Update on DPP-4 Inhibition in T2DM: Implications from Recent and Ongoing … · 2016-12-24 · Update on DPP-4 Inhibition in T2DM: Implications from Recent and Ongoing Trials Richard

Update on DPP-4 Inhibition in T2DM:

Implications from Recent and Ongoing Trials

Richard Pratley, M.D.

Samuel Crockett Chair in Diabetes Research

Director , Florida Hospital Diabetes Institute

Senior Investigator, Translational Research Institute

Adjunct Professor, Sanford Burnham Prebys Medical

Discovery Institute

Orlando, Florida

Disclosures

Advisory Board / Consultant: Boehringer-

Ingleheim, GSK, Lilly, Merck, Novo Nordisk,

Takeda

Research Support: Lilly, Merck, Novo Nordisk,

Sanofi, Takeda

All honoraria directed toward a non-profit

which supports education and research

Outline

Rationale for incretin therapy in T2DM

Pharmacology of DPP-4 inhibitors

Efficacy of DPP-4 inhibitors

DPP-4 inhibitor use in special populations

Elderly

CKD

Multiple Metabolic Defects Contribute to

Hyperglycemia in T2DM

Neurotransmitter

Dysfunction

Decreased Glucose

Uptake

Islet a-cell

Increased

Glucagon Secretion

Increased Glucose

Reabsorption

Increased

HGP

DeFronzo, Diabetes. 2009

Islet b-cell

Impaired

Insulin Secretion

DecreasedIncretin Effect

IncreasedLipolysis

Nauck et al. Diabetologia. 1986;29:46-52.

The Incretin Effect Is Diminished

in Type 2 Diabetes

Normal Glucose Tolerance Type 2 Diabetes

(n=8) (n=14)

IV Glucose

Oral Glucose

0 60 120 180

240

Pla

sm

a G

luc

os

e (

mg

/dL

)

180

90

0

0 60 120 180

Pla

sm

a G

luc

os

e (

mg

/dL

) 240

180

90

0

**

* **

* * *

0 60 120 180

C-P

ep

tid

e (

nm

ol/L

)

Time (min)

30

20

10

00 60 120 180

C-p

ep

tid

e (

nm

ol/

L)

Time (min)

30

20

10

0

*P≤.05

GLP-1 and GIP Augment Insulin Secretion by

the b-Cell in a Glucose-Dependent Manner

Ca2+

KATP channel subunits:

SUR 1=regulatory subunit;

Kir 6.2=inward rectifying channel

Glucose entry

GLUT2

Glucokinase

ADP/ATP

Potassium (KATP)

channel closes

K+

Ca2+

Calcium channel

SUR 1

Glucose metabolism

ADP/ATP

K+Ca2+

Ca2+

Kir 6.2

Insulin secretory granules

opens

Ca2+

Insulin secretion

K+

ATP cAMP

ACG

GLP-1/GIP

PKA

EPAC

No Significant Reduction in GLP-1

Secretion in Patients with Type 2 Diabetes

*P<0.05 compared with control.

Nauck MA et al. Diabetologia. 2011;54:10-18.

Inte

gra

te G

LP

-1 (

% o

f C

on

tro

l)

Individual Studies of Patients with Type 2 Diabetes andWeight-Matched, Non-Diabetic Controls

Oral Glucose

Mixed Meal*

* *

0

2000

4000

6000

8000

Time (Min)

C-P

ep

tid

e (

pm

ol/

L)

GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus

Adapted from Vilsbøll T, et al. Diabetologia. 2002; 45: 1111–1119.

GLP-1 but not GIP Enhances Insulin

Secretion in Patients with T2DM

GLP-1

GIP

Saline

−15 −10 0 5 10 15 20 30 45 60 75 90 105 120 150

Hyperglycemic Clamp

Saline or GIP or GLP-1

Hyperglycemia Downregulates Incretin

Receptor Expression

Xu G, et al. Diabetes. 2007;56:1551-1558.

