XIX Congresso Nazionale AMD
Innovazione nella terapia e nei modelli assistenziali
Gabriele Perriello
Dipartimento di Medicina Interna
Università di Perugia
SITAGLIPTIN: nuove evidenze
scientifiche disponibili
Roma, 30 maggio 2013
Use DPP4-I for treatment of T2DM
Meal
No DPP-4
inhibitor present
Intestinal
GLP-1 & GIP
release
Active
GLP-1 & GIP
DPP-4
DPP-4
inhibitor present
Active
GLP-1 & GIP
DPP-4
DPP-4
inhibitor
GLP-1 & GIP
inactive
GLP-1 & GIP
inactive
(>80% of pool)
DPP-4=dipeptidylpeptidase-4;
GLP-1=glucagon-like peptide-1.
Ahrén et al. Diabetes Care 2003; 26: 2860–2864;
Deacon et al. Diabetes 1995;44:1126–1131;
Deacon, Holst. Biochem Biophys Res Commun 2002;294:1–4;
Demuth et al. Biochem Biophys Res Commun 2002;296:229–232;
Drucker. Diabetes Care 2003;26:2929–2940
Chemical structure of sitagliptin
(β-amino amide derivative)
The first DPP-4 inhibitor approved in 17th October 2006
for the treatment of type 2 diabetes
Substrate-like and Competitive DPP4 Inhibition
Substrato
naturale
(GLP-1,
GIP)
+
+
Inibitore-substrato
Inibitore
competitivo
(Sitagliptin,
Linagliptin)
K-1
Fast
(~1 sec)
K1
K2
K-1
Slow
(~1 h)
Complesso Inibitoresubstrato ed enzima
DPP-4
K1
K-1
DPP-4
+
Inattivo
GLP-1 o GIP
Complesso
GLP-1/DPP-4
DPP-4
+
Inibitore
K2
DPP-4
GLP-1 or GIP
Substrate-like
(Vildagliptin,
Saxagliptin)
K1
Complesso
inibitore/enzima
DPP-4
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1
.
Burkey BF, et al. Poster 0788 presented at EASD 2006; Deacon CF, Holst JJ. Adv Ther. 2009; 26: 488–499;
Miller SA, St Onge EL. Ann Pharmacother. 2006; 40: 1336–1343; Neumiller JJ. J Am Pharm Assoc. 2009; 49: S16–S29;
White JR. Clin Diabetes. 2008; 26: 53–57. Carolyn F Deacon et al. Expert Opin. Investig. Drugs (2010) 19(1):133-140
DPP-4
+
Inibitoresubstrato
inattivo
DPP-4
Selectivity for DPP-4 compared to the DPP gene
family (QPP/DPP-2, DPP-8 and DPP-9)
QPP*/DPP-2
DPP-8
DPP-9
Linagliptin
> 100,000
40,000
> 10,000
Sitagliptin
> 5,500
> 2,660
> 5,500
Vildagliptin
> 100,000
270
32
Saxagliptin
> 50,000
390
77
* Quiescent cell proline dipeptidase
Modified from Deacon CF. Diabetes, Obes Metab. 2011;13(1):7–18.
6
Absorption, availability, half-life and
distribution of DPP4-I
sitagliptin1
vildagliptin2
saxagliptin3-4
linagliptin5
1.5 h
Absorption tmax
1–4 h
1.7 h
2 h (4 h for
active
metabolite)
Bioavailability
~87%
85%
>75 %4
~30%
12.4 h
~2–3 h
2.5 h (parent)
3.1 h
(metabolite)
12 h
38% protein
bound
9.3% protein
bound
Low protein
binding
Half-life (t1/2) at
clinically
relevant dose
Distribution
95% protein
bound
DPP-4=dipeptidyl peptidase-4.
1. JANUVIA EU-SPC 2010. 2. Galvus EU-SPC 2010. 3. Onglyza EU-SPC 2010. 4. European Public Assessment Report for Onglyza. http://www.ema.europa.eu/docs/en_GB/
document_library/EPAR_-_Public_assessment_report/human/001039/WC500044319.pdf. Accessed October 14, 2010.
