2 da fecha no todos los inh dpp4 son iguales (2)

No todos los Inhibidores de
la DPP4 son iguales

Dr. Luis More Saldaña
Hospital Santa Rosa /Clínica San Felipe
Endocrinólogo

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

DPP-4 Inhibitors Differ in Molecular
Structures and Pharmacologic Properties
Chemical
β-Phenethylamines1 Cyanopyrrolidines Aminopiperidine8 Xanthine
Class
Generic
Sitagliptin2,3 Vildagliptin2,4,5 Saxagliptin2,6,7 Alogliptin9,10 Linagliptin11,12
Name

O
F FNH2O H O CN
Molecular H NH2 N
N N
N N H3C N N N
Structure F N N
H N N N N
N N NC O O N O
CF3 HO NC O NH2
HO
NH2

DPP-4
Inhibitory
9.96 ± 1.03 nM 5.28 ± 1.04 nM 3.37 ± 0.90 nM 6.9 ± 1.5 nM ~1 nM
Activity
(IC50)

2.5 h (parent)
Half-life 12.4 h ~2–3 h 12.4–21.4 h 113–131 h
3.1 h (metabolite)

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.

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

Química Metabolización Eliminación

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

Vildagliptina Cianopirrolidina Hidrolizado a metabolito inactivo (P450 Renal (22% como molécula madre,
independent) 55% como metabolito)

Metabolizado en hígado – Metabolito activo Renal (12-29% como madre, 21-52%
Saxagliptina Cianopirrolidina (via P450 3A4/5) como metabolito)

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

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

Selectivity for DPP-4 vs other enzymes

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

44

Sitagliptin: Dose reduction is based on PK data

28
<2-fold AUC increase
Dose-Adjusted (to 50 mg) AUC, μM/h

with mild renal insufficiency
24 vs normal renal function

20
Dose adjustments
CrCl <30 mL/min: ¼ dose
16 CrCl 30–50 mL/min: ½ dose
CrCl >50 mL/min: full dose
12

2× GM of
8 healthy subjects

4
GM of healthy subjects

0
10 30 50 70 90 110 130 150 170 190 210 230
Creatinine Clearance, mL/min
AUC=area under the curve; CrCl=creatinine clearance; GM=geometric mean.
1. Data on file, MSD.

Sitagliptin vs Glipizide in Patients With Type 2 Diabetes
Mellitus and Chronic Renal Insufficiency:
Change From Baseline in Estimated GFR1
APaT, Excluding Data After Initiation of Glycemic Rescue Therapy
GFR Estimation MDRD (mL/min/1.73m2)
Change From Baseline (Mean ± SE)

1

0

-1

-2

-3

-4

-5
0 6 12 18 30 42 54
Week
Sitagliptin Glipizidea
APaT=All Patients as Treated ; GFR=glomerular filtration rate; SE=standard error.
a
Mean dose of glipizide was 7.7 mg per day.
1. Data on file, MSD.

24-hour Weighted Mean Glucose
Change From Baseline at Day 28
Sitagliptin, Linagliptin compared to placebo
Change from Baseline
at Week 24 (Primary End Point)

Baseline-HbA1c 7.17 ± 0.44 7.32 7.47 ± 0.53
± 0.59

5,0 n=38

0,0
24 h- Weighted Mean Glucose

0.1 ± 3.0
–5,0 n=40 n=39
n=40 n=39
[units: mg/dL] Mean ± SD

–1 0,0
–1 5,0
–20,0 * P < 0,001 vs placebo
–25,0
–30,0
-26.1 ± 2.8 -19.8 ± 2.9*

Sitagliptin Linagliptin Placebo
Ref.: clinicaltrials.gov 100 mg/day 5 mg/day

Fasting Plasma Glucose
Change From Baseline at Day 28
Sitagliptin, Linagliptin compared to placebo
Change from Baseline
at Week 24 (Primary End Point)

Baseline-HbA1c 7.17 ± 0.44 7.32 7.47 ± 0.53
± 0.59

5,0 n=38

0,0
[units: mg/dL]

n=41
n=40 n=39
n=39
Mean ± SD

–5,0 -0.1 ± 3.6
FPG

–1 0,0
* P = 0.0283
–1 5,0 vs placebo

–20,0
-15.6 ± 3.1 -10.9 ± 3.5 *

Sitagliptin Linagliptin Placebo
Ref.: clinicaltrials.gov 100 mg/day 5 mg/day

Head to Head Study
Linagliptin versus glimepride, both on top of
metformin Full Analysis Set
0,00%

- 0.16%
-0,10%

- 0.36%
-0,20%
- 0.60%

- 0.38%

-0,30% Glim
Lina
-0,40%
not c ude c 1 Ab H

-0,50% 0,22% 0,20%
Non-inferiority margin:
-0,60% 0.35%
r

52 weeks 104 weeks
Per protocol analysis (more robust)
i

Differences: 0.26% 0.28%

EMA/ European public assessment report Linagliptin

Linagliptin PK interacions
Efects of coadministered drugs on linagliptin
US- PI 2011