GIP

receptor

GLP-1

receptor

Sham Px Px + Phlorizin

A B C

FED

Insulin Response to Physiologic Levels of

GLP-1 Is Impaired in Type 2 Diabetes

1Modified from Højberg PV et al. Diabetologia. 2009;52:199-207.

Physiologic GLP-1 levels1

(0.5 pmol/kg/min)

Plasma GLP-1:46 pmol/LHealthy

Plasma GLP-1:41 pmol/LType 2 diabetes

0

0 30 60 90 120

Time (min)

1000

2000

3000

4000

5000

Ins

uli

n (

pm

ol/

L)

150

Pharmacologic GLP-1 levels2

(1.0 pmol/kg/min)

0

Time (min)

1000

2000

3000

4000

5000

Ins

uli

n (

pm

ol/

L)

0 30 60 90 120 150

Plasma GLP-1:126 pmol/LType 2 diabetes

2Modified from Vilsbøll T et al. Diabetologia. 2002;45:1111–1119.

*P<0.05.

GLP-1 = glucagon-like peptide–1.Adapted from Nauck et al. Diabetologia. 1993;36:741-44.

Glucose Dependent Effects of GLP-1 in T2DM

–30 0 30 60 90 120 150 180 210 240

Time (min)

0

5

10

15

20

25

30

**

* *

GLP-1 infusion

Glucagon (pmol/L)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

**

*

* **

**

–30 0 30 60 90 120 150 180 210 240

Time (min)

GLP-1 infusion

C-Peptide (nmol/L)

0

50

100

150

200

250

300

**

**

**

*

–30 0 30 60 90 120 150 180 210 240

Time (min)

GLP-1 infusion

Glucose (mg/dL)(n=10)

GLP-1 Saline

GLP-1 Addresses Multiple Metabolic

Defects in T2DM

Neurotransmitter

Dysfunction

Decreased Glucose

Uptake

Islet a-cell

Increased

Glucagon Secretion

Increased Glucose

Reabsorption

Increased

HGP

DeFronzo. Diabetes. 2009

Islet b-cell

Impaired

Insulin Secretion

DecreasedIncretin Effect

IncreasedLipolysis

GLP-1

The Incretin Defect in T2DM

Substantial impairment – 40% of normal response

Not due to impaired secretion of GLP-1 or GIP

Absent insulinotropic response to GIP

Beta-cell GIP receptor down-regulation

Decreased response to GLP-1

Can be overcome by achieving higher than physiologic GLP-1 levels

GLP-1 infusions that achieve higher levels effective at enhancing insulin secretion and suppressing glucagon in a glucose-dependent manner

Nauck et al. Diabetologia. 1986;29:46–52. Laakso et al. Diabetologia. 2008;51:502-11. Nauck et al. Diabetologia. 2011;54:10-8.Højberg et al. Diabetologia. 2009;52:199-207. Vilsbøll et al. Diabetologia. 2002;45:1111–19. Nauck et al. Diabetologia. 1993;36:741–44.

Rationale for Using Incretin Therapies in the

Treatment of Type 2 Diabetes

● Incretins play a key and early role in

maintaining glucose homeostasis

● Incretin effects are diminished in patients with

type 2 diabetes

● Incretin-based therapies

Target multiple defects of type 2 diabetes, including

those not addressed by traditional medications

Do not cause hypoglycemia

Have favorable effects on weight

ADA/EASD Position Statement:

Managing Hyperglycemia in Type 2 Diabetes

Monotherapy

Efficacy ( A1C): HighHypoglycemia: Low risk

Lifestyle Changes

METFORMIN

2-drugcombinationsEfficacy ( A1C)

Hypoglycemia

Weight

Side effects

Costs

3-drugcombinations

More complexinsulin strategies Insulin

(multiple daily doses)

