il controllo esagerato della glicemia e della pressione arteriosa patrizio tatti inverclyde hospital...
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Il controllo esagerato della glicemia e della pressione arteriosa
Patrizio Tatti
Inverclyde Hospital
UK
Marcus Tullius Cicero (106–43 BCE)«Ipse dixit»)
Aristotile (384–322 BCE)«αὐτὸς ἔφα»
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disclosureNegli ultimi due anni patrizio tatti ha avuto rapporti di lavoro / consulenza
con i seguenti produttori di farmaci:
Eli LillyNovoAbbottBayer
NovartisRocheMerk
Medtronic
Non possiede azioni e non è in alcun modo shareholder di alcun produttore di farmaci
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I due studi che seguono:
A-riguardano soggetti all’ esordio di malattia
B-sono stati studi di intervento seguiti da studi osservazionali
Ia storia ed il mito
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0.5
1
10
15
0 5 6 7 8 9 10 11
37% decrease per 1% decrement in HbA1c
p<0.0001
Updated mean HbA1c
Haz
ard
ratio
UKPDS 35. BMJ 2000; 321: 405-12
WOLKVAGEN Jetta 1983
DCCT: Rapporto tra HbA1c e rischio di complicanze microvascolari – DMT1
1983-1993
WOLKVAGEN Jetta 2010
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DCCT – Macrovascular complications
I dati del DCCT sono stati impropriamente «esportati» al DMT2
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UKPDS Type 2 DM– microvascular complications
p=0.0099
0%
10%
20%
30%
0 3 6 9 12 15
% o
f pat
ient
s w
ith a
n ev
ent
Years from randomisation
Intensive
Conventional
Risk reduction 25%(95% CI: 7 % to 40%)
1977-97
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Ukpds Study- CHD Relative Risk & HbAUkpds Study- CHD Relative Risk & HbA1c1c
0.5
1
5
0 5 6 7 8 9 10 11Updated mean HbA1c
Haz
ard
ratio
14% decrease per 1%HbA1c decrement, p<0.0001
UKPDS 35. BMJ 2000; 321: 405-12
UKPDS Glucose Study showed:16% decrease for a 0.9% HbA1c difference
p=0.052
Observational analysis
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After median 8.5 years post-trial follow-up
Aggregate Endpoint 1997 2007
Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040
Microvascular disease RRR: 25% 24% P: 0.0099 0.001
Myocardial infarction RRR: 16% 15% P: 0.052 0.014
All-cause mortality RRR: 6% 13% P: 0.44 0.007
RRR = Relative Risk Reduction, P = Log Rank
UKPDS: legacy effect of earlier glucose control
T intensiva: 2729 soggetti T convenzionale: 1138 soggetti
Legacy effectNel periodo 1997 – 2007 sono state usate altre medicine che potevano avere un loro intrinseco effetto cadiovascolare
Riduzione Rischio assoluto 3-4 eventi / 1000 pazienti anno (NNT/anno = 285)
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14% decrease per 10 mmHgSBP decrement, p<0.0001
0.5
1
5
110 120 130 140 150 160 170
Relative Risk for CHD & Blood PressureRelative Risk for CHD & Blood Pressure
Updated mean systolic blood pressure
Haz
ard
ratio
UKPDS 36. BMJ 2000; 321: 412-19
UKPDS Blood Pressure Study showed:21% decrease for a 10 mmHg SBP difference
Observational analysis
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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
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European Heart Journal (2010) 31, 2897–2908doi:10.1093/eurheartj/ehq328
J-curve revisited: an analysis of blood pressure and cardiovascular events in the Treating to New Targets (TNT) Trial
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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)
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Outcomes,Outcomes, intensive vs. intensive vs.
standardstandardACCORDACCORD
ADVANADVANCECE VADTVADT
A1C, %A1C, % 6.4 vs. 6.4 vs. 7.5*7.5*
6.4 vs. 6.4 vs. 7.0*7.0*
6.9 vs. 8.4*6.9 vs. 8.4*
Death from Death from any cause, %any cause, %
5.0 vs. 5.0 vs. 4.0*4.0*
8.9 vs. 9.68.9 vs. 9.6 NANA
Death from CV Death from CV event, % event, %
2.6 vs. 2.6 vs. 1.8*1.8*
4.5 vs. 5.24.5 vs. 5.2 2.1 vs. 1.72.1 vs. 1.7
Nonfatal MI, Nonfatal MI, %%
3.6 vs. 3.6 vs. 4.6*4.6*
2.7 vs. 2.82.7 vs. 2.8 6.1 vs. 6.36.1 vs. 6.3
Major/severe Major/severe hypoglycemia, hypoglycemia, %%
10.5 vs. 10.5 vs. 3.5*3.5*
2.7 vs. 2.7 vs. 1.5*1.5*
21.1 vs. 9.7*21.1 vs. 9.7*
Weight gain, Weight gain, kgkg
3.5 vs. 3.5 vs. 0.4*0.4*
0.0 vs. -0.0 vs. -1.0*1.0*
NANAStatistical difference between groups (P ≤ 0.05)
i
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34533 soggetti, 18315 t. intensiva; 16281 t standard
Mortalità per tutte le cause
Mortalità CV
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Metanalysis: intensive glucose control in T2DMTurnbull FM et Al Diabetologia (2009)52:2288-98
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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)
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Accord Blood PressurePrimary & Secondary Outcomes
Intensive Events (%/yr)
StandardEvents (%/yr) HR (95% CI) P
Primary 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)
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Average after 1st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2
Mean # Meds Intensive: 3.2 3.4 3.5 3.4 Standard: 1.9 2.1 2.2 2.3
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*
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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
Rapporti epidemiologici ed interventistici tra Colesterolo, Pressione arteriosa, HbA1c e malattia CV
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Cu' tanta galle a canta', nun fa' maje juorno.
• 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