XXXIX Congresso Nazionale ANMCOFirenze, 30 maggio- 2 giugno 2008

MinimasterCuore e diabete – Prevenzione delle recidive e aderenza alle terapie

XXXIX Congresso Nazionale ANMCOFirenze, 30 maggio- 2 giugno 2008

MinimasterCuore e diabete – Prevenzione delle recidive e aderenza alle terapie

Cardioprotezione farmacologica Cardioprotezione farmacologica a lungo termine:a lungo termine:

il punto sulle statine il punto sulle statine

Cardioprotezione farmacologica Cardioprotezione farmacologica a lungo termine:a lungo termine:

il punto sulle statine il punto sulle statine

Stefano UrbinatiStefano Urbinati

UOC CardiologiaUOC CardiologiaOspedale Bellaria, BolognaOspedale Bellaria, Bologna

Stefano UrbinatiStefano Urbinati

UOC CardiologiaUOC CardiologiaOspedale Bellaria, BolognaOspedale Bellaria, Bologna

Diagnosi di nuovi casi di diabete:

siamo abbastanza attenti?

EuroHeart Surveyn=3940 pts with known glucometabolic state

Newly detected DMn= 452 (11%)

After a 1-year follow-up period

On treatment for DMn= 77 (17%)

No treatment for DMn= 375 (83%)

0 mortality 25 p<0.002 1 MI 13 1 stroke 5

Anselmino et al, Eur Heart J 2008;29:177-84

Anselmino et al, Eur Heart J 2008;29:177-84

Kaplan Meyer curves for combined CV events in pts with newly detected DM by prescribed or not prescribed

pharmacological treatment

Tx for DM

no Tx for DM

… the general impression is that pts with CAD and DM areinappropriately managed for several reasons…

1. Cardiologists neglect o are inexperienced as regards GL treatments

2. A close collaboration between cardiologists and diabetologists is absent

3. The present findings are due to the well known “clinical inertia” that affect both specialists and primary care physiscians

Anselmino et al, Eur Heart J 2008;29:177-84

Dislipidemia nel diabetico:entità del problema

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High Incidence of Dyslipidemia in the Diabetic PopulationHigh Incidence of Dyslipidemia in the Diabetic Population

Modified from Jacobs MJ et al. Modified from Jacobs MJ et al. Diabetes Res Clin PractDiabetes Res Clin Pract. 2005;70:263-269.. 2005;70:263-269.

0%

20%

40%

60%

80%

100%

Men Women Men Women Men Women

Pa

tie

nts

wit

h d

iab

ete

s (

%)*

0%

20%

40%

60%

80%

100%

Men Women Men Women Men Women

Pa

tie

nts

wit

h d

iab

ete

s (

%)*

LDL-C (mg/dL)LDL-C (mg/dL) Triglycerides (mg/dL)Triglycerides (mg/dL) HDL-C (mg/dL)HDL-C (mg/dL)

130130

100-129100-129

<100<100

200200

150-199150-199

<150<150

Men 40

Women 50

Men 40

Women 50

Men>40

Women>50

Men>40

Women>50

*245 men with diabetes and 253 women with diabetes *245 men with diabetes and 253 women with diabetes aged aged 18 years from NHANES 1999-2000.18 years from NHANES 1999-2000.

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MRFIT*: Cardiovascular Disease (CVD) Mortality 3 Times Greater in Men With Diabetes at All Cholesterol Levels

MRFIT*: Cardiovascular Disease (CVD) Mortality 3 Times Greater in Men With Diabetes at All Cholesterol Levels

0

20

40

60

80

100

120

140

160

<180 180-199 200-219 220-239 240-259 260-279 >279

Serum cholesterol (mg/dL)

Ag

e-ad

just

ed C

VD

dea

th r

ate

(per

10,

000

per

son

-yea

rs)

Men with diabetes (n=5163)

Men without diabetes (n=342,815)

0

20

40

60

80

100

120

140

160

<180 180-199 200-219 220-239 240-259 260-279 >279

Serum cholesterol (mg/dL)

Ag

e-ad

just

ed C

VD

dea

th r

ate

(per

10,

000

per

son

-yea

rs)

Men with diabetes (n=5163)

Men without diabetes (n=342,815)

Stamler J et al. Stamler J et al. Diabetes Care.Diabetes Care. 1993;16:434-444. 1993;16:434-444.**Multiple Risk Factor Intervention TrialMultiple Risk Factor Intervention Trial

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UKPDS*: Order of Importance of CHD Risk FactorsUKPDS*: Order of Importance of CHD Risk Factors

Stepwise selection of risk factors, adjusted for age and sex, in 2693 white patients with diabetes, with dependent variable as time to first CHD event.

Stepwise selection of risk factors, adjusted for age and sex, in 2693 white patients with diabetes, with dependent variable as time to first CHD event.

Turner RC et al. Turner RC et al. BMJ.BMJ. 1998;316:823-828. 1998;316:823-828.

Variable P-value

1. LDL-C1. LDL-C <0.0001<0.0001

2. HDL-C2. HDL-C 0.00010.0001

3. HbA3. HbA1c1c 0.00220.0022

4. Systolic BP4. Systolic BP 0.00650.0065

5. Smoking5. Smoking 0.0560.056

**United Kingdom Prospective Diabetes Study.United Kingdom Prospective Diabetes Study.

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UKPDS: LDL-C Is a Very Strong Predictor of CHD Risk in Patients With DiabetesUKPDS: LDL-C Is a Very Strong Predictor of CHD Risk in Patients With Diabetes

Relation of lipid risk factors* to CHD in 2693 patients with diabetesRelation of lipid risk factors* to CHD in 2693 patients with diabetes

Turner RC et al. Turner RC et al. BMJ.BMJ. 1998;316:823-828. 1998;316:823-828.

0.0

0.5

1.0

1.5

2.0

2.5

<189

189-

223

>223

0.0

0.5

1.0

1.5

2.0

2.5

<189

189-

223

>223

Total cholesterolP<0.0001Total cholesterolP<0.0001

0.0

0.5

1.0

1.5

2.0

2.5

<117

117-

150

>150

0.0

0.5

1.0

1.5

2.0

2.5

<117

117-

150

>150

LDL-CP<0.0001LDL-CP<0.0001

0.0

0.5

1.0

1.5

2.0

2.5

<108

108-

166

>166

0.0

0.5

1.0

1.5

2.0

2.5

<108

108-

166

>166

TriglyceridesP<0.0001TriglyceridesP<0.0001

0.0

0.5

1.0

1.5

2.0

2.5

0.0

0.5

1.0

1.5

2.0

2.5

HDL-CP<0.0001HDL-CP<0.0001

Haz

ard

ra

tio

Haz

ard

ra

tio

Lipid tertiles (mg/dL)Lipid tertiles (mg/dL)

*Age- and sex-adjusted.*Age- and sex-adjusted.

