GIORNATE DIABETOLOGICHE d e l l ’ E M I L I A - R O M A G N A :
RENE CUORE E DIABETE
1 EDIZIONE
1a
Left Ventricular dysfunction in
T2 Diabetes (the DYDA Study)
Marco Comaschi
DYDA
p
, multicenter,, epidemiological
p
g
study
y
Prospective,
Primary objectives
To evaluate the prevalence of left ventricular
dysfunction (LVD)
(LVD), diastolic or systolic in patients with
type II diabetes mellitus in the absence of clinical
signs/symptoms of cardiac abnormalities
To identify the predictors of LVD
LVD = Left Ventricular Dysfunction (systolic and/or diastolic)
Systolic dysfunction (EF ≤50% and/or MFS ≤15%)
Diastolic dysfunction (deceleration time ≤140 or 1.5<E/A<0.75)
Secondary objectives
• To evaluate the incidence of LVD, either systolic or
di t li att 2 year follow-up
diastolic,
f ll
i patients
in
ti t without
ith t LVD att
study entry
• To evaluate
l
the
h incidence
i id
andd the
h characteristics
h
i i of ECG
abnormalities at 2 year follow-up in patients with a
normall ECG at study
d entry
• To evaluate the 2-year incidence of a combined outcome
measure of all-cause death and hospitalizations for CV
causes
• To identify the predictors of CV events (all-cause death
or CV hospitalizations)
p
)
STUDY POPULATION
Inclusion criteria
• Type 2 diabetes
• No symptoms and/or clinical signs of cardiac
diseases
• Age > 45 years
Note: Left ventricular hypertrophy was not
considered
id d as an exclusion
l i criteria
it i
970
patients enrolled
p
10 patients with
protocol violation
960
yp
population
p
study
Baseline characteristics
Total population
(n 960)
(n.
Age (yrs), median IQR [25%-75%]
Females %
Females,
BMI (kg/m2), median IQR [25%-75%]
61 [56-67]
38 1
38.1
28.0 [25.5-31.2]
g ((BMI 25 - <30),
), %
Overweight
43.9
Obese (BMI ≥30), %
pharmacologically treated %
34.7
0.8
HR (bpm), median IQR [25%-75%]
72 [66-80]
SBP (mmHg), median IQR [25%-75%]
137 [130-145]
DBP (mmHg),
(
H ) median
di IQR [25%-75%]
[25% 75%]
80 [75
[75-85]
85]
Waist circonference (cm), median IQR [25%-75%]
Males, median IQR [25%
[25%-75%]
75%]
Females, median IQR [25%-75%]
99 [92-106]
100 [94-107]
[94 107]
98 [90-105]
Waist circonference and BMI
Waist circonference (cm)
Median [25%-75%]
Total population
BMI <25 kg/m2
BMI [25-30) kg/m2
BMI ≥30 kg/m2
99 [92-106]
89 [83
[83-94]
94]
98 [93-102]
108 [102-115]
Males
BMI <25 kg/m2
BMI [[25-30)) kg/m
g 2
BMI ≥30 kg/m2
100 [94-107]
90 [86-95]
98 [[94-102]]
110 [105-116]
BMI <25 kg/m
k / 2
BMI [25-30) kg/m2
BMI ≥30 kg/m2
98 [90-105]
85 [80
[80-92]
92]
96 [89-102]
104 [99-112]
Females
Pharmacological treatment
%
Betablockers
11.5
ACE-inhibitors
31.5
ARBs
25.9
Diuretics
22.3
Ald
Aldosterone
bl k
blockers
09
0.9
CCBs
17.2
ASA
26.9
Other antiplatelets
4.3
Statins
37.9
n-3 PUFA
3.7
Other antihypertensive agents
5.9
Bronchodilators
17
1.7
FANS
1.3
Allopurinol
2.7
Antidepressants
1.6
Benzodiazepine
2.0
DYDA: Total population (n. 970)
LVD = Left Ventricular Dysfunction (systolic and/or diastolic)
DYDA: Patients with ventricular function
measurable (n.
(n 751)
LVD = Left Ventricular Dysfunction (systolic and/or diastolic)
Systolic dysfunction (EF ≤50% and/or MFS ≤15%)
Diastolic dysfunction (deceleration time ≤140 or 1.5<E/A<0.75)
Independent predictors of LV dysfunction
(n 450/751 pts)
(n.