EMA Scientific discussion

EMA webside

Linagliptin Phase III Meta-analysis:
Cardiovascular Endpoints
Favors Linagliptin
 Secondary Endpoints: Hazard Rate Estimates Favors Comparators

CV death, MI, or stroke 0.17 0.36 0.78

All CV events* 0.33 0.55 0.94

FDA-custom MACE† 0.15 0.34 0.75

0.125 0.25 0.5 1 2 4

Ratio (95% CI) of linagliptin to control
*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.
ADA 2011 Poster 30-LB

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

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),

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
Sitagliptin (100 mg qd; n=20)

Vildagliptin (50 mg bid; n=18)
Plasma glucagon (mg/dL)

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

** * * * FPG PPG MPG MAGE
60 * * **

Glucose changes (mg/dL)
* -60

}
}
}
}
* * *
40
-40
*
20
-20
Intact GLP-1 (pmol/L)

30

0
20
*
* *
10 * * * * * MAGE = mean amplitude of glycaemic
*
excursion, determined from arithmetic
0 0 180 300 0 180 300 0 180 300 min
mean of differences between
Breakfast Lunch Dinner consecutive glycaemic peaks and
(+5 h) (+ 10 h) nadirs
Marfella et al J Diabetes Complication 2009

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??

Once-Daily Dosing of JANUVIA Delivers Maximal

DPP-4 Inhibition Over 24 Hours

Percent Plasma DPP-4 Inhibition*
100
Mean Percent Inhibition of DPP-4

90
80
70 Sitagliptin 100 mg QD
Activity (±SE)

60 Saxagliptin 5 mg QD
50 Vildagliptin 50 mg QD **
40 Vildagliptin 50 mg BID **
30 Placebo
20
10
0
0 5 10 15 20 25
Hours
* Single day dosing
** Vildagliptin is not approved in the US
65

OPTIMA : Optimized Glycemic Control With
Vildagliptin vs. Sitagliptin - Study Design1
CGM for
3 days
Inclusion Criteria: CGM for Vildagliptin + Metformin (N=19)
•Age > 18 yrs
3 days
•HbA1c between 6.5
and 8.0% CGM for
•BMI between 22 and R 3 days
45 kg/m2
2-4 Weeks
•Currently on stable,
maximum tolerated
metformin dose Sitagliptin + Metformin (N=19)

8 Weeks

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

67

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


68

Vildagliptin vs. Sitagliptin - Patient Characteristics1
Sitagliptin 100 mg QD Vildagliptin 50 mg BID
(N=19) (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

BID=twice daily; QD=once daily.

69

OPTIMA : Glycemic Variability Results Were Similar
Between Sitagliptin and Vildagliptin Treated Groups 1
P=0.83

At baseline
At 8 weeks
Variable, mg/dL

P=0.61 P=0.89

MAGE SD of 24-h MODD
Mean Glycemia

BID=twice daily; MAGE=mean amplitude of glycemic excursions; MODD=mean of daily differences; QD=once daily; SD=standard deviation.

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

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.

73

Glycemic Variability Results Were Similar Between
Sitagliptin and Vildagliptin Treated Groups1

P=0.83
At baseline
At 8 weeks
Variable, mg/dL

P=0.61 P=0.89

MAGE SD of 24-h MODD
Mean Glycemia

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.

74

Sitagliptin and Vildagliptin Increased the Time Patients
Spent in the Ideal Glycemic Range at 8 Weeks1
P=0.11
At baseline
At 8 weeks
Time, minutes

P=0.09

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

BID=twice daily; QD=once daily.

75

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

Mean Baseline HbA1c 7.12 7.14
N=16 N=14

-0.34a

-0.49b

P=0.42
a
P=0.09 .
b
P<0.001.

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 HbA 1c at 18
Weeks
Primary End Point (Per-Protocol Population; on background of metformin therapy)

Mean baseline HbA1c, % 7.69 7.68 Sitagliptin 100 mg + metformin
0.00 n=343 n=334 Saxagliptin 5 mg + metformin
Adjusted Mean HbA1c (SE), %

–0.15
Change From Baseline in

In the FAS population,
–0.30 numerically greater
HbA1c reductions from
–0.45 baseline were observed
for sitagliptin 100 mg
–0.60 –0.52
compared with saxagliptin
(95% CI: –0.60, –0.45) 5 mg. Difference between
–0.62 groups: 0.17% (95% CI:
–0.75
(95% CI: –0.69, –0.54) 0.06, 0.28)
0.09 (95% CI: –0.01, 0.20)a
(Prespecified noninferiority
margin=0.30%)
CI=confidence interval; FAS=full-analysis-set; SE=standard error.
a
Difference in adjusted change from baseline vs sitagliptin + metformin.
Scheen AJ et al. Diabetes Metab Res Rev. 2010;26(7):540–549.

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