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Cardioprotezione farmacologica a lungo termine: il punto sulle statine

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1 Cardioprotezione farmacologica a lungo termine: il punto sulle statine
XXXIX Congresso Nazionale ANMCO Firenze, 30 maggio- 2 giugno 2008 Minimaster Cuore e diabete – Prevenzione delle recidive e aderenza alle terapie Cardioprotezione farmacologica a lungo termine: il punto sulle statine Stefano Urbinati UOC Cardiologia Ospedale Bellaria, Bologna

2 siamo abbastanza attenti?
Diagnosi di nuovi casi di diabete: siamo abbastanza attenti?

3 EuroHeart Survey n=3940 pts with known glucometabolic state
Newly detected DM n= 452 (11%) After a 1-year follow-up period On treatment for DM n= 77 (17%) No treatment for DM n= 375 (83%) mortality p<0.002 MI stroke Anselmino et al, Eur Heart J 2008;29:177-84

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

5 Anselmino et al, Eur Heart J 2008;29:177-84
… the general impression is that pts with CAD and DM are inappropriately managed for several reasons… Cardiologists neglect o are inexperienced as regards GL treatments 2. A close collaboration between cardiologists and diabetologists is absent 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

6 Dislipidemia nel diabetico:
entità del problema

7 High Incidence of Dyslipidemia in the Diabetic Population
LDL-C (mg/dL) Triglycerides (mg/dL) HDL-C (mg/dL) 130 <100 200 <150 Men 40 Women 50 Men >40 Women >50 *245 men with diabetes and 253 women with diabetes aged 18 years from NHANES Modified from Jacobs MJ et al. Diabetes Res Clin Pract. 2005;70:

8 MRFIT*: Cardiovascular Disease (CVD) Mortality 3 Times Greater in Men With Diabetes at All Cholesterol Levels *Multiple Risk Factor Intervention Trial Stamler J et al. Diabetes Care. 1993;16:

9 UKPDS*: 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. Variable P-value 1. LDL-C <0.0001 2. HDL-C 0.0001 3. HbA1c 0.0022 4. Systolic BP 0.0065 5. Smoking 0.056 *United Kingdom Prospective Diabetes Study. Turner RC et al. BMJ. 1998;316:

10 Lipid tertiles (mg/dL)
UKPDS: 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 diabetes Total cholesterol P<0.0001 LDL-C P<0.0001 Triglycerides P<0.0001 HDL-C P<0.0001 Hazard ratio Lipid tertiles (mg/dL) *Age- and sex-adjusted. Turner RC et al. BMJ. 1998;316:

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

12 Dislipidemia nel diabetico: approccio multidisciplinare
l’importanza di un approccio multidisciplinare

13 Effect of a multifactorial intervention
on mortality in type 2 diabetes Our study was not designed to identify which elements of intensive diabetes therapy contributed most to the reduction in CV risk. Using a risk calculator based on UKPDS, we concluded that the use of statins and antihypertensive drugs have the largest effect in reducing CV risk during the 7.8 yrs of interventions, with hypoglicemic agents and aspirin the next most important interventions. Gaede et al for the STENO-2 Investigators, NEJM 2003;348:383-93

14 Evidenze sull’efficacia delle statine nel diabetico

15 Early Statin Secondary Prevention Trials: Design Overview
Median follow-up: 5.4 years Simvastatin mg/day (n=2221) Placebo (n=2223) 4444 patients 4S Age: years Previous MI or angina TC: mmol/L ( mg/dL) Triglycerides: 2.5 mmol/L (221 mg/dL) 4S Study Group. Lancet. 1994;334: Primary end point: All-cause mortality CARE Age: years MI in previous 3-20 months TC: <240 mg/dL (<6.2 mmol/L) LDL-C: mg/dL ( mmol/L) Triglycerides: <350 mg/dL (<4.0 mmol/L) 4159 patients Pravastatin 40 mg/day (n=2081) Placebo (n=2078) Median follow-up: 5.0 years Primary end point: CHD death + nonfatal MI Sacks F et al. N Engl J Med. 1996;335: LIPID Age: years MI or unstable angina in previous 3-36 months TC: mg/dL ( mmol/L) Triglycerides <445 mg/dL (<5.0 mmol/L) 9014 patients Pravastatin 40 mg/day (n=4512) Placebo (n=4502) Mean follow-up: 6.1 years LIPID Study Group. N Engl J Med. 1998;339: Primary end point: CHD death