Weight: Neutral/loss Side effects: GI/lactic acidosisCosts: Low

Proceed after 3 mo. if needed Order does not indicate preference

METFORMIN +

Proceed after 3 mo. if needed Order does not indicate preference

METFORMIN +

SU +

TZD

DPP4-I

GLP-1-RA

Insulin

or

TZD +

SU

DPP4-I

GLP-1-RA

Insulin

or

DPP4-I +

SU

TZD

Insulinor

GLP-1-RA +

SU

TZD

Insulinor

Insulin +

TZD

DPP4-I

GLP-1-RA

or

SUHigh

Moderate risk

Gain

Hypoglycemia

Low

Proceed after 3-6 mo. if needed Insulin usually in combination with1-2 noninsulin agents

TZDHigh

Low risk

Gain

Edema, HF, Fx

High

DPP4-IIntermediate

Low risk

Neutral

Rare

High

GLP-1-RAHigh

Low risk

Loss

GI

High

Insulin

Highest

High risk

Gain

Hypoglycemia

Variable

Inzucchi et al. Diabetologia. doi: 10.1007/s00125-012-2534-0. Best of the Cardiometabolic Health Congress Regional Conference Series

SGLT2i

High

Low risk

Loss

GU Infection

Variable

SGLT2i +

SU

DPP4-I

GLP-1-RA

or

Outline





Elderly

CKD

Chemical

Classβ-Phenethylamines1 Cyanopyrrolidines Aminopiperidine8 Xanthine

Generic

NameSitagliptin2,3 Vildagliptin2,4,5 Saxagliptin2,6,7 Alogliptin9,10 Linagliptin11,12

Molecular

Structure

DPP-4

Inhibitory

Activity

(IC50)

9.96 ± 1.03 nM 5.28 ± 1.04 nM 3.37 ± 0.90 nM 6.9 ± 1.5 nM ~1 nM

Half-life 12.4 h ~2–3 h2.5 h (parent)

3.1 h (metabolite)12.4–21.4 h 113–131 h

DPP-4 Inhibitors Differ in Molecular

Structures and Pharmacologic Properties

DPP-4=dipeptidyl peptidase-4. IC50 =half maximal inhibitory concentration

1. Kim D et al. J Med Chem. 2005;48:141–151. 2. Matsuyama-Yokono A et al. Biochem Pharmacol. 2008;76:98–107. 3. JANUVIA EU-SPC 2010.

4. Villhauer EB et al. J Med Chem. 2003;46:2774–2789. 5. Galvus EU-SPC 2010. 6. Augeri DJ et al. J Med Chem. 2005;48:5025–5037. 7. Onglyza

EU-SPC 2010. 8. Feng J et al. J Med Chem. 2007;50:2297–2300. 9. Lee B et al. Eur J Pharmacol. 2008;589:306–14. 10. Christopher R et al. Clin

Ther. 2008;30:513–527. 11. Thomas L et al. J Pharmacol Exp Ther. 2008;325:175–182. 12. Heise T et al. Diabetes Obes Metab. 2009;11:786–794.

F

F

F O

N

NH2

N NN

CF3

N N

O

H3C

O N

CN

NH2

N

O

HH

NCHO

NH2

HO

NH

O

N

NC

N

NO

N

N

N

NN

O

NH2

Pharmacokinetic Properties of DPP-4

Inhibitors

Sitagliptin

(Merck)1

Vildagliptin

(Novartis)2

Saxagliptin

(BMS/AZ)3

Alogliptin

(Takeda)5

Linagliptin

(BI)6–8

Absorption tmax

(median)1–4 h 1.7 h

2 h (4 h for active

metabolite)1–2 h 1.34–1.53 h

Bioavailability ~87% 85% >75 %4 N/A 29.5%

Half-life (t1/2) at

clinically relevant

dose

12.4 h ~2–3 h2.5 h (parent)

3.1 h (metabolite)