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Atherogenicity of DiabetesAtherogenicity of Diabetes

Lipid abnormalities may represent an atherogenic phenotype in type 2 diabetes patients that accelerates atherosclerosis and CHD

Characteristic abnormalities of type 2 diabetes include: Decreased HDL-C

Elevated triglycerides

Absolute concentration of LDL-C not significantly increased; however, people with diabetes often have a preponderance of smaller, denser LDL particles, which may increase atherogenicity

Lipid abnormalities may represent an atherogenic phenotype in type 2 diabetes patients that accelerates atherosclerosis and CHD

Characteristic abnormalities of type 2 diabetes include: Decreased HDL-C

Elevated triglycerides

Absolute concentration of LDL-C not significantly increased; however, people with diabetes often have a preponderance of smaller, denser LDL particles, which may increase atherogenicity

American Diabetes Association. American Diabetes Association. Diabetes Care.Diabetes Care. 2003;26:S83-S86. 2003;26:S83-S86.

Dislipidemia nel diabetico:l’importanza di un

approccio multidisciplinare

Gaede et al for the STENO-2 Investigators, NEJM 2003;348:383-93

Our study was not designed to identify which elements ofintensive diabetes therapy contributed most to the reduction in CV risk.

Using a risk calculator based on UKPDS, we concluded thatthe use of statins and antihypertensive drugs have the largest effect in reducing CV risk during the 7.8 yrs ofinterventions, with hypoglicemic agents and aspirin the nextmost important interventions.

Effect of a multifactorial intervention on mortality in type 2 diabetes

Evidenze sull’efficacia delle statine nel diabetico

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Early Statin Secondary Prevention Trials: Design OverviewEarly Statin Secondary Prevention Trials: Design Overview

Primary end point: All-cause mortalityPrimary end point: All-cause mortality

Median follow-up: 5.4 yearsMedian follow-up: 5.4 years

Simvastatin 20-40 mg/daySimvastatin 20-40 mg/day(n=2221)(n=2221)

PlaceboPlacebo(n=2223)(n=2223)

4444 patients4444 patients

4S4S Age: 35-70 yearsAge: 35-70 years Previous MI or anginaPrevious MI or angina TC: 5.5-8.0 mmol/L (213-309 mg/dL)TC: 5.5-8.0 mmol/L (213-309 mg/dL) Triglycerides: Triglycerides: 2.5 mmol/L (2.5 mmol/L (221 mg/dL)221 mg/dL)

CARECARE Age: 21-75 yearsAge: 21-75 years MI in previous 3-20 monthsMI in previous 3-20 months TC: <240 mg/dL (<6.2 mmol/L)TC: <240 mg/dL (<6.2 mmol/L) LDL-C:115-174 mg/dL (3.0-4.5 mmol/L)LDL-C:115-174 mg/dL (3.0-4.5 mmol/L) Triglycerides: <350 mg/dL (<4.0 mmol/L)Triglycerides: <350 mg/dL (<4.0 mmol/L)

4159 patients4159 patients

Pravastatin 40 mg/dayPravastatin 40 mg/day(n=2081)(n=2081)

PlaceboPlacebo(n=2078)(n=2078)

Median follow-up: 5.0 yearsMedian follow-up: 5.0 years

Primary end point: CHD death + nonfatal MIPrimary end point: CHD death + nonfatal MI

Primary end point: CHD deathPrimary end point: CHD death

LIPIDLIPID Age: 31-75 yearsAge: 31-75 years MI or unstable angina in previousMI or unstable angina in previous

3-36 months3-36 months TC: 155-271 mg/dL (4.0-7.0 mmol/L)TC: 155-271 mg/dL (4.0-7.0 mmol/L) Triglycerides <445 mg/dL (<5.0 mmol/L)Triglycerides <445 mg/dL (<5.0 mmol/L)

9014 patients9014 patients

Pravastatin 40 mg/dayPravastatin 40 mg/day(n=4512)(n=4512)

PlaceboPlacebo(n=4502)(n=4502)

Mean follow-up: 6.1 yearsMean follow-up: 6.1 years

4S Study Group. 4S Study Group. LancetLancet. 1994;334:1383-1389.. 1994;334:1383-1389.

Sacks F et al. Sacks F et al. N Engl J MedN Engl J Med. 1996;335:1001-1009.. 1996;335:1001-1009.

LIPID Study Group. LIPID Study Group. N Engl J MedN Engl J Med. 1998;339:1349-1357.. 1998;339:1349-1357.

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4S: Major CHD Event Reduction in Patients With Diabetes*4S: Major CHD Event Reduction in Patients With Diabetes*

PyöräläPyörälä K et al. K et al. Diabetes CareDiabetes Care. 1997;20:614-620.. 1997;20:614-620.*Post-hoc analysis of the secondary end point: *Post-hoc analysis of the secondary end point: CHD death + nonfatal MI.CHD death + nonfatal MI.

40

50

60

70

80

90

100

0 1 2 3 4 5 640

50

60

70

80

90

100

0 1 2 3 4 5 6

RRR=32%RRR=32%PP=0.0001=0.0001

Pat

ien

ts w

ith

ou

t m

ajo

r C

VD

eve

nt

(%)

Pat

ien

ts w

ith

ou

t m

ajo

r C

VD

eve

nt

(%)

Time (years)Time (years)

Diabetes, simvastatin 20-40 mg (n=105)Diabetes, simvastatin 20-40 mg (n=105)

Diabetes, placebo (n=97)Diabetes, placebo (n=97)

No diabetes, simvastatin 20-40 mg (n=2116)No diabetes, simvastatin 20-40 mg (n=2116)

No diabetes, placebo (n=2126)No diabetes, placebo (n=2126)RRR=55% RRR=55% PP=0.002=0.002

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Goldberg RB et al. Goldberg RB et al. CirculationCirculation. 1998;98:2513-2519.. 1998;98:2513-2519.

CARE: CHD Event Reduction in Patients With Diabetes*CARE: CHD Event Reduction in Patients With Diabetes*

*Post hoc analysis of an expanded CHD end point: *Post hoc analysis of an expanded CHD end point: CHD death, nonfatal MI, CABG, and PTCA.CHD death, nonfatal MI, CABG, and PTCA.

0

5

10

15

20

25

30

35

40

45

0 1 2 3 4 5

0

5

10

15

20

25

30

35

40

45

0 1 2 3 4 5

RRR=25%RRR=25%PP=0.05=0.05

Cu

mu

lati

ve in

cid

ence

C

um

ula

tive

inci

den

ce

of

even

ts (

% o

f p

atie

nts

) o

f ev

ents

(%

of

pat

ien

ts)

Time (years)Time (years)

Diabetes, pravastatin 40 mg (n=282)Diabetes, pravastatin 40 mg (n=282)

Diabetes, placebo (n=304)Diabetes, placebo (n=304)

No diabetes, pravastatin 40 mg (n=1779)No diabetes, pravastatin 40 mg (n=1779)

No diabetes, placebo (n=1774)No diabetes, placebo (n=1774)

RRR=23% RRR=23% PP<0.001<0.001

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LIPID: CHD Event Reduction in Patients With Diabetes*LIPID: CHD Event Reduction in Patients With Diabetes*

Keech A et al. Keech A et al. Diabetes CareDiabetes Care. 2003;26:2713-2721.. 2003;26:2713-2721.*Pre-specified diabetes subgroup primary endpoint: *Pre-specified diabetes subgroup primary endpoint: CHD death and nonfatal MI.CHD death and nonfatal MI.