16 4S: Major CHD Event Reduction in Patients With Diabetes*
Patients without major CVD event (%) Diabetes, simvastatin mg (n=105) Diabetes, placebo (n=97) No diabetes, simvastatin mg (n=2116) No diabetes, placebo (n=2126) RRR=32% P=0.0001 RRR=55% P=0.002 Time (years) *Post-hoc analysis of the secondary end point: CHD death + nonfatal MI. Pyörälä K et al. Diabetes Care. 1997;20:

17 CARE: CHD Event Reduction in Patients With Diabetes*
RRR=25% P=0.05 Cumulative incidence of events (% of patients) Time (years) Diabetes, pravastatin 40 mg (n=282) Diabetes, placebo (n=304) No diabetes, pravastatin 40 mg (n=1779) No diabetes, placebo (n=1774) RRR=23% P<0.001 *Post hoc analysis of an expanded CHD end point: CHD death, nonfatal MI, CABG, and PTCA. Goldberg RB et al. Circulation. 1998;98:

18 LIPID: CHD Event Reduction in Patients With Diabetes*
RRR=19% P=0.11 Cumulative incidence of events (% of patients) Time (years) Diabetes, pravastatin 40 mg (n=542) Diabetes, placebo (n=535) No diabetes, pravastatin 40 mg (n=3496) No diabetes, placebo (n=3501) RRR=23% P=0.001 *Pre-specified diabetes subgroup primary endpoint: CHD death and nonfatal MI. Keech A et al. Diabetes Care. 2003;26:

19 HPS: Primary and Secondary Prevention of CVD in Patients With Diabetes
Patient population: Age: years TC: 3.5 mmol/L (135 mg/dL) At least one of: Diabetes mellitus CHD Occlusive noncoronary artery disease Treated hypertension (men aged 65 years) Pre-specified diabetes subgroup end points: Major coronary events Major vascular events Mean follow-up 4.8 years Simvastatin 40 mg/day (n=1455) Without CVD (n=2912) Placebo (n=1457) 5963 patients with diabetes Simvastatin 40 mg/day (n=1523) With CVD (n=3051) Placebo (n=1528) HPS Collaborative Group. Lancet. 2003;361:

20 HPS: Subgroup Evaluation Shows Consistent Benefit in Diabetic Patients Regardless of CVD
RRR 12% RRR 23% RRR 22% RRR 19% RRR 31% Diabetes + CHD No diabetes + CHD Diabetes + other CVD No diabetes + other CVD Diabetes + no CVD 1009 972 5683 5722 519 551 1481 1449 1457 1455 Numbers in bars represent number of patients in category at baseline. HPS Collaborative Group. Lancet. 2003;361:

21 HPS: Consistent Benefit in Diabetic Patients Regardless of Baseline LDL-C
RRR 25% RRR 18% RRR 16% RRR 24% 1207 1219 2197 2170 1778 1759 5085 5121 LDL <116 mg/dL LDL 116 mg/dL Numbers in bars represent number of patients in category at baseline. HPS Collaborative Group. Lancet. 2003;361:

22 2003 European Guidelines for the Management of CVD:
HPS: 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

23 CTT Collaborators, Lancet 2008; 371: 117-125

24 CTT Collaborators, Lancet 2008; 371: 117-125

25 CTT Collaborators, Lancet 2008; 371: 117-125

26 CTT Collaborators, Lancet 2008; 371: 117-125

27 CTT Collaborators, Lancet 2008; 371: 117-125

28 CTT Collaborators, Lancet 2008; 371: 117-125

29 CTT Collaborators, Lancet 2008; 371: 117-125

30 CTT Collaborators, Lancet 2008; 371: 117-125

31 Uno studio randomizzato realizzato espressamente
con statine realizzato espressamente nei diabetici: lo studio CARDS

32 CARDS: 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

33 CARDS: Primary Prevention of CVD With Atorvastatin in Type 2 Diabetes
Patient population: Age: years LDL-C 160 mg/dL Triglycerides 600 mg/dL Type 2 diabetes No prior MI or CHD 1+ CHD risk factor Atorvastatin 10 mg/day (n=1428) 2838 patients Placebo (n=1410) 4-year follow-up Primary end point: Incidence of major cardiovascular events: Cardiovascular-related death Nonfatal MI Stroke Resuscitated cardiac arrest Unstable angina Coronary revascularization procedures Study completion date Anticipated: Early 2005 Actual: Halted 2 years early due to significant results

