farmaci innovativi nella terapia del diabete mellito di tipo 2 · pdf filefarmaci innovativi...
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Giorgio Sesti
Farmaci innovativi nella terapia del diabete
mellito di tipo 2
Università “Magna Graecia” di Catanzaro
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Il Prof Giorgio Sesti dichiara di aver ricevuto negli ultimi due anni compensi o
finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche:
Novo Nordisk, Novartis, MSD, Boehringer‐Ingelheim-Lilly, Bristol-Myers Squibb,
Sanofi e Janssen-Cilag per attività di Relatore/Moderatore ad eventi.
Novo Nordisk, Intarcia, Boehringer‐Ingelheim-Lilly, MSD, Servier, Sanofi,
AstraZeneca e Janssen-Cilag per attività di Consulenza.
Potenziali conflitti di interesse
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1950 1960 1970 1980 1990 2000 2010
Vasodilators
Adrenergic neural blockers
Diuretics
Central α-2 blockers
-blockers
Peripheral α-2 blockers
Ca+ blockers ACE-I
ARBs
Sulphonylureas
Renin inhibitors
Metformin
α-glucosidase inhibitors
TZDs
Glinides
GLP-1R agonists
Amylino mimetics
DPP4-I
Bile acid sequestrants
SGTL2 Inh
Dopamine agonists
Nu
mb
er
of
Me
dic
ati
on
Cla
sse
s
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Decreased Glucose Uptake
Increased Lipolysis and Adipokines
Increased HGP
Islet -cell
Increased Glucagon Secretion
Decreased Incretin Effect
Islet β-cell Impaired Insulin Secretion
HYPERGLYCEMIA
DPP-4 Inh. GLP-1R agonists
SU DPP-4 Inh.
GLP-1R agonists Insulin
DPP-4 Inh. GLP-1R agonists
Metformin TZDs
DPP-4 Inh. GLP-1R agonists
Insulin
TZDs Metformin
Insulin
TZDs Insulin
Increased Glucose Reabsorption
SGTL2 inhibitors
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GLP-1 targets multiple organs to improve glucose control in T2DM
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DPP-4 inhibitors
Liraglutide
Human GLP-1 analogues
Exendin-based therapies
GLP-1 receptor agonists
Incretin-based therapies: launched and in development
Incretin-based therapies
Albiglutide (Phase 3)
Dulaglutide (Phase 3)
Semaglutide (Phase 3)
Sitagliptin Linagliptin Saxagliptin Vildagliptin (Europe and Australia)
Alogliptin (US and Japan)
Teneligliptin (Japan only)
Exenatide OW Exenatide BID Lixisenatide
(Europe)
Anagliptin (Phase 3)
Gemigliptin (Phase 3)
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GLP‐1 receptor agonists structural differences
Werner U, et al. Regul Pept 2010;164:58–64. Sanofi; data on file. Kim et al. Diabetes Care 2007;30:1487-93. Russell-Jones, D. Molecular and Cellular Endocrinology 297 (2009) 137–140
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Short-acting and long-acting GLP-1 receptor agonists
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Consider pathophysiological basis (declining beta-cell function,
glucagon secretion)
Consider efficacy
Consider side effects
Increased risk of hypoglycaemia
Weight gain
Consider effects on CV risk
Challenges in the management of type 2 diabetes
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Beta-cell stimulation by saxagliptin in patients with T2D Insulin secretion rates in the postprandial state
* Values are geometric means; † Adjusted % change from baseline, geometric mean and 95% CI (represented by bar) SAXA: saxagliptin; PBO: placebo; T2D: type 2 diabetes; LOCF, last observation carried forward.
