Diabetes and Cardiovascular Risk
La lezione dai grandi studi di intervento
Rischio di eventi cardiovascolaria 8 anni nel diabete
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
Popolazionegenerale
Diabete DM + IperTx DM+ IpertTx +IperXol
DM+ IpertTx +IperXol + Fumo
(Framingham Study)
CHD Mortality in T2DM and in Non-diabetics with and without Prior AMI
Haffner, N Engl J Med Haffner, N Engl J Med 19981998
Cardiovascular and total mortality in DM and prior MI
Vaccaro, Arch Intern Med 2004
•DM and MI were similarly strong predictors of total mortality.•Higher mortality from non-CVD causes was observed in those with DM only.•Prior MI was more strongly predictive of CHD mortality than DM at any age and level of CVD risk factors.•The difference in CHD mortality between the 2 groups was most evident in the first 10 years of follow-up.
Rischio stimato di malattia cardiovascolare nel DM1
Soedemah-Muthu, General Practice Research Database, Diabetes Care 2006
Casi indice:• 7479 DM1• 5x ControlliLiberi da malattia CV al momento dello studio
Controllo glicemico ed eventi cardiovascolari (UKPDS-33)
02468
101214161820
Eventi/1000 pazienti-anno
EventiCoronarici
Eventi Cerebrali
EventiMicrovascolari
Controllo normale Controllo intensivo
P = 0.052
P = 0.52
P = 0.01
UKPDS Group, Lancet 1998
Controllo glicemico ed eventi cardiovascolari (UKPDS-34)
05
1015
202530
3540
4550
Eventi/10.000 pazienti-anno
Eventi diabete-relati
Eventi coronarici Eventi cerebrali EventiMicrovascolari
Controllo intensivo Intensivo con Metformina
P = 0.01
P = 0.12
P = 0.03
P = 0.39
UKPDS Group, Lancet 1998
Glucose control and micro-/macrovascular complications (UKPDS 35)
Stratton, BMJ 2000
Impatto del diabete su CHD instabile
Malmberg, Circulation 2000
Compenso glicemico e rischio macrovascolare
DCCT/EDIC, NEJM 2005
P = 0.02 P = 0.02
Compenso glicemico e rischio macrovascolare
DCCT/EDIC, NEJM 2003
Systolic blood pressure and micro-/macrovascular complications (UKPDS 36)
Adler, BMJ 2000
Blood pressure control and micro-/macrovascular complications (UKPDS 38)
UKPDS Study Group, BMJ 1998
Metanalysis of BP-lowering regimens on total mortality in pts with and without DM
BP Lowering Treatment Trialists' Collaboration, Arch Intern Med 2005
Metanalysis of BP-lowering regimens on CHD risk in pts with and without DM
BP Lowering Treatment Trialists' Collaboration, Arch Intern Med 2005
Metanalysis of BP-lowering regimens on CV deaths in patients with and without DM
BP Lowering Treatment Trialists' Collaboration, Arch Intern Med 2005
Metanalysis on BP-lowering regimens on major CV events in pts with and without DM
BP Lowering Treatment Trialists' Collaboration, Arch Intern Med 2005
Metanalysis of BP-lowering regimens on stroke risk in pts with and without DM
BP Lowering Treatment Trialists' Collaboration, Arch Intern Med 2005
Fattori di rischio coronarico nel diabete (UKPDS-23)
1,0
1,79 1,93
0,0
0,5
1,0
1,5
2,0
2,5
Rischio Relativo
<190 190-223 >223
Colesterolo Totale
1,0
1,48
2,29
0,0
0,5
1,0
1,5
2,0
2,5
Rischio Relativo
<117 117-150 >150
LDL-Colesterolo
Turner, BMJ 1998
Fattori di rischio coronarico nel diabete (UKPDS-23)
1,0 0,87
0,51
0,0
0,2
0,4
0,6
0,8
1,0
1,2
Rischio Relativo
<37 37-45 >45
HDL-Colesterolo
1,0
1,63
1,93
0,0
0,5
1,0
1,5
2,0
2,5
Rischio Relativo
<108 108-165 >165
Trigliceridi
Turner, BMJ 1998
Long-term CHD primary preventionThe 4S extension
Strandberg, Lancet 2004
Lipid-lowering action of different statins and NCEP-ATPIII goal
From Tuomilehto, Diab Res Clin Pract 2005
Cheung, Br J Clin Pharmacol 2003
Meta-analisys of statin use in CHD prevention
Statina-prevenzione 2aria
Placebo-prevenzione 2aria
Statina-prevenzione 1aria
Placebo-prevenzione 1aria
Adattato da Ballantyne CM. Am J Cardiol 1998; 82 (9A): 3Q-12Q; O’Keefe JH et al. J Am Coll Cardiol 2004; 43 (11): 2142-2146.
mg/dl
25
20
15
10
5
050 70 90 110 130 150 170 190 210
WOSCOPS-P
WOSCOPS-S
AFCAPS-P
AFCAPS-S
LIPID-SCARE-S
4S-S
CARE-P
LIPID-P
4S-P
30
HPS-P
HPS-SLIPS-P
ASCOT-S
ASCOT-PLIPS-S
PROVE-IT APROVE-IT P
TNT 80
TNT 10AtoZ 20
AtoZ 80
Eventi coronarici (%)
C-LDL
LDL e rischio coronarico negli studi clinicidi riduzione dell‘iperlipidemia
Adattato da Grundy SM et al. Circulation 2004;110 (2):227-239.