0

5

10

15

20

25

30

0 1 2 3 4 5 6 7

0

5

10

15

20

25

30

0 1 2 3 4 5 6 7

RRR=19%RRR=19%PP=0.11=0.11

Cu

mu

lati

ve in

cid

ence

C

um

ula

tive

inci

den

ce

of

even

ts (

% o

f p

atie

nts

)o

f ev

ents

(%

of

pat

ien

ts)

Time (years)Time (years)

Diabetes, pravastatin 40 mg (n=542)Diabetes, pravastatin 40 mg (n=542)

Diabetes, placebo (n=535)Diabetes, placebo (n=535)

No diabetes, pravastatin 40 mg (n=3496)No diabetes, pravastatin 40 mg (n=3496)

No diabetes, placebo (n=3501)No diabetes, placebo (n=3501)

RRR=23%RRR=23%PP=0.001=0.001

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Mean follow-up 4.8 yearsMean follow-up 4.8 years

HPS: Primary and Secondary Prevention of CVD in Patients With DiabetesHPS: Primary and Secondary Prevention of CVD in Patients With Diabetes

Without CVDWithout CVD(n=2912)(n=2912)

With CVDWith CVD(n=3051)(n=3051)

5963 patients 5963 patients with diabeteswith diabetes

Pre-specified diabetes subgroupPre-specified diabetes subgroupend points:end points: Major coronary events Major coronary events Major vascular eventsMajor vascular events

Patient population:Patient population: Age: 40-80 yearsAge: 40-80 years TC: TC: 3.5 mmol/L (135 mg/dL)3.5 mmol/L (135 mg/dL) At least one of:At least one of:

– Diabetes mellitusDiabetes mellitus– CHDCHD– Occlusive noncoronary artery diseaseOcclusive noncoronary artery disease– Treated hypertension (men aged Treated hypertension (men aged 65 years)65 years)

Simvastatin 40 mg/daySimvastatin 40 mg/day(n=1455)(n=1455)

Simvastatin 40 mg/daySimvastatin 40 mg/day(n=1523)(n=1523)

PlaceboPlacebo(n=1457)(n=1457)

PlaceboPlacebo(n=1528)(n=1528)

HPS Collaborative Group. HPS Collaborative Group. LancetLancet. 2003;361:2005-2016.. 2003;361:2005-2016.

20

LP267611LP267611HPS: Subgroup Evaluation Shows Consistent Benefit in Diabetic Patients Regardless of CVD

HPS: Subgroup Evaluation Shows Consistent Benefit in Diabetic Patients Regardless of CVD

HPS Collaborative Group. HPS Collaborative Group. LancetLancet. 2003;361:2005-2016.. 2003;361:2005-2016.Numbers in bars represent number of patients Numbers in bars represent number of patients in category at baseline.in category at baseline.

0

10

20

30

40

50

Inc

ide

nc

e o

f m

ajo

r v

as

cu

lar

ev

en

ts (

%)

Placebo

Simvastatin 40 mg

0

10

20

30

40

50

Inc

ide

nc

e o

f m

ajo

r v

as

cu

lar

ev

en

ts (

%)

Placebo

Simvastatin 40 mg

RRRRRR12%12%

RRRRRR23%23%

RRRRRR22%22%

RRRRRR19%19%

RRRRRR31%31%

Diabetes Diabetes + CHD+ CHD

No diabetes No diabetes + CHD+ CHD

Diabetes Diabetes + other CVD+ other CVD

No diabetes No diabetes + other CVD+ other CVD

Diabetes Diabetes + no CVD+ no CVD

10091009 972972 56835683 57225722 519519 551551 14811481 14491449 14571457 14551455

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HPS: Consistent Benefit in Diabetic Patients Regardless of Baseline LDL-CHPS: Consistent Benefit in Diabetic Patients Regardless of Baseline LDL-C

HPS Collaborative Group. HPS Collaborative Group. LancetLancet. 2003;361:2005-2016.. 2003;361:2005-2016.Numbers in bars represent number of patients Numbers in bars represent number of patients in category at baseline.in category at baseline.

0

10

20

30

40

Diabetes No diabetes Diabetes No diabetes

Inc

ide

nc

e o

f m

ajo

r v

as

cu

lar

ev

en

ts (

%) Placebo

Simvastatin 40 mg

0

10

20

30

40

Diabetes No diabetes Diabetes No diabetes

Inc

ide

nc

e o

f m

ajo

r v

as

cu

lar

ev

en

ts (

%) Placebo

Simvastatin 40 mg

RRRRRR25%25%

RRRRRR18%18%

RRRRRR16%16%

RRRRRR24%24%

12071207 12191219 21972197 21702170 17781778 17591759 50855085 51215121

LDL <116 mg/dLLDL <116 mg/dL LDL LDL 116 mg/dL116 mg/dL

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HPS: ImplicationsHPS: Implications

Contributed to changes in treatment recommendations for diabetic patients:

2003 European Guidelines for the Management of CVD:

> total cholesterol <175 mg/dL and LDL-C <100 mg/dL

2004 ADA recommendations:> focus on LDL-C lowering as the primary lipid goal (<100 mg/dL)> statins recommended as the initial pharmacologic approach

2004 NCEP ATP update:> LDL-C goal of <70 mg/dL in very high-risk patients

Contributed to changes in treatment recommendations for diabetic patients:

2003 European Guidelines for the Management of CVD:

> total cholesterol <175 mg/dL and LDL-C <100 mg/dL

2004 ADA recommendations:> focus on LDL-C lowering as the primary lipid goal (<100 mg/dL)> statins recommended as the initial pharmacologic approach

2004 NCEP ATP update:> LDL-C goal of <70 mg/dL in very high-risk patients

CTT Collaborators, Lancet 2008; 371: 117-125

CTT Collaborators, Lancet 2008; 371: 117-125

CTT Collaborators, Lancet 2008; 371: 117-125

CTT Collaborators, Lancet 2008; 371: 117-125

CTT Collaborators, Lancet 2008; 371: 117-125

CTT Collaborators, Lancet 2008; 371: 117-125

CTT Collaborators, Lancet 2008; 371: 117-125

CTT Collaborators, Lancet 2008; 371: 117-125

Uno studio randomizzato con statine

realizzato espressamentenei diabetici:

lo studio CARDS

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CARDS: The RationaleCARDS: The Rationale

Elevated cardiovascular risk associated with type 2 diabetes

The role of lipid-lowering for secondary prevention of CHD in this population, particularly with statins, is clearly defined

No previous statin trial had been exclusively designed to test the benefit of statin intervention in diabetic patients without CHD and with baseline LDL-C levels below contemporary treatment guidelines

Elevated cardiovascular risk associated with type 2 diabetes

The role of lipid-lowering for secondary prevention of CHD in this population, particularly with statins, is clearly defined

