimicking dipeptides

Linagliptin(xanthine-based structure)

Nonpeptidomimetic* DPP4 inhibitorsDPP4 inhibitors directly binding to active site of the

enzyme

Alogliptin†

N

NN

N N

N

N

NH2

O

O

N

NN

N

O

F

F

F

FF

F

NH2

NH2

O

HON

N

OH

N

H

N

ON

ON

NN

NN

O

Indicates peptide-like structure

• Linagliptin belongs to the small molecule class (MW: 473 Da) and is much smaller than the DPP4 enzyme (MW: 85,400 Da)

• Based on the chemical structure of linagliptin and the DPP4 enzyme, it fits perfectly to the active centre of the enzyme

Source: Adapted from Heise T, et al. Diabetes Obes Metab. 2009;11:786–794.

Steady-state

plasma levels

are already

reached after

the third dosing

interval with

linagliptin 5 mg

providing

> 91% of DPP-

4 inhibition at

peak levels

DPP-4 Inhibition (%), at steady-state on day 12 of treatment with linagliptin

Time after administration [h]

Steady-state linagliptin 5 mg

once daily, oral application

Tablet

linagliptin

5mg

Tablet

linagliptin

5 mg

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

Linagliptin provides long-lasting DPP-4

inhibition in patients with T2DM

The majority of linagliptin is excreted via the gut

*At steady state. Note that label statement describes single-dose analyses that don’t add up to 100% (a common effect for this type of analysis):

Following administration of an oral [14C]-linagliptin dose to healthy subjects, ~85% of the administered radioactivity is eliminated via the enterohepatic

system (80%) or urine (5%) within 4 days of dosing.

Source: Linagliptin US PI; Linagliptin EU SmPC.

~5% of orally

administered

linagliptin is

excreted via the

kidneys

~95% of orally

administered linagliptin

is excreted via the bile

and gut

Excretion* Metabolism

~90 %

transferred

unchanged

~10%

(inactive)

metabolite

No dose adjustment

in patients with

renal impairment

No dose adjustment in

patients with hepatic

impairment

Linagliptin is the only licensed DPP4 inhibitor primarily excreted

unchanged in bile via the gut

Linagliptin is the first DPP-4 inhibitor that is

primarily excreted by the biliary system

1. Including metabolites and unchanged drug; excretion after single dose administration of C14 labeled drug.

Source: US prescribing information linagliptin; Vincent SH, et al. Drug Metab Dispos. 2007;35:533538; He H, et al. Drug Metab Dispos.

2009;37:536544. US prescribing information saxagliptin. Christopher R, et al. Clin Ther. 2008;30:513527.

Share of renal excretion1, %

5

87

85

75

Alogliptin 6071

Saxagliptin

Vildagliptin

Sitagliptin

LinagliptinNo dose adjustment and/or

no additional drug

monitoring required

Dose-adjustment required

in patients with renal

impairment and/or drug-

related kidney monitoring

Russo E, et al. Diabetes Metab Syndr Obes. 2013; 6: 161–170.

*Per 100,000

http://www.worldlifeexpectancy.com/cau

se-of-death/kidney-disease/by-country/

accessed 2012 Oct.

Management of CKD in Diabetes

NICE Diabetes with Kidney Disease: Key Facts MARCH 2011

NICE Diabetes with Kidney Disease: Key Facts MARCH 2011

Russo E, et al. Diabetes Metab Syndr Obes. 2013; 6: 161–170.

SUs=sulfonylureas; T2DM=type 2 diabetes melllitus; *Requiring medical assistance or hospital admission

UK Prospective Diabetes Study Group. Diabetes.1995;44:1249–1258.

Cumulative Incidence of Hypoglycemia in T2DM over 6 Years in UKPDS

45

3.3

76

11.2

0

10

20

30

40

50

60

70

80

Sulfonylurea (n=922)

Insulin (n=689)

Sulfonylurea Insulin Sulfonylurea Insulin

Pati

en

ts (

%)

Any hypoglycema Major hypoglycemia*

HbA1c = 7.1% in all groups

70% increased risk

40% increased risk

National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes

and CKD: 2012 update. Am J Kidney Dis. 2012;60(5):850-886.

~7.0%

to prevent or delay

progression of the

microvascular

complications of

diabetes, including

DKD

Not

<7.0%

in patients at risk

of hypoglycemia.

>7.0%

In individuals with

co-morbidities or

limited life

expectancy and risk

of hypoglycemia

CKD: Chronic Kidney Disease.