Model adjusted for
clinical
li i l variables
i bl andd laboratory
l b
examinations
i i
and pharmacological treatments and ECG
Age (continuous
(contin o s variable)
ariable)
HbA1c (continuous variable)
Ti l
Triglycerides
id (continuous
(
i
variable)
i bl )
Metformin
Glitazones
P wave (V1) ≥40msec
Doxazosine
OR
1 05
1.05
1.26
1 003
1.003
1.63
0.53
1.51
2.24
95%CI
1 02 1 07
1.02-1.07
1.08-1.48
1 001 1 005
1.001-1.005
1.11-2.39
0.30-0.94
1.02-2.22
1.03-4.90
Published papers
Inappropriately high left ventricular mass in patients with type 2 diabetes mellitus
and no overt cardiac disease.
disease The DYDA study.
study
Cioffi G, Faggiano P, Lucci D, Di Lenarda A, Mureddu GF, Tarantini L, Verdecchia
P, Comaschi M, Giorda CB, Velussi M, Chinali M, Latini R, Masson S, De
Simone G; DYDA Investigators.
Investigators
J Hypertens. 2011 Oct;29(10):1994-2003.
Analysis of midwall shortening reveals high prevalence of left ventricular
myocardial dysfunction in patients with diabetes mellitus: the DYDA study.
Cioffi G, Giorda CB, Chinali M, Di Lenarda A, Faggiano P, Lucci D, Maggioni AP,
Masson S,, Mureddu GF,, Tarantini L,, Velussi M,, Comaschi M.
Eur J Cardiovasc Prev Rehabil. 2011 Jul 28.
Predictors of early-stage
y
g left ventricular dysfunction
y
in type
yp 2 diabetes: results of
DYDA study.
Giorda CB, Cioffi G, de Simone G, Di Lenarda A, Faggiano P, Latini R, Lucci D,
Maggioni AP, Tarantini L, Velussi M, Verdecchia P, Comaschi M.
Eur J Cardiovasc Prev Rehabil. 2011 Feb 22.
Paper submitted
• NT-proBNP, hsCRP and microalbuminuria
i
i
i
in patients with type-2 diabetes mellitus
without overt cardiac disease : data from
the Left ventricular Dysfunction In
DiAbetes (DYDA) study.
– Solo la MAU ha un sicuro significato
g
di
predittività
– NT-proBNP
p
e hsCRP raggiungono
gg g
la significatività
g
all’analisi univariata, ma la perdono nella
multivariata
Patient disposition
970 pts enrolled
excluded
Baseline
10 pts with protocol violation
960 pts
Study population
ECG
914 pts with ECG available
878 pts with LVH evaluable
2 years
follow up
follow-up
ECHO
833 pts
t with
ith ECHO available
il bl
751 pts with LVD measurable
805 pts with diastolic dysfunction measurable
705 ppts with sistolic dysfunction
y
measurable
3pts lost to follow-up - 2 consent withdrawals
Median follow-up 746 days,
days mean 743±99
CLINICAL DATA
ECG
957pts with data on events available
911 pts with clinical visit
844 pts with ECG available
800 pts with LVH evaluable
LVH=left ventricula hypertrophy
LVD=left ventricular dysfunction
ECHO
727 pts with ECHO available
589 pts with LVD measurable
696 pts with diastolic dysfunction measurable
513 pts with sistolic dysfunction measurable
Follow-up: Clinical events
Death
n. (%)
All
All-cause
d h
death
15 (1
(1.6%)
6%)
CV death
3 (0.3%)
Non CV death
11 (1
(1.2%)
2%)
Unknown cause of death
1 (0.1%)
Hospitalizations
n.