No previous statin trial had been exclusively designed to test the benefit of statin intervention in diabetic patients without CHD and with baseline LDL-C levels below contemporary treatment guidelines

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4-year follow-up4-year follow-up

CARDS: Primary Prevention of CVD With Atorvastatin in Type 2 DiabetesCARDS: Primary Prevention of CVD With Atorvastatin in Type 2 Diabetes

Atorvastatin 10 mg/day(n=1428)

Placebo(n=1410)

2838 patients2838 patients

Primary end point: Incidence of major cardiovascular events:

– Cardiovascular-related death– Nonfatal MI– Stroke– Resuscitated cardiac arrest– Unstable angina– Coronary revascularization procedures

Patient population: Age: 40-75 years LDL-C 160 mg/dL Triglycerides 600 mg/dL Type 2 diabetes No prior MI or CHD 1+ CHD risk factor

Study completion date

Anticipated:Anticipated: Early 2005 Early 2005

Actual:Actual: Halted 2 years early Halted 2 years early due to significant resultsdue to significant results

Study completion date

Anticipated:Anticipated: Early 2005 Early 2005

Actual:Actual: Halted 2 years early Halted 2 years early due to significant resultsdue to significant results

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CARDS: Atorvastatin Significantly Reduces Risk of Major CV Events*CARDS: Atorvastatin Significantly Reduces Risk of Major CV Events*

*Acute CHD event, coronary revascularization, stroke.*Acute CHD event, coronary revascularization, stroke. Colhoun HM et al. Colhoun HM et al. LancetLancet. 2004;364:685-696.. 2004;364:685-696.

0

5

10

15

0 1 2 3 4 5 6

0

5

10

15

0 1 2 3 4 5 6

RRR=37% (95% CI: 17%-52%)RRR=37% (95% CI: 17%-52%)PP=0.001=0.001

Cu

mu

lati

ve in

cid

ence

C

um

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ce

of

even

ts (

% o

f p

atie

nts

) o

f ev

ents

(%

of

pat

ien

ts)

127 events127 events

83 events83 events

Time (years)Time (years)

Atorvastatin 10 mg (n=1428)Atorvastatin 10 mg (n=1428)

Placebo (n=1410)Placebo (n=1410)Trial stopped earlyTrial stopped early(median follow-up 3.9 years)(median follow-up 3.9 years)

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CARDS: Treatment Effect on the Primary End PointCARDS: Treatment Effect on the Primary End Point

Colhoun HM et al. Colhoun HM et al. LancetLancet. 2004;364:685-696.. 2004;364:685-696.

0.2 0.4 0.6 0.8 1.0 1.2 1.40.2 0.4 0.6 0.8 1.0 1.2 1.4

Event Event rate, n (%) Hazard ratio (95% CI) RRR

Placebo Atorvastatin

Event Event rate, n (%) Hazard ratio (95% CI) RRR

Placebo Atorvastatin

Primary end pointPrimary end point 127 (9.0%)127 (9.0%) 83 (5.8%)83 (5.8%) 37%37%

PP=0.001=0.001

Primary end pointPrimary end point 127 (9.0%)127 (9.0%) 83 (5.8%)83 (5.8%) 37%37%

PP=0.001=0.001

Acute coronary Acute coronary 77 (5.5%)77 (5.5%) 51 (3.6%)51 (3.6%) 36% 36%eventseventsAcute coronary Acute coronary 77 (5.5%)77 (5.5%) 51 (3.6%)51 (3.6%) 36% 36%eventsevents

Coronary Coronary 34 (2.4%)34 (2.4%) 24 (1.7%)24 (1.7%) 31%31%revascularizationrevascularizationCoronary Coronary 34 (2.4%)34 (2.4%) 24 (1.7%)24 (1.7%) 31%31%revascularizationrevascularization

StrokeStroke 39 (2.8%)39 (2.8%) 21 (1.5%)21 (1.5%) 48% 48%StrokeStroke 39 (2.8%)39 (2.8%) 21 (1.5%)21 (1.5%) 48% 48%

Placebo betterPlacebo betterAtorvastatin betterAtorvastatin better

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0

1

2

3

4

5

6

0 1 2 3 4 5 6

0

1

2

3

4

5

6

0 1 2 3 4 5 6

CARDS: Atorvastatin Significantly Reduces Risk of StrokeCARDS: Atorvastatin Significantly Reduces Risk of Stroke

Newman C et al. American Heart Association 78th Scientific Sessions, 2005.Newman C et al. American Heart Association 78th Scientific Sessions, 2005.

RRR= 48% (95% CI: 31%-89%)RRR= 48% (95% CI: 31%-89%)PP=0.016=0.016

Cu

mu

lati

ve in

cid

ence

C

um

ula

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den

ce

of

even

ts (

% o

f p

atie

nts

) o

f ev

ents

(%

of

pat

ien

ts)

39 events39 events

21 events21 events

Time (years)Time (years)

Atorvastatin 10 mg (n=1428)Atorvastatin 10 mg (n=1428)

Placebo (n=1410)Placebo (n=1410)Trial stopped earlyTrial stopped early(median follow-up 3.9 years)(median follow-up 3.9 years)

Stroke was a component of the Stroke was a component of the primary endpoint, evaluated primary endpoint, evaluated individually as a secondary survival individually as a secondary survival analysisanalysis..

37

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CARDS: Treatment Effect on the Primary End Point By Median Baseline Lipid LevelCARDS: Treatment Effect on the Primary End Point By Median Baseline Lipid Level

Colhoun HM et al. Colhoun HM et al. LancetLancet. 2004;364:685-696.. 2004;364:685-696.

0.2 0.4 0.6 0.8 1.0 1.2 1.40.2 0.4 0.6 0.8 1.0 1.2 1.4

Lipid parameter Event rate, n (%) Hazard ratio (95% CI) RRR

PlaceboPlacebo AtorvastatinAtorvastatin

Placebo betterPlacebo betterAtorvastatin betterAtorvastatin better

LDL-C (mg/dL) 120120 66 (9.5%)66 (9.5%) 44 (6.1%)44 (6.1%) 38%38% <120 <120 61 (8.5%)61 (8.5%) 39 (5.6%)39 (5.6%) 37%37%

HDL-C (mg/dL) 54 54 62 (8.5%)62 (8.5%) 36 (5.2%)36 (5.2%) 41%41% <54 <54 65 (9.6%)65 (9.6%) 47 (6.4%)47 (6.4%) 34%34%

Triglycerides (mg/dL) 150150 67 (9.6%)67 (9.6%) 40 (5.5%)40 (5.5%) 44%44% <150 <150 60 (8.4%)60 (8.4%) 43 (6.1%)43 (6.1%) 29%29%

Total-C (mg/dL) 209209 71 (10.1%)71 (10.1%) 44 (6.2%)44 (6.2%) 41%41% <209 <209 56 (7.9%)56 (7.9%) 39 (5.5%)39 (5.5%) 33%33%

Tests of heterogeneity not significant Tests of heterogeneity not significant for each lipid parameter.for each lipid parameter.