Jindal A, et al. Endocrinol Metab Clin North Am. 2013 Dec;42(4):789-808

Better glycemic and blood pressure control

Older oral hypoglycemic agents is either contraindicated or requires dosage adjustment in CKD

New medications for diabetes have been approved recently and many can be used safely in patients with CKD

25 mg o.d. 12.5 mg o.d. 6.25 mg o.d.

Sitagliptin1

DPP-4 inhibitors

100 mg o.d. 50 mg o.d. 25 mg o.d.

Saxagliptin2

Alogliptin3

5 mg o.d.Linagliptin4

Vildagliptin5 50 mg o.d.50 mg b.i.d.

Creatinine

clearance (mL/min)

Serum creatinine

Male (mg/dL)

Serum creatinine

Female (mg/dL)

30

3.0

2.5

Mild RI Moderate RI Severe RI

50

1.7

1.5

1. Available at: http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf; 2. Available at: http://www1.astrazeneca-us.com/pi/pi_onglyza.pdf#page=1;

3. Available at: http://general.takedapharm.com/content/file.aspx?FileTypeCode=NESINAPI&cacheRandomizer=7236cffb-eb6c-4b0a-ac79-26810425c89e;

4. Available at: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Tradjenta/Tradjenta.pdf;

5. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000771/WC500020327.pdf

2.5 or 5 mg o.d. 2.5 mg o.d.

o.d. = once daily

b.i.d.= twice daily

Linagliptin is the only DPP-4 inhibitor with no need for dose adjustment even in patients with renal impairment

(RI)

ESRD, end-stage renal disease; HD, haemodialysis.

*Estimated creatinine clearance values were calculated using the Cockcroft–Gault formula; †90% confidence intervals not available; ‡Patient numbers,

90% CI and definitions of RI according to creatinine clearance not available for vildagliptin.

Source: Graefe-Mody U, et al. Diabetes Obes Metab. 2011;13:939–946.

2-fold increase in exposure

0

1

2

3

4

5

6

7

(n = 6) (n = 6) (n = 6) (n = 6) (n = 6)

>80 50 to ≤80 30 to ≤50 <30 <30 on HD

Renal impairment status

Creatinine

clearance*

(mL/min)

Fo

ld in

cre

ase i

n

exp

osu

re r

ela

tive t

o

no

rmal

ren

al

fun

cti

on

Linagliptin

ESRDSevereModerateMildNormal(n = 8) (n = 8) (n = 8) (n = 8) (n = 8)

>80 >50 to ≤80 >30 to ≤50 <30 on HD

Renal impairment status

Creatinine

clearance*

(mL/min)

Fo

ld in

cre

ase i

n

exp

osu

re r

ela

tive t

o

no

rmal re

nal

fun

cti

on

Saxagliptin

(5-hydroxy saxagliptin metabolite)†

ESRDSevereModerateMildNormal(n = 6) (n = 6) (n = 6) (n = 6) (n = 6)

>80 50 to ≤80 30 to ≤50 <30 on HD

Renal impairment status

Creatinine

clearance*

(mL/min)

Fo

ld in

cre

ase i

n

exp

osu

re r

ela

tive t

o

no

rmal

ren

al

fun

cti

on

Sitagliptin

ESRDSevereModerateMildNormal

Renal impairment status

Fo

ld in

cre

ase i

n

exp

osu

re r

ela

tive t

o

no

rmal re

nal

fun

cti

on

Vildagliptin

(LAY151 metabolite)‡

0

1

2

3

4

5

6

7

Normal SevereMild Moderate ESRD

No dosage adjustment required in

renal impairment

0

1

2

3

4

5

6

7

0

1

2

3

4

5

6

7

4. OTHER CONSIDERATIONS

• Age

• Weight

• Sex / racial / ethnic / genetic differences

• Comorbidities

- Coronary artery disease

- Heart Failure

- Chronic kidney disease

- Liver dysfunction

- Hypoglycemia-prone

ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015

Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596

Prevalence of Hepatitis C in Egypt

Linagliptin pharmacokinetics in hepatic

impairment

* Following Child–Pugh Classification.

† Application of six oral doses of 5-mg linagliptin at 24-h intervals.

‡ Not measured; value estimated from single dose by pharmacokinetic modelling.

Source: Graefe-Mody U, et al. Br J Clin Pharmacol. 2012;74:75–85.

