No todos los Inhibidores de la DPP4 son iguales

Dr. Luis More SaldañaHospital Santa Rosa /Clínica San FelipeEndocrinólogo

Advisory: Eli Lilly Speaker: MSD,Eli Lily,Novartis.Investigador Principal : Novartis ,Covance.Takeda ,Sanofi Aventis PPD,Roche ,Johson&Johnson Astrazeneca,GSK.

Conflicto de Interés

Chemical Class

β-Phenethylamines1 Cyanopyrrolidines Aminopiperidine8 Xanthine

Generic Name

Sitagliptin2,3 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 concentration1. 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

OH3C

O N

CN

NH2

N

O

HH

NCHO

NH2

HO

NH

O

N

NC

N

NO

N

N

N

NN

O

NH2

Química Metabolización Eliminación

Sitagliptina Derivado de β-amino acido No metabolizado Renal (~80% inmodificado)

Vildagliptina Cianopirrolidina Hidrolizado a metabolito inactivo (P450 independent)

Renal (22% como molécula madre, 55% como metabolito)

Saxagliptina Cianopirrolidina Metabolizado en hígado – Metabolito activo (via P450 3A4/5)

Renal (12-29% como madre, 21-52% como metabolito)

Alogliptina Pirimidinediona modificada No metabolizado Renal (>70% inmodificado)

Linagliptina Derivado xantinico No metabolizado Biliar (inmodificado); <6% via renal

Características de los inhibidores DPP-4 (Deacon C, 2010)

Selectivity for DPP-4 vs other enzymes

C. Deacon Diabetes, Obesity and Metabolism 13: 7–18, 2011

Chemical Class

β-Phenethylamines1 Cyanopyrrolidines Aminopiperidine8 Xanthine

Generic Name

Sitagliptin2,3 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 concentration1. 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

OH3C

O N

CN

NH2

N

O

HH

NCHO

NH2

HO

NH

O

N

NC

N

NO

N

N

N

NN

O

NH2

Química Metabolización Eliminación

Sitagliptina Derivado de β-amino acido No metabolizado Renal (~80% inmodificado)

Vildagliptina Cianopirrolidina Hidrolizado a metabolito inactivo (P450 independent)

Renal (22% como molécula madre, 55% como metabolito)

Saxagliptina Cianopirrolidina Metabolizado en hígado – Metabolito activo (via P450 3A4/5)

Renal (12-29% como madre, 21-52% como metabolito)

Alogliptina Pirimidinediona modificada No metabolizado Renal (>70% inmodificado)

Linagliptina Derivado xantinico No metabolizado Biliar (inmodificado); <6% via renal

Características de los inhibidores DPP-4 (Deacon C, 2010)

44

Sitagliptin: Dose reduction is based on PK data

AUC=area under the curve; CrCl=creatinine clearance; GM=geometric mean.1. Data on file, MSD.

<2-fold AUC increasewith mild renal insufficiency

vs normal renal function

Dose adjustmentsCrCl <30 mL/min: ¼ dose

CrCl 30–50 mL/min: ½ doseCrCl >50 mL/min: full dose

Do

se-A

dju

sted

(to

50

mg

) A

UC

, μM

/h

0

4

8

12

16

20

24

28

Creatinine Clearance, mL/min10 30 50 70 90 110 130 150 170 190 210 230

GM of healthy subjects

2× GM ofhealthy subjects

APaT, Excluding Data After Initiation of Glycemic Rescue Therapy

Sitagliptin vs Glipizide in Patients With Type 2 Diabetes Mellitus and Chronic Renal Insufficiency: Change From Baseline in Estimated GFR1

GF

R E

stim

atio

n M

DR

D (

mL

/min

/1.7

3m2 )

C

han

ge

Fro

m B

asel

ine

(Mea

n ±

SE

)

Week0 6 12 18 30 42 54

1

0

-1

-2

-3

-4

-5

Sitagliptin Glipizidea

APaT=All Patients as Treated ; GFR=glomerular filtration rate; SE=standard error.aMean dose of glipizide was 7.7 mg per day.1. Data on file, MSD.