5. Christopher R et al. Clin Ther. 2008;30(3):513–527.
Percentuale di pazienti con DM2 con
HbA1c ≤7.0% al follow-up
Grado di
scompenso
al basale (HbA1c)
EXENATIDE
FUP A 4 MESI
FUP A 8 MESI
N.
TOT
%
N
TOT
%
Tra 7.1 e 8.0%
523
1007
51,9
267
489
54,6
Tra 8.1 e 9.0%
390
1367
28,5
226
620
36,4
≥ 9.1%
229
1359
16,8
119
579
20,5
Totale
1142
3733
30,6
612
1688
36,3
Grado di
scompenso
al basale (HbA1c)
SITAGLIPTIN
FUP A 4 MESI
FUP A 8 MESI
N
TOT
%
N
TOT
%
Tra 7.1 e 8.0%
1213
2190
55,4
579
967
59,9
Tra 8.1 e 9.0%
385
1290
29,8
204
554
36,8
≥ 9.1%
171
665
25,7
90
272
33,1
Totale
1769
4145
42,7
873
1793
48,7
Registro Farmaci Antidiabetici sottoposti a Monitoraggio; 3° report quedrimestrale; marzo 2009
Appropriatezza d’uso dei farmaci
incretinici in Italia
Trattamen
to
In associazione solo
con Metformina
Byetta/
Exenatide
In associazione solo
con Sulfaniluree
4002
In associazione
con Met+Sulf
633
Senza
associazione
Totale
pazienti
0
9449
4814
42%
Trattamento
In associazione
con
Metformina
In associazione
con Glitazoni
Senze
associazione
Totale
pazienti
Januvia
8129
720
31
8880
Xelevia
1493
140
4
1637
Tesavel
575
48
0
623
10197
908
35
11140
Totale
Sitagliptin
92%
Registro Farmaci Antidiabetici sottoposti a Monitoraggio; 3° report quedrimestrale; marzo 2009
L’associazione Sitagliptin/Metformina ha un
effetto additivo sull’attività del GLP-1 nativo
“Data on file MSD”
Efficacia di Sitagliptin in diverse
condizioni sperimentali controllate
TRIAL
DURATION
Δ HbA1c
L’associazione Sitagliptin/Metformina determina
una riduzione di 1,7% della HbA1c a 2 anni
HbA1c (mean change, %)
24-Week Phase*
Continuation Phase**
Extension Phase***
9
8.5
8
7.5
7
6.5
6
0
6
12 18 24 30
38
46
54
62
70
78
91
Time (weeks)
Sita 100 mg q.d. (n=50)
Sita = sitagliptin; Met = metformin
Met 1000 mg b.i.d. (n=87)
*Goldstein et al, Diabetes Care 2007;30:1979-87
**Williams-Herman et al. Curr Med Res Opin.2009; 25: 569–583
***Qi et al, presented at EASD, September 2008
Sita 50 mg b.i.d. + Met 1000 mg b.i.d. (n=105)
104
12
Similar Proportions of Patients Receiving Sitagliptin or
Glipizide Achieved HbA1c Levels <7.0% at 104 Weeks
Patients With
HbA1c <7%, %
2-Year Per-Protocol Population
(Patients Inadequately Controlled on Metformin)
Sitagliptin + metformin
Glipizide + metformin
n=248
Seck T et al. Int J Clin Pract. 2010;64(5):562–576.
n=256
n=193
n=196
Sitagliptin vs Glipizide: Weight Change and
Incidence of Hypoglycemia
Body weight at week 104
Hypoglycemia over 104 weeks
Between-groups difference = –28.8%
(95% CI: –33.0, –24.5)
Patients With
at Least 1 Episode, %
LS Mean (±95% CI) Body Weight
Change From Baseline, kg
Between-groups difference = –2.3 kg
(95% CI: –3.0, –1.6)
n=588
Sitagliptin + metformin
Glipizide + metformin
Seck T et al. Int J Clin Pract. 2010;64(5):562–576.
n=584
Effetti metabolici dell’aggiunta di
sitagliptin all’insulina
Popolazione FAS a settimana 24 (LOCF)a
Sitagliptin (n=305)
Placebo (n=312)
aEsclusi
0
P<0,001
0,0
(–0,1, 0,1)
–0.5
–0,6
(–0,7; 0,5)
–1
Differenza = –
0,6%
(P<0.001)
I dati dopo terapia rescue.