Linagliptin exposure in patients with mild, moderate, and severe hepatic impairment,* mean AUC

Single

dose 5 mg

0

1

2

Fold increase in exposure relative to normal hepatic function

Healthy (n = 8)

1.00

Severe (n = 8)Moderate (n = 9)Mild (n = 7)

Hepatic impairment group

0

1

2

Fold increase in exposure relative to normal hepatic function

Healthy (n = 8)

1.00

Severe‡ (n = 8)Moderate (n = 9)Mild (n = 7)

Hepatic impairment group

No dose adjustment for

linagliptin is necessary for

patients with mild,

moderate or severe hepatic

impairmentSteady

state†

Linagliptin provides a unique set of pharmacological features

Source: Linagliptin US prescribing information; Scheen AJ, et al. Diabetes Obes Metab. 2010;12:648-658; Deacon CF. Diabetes Obes Metab.

2011;13:7–18; Vincent SH, et al. Drug Metab Dispos. 2007;35:533–538; He H, et al. Drug Metab Dispos. 2009;37:536–544; US

prescribing information saxagliptin; Christopher R, et al. Clin Ther. 2008;30:513–527.

Do

sin

g

an

d

mo

nit

ori

ng Dose

adjustment or limitations in RI3

Drug-related monitoring

Excre

tio

n Main route of excretion

Share of renal excretion2

Meta

bo

lism

Active metabolites

Relevant organ for metabolism1

1. If metabolized to a relevant degree.

2. Including metabolites and unchanged drug; excretion after single dose administration of C14 labelled drug.

3. As recommended in countries, where respective DPP-4 inhibitor is available.

Linagliptin

5 mg QD

Sitagliptin

100 mg QD

Vildagliptin

50 mg BID

Saxagliptin

5 mg QD

Alogliptin

25 mg QD

None None Liver Liver None

No No No Yes No

Bile & gut Kidney Kidney Kidney Kidney

5% 87% 85% 75% 60–71%

No Yes Yes Yes Yes

NoKidney

function

Kidney and

liver function

Kidney

function

Kidney

function

Characteristics of DPP-4 inhibitors in

Special Population

Renal Impairment* Hepatic Impairment

Inhibitor

Linagliptin

Sitagliptin Not recommended (EU)

½ dose (US)1

Not recommended (EU)

¼ dose (US)1 Not recommended1

Vildagliptin2 Not recommended1 Not recommended1 Not recommended Not recommended

Saxagliptin3

½ dose (EU)

½ dose (US)1

½ dose (use with

caution)not recommended in ESRD (EU)

½ dose (US)1

(Moderate: use with

caution)

Not recommended1

CrCl = Creatinine clearance; ESRD = end-stage renal disease

* Assessment of renal function recommended prior to initiation of treatment and periodically thereafter

1. Not studied/no clinical experience

2. Assessment of hepatic function recommended prior to initiation of vildagliptin and periodically thereafter

3. Dose reduction (2.5 mg) when saxagliptin co-administered with strong CYP450 3A4/5 inhibitors (e.g. ketoconazole)

Adapted from Deacon CF. Diabetes, Obes Metab. 2011;13(1):7–18.

DP

P-4

en

zym

e a

cti

vit

y [%

co

ntr

ol]

Sitagliptin

Linagliptin

Saxagliptin

Alogliptin

Vildagliptin

Highest potency

of linagliptin in

inhibiting DPP-4

enzyme activity

Log dose [M]

0

20

40

60

80

100

120

- 12 - 10 - 8 - 6

IC501 [nM]

mean

Linagliptin 1

Sitagliptin 19

Alogliptin 24

Saxagliptin 50

Vildagliptin 62

Linagliptin – highest potency to inhibit DPP-4 enzyme

activity in direct comparison to other DPP-4 inhibitors

1. Concentration of compound needed to inhibit 50% of DPP-4 activity, i.e., the lower the IC50, the higher the potency to inhibit

DPP-4 activity. Adapted from Thomas L, et al. J Pharmacol Exp Ther. 2008;325:175–182.