Insulin secretion rate during IV-Oral hyperglycaemic clamp: adjusted % change from baseline at Week 12
Adapted from Henry R, et al. Diabetes Obes and Metab 13: 850–858, 2011
SAXA 5 mg (n=16) PBO (n=15)
30
-10
10
20
Ge
om
etr
ic m
ea
n %
ch
an
ge
fro
m b
ase
lin
e
-20
0
-
-
-
-
-
-2.2†
15.9†
4.2
Adjusted % difference PBO (95% CI): 18.5 (1.3, 38.7)
P=0.035
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Restoration of Insulin Release with Lixisenatide in Patients with Type 2 Diabetes
Adapted from Becker R et al. Diabetes 2010;59(Suppl 1):552-P
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Glucagon secretion
Pancreatic cells: -cell -cell -cell
Hepatic glucose production
Insulin secretion
Eccessive hepatic glucose production
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Vilda=Vildagliptin; PBO=Placebo, AUE=Area Sotto La Curva Effetto Δ si riferisce a AUE 0-840 min P<0.05 vs. PBO
Data on file, Novartis Pharmaceuticals, LAF237A2346
Singola dose orale di vildagliptin (100 mg) prima di cena
cena dose
Δ = 94% P = 0.02 *
* * * *
*
*
*
* *
* -60
-50
-40
-30
-20
-10
0
10
20
-60 0 60 120 180 240 300 360 420 480 540 600 660 720 780 840
Tempo (min)
De
lta
Glu
ca
go
ne
(n
g/L)
Placebo (16)
Vilda 100 mg (16)
Vildagliptin inibisce la secrezione di glucagone nel corso della notte
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Vilda = Vildagliptin; PBO = Placebo, AUE = Area Sotto La Curva Effetto RaE velocità di comparsa del glucosio endogeno; Δ si riferisce alla AUE 0-840 min; *P<0.05 vs. PBO
Data on file, Novartis Pharmaceuticals, LAF237A2346
Singola dose orale di vildagliptin (100 mg) prima di cena
Δ = 59% P = 0.004
*
* * * * *
* * * * *
* * *
* -1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
-60 0 60 120 180 240 300 360 420 480 540 600 660 720 780 840
Tempo (min)
De
lta
EG
P (
mg
/k
g/m
in)
cena dose
Placebo (16)
Vilda 100 mg (16)
Vildagliptin sopprime la produzione endogena di glucosio nel corso della notte
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Placebo BID Exenatide 0.1 µg/kg BID
Exenatide or Placebo Standardized Breakfast
Pla
sm
a G
luca
go
n (
pg
/m
L)
Time (min)
Single-blind, placebo-controlled crossover study (with two 5-d periods) of patients with T2D, n = 20 Mean ± SE; *P = 0.0123; BID indicates twice daily
Adapted from Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88:3082-3089.
0 120 180 60
50
100
150
200
• Exenatide significantly reduced AUC0-180 min
Exenatide Suppresses Inappropriately Elevated Postprandial Glucagon Secretion in T2D
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Consider pathophysiological basis (declining beta-cell function,
glucagon secretion)
Consider efficacy
Consider side effects
Increased risk of hypoglycaemia
Weight gain
Consider effects on CV risk
Challenges in the management of type 2 diabetes
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Network meta-analysis of pairwise comparisons of randomized controlled trials evaluating the use of anti-hyperglycemic agents in addition to metformin vs.
placebo: mean change from baseline in A1C
Liu S-C et al. Diabetes Obes and Metab 14: 810–820, 2012
-0,82
-0,71
-0,82
-0,66 -0,69
-1,02
-0,88
-1,07
-1,2
-1
-0,8
-0,6
-0,4
-0,2
0
SU Glinides TZDs Acarbose DPP-4 GLP-1R Basal Biphasic inhibitors agonists insulin insulin
Me
an
ch
an
ge
fro
m b
ase
lin
e i
n A
1C
le
ve
l
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Efficacy of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial
Bergenstal RM et a. Lancet 376: 431-9, 2010
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Consider pathophysiological basis (declining beta-cell function,
glucagon secretion)
Consider efficacy
Consider side effects
Increased risk of hypoglycaemia
Weight gain
Consider effects on CV risk
Challenges in the management of type 2 diabetes