Selectivity for DPP-4 vs other enzymes

C. Deacon Diabetes, Obesity and Metabolism 13: 7–18, 2011

FDA requirement

24-hour Weighted Mean Glucose Change From Baseline at Day 28

Sitagliptin, Linagliptin compared to placebo

Ref.: clinicaltrials.gov

* P < 0,001 vs placebo

n=40 n=39

-19.8  ± 2.9*-26.1  ± 2.8

Sitagliptin

100 mg/day

Linagliptin

5 mg/day

Change from Baselineat Week 24 (Primary End Point)

–30,0

–25,0

–20,0

–15,0

–10,0

–5,0

0,0

5,0

24 h

- W

eigh

ted

Mea

n G

luco

se[u

nits

: m

g/d

L] M

ean

± S

D

7.32  ± 0.59

7.17  ± 0.44  Baseline-HbA1c

Placebo

7.47  ± 0.53

0.1  ± 3.0

n=38

n=39n=40

Fasting Plasma Glucose Change From Baseline at Day 28

Sitagliptin, Linagliptin compared to placebo

Ref.: clinicaltrials.gov

* P = 0.0283 vs placebo

n=40 n=39

-10.9  ± 3.5 *-15.6  ± 3.1

Sitagliptin

100 mg/day

Linagliptin

5 mg/day

Change from Baselineat Week 24 (Primary End Point)

–20,0

–15,0

–10,0

–5,0

0,0

5,0

FP

G[u

nits

: m

g/d

L]M

ean

± S

D

7.32  ± 0.59

7.17  ± 0.44  Baseline-HbA1c

Placebo

7.47  ± 0.53

-0.1  ± 3.6  

n=38

n=39n=41

Head to Head StudyLinagliptin versus glimepride, both on top of metformin

EMA/ European public assessment report Linagliptin

-0,60%

-0,50%

-0,40%

-0,30%

-0,20%

-0,10%

0,00%

52 weeks 104 weeks

Glim

Lina

Full Analysis Set

Non-inferiority margin:0.35%

0,22% 0,20%

- 0.

60%

- 0.

38%

- 0.

36%

- 0.

16%

Per protocol analysis (more robust)Differences: 0.26% 0.28%

HbA

1c

redu

ctio

n

Linagliptin PK interacionsEfects of coadministered drugs on linagliptinUS- PI 2011

EMA webside

EMA Scientific discussion

Linagliptin Phase III Meta-analysis:Linagliptin Phase III Meta-analysis:Cardiovascular EndpointsCardiovascular Endpoints

Secondary Endpoints: Hazard Rate Estimates

0.15 0.34 0.75

0.125 0.25 0.5 1 2 4

0.33 0.55 0.94

0.17 0.36 0.78

Ratio (95% CI) of linagliptin to control

Favors Linagliptin

Favors Comparators

CV death, MI, or stroke

All CV events*

FDA-custom MACE†

ADA 2011 Poster 30-LB

*All major CV events include CV death, MI, stroke, transient ischemic attack, UAP, and stable angina pectoris.†FDA-custom MACE includes 34 unadjudicated MedRA preferred terms for MI and stroke.

Linagliptin Product information Canada

G. Schernthaner et al. Diabetes, Obesity and Metabolism 2012

Lina CV safety

G. Schernthaner et al. Diabetes, Obesity and Metabolism 2012

FDA requirement

Conclusion Linagliptin

Only limited clinical experience

Less indications

No RCTs in patients with moderate/severe renal failure and dialysis

Xanthin based molecule: HR increase, proarrythmic?

No CV benefit over Placebo in pooled safety analysis

Why inhibit FAP?

Glucose lowering efficacy? (Lina/Sita 24h WMG study)

Vildagliptin

Main points to note:– Need to check hepatic enzymes– BID dosing– No CV outcome trial– Poorer in vitro selectivity than other DPP4 inhibitors– Pre-clinical tox issues - maybe due to DPP8 and DPP9

inhibitory activity

The Marfella issue

• Repeat nonsense* until it is believed

• * retrospective analysis of as much data as possible until you find a difference that probably occured by chance

• The only way to compare compounds is with appropriately powered, prospective randomised clinical trials

Cross-Sectional Study: Sitagliptin vs Vildagliptin in Patients With Type 2 Diabetes Uncontrolled on

Metformin

Journal of Diabetes and Its Complications, Marfella R, Barbieri M, Grella R, et al., Effect so vildagliptin twice daily vs. sitagliptin once daily on 24-hour acute glucose fluctuations, Vol. 24(2),79-83 (2010),