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CARDS: ImplicationsCARDS: Implications

Established the efficacy and safety of atorvastatin 10 mgin reducing the risk of a first CVD event in patients with diabetes without high LDL-C

Authors questioned whether any patients with diabetes are at sufficiently low CVD risk for statin therapy to be withheld

Contributed to further update of ADA recommendations in 2005 In patients with diabetes aged >40 years without overt CVD, with

total cholesterol 135 mg/dL (3.5 mmol/L), statin therapy recommended to achieve LDL-C reduction of 30-40% regardless of baseline LDL-C

Primary goal is an LDL-C of <100 mg/dL (2.6 mmol/L)

Patients with diabetes and overt CVD should be treated with a statin to achieve an LDL-C goal of <70 mg/dL (1.8 mmol/L)

Established the efficacy and safety of atorvastatin 10 mgin reducing the risk of a first CVD event in patients with diabetes without high LDL-C

Authors questioned whether any patients with diabetes are at sufficiently low CVD risk for statin therapy to be withheld

Contributed to further update of ADA recommendations in 2005 In patients with diabetes aged >40 years without overt CVD, with

total cholesterol 135 mg/dL (3.5 mmol/L), statin therapy recommended to achieve LDL-C reduction of 30-40% regardless of baseline LDL-C

Primary goal is an LDL-C of <100 mg/dL (2.6 mmol/L)

Patients with diabetes and overt CVD should be treated with a statin to achieve an LDL-C goal of <70 mg/dL (1.8 mmol/L)

Atorvastatin study in the prevention of CV endpoints in subjects with DM: the ASPEN study

Knopp RH et al, Diabetes Care 2006; 29: 1478-85

Objective

To evaluate atorvastatin 10 mg vs placebo

in pts with DM and LDL cholesterol levels

below the current guidelines cut-offs

Atorvastatin study in the prevention of CV endpoints in subjects with DM: the ASPEN study.

Knopp RH et al. Diabetes Care 2006; 29: 1478-85

Cosa consigliano le LLGGnel 2008

Nel pz a basso rischio (LDL<100, TG<150, HDL>50) controlli ogni 2 aa

Nel pz con LDL > 100• CVD • > 40 aa con un fattore di rischio (retinopatia,nefropatia, ipertensione arteriosa, sindrome metabolica)

aggiungere una statina con obiettivo LDL<100(eventualmente <70 se il profilo di rischio è molto elevato)

ADA 2008-Diabetes Care 2008; 31: S5-S11

* Non approvata per uso clinico

Atorva Simva Lova Prava Fluva Rosuva LDL-C

-- 10 20 20 40 -- 22-28

10 20 40 40 80 -- 30-35

20 40 80 -- -- 10 37-43

40 80 -- -- -- 20 42-50

80 160* -- -- -- 40 50-60

Dose (mg) farmaco Riduzione%

Efficacia comparata delle diverse statine

Roberts WC. Am J Cardiol. 1997;80:106-107Roberts WC. Am J Cardiol. 1997;80:106-107Stein E et al. J Cardiovasc Pharmacol Therapeut. 1997;2:7-16Stein E et al. J Cardiovasc Pharmacol Therapeut. 1997;2:7-16Olsson A. Cardiovasc Drug Rev 2002;20:303–328Olsson A. Cardiovasc Drug Rev 2002;20:303–328

Perché l’utilizzo delle statinenei diabetici è ancora

così basso?

Barriere all’aderenza all’utilizzo delle statine nel diabetico

Efficacia e sicurezza dell’alto dosaggio

Anziani

Insufficienza renale

Donne

Uno studio randomizzato con statine

ad alto dosaggionei diabetici:

lo studio TNT-diabete

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Patient population:Patient population: Age: 35-75 yearsAge: 35-75 years CHDCHD LDL-C: 130-250 mg/dL (3.4-6.5 mmol/L)LDL-C: 130-250 mg/dL (3.4-6.5 mmol/L) Triglycerides: Triglycerides: 600 mg/dL (600 mg/dL (6.8 6.8

mmol/L)mmol/L)

Primary end point:Primary end point: Time to occurrence of a major CV event:Time to occurrence of a major CV event:

– CHD deathCHD death– Nonfatal, nonNonfatal, non––procedure-related MIprocedure-related MI– Resuscitated cardiac arrestResuscitated cardiac arrest– Fatal or nonfatal strokeFatal or nonfatal stroke

Atorvastatin 10 mg

Open-label run-inOpen-label run-in

8 weeks8 weeks1-8 weeks1-8 weeks

Screening and wash-out

Screening and wash-out

Atorvastatin 10 mgLDL-C target: 100 mg/dL (2.6 mmol/L)

Median follow-up = 4.9 yearsMedian follow-up = 4.9 years

Atorvastatin 80 mgLDL-C target: 75 mg/dL (1.9 mmol/L)

Double-blind periodn=1501

LDL-C: <130 mg/dL (<3.4 mmol/L)

Double-blind periodn=1501

LDL-C: <130 mg/dL (<3.4 mmol/L)

n=748n=748

n=753n=753

BaselineBaseline

TNT Study Design: Patients With DiabetesTNT Study Design: Patients With Diabetes

Shepherd J et al. Shepherd J et al. Diabetes CareDiabetes Care. 2006;29:1220-1226.. 2006;29:1220-1226.

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FinalFinalScreenScreen 00 33 1212 2424 3636 4848 6060

BaselineBaseline

TNT: Changes in LDL-C By Treatment Group in Patients With DiabetesTNT: Changes in LDL-C By Treatment Group in Patients With Diabetes

0

20

40

60

80

100

120

140

160

180

Study visit (months)

Mea

n L

DL

-C (

mg

/dL

)

Atorvastatin 10 mg (n=753)

Atorvastatin 80 mg (n=748)

0

20

40

60

80

100

120

140

160

180

Study visit (months)

Mea

n L

DL

-C (

mg

/dL

)

Atorvastatin 10 mg (n=753)

Atorvastatin 80 mg (n=748)

Final LDL-C = 77.0 mg/dL (2.0 mmol/L) Final LDL-C = 77.0 mg/dL (2.0 mmol/L)

Final LDL-C = 98.6 mg/dL (2.5 mmol/L)Final LDL-C = 98.6 mg/dL (2.5 mmol/L)

Shepherd J et al. Shepherd J et al. Diabetes CareDiabetes Care. 2006;29:1220-1226.. 2006;29:1220-1226.

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TNT: Time to First Major Cardiovascular Event* in Patients With DiabetesTNT: Time to First Major Cardiovascular Event* in Patients With Diabetes

*CHD death, nonfatal non*CHD death, nonfatal non––procedure-related MI, procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke. resuscitated cardiac arrest, fatal or nonfatal stroke.

