Marcus Tullius Cicero (106–43 BCE)
«Ipse dixit»)
Aristotile (384–322 BCE)
«αὐτὸς ἔφα»
Il controllo esagerato della glicemia e
della pressione arteriosa
Patrizio Tatti
Inverclyde Hospital
UK
disclosure
Negli ultimi due anni patrizio tatti ha avuto rapporti di lavoro / consulenza
con i seguenti produttori di farmaci:
Eli Lilly
Novo
Abbott
Bayer
Novartis
Roche
Merk
Medtronic
Non possiede azioni e non è in alcun modo shareholder di alcun
produttore di farmaci
Ia storia ed il mito
I due studi che seguono:
A-riguardano soggetti all’ esordio di malattia
B-sono stati studi di intervento seguiti da studi osservazionali
DCCT: Rapporto tra HbA1c e rischio di
complicanze microvascolari – DMT1
15
p<0.0001
Hazard ratio
10
WOLKVAGEN Jetta 1983
WOLKVAGEN Jetta 2010
1983-1993
1
37% decrease per 1% decrement in HbA1c
0 .5
0
5
6
7
8
9
10
Updated mean HbA1c
UKPDS 35. BMJ 2000; 321: 405-12
11
DCCT – Macrovascular complications
I dati del DCCT sono stati impropriamente «esportati» al DMT2
UKPDS Type 2 DM– microvascular
complications 1977-97
% of patients with an event
30%
Conventional
Intensive
p=0.0099
20%
10%
Risk reduction 25%
(95% CI: 7 % to 40%)
0%
0
3
6
9
12
Years from randomisation
15
Ukpds Study- CHD Relative Risk & HbA1c
Observational analysis
Hazard ratio
5
14% decrease per 1%
HbA1c decrement, p<0.0001
1
UKPDS Glucose Study showed:
16% decrease for a 0.9% HbA1c difference
p=0.052
0.5
0 5
6
7
8
9
Updated mean HbA1c
UKPDS 35. BMJ 2000; 321: 405-12
10
11
UKPDS: legacy effect of earlier glucose control
After median 8.5 years post-trial follow-up
Aggregate
Endpoint
Riduzione
Rischio assoluto
eventi /related
1000 pazienti
Any3-4
diabetes
endpoint
anno (NNT/anno = 285)
1997
2007
RRR:
P:
12%
0.029
9%
0.040
Microvascular disease
RRR:
P:
25%
0.0099
24%
0.001
Myocardial infarction
RRR:
P:
16%
0.052
15%
0.014
All-cause mortality
RRR:
P:
6%
0.44
13%
0.007
Legacy effect
Nel periodo 1997 – 2007
state
usate altre
RRR =sono
Relative
Risk Reduction,
P = medicine
Log Rank che potevano
avere un loro intrinseco effetto cadiovascolare
T intensiva: 2729 soggetti
T convenzionale: 1138 soggetti
Relative Risk for CHD & Blood Pressure
Observational analysis
Hazard ratio
5
14% decrease per 10 mmHg
SBP decrement, p<0.0001
1
UKPDS Blood Pressure Study showed:
21% decrease for a 10 mmHg SBP difference
0.5
110
120
130
140
150
160
170
Updated mean systolic blood pressure
UKPDS 36. BMJ 2000; 321: 412-19
UKPDS
• “This paper reports that patients with hypertension and type 2
diabetes assigned to tight control of blood pressure achieved a
significant reduction in risk …(omissis)…………..The mean blood
pressure over nine years was 144/82mm Hg on tight control compared
with a less tight control mean of 154/87mm Hg”
BMJ 1998;317(7160):703-713
• UKPDS observational study showed that “risk of diabetic complications
was strongly associated with raised blood pressure. Any reduction in
blood pressure is likely to reduce the risk of complications, with the
lowest risk being in those with systolic blood pressure less than 120
mm Hg.”