Marfella et al J Diabetes Complication 2009

Inta

ct G

LP-1

(pm

ol/L

)

30

20

10

0

** * *

**

***

Breakfast Lunch Dinner (+5 h) (+ 10 h)

0 180 300 0 180 300 0 180 300 min

80

60

40

20

Pla

sma

gluc

agon

(m

g/dL

)

* ***

* **

** **

**-60

-40

-20

0G

luco

se c

hang

es (

mg/

dL) } } } }FPG PPG MPG MAGE

*

Inadequate glycaemic control while on max metformin (3000 mg/d)

Sitagliptin (100 mg qd; n=20)

Vildagliptin (50 mg bid; n=18)

MAGE = mean amplitude of glycaemic excursion, determined from arithmetic mean of differences between consecutive glycaemic peaks and nadirs

Effects of vildagliptin twice daily vs sitagliptin once daily on 24-hour acute glucose fluctuations Marfella R et al.

Method: Not a prospective, randomized, blinded clinical trial

Why don’t we like this analysis

Small study Not sufficiently powered Retrospective analysis SD is a more typical measure of variability We have no problems convincing SLs about the weakneses

of this study – but primary health care physicians??

65

0

10

20

30

40

50

60

70

80

90

100

Percent Plasma DPP-4 Inhibition*

Mea

n P

erce

nt

Inh

ibit

ion

of

DP

P-4

A

ctiv

ity

(S

E)

Hours

Sitagliptin 100 mg QD

Vildagliptin 50 mg BID **

Saxagliptin 5 mg QD

Vildagliptin 50 mg QD **

Placebo

* Single day dosing** Vildagliptin is not approved in the US

Once-Daily Dosing of JANUVIA Delivers Maximal

DPP-4 Inhibition Over 24 Hours

0 5 10 15 20 25

OPTIMA : Optimized Glycemic Control With Vildagliptin vs. Sitagliptin - Study Design1

CGM=continuous glucose monitoring.1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.

R

Inclusion Criteria:•Age > 18 yrs•HbA1c between 6.5 and 8.0% •BMI between 22 and 45 kg/m2

•Currently on stable, maximum tolerated metformin dose

8 Weeks

Vildagliptin + Metformin (N=19)

Sitagliptin + Metformin (N=19)

CGM for 3 days

CGM for 3 days

CGM for 3 days

2-4 Weeks

OPTIMA : Optimized Glycemic Control With Vildagliptin vs. Sitagliptin - Study Objectives1

Primary Objective:– Change in mean amplitude of glycemic excursions (MAGE) after 8

weeks of treatment Secondary Objectives:

– Time spent in the optimal glycemic range, ≥ 70 and ≤ 140 mg/dL – Time spent in hyperglycemic range, ≥140 and ≥180 mg/dL– Time spent in hypoglycemic range, < 70 mg/dL

67

1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.

OPTIMA : Optimized Glycemic Control With Vildagliptin vs. Sitagliptin - Patient Characteristics1

Sitagliptin 100 mg QD(N=19)

Vildagliptin 50 mg BID(N=19)

Mean age, yrs 53.5 59.1

Males, n (%) 11 (57.9) 10 (52.6)

Body Weight, kg 87.6 86.1

BMI, kg/m2 30.9 31.2

Mean HbA1c, % 7.09 7.16

Mean metformin dose, mg/day 2113 2115

Duration of disease, yrs 6.3 7.6

68

BID=twice daily; QD=once daily.1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.

OPTIMA : Glycemic Variability Results Were Similar Between Sitagliptin and Vildagliptin Treated Groups1

69

At baselineAt 8 weeks

BID=twice daily; MAGE=mean amplitude of glycemic excursions; MODD=mean of daily differences; QD=once daily; SD=standard deviation. 1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.

SD of 24-h Mean Glycemia

MAGE

Varia

ble,

mg/

dL

MODD

P=0.61

P=0.83

P=0.89

2 abstracts/posters published in 1Q/2012

Poster at ATTD meeting – Barcelona, Spain.February 2012

Poster at SFD congress in France March 2012 (arguably the most important national diabetes congress in France)

Methods

A multicentre, prospective, randomised, open label study with blinded endpoint.