0

5

10

15

20

0 1 2 3 4 5 6

0

5

10

15

20

0 1 2 3 4 5 6

RRR=25% (95% CI: 3%-42%)RRR=25% (95% CI: 3%-42%)PP=0.026=0.026

Cu

mu

lati

ve in

cid

ence

C

um

ula

tive

inci

den

ce

of

even

ts (

% o

f p

atie

nts

)o

f ev

ents

(%

of

pat

ien

ts)

135 events135 events

103 events103 events

Time (years)Time (years)

Atorvastatin 10 mg (n=753)Atorvastatin 10 mg (n=753)

Atorvastatin 80 mg (n=748)Atorvastatin 80 mg (n=748)

Shepherd J et al. Shepherd J et al. Diabetes CareDiabetes Care. 2006;29:1220-1226.. 2006;29:1220-1226.

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Hazard Ratios in Patients With and Without Diabetes: Secondary Efficacy OutcomesHazard Ratios in Patients With and Without Diabetes: Secondary Efficacy Outcomes

Major CV event 17.9% 13.8%9.7%

7.8%

Major CV event 17.9% 13.8%9.7%

7.8%Any CV event 44.1% 39.8%31.6%

26.1%

Any CV event 44.1% 39.8%31.6%

26.1%Major coronary 12.9% 10.6%7.5%

6.0%

Major coronary 12.9% 10.6%7.5%

6.0%Any coronary 32.0% 29.3%25.5%

20.2%

Any coronary 32.0% 29.3%25.5%

20.2%Cerebrovascular 10.0% 7.0%4.2%

3.4%

Cerebrovascular 10.0% 7.0%4.2%

3.4%CHF with hosp. 8.2% 7.2%2.4%

1.6%

CHF with hosp. 8.2% 7.2%2.4%

1.6%PAD 8.9% 9.1%5.1%

4.9%

PAD 8.9% 9.1%5.1%

4.9%All-cause mortality 9.8% 10.8%4.9%

4.8%

All-cause mortality 9.8% 10.8%4.9%

4.8%

Atorvastatin 80 mg betterAtorvastatin 80 mg better Atorvastatin 10 mg betterAtorvastatin 10 mg better

0.4 0.6 0.8 1.0 1.2 1.4 1.60.4 0.6 0.8 1.0 1.2 1.4 1.6

Event rate (diabetes) Event rate (no diabetes)

10 mg 80 mg 10 mg 80 mg

Event rate (diabetes) Event rate (no diabetes)

10 mg 80 mg 10 mg 80 mg

Shepherd J et al. Shepherd J et al. Diabetes CareDiabetes Care. 2006;29:1220-1226.. 2006;29:1220-1226.

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TNT: SummaryTNT: Summary

The TNT study confirmed findings from prior studies that incidence of CV events is higher in patients with diabetes than in those without diabetes

25% reduction in risk of major CV events with atorvastatin 80 mg vs atorvastatin 10 mg (P=0.026) in patients with stable CHD and diabetes

Lower event rates observed in TNT than in other secondary prevention regimens in patients with CHD and diabetes

The TNT study strengthens the evidence for the recent recommendation of an LDL-C <70 mg/dL (1.8 mmol/L) as a therapeutic option in diabetic patients with CVD

The TNT study confirmed findings from prior studies that incidence of CV events is higher in patients with diabetes than in those without diabetes

25% reduction in risk of major CV events with atorvastatin 80 mg vs atorvastatin 10 mg (P=0.026) in patients with stable CHD and diabetes

Lower event rates observed in TNT than in other secondary prevention regimens in patients with CHD and diabetes

The TNT study strengthens the evidence for the recent recommendation of an LDL-C <70 mg/dL (1.8 mmol/L) as a therapeutic option in diabetic patients with CVD

Barriere all’aderenza all’utilizzo delle statine nel diabetico

Efficacia e sicurezza dell’alto dosaggio

Anziani

Insufficienza renale

Donne

Statins for secondary prevention in elderly patients (> 65 yrs)

Afilalo et al, JACC 2008; 51: 37-45

All cause mortality

DM in 5-29%of pts

Statins for secondary prevention in elderly patients (>65 yrs)

Afilalo et al, JACC 2008; 51: 37-45

Coronary artery disease mortality

Risk difference by FDA-approved statins

Kashani A et al, Circulation 2006;114:2788-2797

Lowest Success Rates in Patients at Highest Risk

Pearson TA, et al. Arch Intern Med. 2000;160:459-467.Pearson TA, et al. Arch Intern Med. 2000;160:459-467.

Low-risk Low-risk (n=861)(n=861)

CHD CHD (n=1352)(n=1352)

High-risk High-risk (n=1924)(n=1924)

Overall Overall (n=4137)(n=4137)

0

20

40

60

80

100

Patie

nts

Ach

ievi

ng L

DL-

C

Patie

nts

Ach

ievi

ng L

DL-

C

Goa

l (%

)G

oal (

%)

The high-risk paradox

Barriere all’aderenza all’utilizzo delle statine nel diabetico

Efficacia e sicurezza dell’alto dosaggio

Anziani

Insufficienza renale

Donne

Sheperd J et al. JACC 2008; 51: 1448-54DM in 18%

of pts

Statin therapy and mortality in elderly and very elderly patients (> 80 yrs)

Allen Maycock CA et al, JACC 2002; 40: 1777-85

statins

not usingstatins

statin prescription

28% 21% 20% DM in 5-18%of pts

Time to first CV event by treatment in pts with kidney disease (eGFR <60)

Sheperd J et al. JACC 2008; 51: 1448-54

An assessment of statin safety by nephrologists

Kasiske BL et al. Am J Cardiol 2006;97:82C-85C

Barriere all’aderenza all’utilizzo delle statine nel diabetico

Efficacia e sicurezza dell’alto dosaggio

Anziani

Insufficienza renale

Donne

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At same lipid levels, women with cardiovascular disease have lower mortality risk compared to men; women with diabetes have same or greater mortality risk compared to men

At same lipid levels, women with cardiovascular disease have lower mortality risk compared to men; women with diabetes have same or greater mortality risk compared to men

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Studies on diabetes and womenStudies on diabetes and women

Patients of physicians participating in the ADA Provider Recognition Program (n=7364)

Patients with diabetes at Kaiser Permanente Georgia (n=14,671)

Patients participating in the UCI Diabetes Coached Care Program (n=272)

Patients of physicians participating in the ADA Provider Recognition Program (n=7364)

Patients with diabetes at Kaiser Permanente Georgia (n=14,671)

Patients participating in the UCI Diabetes Coached Care Program (n=272)

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Gender differences in overall quality of diabetes care: PRPGender differences in overall quality of diabetes care: PRP

Quality Measure Males Females P-value

Annual HbA1c 97.7 98.4 NS

Annual urine protein 49.7 48.6 NS

Annual eye exam 68.5 69.0 NS

Annual foot exam 94.3 94.2 NS

HbA1c < 8 mg/dl 65.8 66.7 NS

BP <130/80 41.9 41.6 NS

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Gender differences in overall quality of diabetes care: KPGGender differences in overall quality of diabetes care: KPG

Quality Measure Males Females P-value

Annual HbA1c 67.3 62.7 <.001

Annual blood pressure 71.1 64.8 <.01

HbA1c < 8 mg/dl 53.4 57.3 <.001

BP <130/80 35.0 35.4 NS

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Gender differences in overall quality of diabetes care: UCIGender differences in overall quality of diabetes care: UCI