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Correlation between risk of severe hypoglycemia and cardiovascular death associated with intensive treatment: ACCORD, ADVANCE, PROACTIVE, UKPDS and VADT
meta-analysis
Mannucci E. et al. Nutr Metab Cardiovasc Dis 19:604-612, 2009
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Network meta-analysis of pairwise comparisons of randomized controlled trials evaluating the use of anti-hyperglycemic agents in addition to metformin vs. placebo: At
least one event of overall hypoglycaemia (odds ratio)
Liu S-C et al. Diabetes Obes and Metab 14: 810–820, 2012
8,86
10,51
0,45 0,4 1,13 0,92
4,77
17,78
0
2
4
6
8
10
12
14
16
18
20
SU Glinides TZDs Acarbose DPP-4 GLP-1 Basal Biphasic inhibitors agonists insulin insulin
At
lea
st
on
e e
ve
nt
of
ove
rall
hyp
og
lyca
em
ia
(o
dd
s r
ati
o)
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Consider pathophysiological basis (declining beta-cell function,
glucagon secretion)
Consider efficacy
Consider side effects
Increased risk of hypoglycaemia
Weight gain
Consider effects on CV risk
Challenges in the management of type 2 diabetes
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Network meta-analysis of pairwise comparisons of randomized controlled trials evaluating the use of anti-hyperglycemic agents in addition to metformin vs. placebo:
Mean change from baseline in body weight
Liu S-C et al. Diabetes Obes and Metab 14: 810–820, 2012
2,17
1,4
2,46
-1,01
0,23
-1,66
1,38
3,41
-2
-1
0
1
2
3
4
SU Glinides TZDs Acarbose DPP-4 GLP-1 Basal Biphasic inhibitors agonists insulin insulin
Me
an
ch
an
ge
fro
m b
ase
lin
e i
n b
od
y w
eig
ht
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Pratley RE et al. Lancet 375: 1447–1456, 2010
Liraglutide vs. sitagliptin for type 2 diabetes patients who did not have adequate glycaemic control with metformin: Change in body weight
–3.38 kg
–2.86 kg
–0.96 kg
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Consider pathophysiological basis (declining beta-cell function,
glucagon secretion)
Consider efficacy and durability
Consider side effects
Increased risk of hypoglycaemia
Weight gain
Consider effects on CV risk
Challenges in the management of type 2 diabetes
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Odds ratio [95% CI]
p-value
Major CV event1 0.71 [0.59, 0.86] < 0.001
Acute MI 0.64 [0.44, 0.94] 0.023
Stroke 0.77 [0.48, 1.24] 0.29
Mortality 0.60 [0.41, 0.88] 0.008
CV mortality 0.67 [0.39, 1.14] 0.14
Meta-analysis of 70 short- and medium-term trials, with 41,959 patients and mean follow-up of 44.1 weeks
DPP4 inhibitor better
Comparator better
In a large meta-analysis of CV events, DPP-4i were better than the comparator in terms of CV safety
AMI, acute myocardial infarction; CV, cardiovascular; DPP4i, dipeptidyl peptidase-4 inhibitors; MACE, major CV events.
Monami M, et al. Diabetes Obes Metab 15:112–120, 2013
0.0 1.0 10.0
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FREEDOM-CVO (ITCA 650, GLP-1 in DUROS) n=2-3,000; duration ~2 yrs
end Q3 2018
Cardiovascular outcomes trials for GLP-1 and DPP4i
Source: ClinicalTrials.gov (October 2013) and LLY Investor call ADA 2013
TECOS (Sitagliptin, DPP4i)
n=14,000; duration ~4-5yrs end Q4 2014
CAROLINA (Linagliptin, DPP4i vs SU) n= 6,000; duration ~8 yrs
end Q3 2018
ELIXA (Lixisenatide, GLP-1)
n=6,000; duration ~4 yrs end Q3 2014
REWIND (Dulaglutide, QW GLP-1) n=9,622; duration ~8 yrs
end Q2 2019
SUSTAIN 6 (Semaglutide, GLP-1)
n=3,260; duration ~2.8 yrs end Q1 2016
Pre-approval Post-approval Pre + post approval
Other
LEADER (Liraglutide, GLP-1)
n=9,340; duration 3.5-5 yrs end Q1 2016
SAVOR TIMI-53 (Saxagliptin, DPP4i)
n=16,492; follow-up ~2 yrs end Q2 2013 - RESULTS
CARMELINA (Linagliptin, DPP4i)
n= 8,300; duration ~4 yrs end Q1 2018