Selectivity for DPP-4 relative to DPP gene family (QPP/DPP-2, DPP-8 and DPP-9)2

QPP/DPP-2 DPP-8 DPP-9

Linagliptin > 100,000 40,000 > 10,000

Sitagliptin > 5,500 > 2,660 > 5,550

Vildagliptin > 100,000 270 32

Saxagliptin > 50,000 390 77

Alogliptin >14,000 >14,000 >14,000

Except for DPP-4, the function of the members of

the family, is to a large extent, still unclear

‘Off-target’ DPP inhibition (i.e., inhibition of DPP-8/-

9) has shown severe toxicity in preclinical studies3

Linagliptin has leading selectivity in class for DPP-4

compared with QPP1/DPP-2, DPP-8 and DPP-9

1. Quiescent cell proline dipeptidase.

2. Drucker DJ. Diabetes Care. 2007;30:1335–1343.

3. Demuth HU, et al. Biochim Biophys Acta. 2005;1751:33–44.

Modified from Deacon CF. Diabetes Obes Metab. 2011;13:7–18.

Vildagliptin

> 267

Sitagliptin

219

Saxagliptin*

~10.1

Linagliptin

0.35

Concentration of free circulating DPP4 inhibitorAverage daily concentration in nmol/l

Scherntharner, et al. Diabetes Obes Metab. 2012;14:470–478 .

A low free-drug concentration in conjunction with high selectivity for DPP4 favors the avoidance of off-target effects

Linagliptin has the lowest free drug concentration within the DPP-4 inhibitor class

*The calculated value for saxagliptin is conservative as its major active metabolite has 2- to 7-fold higher plasma

exposure than the parent compound

Linagliptin achieves HbA1c decrease up to -1.3%

in poorly controlled1 Type 2 diabetes patients

1. Poorly controlled = baseline HbA1c ≥ 9%; 2. FAS (LOCF);

3. Model includes continuous baseline HbA1c and treatment; 4. Versus placebo; 5. Full analysis set, last observation carried forward. .

Source: Del Prato S, et al. J Diabetes Complications. 2013;27:274–279

-0.37

0.18

-0.25

-0.56

-1.2

-0.86 -0.90

-1.30

-0.79

-1.04

-0.65-0.74

-1.5

-1.0

-0.5

0.0

0.5

Linagliptin placebo-correctedLinagliptinPlacebo

Add-on to

metformin

p = 0.00624

Linagliptin

monotherapy

p = 0.00054

Add-on to metformin

and sulphonylurea

p < 0.00014

Adjusted3

mean

change in

HbA1c (%)

from

baseline at

Week 24

Mean baseline

HbA1c, percent

9.5 9.49.59.59.4

n5 24 962955 13648

9.4

Significant HbA1c reduction in patients with baseline HbA1c ≥ 9%

Pooled data

p < 0.00014

9.4 9.4

101 287

-2.81

-2.02

-3

-2

-1

0

Lina (5 mg) + Met

(n = 132)Lina (5 mg)

(n = 113)

Change in HbA1c (%) from baseline at Week 24

BL, baseline; CI, confidence interval; FAS, full analysis set; HbA1c, glycosylated haemoglobin; Lina, linagliptin; LOCF, last observation carried forward; Met,

metformin; OC, observed cases; PPCC, per-protocol completers’ cohort; SE, standard error.

*ANCOVA model includes treatment as a fixed effect and baseline HbA1c as a linear covariate.

Source: Ross SA, et al. Diabetes Obes Metab. 2014; 8 Oct; DOI: 10.1111/dom.12399.

Hb

A1

c(%

) ch

ang

e f

rom

base

line

Ad

juste

d*

mea

n ±

SE

Treatment differences = -0.79

95% CI: -1.13, -0.46; p < 0.0001

PPCC (OC)

BL HbA1c, % 9.73 9.69

-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Treatment duration Weeks226 227 219 217 202 193 175234 167 15

7

15

3

n2

Change from baseline HbA1c

Mean over time ± SE, percentOpen-label

extension

Placebo-controlled

double-blind

6 12 18 24 30 42 540 66 78 90 10

214

4

HbA1c sustained over 102 weeks with linagliptin in combination with

pioglitazone1

.

1. Open-label extension of double-blind, randomized, controlled trial over 24 weeks. Patients randomized to linagliptin treatment for the first 24 weeks continued on linagliptin for an extension of 78 weeks. The analysis shown is restricted to this arm of the trial. Analysis of secondary endpoint in full analysis set, observed cases; 2. Full

analysis set, observed cases.

Source: Gomis R, et al. Int J Clin Pract. 2012;66:731–740.