BMJ 2000;321(7258):412-419
J-curve revisited: an analysis of
blood pressure and cardiovascular
events in the Treating to New Targets
(TNT) Trial
European Heart Journal (2010) 31,
2897–2908
doi:10.1093/eurheartj/ehq328
ACCORD
ADVANCE
VADT
No. of participants
10,251
11,140
1791
Participant age,years
62
66
60
Participants – male, %
62
58
97
Duration of DM at entry,
years
10
8
11.5
A1C at Baseline, %
8.1
7.2
9.4
Participants with prior CV
event, %
35
32
40
Duration of follow-up,
years
3.4
5.0
6
Statistical difference between groups (P ≤ 0.05)
Outcomes,
intensive vs. standard
ACCORD
ADVANCE
A1C, %
6.4 vs. 7.5*
6.4 vs. 7.0*
6.9 vs. 8.4*
Death from any
cause, %
5.0 vs. 4.0*
8.9 vs. 9.6
NA
Death from CV
event, %
Nonfatal MI, %
2.6 vs. 1.8*
4.5 vs. 5.2
2.1 vs. 1.7
3.6 vs. 4.6*
2.7
i vs. 2.8
6.1 vs. 6.3
10.5 vs.
3.5*
2.7 vs. 1.5*
21.1 vs. 9.7*
3.5 vs. 0.4*
0.0 vs. -1.0*
NA
Major/severe
hypoglycemia, %
Weight gain, kg
Statistical difference between groups (P ≤ 0.05)
VADT
34533 soggetti, 18315 t. intensiva; 16281 t standard
Mortalità per
tutte le cause
Mortalità CV
Metanalysis: intensive glucose control in T2DM
Turnbull FM et Al Diabetologia (2009)52:2288-98
Figure 1
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
(Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)
Accord Blood Pressure
Primary & Secondary Outcomes
Intensive
Standard
Events (%/yr) Events (%/yr)
Primary
HR (95% CI)
P
208 (1.87)
237 (2.09)
0.88 (0.73-1.06)
0.20
Total Mortality
150 (1.28)
144 (1.19)
1.07 (0.85-1.35)
0.55
Cardiovascular
Deaths
60 (0.52)
58 (0.49)
1.06 (0.74-1.52)
0.74
Nonfatal MI
126 (1.13)
146 (1.28)
0.87 (0.68-1.10)
0.25
Nonfatal Stroke
34 (0.30)
55 (0.47)
0.63 (0.41-0.96)
0.03
Total Stroke
36 (0.32)
62 (0.53)
0.59 (0.39-0.89)
0.01
Also examined Fatal/Nonfatal HF (HR=0.94, p=0.67), a composite of fatal
coronary events, nonfatal MI and unstable angina (HR=0.94, p=0.50) and a
composite of the primary outcome, revascularization and unstable angina
(HR=0.95, p=0.40)
Mean # Meds
Intensive:
Standard:
3.2
1.9
3.4
2.1
3.5
2.2
3.4
2.3
Average after 1st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2
*
*
*
*
Rapporti epidemiologici ed interventistici tra Colesterolo, Pressione arteriosa, HbA1c e
malattia CV
Variabile
IMA fatale+ nonfatale +morte
improvvisa
Ictus (tutti)
Malattia CV
Colesterolo (1mmol/l)
•
Dati Epidemiologici (%)
-30
-10
•
Studi intervento (%)
-23
-17
•
NNT per 5 aa
59.2
177.7
44.4
Pressione arteriosa (10/5 mmHg)
•
Dati Epidemiologici (%)
-25
-36
•
Studi intervento (%)
-22
-41
•
NNT per 5 aa
61.8
73.7
33.6
Glicemia (HbA1c 0.9%; 10 mmol)
•
Dati Epidemiologici (%)
-12
-15
•
Studi intervento (%)
-9.7
-4.0
•
NNT per 5 aa
140.3
767.7
118.5
J. S. Yudkin & B. Richter & E. A. M. Gale. Intensified glucose lowering in type 2
diabetes: time for a reappraisal. Diabetologia (2010) 53:2079–2085
• Non esiste prova definitiva che riducendo
indiscriminatamente la glicemia e la HbA1c si stia
riducendo il danno CV. Anzi si potrebbe aumentare la
mortalità
• Non esiste prova che riducendo la PA al di sotto di
140/80 mmHg si stia riducendo il danno CV. Anzi si
potrebbe aumentare la mortalità
• La miglior dote del medico rimane il buon senso, non
le linee guida
Cu' tanta galle a canta', nun fa' maje juorno.