12.4–21.4 h

(25–800 mg)

113–131 h

(1–10 mg)

Distribution 38% protein bound 9.3% protein bound Low protein binding N/A

Prominent

concentration-

dependent protein

binding:

<1 nM: ~99%

>100 nM: 70%–80%

Metabolism ~16% metabolized

69% metabolized

mainly renal

(inactive metabolite)

Hepatic

(active metabolite)

CYP3A4/5

<8% metabolized ~26% metabolized

EliminationRenal 87%

(79% unchanged)

Renal 85%

(23% unchanged)

Renal 75%

(24% as parent; 36% as

active metabolite)

Renal

(60%–71%

unchanged)

Feces 81.5%

(74.1% unchanged);

Renal 5.4%

(3.9% unchanged)

DPP-4=dipeptidyl peptidase-4.

1. JANUVIA EU-SPC 2010. 2. Galvus EU-SPC 2010. 3. Onglyza EU-SPC 2010. 4. EPAR for Onglyza. Available at: http://www.ema.europa.eu/.

Accessed September 17, 2010. 5. Christopher R et al. Clin Ther. 2008;30:513–527. 6. Heise T et al. Diabetes Obes Metab. 2009;11:786–794.

7. Reitlich S et al. Clin Pharmacokinet. 2010;49:829–840. 8. Fuchs H et al. J Pharm Pharmacol. 2009;61:55–62.

Inhibition of DPP-4 Increases Active GLP-1 and GIP to Lower Glucose

ActiveGIP

ActiveGLP-1DPP-4 DPP-4

DPP-4

inhibitor

DPP-4

inhibitor

Inactive GLP-1

Inactive GIP

ActiveGLP-1

ActiveGIP

Incretin effects• Augments glucose-induced

insulin secretion

• Inhibits glucagon secretion and

hepatic glucose production

• Increases glucose disposal

Thomas Rauch, et al. Diabetes Ther. 2012 December;3(1):10.

Linagliptin Increases Active GLP-1 and GIP

and Suppresses Glucagon

Vilda Wk 0

Vilda Wk 12

After washout40

60

80

100

120

140

160

180

-6 -4 -2 0 2 4 6 8 10 12

Time (min)

Insu

lin

(p

mo

l/L

)

*

*

*

*

D’Alessio, et al. JCEM 2009

238% increase in AIRg

(P<0.001 vs wk 0, P<0.05 vs PBO)

Effect of DPP-4 Inhibition on Insulin

Secretion in Drug-naïve Patients

0

50

100

150

200

Dis

po

sit

ion

In

dex

a, b

a

Baseline 12-Weeks 14-Weeks

DPP-4 Inhibition Enhances α-cell

Sensitivity to Glucose

12

14

16

18

20

22

24

4.0 8.0 12.0 16.0 20.0 24.0 28.0

Glucose (mmol/L)

Glu

cag

on

(p

mo

l/L

)

PBO week 0 (n=14)

PBO week 12 (n=14)Vilda week 0 (50 mg twice daily, n=14)

Vilda week 12 (50 mg twice daily, n=14)

12

14

16

18

20

22

24

4.0 8.0 12.0 16.0 20.0 24.0 28.0

Glucose (mmol/L)

Glu

cag

on

(p

mo

l/L

)

**

**

Vildagliptin Placebo

PBO=placebo; vilda=vildagliptin

*P <0.05 vs week 0.

D’Alessio DA, et al. JCEM 2009

*

Mean difference=

0.65 mg/kg/min

95% CI (0.03, 1.26)

P=0.040

*P<0.05 or better vs PBO

PBO

Vilda

DPP-4 Inhibition Improves Insulin

Sensitivity

7.0

6.5

6.0

5.5

5.0

4.5

4.0

Glu

cose R

d (

mg/k

g/m

in)

High Clamp

DPP-4 Inhibition Improves Postprandial

Lipid and Lipoprotein Metabolism

TG=triglycerides; vilda=vildagliptin

Matikainen N, et al. Diabetologia 2006; 49: 2049-2057.

