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