FAS=full analysis set; LOCF=last observation carried forward.
Vilsbøll T et al. Diabetes Obes Metab. 2010;12(2):167–177.
Pazienti a goal di HbA1c, %
Variazione media della HbA1c
dal basale, % - LS(95% CI)
0.5
HbA1c Goal <7%
15
Aggiunta di sitagliptin all’insulina
Ipoglicemie nelle 24 ore 20
17,5
18
Aggiunta di Sitaglip8n (n=61) Dose Crescente di Insulina (n=63) 16
14
12
10
8
8,2
P <0.05 4,8
6
4
1,6
2
0
Hypoglycemia
Ipoglicemia
* Hong ES et al. Diabetes Obes Metab. 2012 Severe
Hypoglycemia
Ipoglicemia
Severa
LS media della variazione in perso corporeo (kg) PazienJ con numero di ipoglicemie >1 (%) P <0.05 Differenza in Peso Corporeo a 24 se1 Δ = –1.7 kg (95% IC, –2.5, –0.5; P <0.05) 1.1 (95% CI, 0.2, 1.8) –0.7 (95% CI, –1.4, –0.1) 16
Sitagliptin in Older Patients With Type 2 Diabetes:
Change in HbA1c From Baseline at 24 Weeks
Full Analysis Set
HbA1c LS Mean (± SE)
Change From Baseline, %
0.4
0.2%
0.2
0.0
LS mean difference
–0.7%; P<0.001
–0.2
–0.4
–0.5%
–0.6
0
6
12
Week
Placebo (n=91)
Mean baseline HbA1c=7.71%
LS=least-squares; SE=standard error.
Curr Med Res Opin 2011, vol 27, 5: 1049-1058
18
24
Sitagliptin (n=101)
Mean baseline HbA1c=7.82%
Sitagliptin vs Glipizide in Patients With Type 2
Diabetes Mellitus and Moderate-to-Severe Chronic
Renal Insufficiency: HbA1c Results at 54 Weeks
LS Mean Change From
Baseline, % (95% CI)
Per Protocol Population
0.0
–0.1
−0.2
−0.3
−0.4
−0.5
−0.6
−0.7
−0.8
−0.9
−1.0
Baseline HbA1c; sitagliptin = 7.8%; glipizide = 7.8%
LS Mean Between-Groups Difference (95% CI):
–0.1% (–0.3, 0.1)
Noninferiority: upper bound of the 95% CI
around the between-group difference < 0.4%.
−0.6%
−0.8%
0
6
12
18
24
30
36
42
48
54
Week
Sitagliptin (n=135)
Glipizidea (n=142)
CI=confidence interval.
aMean dose of glipizide was 7.7 mg per day.
1. Arjona Ferreira JC et al. Diabetes Care. 2012 December 17. [Epub ahead of publication].
Symptomatic Hypoglycaemia AEs
Percent of Patients
-10.8
(-17.1, -4.8)
p=0.001
-1.4
(-4.8, 1.5)
All
Hypoglycaemia
AEs
Δ (95% CI)
Severe
Hypoglycaemia
AEs
Sitagliptin (N=210)
-1.5
(-4.2, 0.3)
Required
Non-medical
Assistance
-0.9
(-4.2, 2.0)
Required
Medical
Assistance
Glipizide (N=212)
1. Arjona Ferreira JC et al. Diabetes Care. 2012 December 17. [Epub ahead of publication].
Change from Baseline in Body Weight
Week 54
2
1
0
-1
-2
0
6
12
18
24
30
38
46
54
Body Weight (kg) Change from
Baseline (LS Mean, 95% CI)
Body Weight (kg) Change from
Baseline (LS Mean ±SE)