–1.5% HbA1c

reduction at

102 weeks

HbA1c reductions were sustained over 102 weeks1

1. Open-label extension of four double-blind, randomized, controlled trials over 24 weeks. Patients randomized to linagliptin treatment for the first 24 weeks continued on linagliptin for an extension of 78 weeks. The analysis shown is restricted to this arm of the trial. Analysis of secondary endpoint in full analysis set,

observed cases. 2. Coefficient of durability (COD) is defined as HbA1c at Week 102 visit subtracted by HbA1c at Week 24 visit; 3. Full analysis set, observed cases.

Source: Gomis R, et al. Int J Clin Pract. 2012;66:731–740.

-1.2

-0.8

-0.4

0.0

6 12 18 24 30 42 54

Treatment duration Weeks

0 66 78 90 102

1490 1463 1440 1427 1310 1221 11151531 1031 952 896 853n3

Sustained efficacy as measured by coefficient of durability2 of 0.14% meaning no relevant increase in HbA1c from Week 24 to Week 102 (p < 0.0001)

Change from baseline HbA1c

Mean over time ± SE, percent; mean baseline HbA1c: 7.4%

Open-label extensionPlacebo-controlled

double-blind

–0.8% HbA1c

reduction at 102 weeks

Efficacy and sustainability of effect of linagliptin compared with glimepiride*

*2-year randomized study comparing linagliptin and glimepiride as add-on to metformin; similar reduction in HbA1c was observed in the glimepiride arm

(-0.6% HbA1c reduction at 104 weeks).†Model includes treatment, baseline HbA1c and number of prior oral glucose-lowering drugs.‡As described previously by Seck T, et al. Int J Clin Pract. 2010;64:562–576.

Source: Gallwitz B, et al. Lancet. 2012;380:475–483.

Completers cohort: linagliptin, n = 233; glimepiride, n = 271

Mean baseline HbA1c: linagliptin, 7.17%; glimepiride, 7.31%

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105

Mean (± SE) of HbA1c (%)

7.5

7.0

6.5

6.0

Treatment duration (weeks)

Completers cohort (CC) post-hoc analysis: All patients who completed the full 104 weeks on treatment in the FAS without important protocol violation who did not receive rescue medication and did achieve defined HbA1c goals as described previously.‡ All observed cases were included

-0.6

-0.6

HbA1c change over 2 years

Adjusted† mean over time ± SE (%)

Linagliptin Glimepiride

Significant relative weight loss and lower

incidence of hypoglycaemia with linagliptin

compared with glimepiride

1. Descriptive statistics; 2. Hypoglycaemic episode defined by a blood glucose ≤ 70 mg/dL; 3. Event requiring assistance of another

person to actively administer carbohydrate, glucagon or other resuscitative actions.

Source: Gallwitz B, et al. Lancet. 2012;380:475–483.

Mean1 change in body weight from baseline ± SE

Kg - FAS (LOCF)

Glimepiride

Linagliptin

0

10

20

30

40

50

LinagliptinGlimepiride

Patients with severe

hypoglycaemic episode3 (%

of patients with hypoglycaemia)

1 (2)12 (4)

Incidence of hypoglycaemia2

Percent of patients - Treated set

58 (7)280 (36)Number of patients with

hypoglycaemia (% of total)

776775 Number of patients

Significant relative weight loss with linagliptin as compared with

glimepiride (p < 0.0001)

Significantly lower incidence of hypoglycaemia with linagliptin as

compared to glimepiride (p < 0.0001)

-0.5

-1.0

-1.5

1.5

1.0

0.5

0

2.0

-2.0-2.7

12 28 104weeks

52 78

+1.4

-1.3

4.8x

lower

Linagliptin significantly improves β-cell function

1. All data given as placebo-corrected adjusted mean difference ± SE. Change from baseline at Week 24. FAS, observed cases; 2. Linagliptin n = 157 (baseline 66.9 mU/mmol), placebo n = 57 (baseline 62.3 mU/mmol);

3. Linagliptin n = 142 (baseline 0.20), placebo n = 47 (baseline 0.18); 4. Relative change with linagliptin (placebo corrected) compared with baseline. Source: Del Prato S, et al. Diabetes Obes Metab. 2011;13:258–267.