All-cause hospitalizations
181
CV hospitalizations
48
Hospitalizations for non CV cause
133
CV = cardiovascular
Follow-up: Patients with clinical events
n. (%)
All-cause death
15 (1.6%)
CV death
3 (0.3%)
Non CV death
11 (1.2%)
Unknown
k
cause off death
d h
1 (0.1%)
(0 1%)
P i
Patients
admitted
d i d
Patients admitted for a CV reason
139 (14
(14.5%)
5%)
43 (4.5%)
Patients admitted for a non CV reason
104 (10
(10.8%)
8%)
All-cause
All
cause death or hospitalization
142 (14
(14.8%)
8%)
All-cause death or CV hospitalization
p
admission for CV cause
CV death or hospital
Non CV death or hospital admission for non CV cause
CV = cardiovascular
53 (5.5%)
44 ((4.6))
107 (11.2%)
Independent predictors of all-cause death or
hospitalization
2,01
Repaglinide (yes vs no)
3,49
Claudicatio
C
aud cat o (yes vs no)
1,39
LDL (continuous variable)
(134 vs 93 mg/dL)
HDL (continuous variable)
((57.0 vs 42.5 mg/dL)
g )
HbA1c (continuous variable)
(7.6 vs 6.0 %)
Age (continuous variable)
(67 vs 56 years)
0,76
1,30
1,41
0,00 1,00 2,00 3,00 4,00 5,00 6,00 7,00 8,00
Left Ventricular Dysfunction
960 pts study population
excluded
940 pts
analyzed
20 pts with major coronary events
(admission for: HF, MI, unstable
angina, revascularization, atrial
tachyarrhythmias)
Systolic/Diastolic
Systolic
Diastolic
Baseline/2 years
(699 pts)
Baseline/2 years
(529
(5
9 pts)
Baseline/2 years
(696 pts)
616 (88.1%)
338 (63.9%)
463 (66.5%)
Independent predictors of LVD
1,28
HR (continuous variable)
(80 vs 68 bpm)
1,47
HbA1c (continuous variable)
((7.6 vs 6.0 %)
2 15
2,15
Age (continuous variable)
A
(67 vs 56 years)
0,00
1,00
2,00
3,00
4,00
Independent predictors of diastolic dysfunction
Age (continuous variable)
(67 vs 56 years))
DBP (continuous variable)
(90 vs 78 mmHg)
HR (continuous variable)
(80 vs 68 bpm)
HbA1c (continuous variable)
(7.6 vs 6.0 %)
OR
95%CI
p
2.45
1.86-3.23
<.0001
2.29
1.41-3.72
0.0072
1.23
1.03-1.47
0.0245
1.25
1.01-1.54
0.0382
Independent predictors of systolic dysfunction
Waist circonference ((continuous variable))
(106 vs 92 cm)
OR
95%CI
p
1 39
1.39
1 05 1 84
1.05-1.84
0 0196
0.0196
Left Ventricular Dysfunction
Systolic Dysfunction (388 pts)
no
(EF≤50% and/or MFS≤15%)
no
83
90
(18.3%) (19.8%)
Baseliine
Baselline
LVD (454 pts)
t )
no
yes
55
226
yes
(12.1%) (49.8%)
B
Baselin
ne
24 months
191
66
no
(49.2%) (17.0%)
54
77
yes
(13 9%) (19
(13.9%)
(19.9%)
9%)
no
yes
233
126
no
((40.7%)) ((22.0%))
yes
yes
92
121
(16.1%) (21.2%)
24 months
24 months
Di t li Dysfunction
D f
ti
Diastolic
(572 pts)
Conclusions 1
Conclusions-1
• In patients with type II diabetes mellitus without
clinical signs or symptoms of cardiac
abnormalities,
b
li i LVD,
LVD either
i h systolic
li or diastolic
di
li
detected at echo, is a frequent finding
• All-cause death or hospitalization occur at 2 year
follow-up in nearly 15% of the cases,
cases being the
great majority of them of non cardiac reason
Conclusions-2
• Older age, high LDL, low HDL, high Hb1Ac,
symptomatic peripheral arterial disease and treatment
with repaglinide were independently associated with
all-cause death or hospitalizations
• Older age, high Hb1Ac and high HR independently
predict the presence of LVD
• The
Th same variables
i bl plus
l high
hi h DBP independently
i d
d tl
predict diastolic dysfunction, while systolic dysfunction
was independently
i d
d l predicted
di d by
b large
l
waist
i
circumference only
Take home messages
g
• Che cosa davvero possiamo portarci a casa dei
risultati del DYDA?
– È uno studio
di “osservazionale”,
“
i l ” e come tale
l non è
in grado di proporre messaggi di comportamento
clinico
li i
– Tuttavia, i risultati sono molto significativi, e
indicano con chiarezza che la fisiopatologia del
diabete di tipo 2, e la gestione del controllo
metabolico, hanno una rilevanza ancora superiore
all’attesa
Take home messages
• Le implicazioni
i li i i principali
i i li sono proprio
i di ordine
di
fisiopatologico, e indicano nella resistenza
all’insulina
ll’i li la
l causa del
d l danno
d
miocardico
i
di
• Studi di intervento specifici, basati sulla
valutazione della popolazione del DYDA in
risposta a particolari trattamenti del diabete
possono aprire
i orizzonti
i
i importanti
i
i
• In particolare, alcuni riscontri sulle terapie che si
basano sull’asse incretinico possono indirizzare
gli studi di intervento
Participating centres
Torino (Aurora Grassi,
Grassi Alfredo Pizzuti); Chieri (Tecla Marchese,
Marchese Lidia M.T.