Type 2 patients who were treated with either vilda or sita as an add-on to metformin in patients with starting HbA1c levels in rage 6.5-8.0.

NB Starting HbA1c is 7.1 – compared to Marfella study (8.3-8.4 Blood glucose was continuously monitored over two 72-hour periods:

– First Observation – pts on metformin alone– Second Observation - eight weeks after the addition of either vildagliptin

(n=14) or sitagliptin (n=16). CGM recordings were centrally analysed in a blinded fashion

Results Primary Endpoint – Glycaemic Variability (eg MAGE)

– Both vilda and sita significantly improved MAGE, SD and MODD– No differences between vilda and sita

Secondary Endpoints – Effect on HbA1c was similar with both compounds: Sita: decrease of 0.34 from a

baseline of 7.12, Vilda decrease of 0.49 from a baseline of 7.14– Time spent in the optimal glycaemic range (70-140 mg/dL) increased significantly by

vilda, although no difference between the 2 inhibitors is evident– Time spent at hyperglycaemic levels (AUC Total: AUC>/=100 mg/dl over the full 24-hour

period; • Reduced by 37% by vildagliptin Sig (level?)• Reduced by 9% on sitagliptin, NS• Again, no difference was observed between the 2 inhibitors

– Time spent at hyperglycaemic levels (>/= 140 mg/dL) • Poster: Only patients in the vildagliptin group had a significant decrease in time spent above 140

mg/dL. Decrease observed with sitagliptin was not sinificant• Again, the between-group difference did not achieve statistical significance.

Glycemic Variability Results Were Similar Between Sitagliptin and Vildagliptin Treated Groups1

73

At baselineAt 8 weeks

BID=twice daily; MAGE=mean amplitude of glycemic excursions; MODD=mean of daily differences; QD=once daily; SD=standard deviation. 1. Guerci B et al. Poster.

SD of 24-h Mean Glycemia

MAGE

Varia

ble,

mg/

dL

MODD

P=0.61

P=0.83

P=0.89

Sitagliptin and Vildagliptin Increased the Time Patients Spent in the Ideal Glycemic Range at 8 Weeks1

74

At baselineAt 8 weeks

Tim

e, m

inut

es

Glucose levels 70 – 140 mg/dL Glucose levels >140 mg/dL

BID=twice daily; QD=once daily. 1. Guerci B et al. Poster.

P=0.11

P=0.09

Sitagliptin Reduced HbA1c Levels at a Similar Rate From Baseline Compared With Vildagliptin1

75

N=16 N=14

-0.34a

-0.49b

7.12 7.14Mean Baseline HbA1c

P=0.42aP=0.09 .bP<0.001.1. Guerci B et al. Poster.

Other Notes/Questions

Publication of full paper: Within one year (Valensi – personal communication to Elisabeth Eymard)

Some (secondary?) endpoints quoted on posters do not appear to have been pre-specified – ie retrospective data analysis

No incretin or pancreatic endocrine data presented – it is unclear whether the protocol includes measurement of these hormones.

One imagines an attempt will be made to link this data to differences in binding of the two inhibitors (although we have commented publically on the limitations of this linkage)

Study was small – statistical power calculation?

Saxagliptin Was Noninferior to Sitagliptin in Reducing HbA1c at 18 Weeks

Primary End Point (Per-Protocol Population; on background of metformin therapy)

Mean baseline HbA1c, %

Cha

nge

From

Bas

elin

e in

A

djus

ted

Mea

n H

bA1c

(SE)

, %

0.09 (95% CI: –0.01, 0.20)a

(Prespecified noninferiority margin=0.30%)

Sitagliptin 100 mg + metformin

Saxagliptin 5 mg + metformin

In the FAS population, numerically greater

HbA1c reductions from baseline were observed

for sitagliptin 100 mg compared with saxagliptin 5 mg. Difference between groups: 0.17% (95% CI:

0.06, 0.28)

7.69 7.68

–0.62(95% CI: –0.69, –0.54)

–0.52(95% CI: –0.60, –0.45)

–0.60

–0.45

–0.30

–0.15

0.00

–0.75

CI=confidence interval; FAS=full-analysis-set; SE=standard error.aDifference in adjusted change from baseline vs sitagliptin + metformin.Scheen AJ et al. Diabetes Metab Res Rev. 2010;26(7):540–549.

n=343 n=334

Thank you