EXAMINE (Alogliptin, DPP4i)
n=5,380; follow-up ~1.5 yrs end Q2 2013 - RESULTS
2019 2011 2015 2012 2013 2014 2016 2017 2018
EXSCEL (Exenatide QW GLP-1)
n=9,500; duration ~5.5 yrs end Q1 2017
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Scirica BM et al. N Engl J Med 2013
16,492 patients, median followup 2.1 years
Saxagliptin and cardiovascular outcomes in patients with T2DM SAVOR-TIMI
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White WB et al. N Engl J Med 2013
Alogliptin after acute coronary syndrome in patients with T2DM EXAMINE
5380 patients, median follow-up 18 months
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Effect of GLP-1 receptor agonists on fatal and nonfatal major cardiovascular events (MACE)
Monami M et al. Diabetes Obes Metab 16: 38–47, 2014
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Alterata omeostasi glucidica
Glucosuria
Alterata secrezione insulinica
Insulino-resistenza
Aumentata produzione di
glucosio 200 mg/dl
Glicemia a digiuno
<100 mg/dl
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Riassorbimento del glucosio nel rene
SGLT2
90%
Glucose Sodium-glucose cotransporters 1 and 2 (SGLT1 e SGLT2)
10%
SGLT1
Escrezione di glucosio
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Sodium glucose transportation
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Escrezione renale del glucosio
600
400
200
0 0 200 400 600 800
Ve
locit
à d
i fi
ltra
zio
ne
de
l g
luco
sio
/
Ria
sso
rbim
en
to/E
scre
zio
ne
(m
g/m
in)
Glucosio plasmatico (mg/dL)
Glucosio
filtrato
Glucosio
escreto
Glucosio
Riassorbito
Soglia
Silverman M, Turner RJ. Handbook of Physiology. Windhager EE, ed. 1992; Oxford University Press: 2017-2038. (has graph for normal) Katsuno K, et al. J Pharm Exp Therap. 2007;320:323-330
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Escrezione renale del glucosio con inibitori del SGLT2
600
400
200
0 0 200 400 600 800
Ve
locit
à d
i fi
ltra
zio
ne
de
l g
luco
sio
/
Ria
sso
rbim
en
to/E
scre
zio
ne
(m
g/m
in)
Glucosio plasmatico (mg/dL)
Glucosio
filtrato
Glucosio
escreto
Inibitori del SGLT2
Soglia
Silverman M, Turner RJ. Handbook of Physiology. Windhager EE, ed. 1992; Oxford University Press: 2017-2038. (has graph for normal) Katsuno K, et al. J Pharm Exp Therap. 2007;320:323-330
Glucosio
Riassorbito
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Expected clinical effects of SGLT2 inhibition based on the mode of action
Increased Glucose Excretion
Increased Sodium Excretion
Reduced sodium load
Blood Pressure
Loss of energy (calories) Body weight
Reduced glycaemia FPG PPG HbA1c
Modified from Abdul-Ghani MA, et al. Endocr Rev. 2011; 32:515–31 SGLT2: sodium-glucose transporter 2
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Chemical structure of SGLT2 inhibitors in late-stage clinical trials
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Efficacy of Canagliflzoin on HbA1c in placebo-controlled studies*: Change from baseline
-0.26% -0.16% -0.21% -0.14% -0.09% -0.09% -0.13% ∆ 300 mg vs 100 mg
8.01% 7.94% 8.13% 7.9% 8.27% 8.35% 7.7% Baseline HbA1c
0,14
-0,17-0,13
-0,26
0,010,04
-0,03
-0,77-0,79
-0,85-0,89
-0,63
-0,7
-0,6
-1,03
-0,95
-1,06-1,03
-0,72
-0,79
-0,73
-1,2
-1
-0,8
-0,6
-0,4
-0,2
0
0,2
Hb
A1
c (%
)
PBO
CANA 100 mg
CANA 300 mg
P <0.05 vs PBO for both
CANA doses in all studies
*excluding the study in patients with chronic renal impairment
•DIA3005 •+ Diet/Ex
DIA3006 + MET
DIA3002 + MET/SU
DIA3012 + MET/Pio
DIA3008 + insulin
DIA3008 + SU
DIA3010 + Any
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Changes from baseline in HbA1C in Phase 3 Dapagliflozin studies
Wilding JPH, et al. Abstract 78-OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010; Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224; Bailey CJ, et al. Lancet. 2010;375(9733):2223-2233.