Before vilda, week 0 (n=13)

Vilda 50 mg twice daily,

week 4 (n=15)

0.8

0.6

0.4

0.2

0.0−1 0 1 2 3 4 5 6 7 8

Time (h)

0.08

0.06

0.04

0.02

0.00−1 0 1 2 3 4 5 6 7 8

Time (h)

0.50

0.40

0.30

0.20

0.10

0.00−1 0 1 2 3 4 5 6 7 8

Time (h)

4.0

3.5

3.0

2.5

2.0

1.5

1.0−1 0 1 2 3 4 5 6 7 8

Time (h)

Plasma TG Chylomicron TG

Chylomicron apo B-48 Chylomicron cholesterol

mm

ol/L

mm

ol/L

mm

ol/L

mg

/L

Outline





Elderly

CKD

Efficacy of DPP-4 Inhibitor Therapy Added

to Metformin

26

1. Charbonnel. Diabetes Care. 2006;29:2638-43. 2. Raz et al. Curr Med Res Opin. 2008;24:537-50.3. Scott et al. Diabetes Obes Metab. 2008;10:959-69. 4. DeFronzo et al. Diabetes Care. 2009;32:1649-55.5. Taskinen et al. Diabetes Obes Metab. 2011;13:65-74. 6. Nauck et al. Int J Clin Pract. 2009;63:46-55.

BL A

1C

(%

)

8.0

≥7–≤1

0

7.7

7.7

7.7

≥7–≤1

0

≥7–≤1

0

≥7–≤1

0

8.1

8.1

≥7–≤1

0

n=701

n=190

n=273n=273

n=273

n=743

n=743

n=743

n=743

n=701

n=701

n=527

Sitagliptin 100 mg

Rosiglitazone

Placebo

Saxagliptin 2.5 mg

Saxagliptin 5 mg

Saxagliptin 10 mg

Linagliptin 5 mg

Alogliptin 12.5–25 mg

—

Sitagliptin Saxagliptin Linagliptin Alogliptin

-1,3

-0,7 -0,7

-1,2

-0,80

-0,10 -0,10

-1,07

-2

-1

0

1

Δ A

1C

, %

fro

m B

L

DPP-4 Inhibitors: Glycemic Efficacy When

Added as a Third Oral Agent

a ALO: 26-wk trial; PIO, 15 mg.b LINA: 24-wk trial, BL A1C 8.1-8.2%.c SAXA: 24-wk trial, BL A1C 8.2-8.4%.d SITA/SAXA: 24-wk trial, BL A1C 8.5-8.9%; OAD: GLIM, AGI, or PIO.

1. Drugs@FDA.

2. Li CJ, et al. Diabetol Metab Syndr. 2014;6:69.

Added to

PIO + MET1,a

Added to

MET + SU1,b

Added to

MET + SU1,c

Added to

MET + OAD2,d

P ≤ .01 vs

PIO + METa

P ≤ .05 vs PBO

SAXA and SITA

P < .01 vs BL

P < .0001 vs PBO

ALO (25 mg) SAXA (5 mg) PBOLINA (5 mg) SITA (100 mg)

DPP-4 Inhibitors Offer Improved Glycemic

Efficacy When Added to Insulin Regimens

-0,5-0,6

-0,7-0,6

0,0

0,1

-0,3-0,1

-2

-1

0

1

Δ A

1C

Fro

mB

L, %

a ALO: 26-wk trial, BL A1C 9.3%, 55 units insulin median TDD at BL.b LINA: 24-wk trial, BL A1C 8.3%. 40-42 units insulin mean TDD at BL.c SAXA: 24-wk trial, BL A1C 8.7%, 53-55 units insulin mean TDD at BL. intermediate, long-acting, or premixed INS only.d SITA: 24-wk trial, BL A1C 8.6-8.7%. 42-45 units insulin median TDD at BL, intermediate, long-acting, or premixed INS only. 1. Drugs@FDA.