Δ = -1.8 kg; p<0.001
Week
Sitagliptin
Glipizide
1. Arjona Ferreira JC et al. Diabetes Care. 2012 December 17. [Epub ahead of publication].
Sitagliptin (N=143)
Glipizide (N=148)
Exposure-adjusted Incidence Rate of Confirmed,
Adjudicated CV Serious AEs and Heart Failure
During Week 0 to Week 54 + 28 Days
Number of Patients With ≥ 1 Event/
Patient-Years Follow-up Time (100- Difference in Incidence
Rate vs. Glipizide
Patient-Years Incidence Rate)
Sitagliptin
N=64
Glipizide
N=65
Estimate (95% CI)
Cardiovascular death or sudden death
2/69.2 (2.9)
4/71.0 (5.6)
-3.2 (-12.8, 5.2)
Cardiovascular death
2/69.2 (2.9)
1/72.1 (1.4)
1.1
Sudden death
0/71.3 (0.0)
3/71.6 (4.2)
-4.4
Cardiac events, excluding heart failure
2/69.5 (2.9)
1/72.1 (1.4)
1.9 (-5.1, 10.2)
Resuscitated cardiac arrest
1/70.3 (1.4)
1/72.1 (1.4)
0.3
Unstable angina pectoris
1/70.5 (1.4)
0/72.7 (0.0)
1.6
Cerebrovascular events
0/71.3 (0.0)
1/71.7 (1.4)
-1.5 (-8.4, 4.0)
Stroke, unknown mechanism
0/71.3 (0.0)
1/71.7 (1.4)
-1.5
Peripheral vascular events (peripheral
arterial thrombosis/thromboembolism)
0/71.3 (0.0)
0/72.7 (0.0)
0.0 (-5.6, 5.5)
Heart failure
2/69.9 (2.9)
2/71.0 (2.8)
-1.5 (-10.5, 5.8)
Arjona Ferreira JC et al. Am J Kidney Dis 2013
Safety and tolerability of sitagliptin in T2DM: pooled analysis of 25 clinical studies
Engel et al. Diabetes Ther (published online 23 may 2013)
7 years later…..
Sitagliptin is a highly-selective DPP-4 inhibitor
● Sitagliptin has a favorable PK/PD profile
● Sitagliptin combination therapy with metformin
provided substantial and durable glucoselowering efficacy
● Sitagliptin is advantageous when combined to
insulin
•  Sitagliptin should be preferred in older
individuals
•  Sitagliptin may be safely used in moderate-tosevere chronic renal insufficiency
● Sitagliptin
has been shown to have a
favorable risk-to-benefit profile
●
Effect of Sitagliptin on Myocardial Response to Dobutamine
Stress in Patients with Coronary Artery Disease
Ejection Fraction (%)
A single 100 mg sitagliptin or P and 75 g of glucose
Read PJ, Circ Cardiovasc Imaging. 2010 Mar;3(2):195-201
LEADER
Jan 2016
Liraglutide 1.8 mg QD
vs Placebo
8,754
CV death, nonfatal MI or stroke;
expanded composite CV
EXSCEL
Mar 2017
Exenatide LAR 2 mg
OW
vs Placebo
9,500
All-cause mortality, MACE, or
hospitalization for ACS or heart
failure
ELIXA
-
Lixisenatide 20 µg QD
vs Placebo
6,000
Nonfatal MI, nonfatal stroke,
hospitalization for unstable angina,
or CV death
REWIND
-
Dulaglutide 20 µg OW
vs Placebo
9,600
Nonfatal MI, nonfatal stroke, or
CV death
SAVOR-TIMI
Jun 2015
Saxagliptin 5 mg or 2.5
mg
vs Placebo
16,000
CV death, nonfatal MI or ischemic
stroke; hospitalization for heart
failure, unstable angina pectoris, or
coronary
Revascularization
TECOS
Dec 2014
Sitagliptin 100 mg (50
mg in CDK)
vs Placebo
14,000
CV-related death, nonfatal MI or
stroke, or unstable angina requiring
hospitalization
CAROLINA
Sep 2018
Linagliptin 5 mg
vs Glimepiride 1-4 mg
6,000
CV death, non-fatal MI or stroke, or
hospitalisation for unstable angina
pectoris
XIX Congresso Nazionale AMD
Innovazione nella terapia e nei modelli assistenziali
Gabriele Perriello
Dipartimento di Medicina Interna
Università di Perugia
Grazie per la
vostra attenzione
Roma, 30 maggio 2013