190
Rischio elevato di CHD o equivalenti di rischio
coronarico(rischio a 10 anni > 20%)
Livelli di C-LDL
160
130
100
70Rischio
moderatamente alto≥2 fattori di rischio
(rischio a 10 anni 10-20%)
Rischio moderato≥2 fattori di rischio
(rischio a 10 anni < 10%)
Basso rischio< 2 fattori di rischio
Target 130mg/dL
Target 130mg/dL
Target 160mg/dL
Target 100mg/dL
or optional 70
mg/dL
or optional 100mg/dL
The lower the betterATP III aggiorna gli obiettivi di C-LDL nel 2004
Meta-analysis on primary CHD prevention by statins (8 trials)
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5
Total mortality
Serious AE
CV events
CHD events (females)
CV events (>65 yrs)
Abramson & Wright, Lancet 2007
Yusuf, Lancet 2002
CHD secondary prevention
In smokers, an additional 50% reduction is expected, lowering the RR by 80% (to 20% of basal values)
Keech, Diabetes Care 2003
Diabetes & CV RiskPravastatin secondary prevention (LIPID study)
1077 with DM and 940 IGT (out of 9014 overall population)
• Pravastatin, 40 mg• Age, 31-75 years• T-Xol, 4.0 - 7.0 mmol/L
Keech, Diabetes Care 2003
Diabetes & CV RiskMeta-analisys of secondary prevention (LIPID study)
Diabetes & CV RiskEffect of aggressive treatment (TNT study)
• 1.501 Pts with DM and overt CHD
• LDL-Xol <130 mg/dL• Follow-up, 4.9 yrs(out of 10.001 total pts with CHD)
•Significant differences in most individual outcomes
•No differences in total mortality
Sheperd, Diabetes Care 2006
Sheperd, Diabetes Care 2006
Diabetes & CV RiskEffect of aggressive treatment (TNT study)
An average 3-5% ARR is observed across different groups, independent of metabolic control (HbA1c), age, entry LDL-Xol, duration of diabetes.
CHD primary prevention in DMThe CARDS trial
Colhoun, Lancet 2004
2838 Pts, with no previous history of CHD;
LDL-Xol < 4.14 mMol,
TG < 6.78 mMol
Tx: Atorvastatin 10 mg vs. Pl
The study was prematurely halted
CHD primary prevention in DMThe CARDS trial
Colhoun, Lancet 2004
CHD primary prevention in DM
Garg, Lancet 2004
Intervento multifattoriale e rischio CV nel DM2 (STENO-2) RCT trattamento convenzionale vs. trattamento intensivo 160 Pazienti con DM2 Età, 55 anni; Follow-up, 7.8 anni Trattamento intensivo:
• Progressiva educazione per modificare lo stile di vita
• Stretto controllo della glicemia, ipertensione, dislipemia, microalbuminuria con terapia farmacologica intensiva (+ aspirina).
Outcome primario: Morte per causa CV, infarto non fatale, stroke non fatale, necessità di rivascolarizzazione, amputazione.
Gaede, NEJM 2003
STENO-2: percentuale di pazienti a target
Gaede, NEJM 2003
STENO-2: risultati sull’outcome primario composito
Gaede, NEJM 2003
Outcome primario:•Morte per causa CV•infarto non fatale•stroke non fatale•necessità di chirurgia vascolare•amputazione
STENO-2: risultati sullo sviluppo di complicanze
Gaede, NEJM 2003
Dormandy, Lancet 2005
Pioglitazone and macrovascular events (PROACTIVE study)
5238 Pts with T2DM and macrovascular disease
PIO 15-45 mg/d
Average F-up, 34.5 mo
Primary outcome: composite end-point - not different
Dormandy, Lancet 2005
Pioglitazone and macrovascular events (PROACTIVE study)
Significant differences in a secondary end-point (composite)
Concern for fluid retention
Cumulative Incidence
Time since Randomization, y
Development of MS by intervention group in the DPP
Orchard, Ann Intern Med 2005
DPS - risultati a lungo termine
Lindstrom, Lancet 2006
Durante il follow-up si allarga ulteriormente la differenza tra gruppo di controllo e di intervento
Lo spostamento sull’asse delle ascisse supera i 4 anni
DPS - risultati a lungo termine
Lindstrom, Lancet 2006
Durante il follow-up si allarga ulteriormente la differenza tra gruppo di controllo e di intervento
Lifestyle vs. farmaci - metaanalisi
Gillies, BMJ 2007
Lifestyle treatment of HtxThe PREMIER experience
PREMIER Collaborative Research Group, JAMA 2003
RCT on the effects on BP of behavioral approach ± DASH (dietary approach to stop Htx)
• 810 pts with above optimal BP• Outcome
• Htx status at 6 mo• Behavior intervention
• 4 individual + 14 group sessions• Format
• recording of food diaries, physical activity, calorie and Na intake
• +DASH: fruit, vegetables, fat snd
dairy product intake
Lifestyle treatment of HtxThe PREMIER experience
PREMIER Collaborative Research Group, JAMA 2003
Incident DM in RCT of hypertensionA network meta-analysis
48 groups in 22 RCT on pharmacologic treatment of Htx
143.153 pts without DM at entry
Main outcome: proportion of Pts who develops DM
Elliott & Meyer, Lancet 2007
Incident DM in RCT of hypertensionA network meta-analysis
Elliott & Meyer, Lancet 2007