ALO (25 mg) SAXA (5 mg) PBOLINA (5 mg) SITA (100 mg)

Added to

MET + INS1,a

P < .01 vs PBO P < .05 vs PBO

Added to

± MET ± PIO1,b

Added to

± MET1,c

Added to

± MET1,d

P < .05 vs PBO P < .001 vs PBO

Glycemic Control With DPP-4 Inhibitors

in a Head-to-Head Clinical Trial

-0.62-0.52

-1.5

-1

-0.5

0

A1C

Ch

an

ge f

rom

Baseli

ne (

%,

SE

)

Study design

18-week study

N = 677

BL A1C = 7.7%

Add-on to MET

Results

Noninferior glycemic control for SAXA vs SITA

No differences in weight loss (0.4 kg) or AE occurrences

Scheen AJ, et al. [Published online ahead of print September 7, 2010.] Diabetes Metab Res Rev.

SITA

(100 mg)SAXA

(5 mg)

Linagliptin

5mg4

Alogliptin

25mg1

Sitagliptin

100mg2

Saxagliptin

5mg3

Study duration 104-week 104-week 104-week 52-week

extension of

52-week study

Add-on to Metformin Metformin Metformin Metformin

Comparator Glimepiride Glipizide Glipizide Glipizide

Average SU dose 3.0mg 5.2mg 9.2mg 15mg

Baseline HbA1c (%) 7.43–7.53 7.59–7.61 7.30–7.31 7.65

HbA1c reduction: DPP-4i

(PPS) SU

-0.35

-0.53

Non-inferior

-0.72

-0.59

Superior

-0.54

-0.51

Non-inferior

-0.41

-0.35

Non-inferior

Body weight (kg) DPP-4i

SU

-1.4

+1.3

-0.95

+0.89

-1.6

+0.7

-1.5

+1.3

hypoglycaemia DPP-4i

SU

7%

36%

1.4%

23.2%

5.3%

34.1%

3.5%

38.4%

1. Del Prato S, et al. Study 305 2-year data. Poster presented at ADA 2013. 2. Seck T, et al. Int J Clin Pract 2010;64:562–576. 3. Göke B, et al. Int J Clin Pract

2013;67:307–316. 4. Gallwitz B, et al. Lancet 2012;380:475–483

Long-term Studies of DPP-4 Inhibitors

vs. Sulfonylureas

Alogliptin + metformin vs glipizide1

104 weeks (PPS)

Sitagliptin + metformin vs glipizide2

104 weeks (PPS)

Saxagliptin + metformin vs glipizide3

52-week extension of 52-week study (FAS)

Linagliptin + metformin vs glimepiride4

104 weeks (PPS)

1. Del Prato S, et al. Study 305 2-year data. Poster presented at ADA 2013. 2. Seck T, et al. Int J Clin Pract 2010;64:562–576. 3. Göke B, et al. Int

J Clin Pract 2013;67:307–316. 4. Gallwitz B, et al. Lancet 2012;380:475–483

PPS=per protocol set; FAS=full analysis set

Comparison of HbA1c Change in Long-

Term Studies of DPP-4 Inhibitors

Ji L, Zinman B, Patel S, Ji J, Bailes Z, Thiemann S, Seck T. Adv Ther. 2015 Mar;32(3):201-15.

Initial Combination Therapy With Linagliptin

and Metformin in Patients with T2DM

Initial Combination Therapy with

Empagliflozin and Linagliptin in T2DM

N=674 individuals with T2DM who had not received diabetes therapy for ≥12 weeks (week 24 data).

Lewin A, et al. Diabetes Care. 2015;38(3):394-402.