Linagliptin 5 mg improves β-cell function and the proinsulin:insulin ratio after 24 weeks1

Effect of linagliptin monotherapy

on HOMA-%B2

Effect of linagliptin monotherapy

on proinsulin:insulin ratio3

0

5

10

15

20

25

30

35

22.2

-0.06

-0.05

-0.04

-0.03

-0.02

-0.01

0.00

+0.01

-0.04

p < 0.05 p < 0.05

33% improvement of HOMA-

%B4

20% reduction of

proinsulin:insulin ratio4

Pla

ceb

o-c

orr

ecte

d a

dju

ste

d m

ean

ch

an

ge i

n p

roin

su

lin

:in

su

lin

rati

o

fro

m b

aseli

ne a

t W

eek 2

4

Pla

ceb

o-c

orr

ecte

d a

dju

ste

d m

ean

ch

an

ge i

n H

OM

A-%

B [

mU

/mm

ol]

fro

m b

aseli

ne a

t W

eek 2

4

Linagliptin: +5.0 mU/mmol

Placebo: –17.2 mU/mmol

Linagliptin: –0.02

Placebo: +0.02

Linagliptin: Use in diverse clinical

scenarios

Hepatic

function

Renal

function

Disease

duration

Adult age group

(including geriatrics*)

Efficacy and

tolerability

confirmed

regardless

of…

No dose adjustment

Linagliptin: Use in diverse clinical scenarios

+ Insulin

therapy

High CV and

renal risk

*Clinical experience in patients aged >80 years is limited; caution should be exercised when treating this population.

Source: Linagliptin US PI; Linagliptin EU SmPC.

Renal

function

Disease

duration

Adult age group

(including geriatrics*)

Efficacy and

tolerability

confirmed

regardless of…

No dose adjustment

Linagliptin: Use in diverse clinical scenarios

+ Insulin

therapy

High CV and

renal risk

*Clinical experience in patients aged >80 years is limited; caution should be exercised when treating this population.

Source: Linagliptin US PI; Linagliptin EU SmPC.

Hepatic

function

Linagliptin provides reliable HbA1c reductions across

patients at different stages of declining renal function

eGFR, estimated glomerular filtration rate; calculated using the Cockcroft–Gault formula.

Note: Prespecified subgroup analysis on pooled data from three pivotal Phase III, randomized, placebo-controlled trials:

treatment in monotherapy, add-on to metformin, and add-on to metformin plus sulphonylurea. P-values for between-group

differences (versus placebo); 1. Model includes continuous baseline HbA1c, baseline body mass index (BMI; cat.), washout

period, treatment, study, age group, sex, time since diagnosis of diabetes, race, renal impairment (Cockcroft−Gault) and

treatment*renal impairment (Cockcroft−Gault); Source: Cooper M, et al. ADA 2011, Poster 1068-P.

Change from baseline HbA1c by degree of renal impairment

Adjusted1 mean at 24 weeks of treatment, percent

p < 0.05p < 0.001p < 0.001

n

Mean baseline

HbA1c, percent

468

8.1

27

8.3

12

8.3

314

8.0

104

8.0

1,216

8.1

eGFR 30 to < 50 mL/min50 to < 80 mL/min≥ 80 mL/min

LinagliptinPlacebo

Adjusted1

mean change

in HbA1c (%)

from baseline

at Week 24

0.1 0.10

-0.6 -0.6-0.7-0.8

-0.6

-0.4

-0.2

0

0.2

Linagltipin1 does not affect renal function

Renal

function

baseline2

Diabetes

treatment

Renal function

at end of trial2

Normal

(GFR ≥ 80 mL/min)

(n = 1,216)Linagliptin

Mild impairment

(GFR 50 to < 80

mL/min)

(n = 314)

Linagliptin

Moderate

impairment (GFR 30

to < 50 mL/min) (n =

27)

Linagliptin

120 ± 33

67 ± 8

45 ± 5

119 ± 34

69 ± 13

48 ± 8

Mean GFR remains unchanged after

treatment initiation with linagliptin up to

24 weeks

Renal

function

1. For fixed-dose combinations with metformin, similar contraindications and special precautions

listed in metformin prescribing information apply; 2. Mean GFR ± SD according to Cockcroft–Gault in

mL/min for normal, mild and moderate renal impairment; 24 weeks’ trial duration for normal, mild and

moderate RI (pooled analysis of three Phase III trials).

Source: Cooper M, et al. ADA 2011, Poster 1068-P.

Efficacy and hypoglycaemia risk in patients with moderate-to-severe renal impairment on

linagliptin

Source: Laakso M, et al. ADA 2013, Abstract 2013-A-16280.

HbA1c

Adjusted mean (SE) change in HbA1c (%)

from baseline at Week 12

Placebo

n = 122

Linagliptin

n = 113

41.036.6

0

20

40

60

80

100

Placebo Linagliptin

Hypoglycaemia

% patients with ≥1 event at 12 weeks

-0.08

-0.50

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

-0.42%

p < 0.0001

Efficacy and hypoglycaemia risk in patients

with severe renal impairment on linagliptin

Source: McGill JB, et al. Diabetes Care. 2012;36:237–244.