Quality Measure Males Females P-value

Annual HbA1c 100 100 NS

Annual foot exam 90.2 98.1 <.01

HbA1c < 8 mg/dl 89.2 92.5 <.001

BP <130/80 35.0 35.4 NS

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Gender Differences in Lipid Monitoring and ControlGender Differences in Lipid Monitoring and Control

Quality Measure Sample Males Females P-value

Monitoring lipids PRP 86.8 84.3 NS

LDL < 100mg/dl 38.1 31.2 <.001

Monitoring lipids KPG 67.3 65.3 NS

LDL < 100mg/dl 34.4 24.7 <.001

Monitoring lipids UCI 100 100 NS

LDL < 100mg/dl 61.7 51.8 <.001

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With no differences in the overall quality of diabetes care, nor in monitoring of lipids, women have poorer lipid control

Women with diabetes and poor lipid control significantly less likely to be on statins (HR 0.77, p< 0.001)

With no differences in the overall quality of diabetes care, nor in monitoring of lipids, women have poorer lipid control

Women with diabetes and poor lipid control significantly less likely to be on statins (HR 0.77, p< 0.001)

Come migliorare l’aderenza alla terapia farmacologica

(e alle raccomandazioni sullo stile di vita)nel paziente diabetico e dislipidemico

Long-term adherence with cardiovascular regimensBasal prescription and discontinuation (gray bar) after 1 yr

n= 1326 CAD pts, Duke University

Kulkarni sp et al. Am Heart J 2006;151: 185-91

Cumulative probability to returning to treatment with statins

Brookhart MA et al. Arch Intern Med 2007; 167:847-52

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Terapia con statine nel diabetico:

come garantire l’aderenza

Terapia con statine nel diabetico:

come garantire l’aderenza

- comunicarecomunicare- responsabilizzareresponsabilizzare- gratificaregratificare

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Helping pts with DM make treatment decisionHelping pts with DM make treatment decision

Weymiller AJ et al, Arch intern Med 2007; 167: 1076-82Weymiller AJ et al, Arch intern Med 2007; 167: 1076-82

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ConclusionsConclusions

Early clinical trials including have shown that statins benefit CHD patients with type 2 diabetes

Pre-specified analyses of patients with diabetes with and without CHD (ASCOT-LLA, HPS, LIPID) have shown significant benefits of statins in reducing cardiovascular events including stroke

CARDS—the first prospective statin trial in patients with diabetes—was terminated ~2 years earlier than anticipated due to a highly significant reduction in major cardiovascular events compared with placebo

High-dose statin therapy in patients with CHD and diabetes (TNT) has shown a significant reduction in cardiovascular events compared with lower-dose statin therapy

These trials have contributed to changes in guidelines focusing on intensive LDL-C management in patients with diabetes

Early clinical trials including have shown that statins benefit CHD patients with type 2 diabetes

Pre-specified analyses of patients with diabetes with and without CHD (ASCOT-LLA, HPS, LIPID) have shown significant benefits of statins in reducing cardiovascular events including stroke

CARDS—the first prospective statin trial in patients with diabetes—was terminated ~2 years earlier than anticipated due to a highly significant reduction in major cardiovascular events compared with placebo

High-dose statin therapy in patients with CHD and diabetes (TNT) has shown a significant reduction in cardiovascular events compared with lower-dose statin therapy

These trials have contributed to changes in guidelines focusing on intensive LDL-C management in patients with diabetes

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Diapositive aggiuntive Diapositive aggiuntive

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Secondary Prevention of CVD With Statins in Patients With Diabetes

Secondary Prevention of CVD With Statins in Patients With Diabetes

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Primary Prevention of CVD With Statins in Patients With DiabetesPrimary Prevention of CVD With Statins in Patients With Diabetes

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ASCOT-LLA: Primary Prevention in Patients at Modest Risk of CHD ASCOT-LLA: Primary Prevention in Patients at Modest Risk of CHD

Highlighted boxes indicate diabetes patients enrolled in lipid-lowering arm.Highlighted boxes indicate diabetes patients enrolled in lipid-lowering arm.

-blocker ± diuretic-blocker ± diuretic CCB ± ACE inhibitorCCB ± ACE inhibitor

TC >250 mg/dLTC >250 mg/dL (>6.5 mmol/L) (>6.5 mmol/L)

2532 TC 250 mg/dL(6.5 mmol/L)

TC >250 mg/dLTC >250 mg/dL (>6.5 mmol/L) (>6.5 mmol/L)

Open lipid loweringOpen lipid lowering1258

Atorvastatin 10 mg1274

PlaceboOpen lipid loweringOpen lipid lowering

19,342 patients19,342 patients

RandomizedRandomized

RandomizedRandomized

Primary end point: Composite of fatal CHD and nonfatal MI Primary end point: Composite of fatal CHD and nonfatal MI

Adapted from Sever PS et alAdapted from Sever PS et al. J Hypertens. . J Hypertens. 2001;19:1139-1147.2001;19:1139-1147.

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ASCOT-LLA Post hoc Analysis: Total CV Events and Procedures in Patients With DiabetesASCOT-LLA Post hoc Analysis: Total CV Events and Procedures in Patients With Diabetes

Sever PS et al. Sever PS et al. Diabetes CareDiabetes Care. 2005;28:1151-1157.. 2005;28:1151-1157.

0

5

10

15

0 1 2 3 4 5 6

0

5

10

15

0 1 2 3 4 5 6

RRR=23% RRR=23% PP=0.036=0.036

151 events151 events

116 events116 events

Trial stopped earlyTrial stopped early(median follow-up 3.3 years) (median follow-up 3.3 years)

Cu

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of

even

ts (

% o

f p

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ents

(%

of

pat

ien

ts)

Time (years)Time (years)

Atorvastatin 10 mgAtorvastatin 10 mg

PlaceboPlacebo

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ASCOT-LLA: SummaryASCOT-LLA: Summary

In hypertensive patients with diabetes but no history of CHD, relative risk reductions in all cardiovascular events and procedures with atorvastatin were similar to those in the nondiabetic subgroup, and were evident early in the trial

Small numbers of events in the individual components of the composite end point, resulting in part from early stopping of the trial, reduced the power to test significant reductions in CHD and stroke There was no significant heterogeneity among subgroups

ASCOT-LLA provides further support for the findings in CARDS concerning the benefits of atorvastatin 10 mg in patients with diabetes and without CHD

In hypertensive patients with diabetes but no history of CHD, relative risk reductions in all cardiovascular events and procedures with atorvastatin were similar to those in the nondiabetic subgroup, and were evident early in the trial

Small numbers of events in the individual components of the composite end point, resulting in part from early stopping of the trial, reduced the power to test significant reductions in CHD and stroke There was no significant heterogeneity among subgroups

ASCOT-LLA provides further support for the findings in CARDS concerning the benefits of atorvastatin 10 mg in patients with diabetes and without CHD