Ch

an

ge

Fro

m B

as

elin

e

in A

1c

, %

Mean Baseline

-0.14 (-0.33, 0.06)P=0.179

-0.41 (-0.61, -0.21)P<0.001

-0.57 (-0.76, -0.21)P<0.001

-0.41 (-0.61, -0.21)P<0.001

Ch

an

ge

Fro

m B

as

elin

e

in B

od

y W

eig

ht,

kg

Mean Baseline

0.1 (-0.9, 1.1)P=0.801 -0.5 (-1.5, 0.5)

P=0.362

-2.0 (-3.0, -1.0)P<0.001

-1.2 (-2.2, -0.2)P=0.018

Empagliflozin 25 mg/Linagliptin 5 mg

Empagliflozin 10 mg/Linagliptin 5 mg

Empagliflozin 25 mg

Empagliflozin 10 mg

Linagliptin 5 mg

Outline





Elderly

CKD

Other adverse reactions reported in clinical studies with treatment of linagliptin were

hypersensitivity

(eg, urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and

myalgia

The overall incidence of adverse events with linagliptin was similar to placebo

Adverse Reactions Reported in ≥2% of Patients

Treated With Linagliptin and Greater Than Placebo

in Placebo-controlled Trials

35

Percentage of Patients (n)

Linagliptin 5 mg

n=3625

Placebo

n=2176

Nasopharyngitis 7.0% (254) 6.1% (132)

Diarrhea 3.3% (119) 3.0% (65)

Cough 2.1% (76) 1.4% (30)

Tradjenta® (linagliptin) tablets [package insert]. Ridgefield, CT: Boehringer Ingelheim International GmbH; 2014.

Hypoglycemia May be a Barrier to Glycemic

Control in Patients With Type 2 Diabetes

Hypoglycemia is an important limiting factor in glycemic management.

It may be a significant barrier in terms of treatment adherence and achievement of a lifelong goal of attaining normal glycemic levels.

Fear of hypoglycemia is an additional barrier to control.

A study in patients with type 2 diabetes showed increased fear of hypoglycemia as the number of mild/moderate and severe hypoglycemic events increased.

Amiel SA et al. Diabet Med. 2008;25(3):245–254.

1. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258-267. 2. Gomis R, et al. Diabetes Obes Metab. 2011;Mar 15. Epub ahead of

print. 3. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 4. Owens DR, et al. Diabetes. 2010;59(suppl 2): Abstr. 548-P.

Hypoglycemia With Linagliptin:

Mono and Combination Therapy

0,6 02,3

14,8

0,3 1,2 0,4

22,7

0

5

10

15

20

25

Monotherapy

24 Weeks1

Initial Combo

w/ Pioglitazone

24 Weeks2

Add-on to Metformin

24 Weeks3

Add-on to Metformin

+ SU

24 Weeks4

N 503 389 700 1055

Treatment PBO Lin Pio Lin +

Pio

Met Lin +

Met

Met + SU Lin +

Met + SU

Patients

Report

ing

Hypogly

cem

ia (

%)

Canadian Journal of Diabetes 2016 40, 50-57DOI: (10.1016/j.jcjd.2015.06.010)

Hypoglycemia in Patients with T2DM on Basal

Insulin Treated With Linagliptin vs. Placebo

Common – 40% of all patients with diabetes

Optimal glycemic targets unknown

Optimal therapeutic approaches unknown

Clinical heterogeneous population

Variable life expectancies

Variable comorbidities and functional status

Polypharmacy and geriatric syndromes

Lack of Grade A evidence

Exclusion from large RCTs

Individualize Goals for DM management

The Problem of Diabetes in Older Adults

-0,8

-0,6

-0,4

-0,2

0,0

0,2

Baseline Week 6 Week 12 Week 18 Week 24

Linagliptin Reduced A1C vs Placebo at 24

Weeks in Patients Aged ≥70 Years

1. Boehringer Ingelheim. Data on file. 2. Barnett AH, et al. Lancet. 2013;382:1413-1423.

*P<0.0001. †Placebo corrected.