HbA1c

Adjusted mean (SE) change in HbA1c (%) from baseline

Hypoglycaemia

% patients with hypoglycaemia at 52 weeks

-0.15

0.01

-0.6

-0.72

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

-0.6%

p < 0.0001

-0.7%

p < 0.0001

35.4

33.8

55.9

35.4

0

10

20

30

40

50

60

70

80

90

100Week 12 Week 52

Asymptomatic Symptomatic

Linagliptin, n = 66Placebo, n = 62

Linagliptin, n = 68Placebo, n = 65

Linagliptin permits the reduction of insulin dose in patients with severe renal impairment over 52 weeks

1. Change-from-baseline HbA1c at week 24 is the primary endpoint .

Source: Study 1218.43, linagliptin as add-on to pre-existing ant diabetic therapy in patients with severe renal impairment, data on file.

Pre-specified subgroup analysis of patients who took Linagliptin as add-on to background insulin therapy

(± other OADs)

Free insulin doseStable insulin

dose

Descriptive statistics for mean (SE) of mean insulin dose (IU) change from baseline (SE), FAS (LOCF-ROC)

LinagliptinPlacebo

Treatment

week

-10.2 U reduction of insulin dose from baseline with linagliptin

Renal events in patients taking linagliptin

versus placebo: A meta-analysisTo evaluate renal safety and outcomes with linagliptinStudy objective

Meta-analysis of 13 randomized, double-blind, placebo-

controlled, Phase 3 trials ≥12 weeks’ duration with data

available on or before cut-off (12 February 2011)

Study design

Composite primary renal endpoint of new onset of:

• Microalbuminuria (UACR ≥30 mg/g)

• Macroalbuminuria (UACR ≥300 mg/g)

• CKD (serum creatinine increase ≥2.83 mg/dL [250

μmol/L])

• Worsening of CKD (eGFR reduction >50% versus

baseline)

• Acute renal failure

• Death of any cause

Study

endpoints

Source: von Eynatten TH. ASN 2012, Poster 530.

308.9266.8

0

50

100

150

200

250

300

350

Placebo Linagliptin

*Meta-analysis including all randomized, double-blind, placebo-controlled Phase 3 trials ≥12 weeks’ duration with interim or final database lock

completed on/before 12 February 2011. †Composite renal safety endpoint; new onset of: microalbuminuria (UACR ≥30 mg/g), macroalbuminuria (UACR ≥300 mg/g), CKD (serum creatinine

increase ≥2.83 mg/dL), worsening of CKD (loss in eGFR >50% vs baseline), acute renal failure, death of any cause.

Source: von Eynatten TH. ASN 2012, Poster 530.

Incid

en

ce r

ate

per

1,0

00

pati

en

t-yea

rsIncidence of renal events†

Hazard Ratio 0.84[95% CI 0.72, 0.97]

~16% reduction in renal events with linagliptin versus placebo

Renal events in patients taking linagliptin versus placebo: A meta-analysis*

Diabetes Care Publish Ahead of Print, published online September 11, 2013

Pooled analysis of albuminuria data:Linagliptin versus placebo

Adjusted mean change in albuminuria, %(24 weeks)1

-28% in albuminuria versus placebo after 24 weeks’ treatment on top of

recommended standard treatment for diabetic nephropathy

-6

-32-40

-30

-20

-10

0Placebo Linagliptin

n 55 162

-28%p = 0.0357

[95% CI -47%, -2%]

Baseline UACR,

mg/g, median (range)

80.5 (30.9–1,538.2) 73.8 (30.1–2,534.4)

Source: Groop P-H. Diabetes Care. 2013;36:1–9.

Diabetes Care Publish Ahead of Print, published online September 11, 2013

DPP4 inhibitors and CV risk

Linagliptin CVS Meta-analysis2015

Linagliptin and CV risk: Meta-analysis

*Primary endpoint; compositAe of occurrence or time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization

for unstable angina.

Source: Linagliptin EU SmPC, May 2013; Johansen O-E, et al. ADA 2013, Abstract 376-OR.