M T Brero); Cuneo
(Gianpaolo Magro, Franca Margaria); San Paolo, Milano (Anna Veronelli, Francesca Carletti);
San Raffaele, Milano (Piermarco Piatti, Eustachio Agricola); Bergamo (Alessandro R. Dodesini,
Michele Senni); Brescia, (Liliana Rocca, Pompilio Faggiano); Rozzano (Luca Genovese); Sesto
San Giovanni (Ezio Faglia, Roberto Mattioli); Mirano, (Loris Bortolato, Albino Zanocco); Osp.
Riuniti, Trieste, (Maurizio Fonda, Bruno Pinamonti); Aurisina, (Mario Velussi, Bruno
Pinamonti);
); Azienda Servizi,, Trieste ((Elena Manca,, Bruno Pinamonti);
); Sanremo,, ((Roberto
Sturaro, Silvia Ubaldi); San Martino, Genova (Alberto De Micheli, Roberto Delfino); Villa
Scassi, Genova (Alberto Aglialoro, Ornella Magaja); Arenzano (Paola Ponzani, Alberto
Camerini); DIMI - DISEM, Genova (Davide Maggi, Paolo Spallarossa); Montecchio Emilia
(Valeria Manicardi, Elisabetta Catellani); Scandiano (Elisa Monzali, Gian Paolo Gambarati);
Bologna (Alessandra Sforza, Riccardo Rambaldi); Rimini (Mario Parenti, Silvia Amati); Prato
(Adolfo Arcangeli, Toni Badia); Nuovo San Giovanni di Dio, Firenze (Anna Leopardi, Antonio
Sulla); Careggi, Firenze (Gianluca Bardini, Mauro Lenuzza); Grosseto (Gigliola Sabbatini,
Francesca Cesareo); Perugia (Giampaolo Reboldi, Paolo Biagioli); Terni (Augusto Travaglini,
Daniella Bovelli); Ancona (Massimo Boemi, Roberto Mocchegiani); San Benedetto Del Tronto
(Gi
(Giacomo
V
Vespasiani,
i i Guglielmo
G li l
D Curtis);
De
C i ) Marino
M i (Patrizio
(P i i Tatti,
T i Paolo
P l Midi);
Midi) Napoli
N li (Sandro
(S d
Gentile, Domenico Cozzolino); San Giovanni Rotondo (Simonetta Bacci, Aldo Russo); Catania
(Rosa Maria Motta, Giuseppe Leonardi); Iglesias (Angelo Corda, Luisa Pitzalis); Cagliari
(L i
C b i Cristiana
C i ti
M t ld ) Oristano
Oit
(Gi f
M d Sergio
S i Mariano
M i
M hi)
(Luciano
Carboni,
Montaldo);
(Gianfranco
Madau,
Marchi)
DYDA
Steering Committee
Marco Comaschi (Chairman), Andrea Di Lenarda (Co-Chairman)
Pompilio Faggiano, Carlo Giorda, Luigi Tarantini, Mario Velussi
Working Group of the ecocardiographic substudy on hypertension
and left ventricular dysfunction
Pompilio Faggiano
gg
((Coordinator),
) Gianni Cioffi, Giovanni de Simone,
Gianfrancesco Mureddu, Paolo Verdecchia
Executive Committee
M
Marco
Comaschi,
C
hi Andrea
A d
Di Lenarda,
L
d Aldo
Ald Pi
Pietro
t M
Maggioni
i i
Biomakers core laboratory
Serge Masson, Roberto Latini (Istituto Mario Negri, Milano), Tarcisio
Vago (Ospedale Luigi Sacco, Milano)
ECG core laboratory
Fabio Angeli, Giovanni Mazzotta, Salvatore Repaci
ECO core laboratory
Gi
i De
D Simone,
Si
Il i Botta,
B tt Giusy
Gi
C l
M
ll Chinali,
Chi li Daniela
D i l
Giovanni
Ilaria
Casalnuovo,
Marcello
Girfoglio
Thank you for your kind
attention