Baseline A1C: 7.8% for linagliptin-treated group and 7.7% for placebo group; full analysis set; last observation carried forward.

Placebo (n=78) Linagliptin 5 mg (n=160)

Clinical experience with TRADJENTA has not identified differences in response between the elderly and younger patients;

however, greater sensitivity of some older individuals cannot be ruled out.

SE=standard error.

Difference

-0.6%*

0.04

-0.6

Primary Endpoint: Placebo-Adjusted Mean Difference in

A1C (%) at 24 Weeks

Pratley. Clin Interv Aging. 2014;9:1109-1114.

Low Rates of Hypoglycemia With Linagliptin

vs. Placebo in Patients Aged ≥70 Years

DPP-4 Inhibitors: Dosing in Renal Disease

Linagliptin1 Sitagliptin2 Saxagliptin3 Alogliptin4

Moderate impairment

CrCl: 30-50 mL/min

or

Serum Cr (mg/dL):

Men >1.7– ≤3.0

Women >1.5– ≤2.5

No dose

adjustment

50 mg once

daily

2.5 mg once

daily

12.5 mg

once daily

Severe impairment/

ESRD

CrCl <30 mL/min

or

Serum Cr (mg/dL):

Men >3.0

Women >2.5

or dialysis

No dose

adjustment

25 mg once

daily

2.5 mg once

daily

6.25 mg

once daily

1. Linagliptin full prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201280lbl.pdf

2. Sitagliptin full prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021995s007lbl.pdf

3. Saxagliptin full prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022350lbl.pdf.

4. Alogliptin full prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022271s000lbl.pdf

Linagliptin Lowers HbA1c Over 52 weeks in

Patients with Renal Impairment

Janet B McGill et al. Diabetes and Vascular Disease Research 2015;12:249-257

Mild RI Moderate RI

Severe RI

Incidence of Renal Adverse Events in T2DM

Patients Treated with Linagliptin vs. Control


Safety of Linagliptin in T2DM Patients

with CKD


Pancreatitis Risk With DPP-4 Inhibitors

The available evidence suggests that incretin-based therapies do

not themselves increase the risk of pancreatitis in patients with

T2DM1

But other factors may increase the risk of pancreatitis with use of

DPP-4 inhibitors2:

Obesity

Hypertriglyceridemia

Gallstones

Biliary/pancreatic cancer, or neoplasm

Alcohol and/or tobacco use

Current prescribing recommendations3

Educate patients—ask about pancreatitis history/risk factors

Monitor for pancreatitis signs and symptoms—discontinue promptly if they occur

1. Li L, et al. BMJ. 2014;348:g2366.2. Singh S, et al. JAMA Intern Med. 2013;173:534-539.3. US FDA. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/ cder/DrugsatFDA.

Oral therapy, once daily

Endogenous GLP-1 and GIP levels are increased in response to meals and are transient

Clinically significant A1c reductions

Comparable efficacy to SUs

Complementary mechanism of action with many drugs

Don’t use with GLP-1 receptor agonists

Very well tolerated

No GI sx, no weight gain, low hypoglycemia, no edema

Adjust dose for CKD: except linagliptin

Low risk for drug-drug interactions

Neutral effects on BP, lipids, CVD

DPP-4 Inhibition: Role in T2DM Therapy

Ideal Patient with T2DM for DPP-4 Inhibitor

Therapy

Metformin intolerant

Combination with metformin

Weight issues or hypoglycemia risk

Elderly

Chronic kidney disease

Cardiovascular disease

Convenience of once-daily, well tolerated

medication

Documents

Update on DPP-4 Inhibition in T2DM: Implications from Recent and Ongoing … · 2016-12-24 · Update on DPP-4 Inhibition in T2DM: Implications from Recent and Ongoing Trials Richard