Incidence rate of primary CV events*Number and percentage of patients

18.9

13.4

0

5

10

15

20

Incid

en

ce r

ate

(per

1,0

00 p

ati

en

t-yea

rs)

Comparator

(pooled active and

placebo comparators)

Linagliptin

62 events out

of 3,612

patients

Hazard ratio 0.78 [95% CI 0.55, 1.12]

No significant difference

Proportion of patients with CV events was similar between linagliptin (1.03%) and placebo (1.35%)

In a prospective meta-analysis (19 trials), linagliptin was not associated

with an increased cardiovascular risk versus comparators

60 events out

of 5,847

patients

2015

In a randomised trial , linagliptin showed a 54% lower risk of CV events vs. glimepiride, Head to head trial

Confidential and Proprietary. For internal use only.

Do not distribute or reproduce. 60

2-year randomised study comparing linagliptin and glimepiride as add-on to metformin; similar reduction in HbA1c was observed in the glimepiride arm (-0.6% HbA1c reduction at 104 weeks). All events independently adjudicated by CEC, all endpoints prespecified (also for individual studies) from CV meta-analysis statistical plan. Individual events may not add up to total of the composite endpoint, because one patient could have experienced more than one CV event.

CEC, clinical events committee; CV, cardiovascular; MI myocardial infarction; SU, sulphonylurea; UAP, unstable angina pectoris.

* CV death, MI, stroke, hospitalisation due to unstable angina. †With continuity correction of 0.5 (χ2 test). ‡With continuity correction of 0.5.

Source: Gallwitz B, et al. Lancet. 2012;380:475–483.

N Relative risk‡

Linaglipti

nSU HR (95% Cl) p value

†

12 26 0.46 (0.23, 0.91) 0.02

CV death 2 2 1.00 (0.14, 7.07) 0.99

Nonfatal Ml 6 10 0.60 (0.22, 1.64) 0.31

Nonfatal

stroke3 11 0.27 (0.08, 0.97) 0.03

Hospitalisati

on due to

UAP

3 3 1.00 (0.20, 4.93) 0.99

Linagliptin better SU better

IndividualCV

endpoints (events)

Composite endpoint

(patients)*

11/21/41/8 2 4 8

Linagliptin trial programme

Comparator PlaceboGlimepiride

Endpoint measures 1. Change from baseline in HbA1c at Week 24

2. Time weighted average of percentage change from baseline in UACR at Week 24

Time to first occurrence of primary CV composite endpoint*

Population T2DM patients with albuminuria on ACEi or ARB

T2DM patients at high CV risk

Trial type EfficacyCV outcome

*CV composite endpoint: CV death (including fatal stroke and fatal MI); nonfatal MI; nonfatal stroke;

hospitalization for unstable angina pectoris.

**Renal composite endpoint: renal death; sustained ESRD; sustained decrease of ≥ 50% eGFR.

Source: 1. ClinicalTrials.gov CT01897532; 2. ClinicalTrials.gov NCT01243424; 3. ClinicalTrials.gov NCT01792518.

1 2 3

Placebo

1. Time to first occurrence of primary CV composite endpoint*

2. Time to first occurrence of renal composite endpoint**

T2DM patients with vascular complications and albuminuria or renal-related end-organ damage

CV and renal microvascular outcome

Linagliptin: Efficacy, safety and dosing convenience

*Please consult the linagliptin PI or SmPC before prescribing.†In combination with sulphonylurea. Adverse reactions are uncommon (or not known) in monotherapy or in combination with metformin or insulin.‡Linagliptin US PI, pooled analysis of monotherapy and combination therapy trials. #To date, there is no evidence for an increased CV risk; but the number of events in the clinical studies was low, precluding firm conclusions.

Source: Linagliptin US PI; Linagliptin EU SmPC.

Simplicity and convenience

Always on the right dose*

Once daily

With or without food

Jentadueto® – linagliptin plus metformin in

three fixed twice-daily doses

Regardless of any degree of renal

or hepatic function

Primarily excreted via bile

and gut (renal excretion ~5%)

No additional drug monitoring

No dose adjustment*

Overall favourable safety profile and a

tolerability profile similar to placebo†

– Weight neutral

– Low risk of hypoglycaemia when

not used with sulphonylurea

Efficacy

Significant efficacy across a broad range of

glucose-lowering background therapies

Durable efficacy in longer-term

treatment up to 2 years

Efficacy in specific

patient populations

(elderly, declining

renal function, etc)

Safety and tolerability

Not associated with increase

in CV risk#

Linagliptin

Significant efficacy and

well tolerated in a broad

range of patients in one

appropriate

dose

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