-0,23
-0,59
-0,79
-0,89
-0,3
-0,68-0,7
-0,85
-0,12
-0,59
-0,65
-0,81
-0,3
-0,75
-0,82
-0,91
-1
-0,9
-0,8
-0,7
-0,6
-0,5
-0,4
-0,3
-0,2
-0,1
0
Placebo Dapa 2.5mg Dapa 5mg Dapa 10mg
Monotherapy
Add-on Met
Add-on SU
Add-on Insulin
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Dapagliflozin: Weight loss after 24 weeks
• *p<0.05, **p<0.001 vs placebo CI, confidence interval; Dapa, dapagliflozin; PIO, pioglitazone; SU, sulphonylurea Bristol-Myers Squibb/AstraZeneca briefing document
Placebo-corrected mean weight reductions over 24 weeks ranged from 0.46 to 2.16 kg
ΔW
eig
ht
(kg
) w
ith
95
% C
I
Baseline
–4.5
–3.5
–2.5
–1.5
–0.5
0.5
1.5
2.5
–2.7*
–2.6*
–2.7*
–1.0
–3.3
–2.8 –3.2
–2.2
–2.2**
–3.0**
–2.9**
–0.9 –1.2
–1.6*
–2.3**
–0.7
0.1**
–0.1**
1.6
–1.0** –1.0**
–1.7**
0.0
Dapa 1.0 mg Dapa 2.5 mg Dapa 5.0 mg Dapa 10.0 mg Placebo
86.9 kg
Low-dose monotherapy
90.2 kg
Monotherapy
85. 9 kg
Add-on to metformin
81.1 kg
Add-on to SU
86.3 kg
Add-on to PIO
93.8 kg
Add-on to insulin
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Percent Change in Body Weight (LOCF)*
45
LS
mean
% c
han
ge (
±S
E)
fro
m b
ase
lin
e
GLIM CANA 100 mg CANA 300 mg
0 8 12 18 26 36 44 52
Time point (wk)
Baseline (kg)
64 78 88 104
LS mean % change
–4.2% (–3.6 kg)
–4.1% (–3.6 kg)
0.9% (0.8 kg)
–5.1% (95% CI: –5.6, –4.5) (–4.3 kg) ([95% CI: –4.8, –3.8])
–5.2% (95% CI: –5.7, –4.6) (–4.4 kg) ([95% CI: –4.9, –3.9])
86.6 86.8 86.6
4
*N = 1,450 (Baseline); N = 1,425 (Week 4); N = 1,436 (Week 8); N = 1,438 (Weeks 12, 18, 26, 36, 44, 52, 64, 78, 88, and 104).
–6
–5
–4
–3
–2
–1
0
1
2
Cefalu WT et al. Poster presented at the 73rd Scientific sessions of the American Diabetes Association (ADA), 2013; Jun. 21-25; Chicago, (65-LB).
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Proportion of subjects with documented hypoglycemia episodes through week 104
46
40,9
6,8 8,2
0
20
40
60
80
100
GLIM
CANA 100 mg
CANA 300 mg
Pe
rce
nta
ge
of
su
bje
cts
Rates of severe hypoglycemia were lower with CANA 100 and 300 mg relative to GLIM (0.6%, 0.2%, and 3.3%, respectively).
Cefalu WT et al. Poster presented at the 73rd Scientific sessions of the ADA, 2013; Jun. 21-25; Chicago, Illinois, (65-LB).
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Efficacy of Canagliflozin on Systolic Blood Pressure: Change from Baseline-Placebo-controlled Phase 3 Studies
-3.7*
-5.4* -0.1
-2,2
-4.1†
-2.6*
-4.6*-5.4*
-6.6* -1.8
-1,6
-3.5† -4.4*
-7.9*-12,0
-10,0
-8,0
-6,0
-4,0
-2,0
0,0
2,0
4,0
6,0
8,0
* p<0.001; ** p<0.05 Based on ANCOVA models, data prior to rescue (LOCF)
127.7 BL Mean
SBP (mmHg) 128.2 136.2 130.5 127.2 137.8
-1.33 -0.95 -4.03 -0.16 1.02 -0.70 -0.24 -3.75 -0.53 -0.08 -1.11 -0.22
Pla
ce
bo
-su
btr
acte
d L
S M
ea
n C
ha
ng
e
in S
ysto
lic B
P (
mm
Hg
) (9
5%
CI)
-1.18 0.22
CANA 100 mg CANA 300 mg
131.1
Pulse rate (bpm) LS mean change
No clinically meaningful changes in pulse rate
Monotherapy (DIA3005)
N =584
Metformin (DIA3006) N = 1284
SU (DIA3008)
N = 127
Met/SU
(DIA3002) N = 469
Met/Pio
(DIA3012) N = 342
Insulin (DIA3008) N = 1718
Current Therapy in Older Subjects
(DIA3010) N = 714
Add-on combinations with
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Vasilakou D et al Ann Intern Med 159: 262-274, 2013
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Flow-chart per la terapia del diabete mellito di tipo 2
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THANK YOU !
Now it’s time for discussion.
Sesti lecture