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Diabetes + vascular disease

Coronary heart disease 779 (30.3) 918 (36.2) 18% (P<0.0001)Other vascular disease 127 (15.8) 156 (20.7) 22% (P=0.02)Subtotal 906 (26.8) 1074 (32.6) 19%

Diabetes + vascular disease

Coronary heart disease 779 (30.3) 918 (36.2) 18% (P<0.0001)Other vascular disease 127 (15.8) 156 (20.7) 22% (P=0.02)Subtotal 906 (26.8) 1074 (32.6) 19%

Cholesterol Treatment Trialists Collaboration: Major Vascular Events in Diabetes PatientsCholesterol Treatment Trialists Collaboration: Major Vascular Events in Diabetes Patients

Baseline vascular disease/ Event rate, n (%) Hazard ratio (CI*) Relative riskhypertension Statin Control reductionBaseline vascular disease/ Event rate, n (%) Hazard ratio (CI*) Relative riskhypertension Statin Control reduction

Diabetes, no vascular disease

Hypertension 422 (10.0) 504 (12.0) 25% (P=0.0003)No hypertension 137 (7.7) 204 (11.2) 30% (P<0.0001)Subtotal 559 (9.3) 708 (11.8) 27%

Diabetes, no vascular disease

Hypertension 422 (10.0) 504 (12.0) 25% (P=0.0003)No hypertension 137 (7.7) 204 (11.2) 30% (P<0.0001)Subtotal 559 (9.3) 708 (11.8) 27%

All diabetes patients 1465 (15.6) 1782 (19.2) 21%All diabetes patients 1465 (15.6) 1782 (19.2) 21%

Placebo betterPlacebo betterStatin betterStatin better

0.5 1.0 1.50.5 1.0 1.5

N=18,686 patients with diabetesN=18,686 patients with diabetes

** 95% CI95% CI 99% CI99% CI

Cholesterol Treatment Trialists. Presentation at the American Diabetes Association 66Cholesterol Treatment Trialists. Presentation at the American Diabetes Association 66 thth Scientific Sessions, 2006. Scientific Sessions, 2006.

ESC on diabetes and pre-diabetes EHJ 2007; 28:88-136In prevenzione secondaria nessuno studio ad hoc

>5000 pts in analisi post-hoc 4S 483 pts DM sim riduce 42% major coro events

Haffner Arch Int Med 99;159:2661-7 HPS 3050 pts DM sim riduce 18% major coro, stroke, rev

CARE 586 pts DM prava riduce 25% major coro events LIPID 782 pts DM prava riduce 19% major coro events e rev LIPS 202 pts DM fluva riduce 47% major coro events e rev

GREACE 313 pts DM atorva riduce 58% major e stroke e revNell’alto dosaggio i vantaggi osservati enl PROVE IT e nel TNT sono stati

simili anche per il pt con DM

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Total CV events and procedures

Diabetes 23% 0.82

No diabetes 20%

Subtotal: 21% (P<0.001)

Total CV events and procedures

Diabetes 23% 0.82

No diabetes 20%

Subtotal: 21% (P<0.001)

ASCOT-LLA: Lack of Heterogeneity of Effect in Patients With or Without DiabetesASCOT-LLA: Lack of Heterogeneity of Effect in Patients With or Without Diabetes

Hazard ratio (95% CI) Relative risk P value forreduction heterogeneity

Hazard ratio (95% CI) Relative risk P value forreduction heterogeneity

Sever PS et al. Sever PS et al. Diabetes CareDiabetes Care. 2005;28:1151-. 2005;28:1151-1157.1157.

Nonfatal MI + fatal CHD

Diabetes 16% 0.14

No diabetes 44%

Subtotal: 36% (P<0.001)

Nonfatal MI + fatal CHD

Diabetes 16% 0.14

No diabetes 44%

Subtotal: 36% (P<0.001)

Fatal and nonfatal stroke

Diabetes 33% 0.66

No diabetes 24%

Subtotal: 27% (P<0.024)

Fatal and nonfatal stroke

Diabetes 33% 0.66

No diabetes 24%

Subtotal: 27% (P<0.024)

Placebo betterPlacebo betterAtorvastatin betterAtorvastatin better

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.60.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6

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Lipid Treatment Guidelines: Which Diabetes Patients Should Be Treated?Lipid Treatment Guidelines: Which Diabetes Patients Should Be Treated?

Guidelines Lipid targets in diabetes patients Treatment recommendations

NCEP ATP IIINCEP ATP III11 LDL-C <100 mg/dL (2.6 mmol/L)LDL-C <100 mg/dL (2.6 mmol/L)

Optional LDL-C goal: <70 mg/dL Optional LDL-C goal: <70 mg/dL (1.8 mmol/L)(1.8 mmol/L)

Intensity of therapy should be sufficient to Intensity of therapy should be sufficient to achieve a 30-40% reduction in LDL-Cachieve a 30-40% reduction in LDL-C

ADAADA22 Patients without CVD LDL-CLDL-C <100 mg/dL (2.6 mmol/L) <100 mg/dL (2.6 mmol/L)

Age >40 years: Statin therapy to achieve Age >40 years: Statin therapy to achieve LDL-C reduction of 30-40%, irrespective of LDL-C reduction of 30-40%, irrespective of baseline LDL-Cbaseline LDL-C

Patients with CVDOptional Optional LDL-CLDL-C goal: <70 mg/dL goal: <70 mg/dL (1.8 mmol/L)(1.8 mmol/L)

All patients should be treated with a statin to All patients should be treated with a statin to achieve LDL-C reduction of 30-40%achieve LDL-C reduction of 30-40%

Joint European Joint European SocietiesSocieties33

TC <4.5 mmol/L (175 mg/dL)TC <4.5 mmol/L (175 mg/dL)

LDL-C <2.5 mmol/L (100 mg/dL)LDL-C <2.5 mmol/L (100 mg/dL)

Joint British Joint British SocietiesSocieties44

TC <4.0 mmol/L (155 mg/dL)TC <4.0 mmol/L (155 mg/dL)

LDL-C <2.0 mmol/L (77 mg/dL)LDL-C <2.0 mmol/L (77 mg/dL)

Treat to TC and LDL-C targets (or a 25% Treat to TC and LDL-C targets (or a 25% and a 30% reduction, respectively), using and a 30% reduction, respectively), using statins at doses whose efficacy and safety statins at doses whose efficacy and safety have been shown in trialshave been shown in trials

1.1. Grundy SM et al. Grundy SM et al. CirculationCirculation. 2004;110:227-39.. 2004;110:227-39.2.2. American Diabetes Association. American Diabetes Association. Diabetes CareDiabetes Care. 2006;29(suppl 1):S4-S42.. 2006;29(suppl 1):S4-S42.3.3. De Backer G et al. De Backer G et al. Eur J Cardiovasc Prevent RehabilEur J Cardiovasc Prevent Rehabil. 2003;10(suppl 1):S1-S78.. 2003;10(suppl 1):S1-S78.4.4. British Cardiac Society et al. British Cardiac Society et al. HeartHeart. 2005;91(suppl v):v1-v52.. 2005;91(suppl v):v1-v52.