34 CARDS: Atorvastatin Significantly Reduces Risk of Major CV Events*
Atorvastatin 10 mg (n=1428) Placebo (n=1410) Trial stopped early (median follow-up 3.9 years) 127 events Cumulative incidence of events (% of patients) 83 events RRR=37% (95% CI: 17%-52%) P=0.001 Time (years) *Acute CHD event, coronary revascularization, stroke. Colhoun HM et al. Lancet. 2004;364:

35 CARDS: Treatment Effect on the Primary End Point
Event Event rate, n (%) Hazard ratio (95% CI) RRR Placebo Atorvastatin Primary end point 127 (9.0%) 83 (5.8%) 37% P=0.001 Acute coronary 77 (5.5%) 51 (3.6%) 36% events Coronary 34 (2.4%) 24 (1.7%) % revascularization Stroke 39 (2.8%) 21 (1.5%) % Atorvastatin better Placebo better Colhoun HM et al. Lancet. 2004;364:

36 CARDS: Atorvastatin Significantly Reduces Risk of Stroke
Atorvastatin 10 mg (n=1428) Placebo (n=1410) Trial stopped early (median follow-up 3.9 years) Cumulative incidence of events (% of patients) 39 events 21 events RRR= 48% (95% CI: 31%-89%) P=0.016 Stroke was a component of the primary endpoint, evaluated individually as a secondary survival analysis. Time (years) Newman C et al. American Heart Association 78th Scientific Sessions, 2005.

37 CARDS: Treatment Effect on the Primary End Point By Median Baseline Lipid Level
Lipid parameter Event rate, n (%) Hazard ratio (95% CI) RRR Placebo Atorvastatin LDL-C (mg/dL)  (9.5%) 44 (6.1%) 38% < (8.5%) 39 (5.6%) 37% HDL-C (mg/dL)  (8.5%) 36 (5.2%) 41% <54 65 (9.6%) 47 (6.4%) 34% Triglycerides (mg/dL)  (9.6%) 40 (5.5%) 44% < (8.4%) 43 (6.1%) 29% Total-C (mg/dL)  (10.1%) 44 (6.2%) 41% < (7.9%) 39 (5.5%) 33% Atorvastatin better Placebo better Tests of heterogeneity not significant for each lipid parameter. Colhoun HM et al. Lancet. 2004;364:

38 CARDS: Implications Established the efficacy and safety of atorvastatin 10 mg in 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)

39 To evaluate atorvastatin 10 mg vs placebo
Atorvastatin study in the prevention of CV endpoints in subjects with DM: the ASPEN study Objective To evaluate atorvastatin 10 mg vs placebo in pts with DM and LDL cholesterol levels below the current guidelines cut-offs Knopp RH et al, Diabetes Care 2006; 29:

40 Atorvastatin study in the prevention of CV endpoints
in subjects with DM: the ASPEN study. Knopp RH et al. Diabetes Care 2006; 29:

41 Cosa consigliano le LLGG
nel 2008

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

43 Efficacia comparata delle diverse statine
Dose (mg) farmaco Riduzione% Atorva Simva Lova Prava Fluva Rosuva LDL-C 80 160* * Non approvata per uso clinico Roberts WC. Am J Cardiol. 1997;80: Stein E et al. J Cardiovasc Pharmacol Therapeut. 1997;2:7-16 Olsson A. Cardiovasc Drug Rev 2002;20:303–328

44 Perché l’utilizzo delle statine
nei diabetici è ancora così basso?

45 Barriere all’aderenza all’utilizzo delle statine nel diabetico
Efficacia e sicurezza dell’alto dosaggio Anziani Insufficienza renale Donne

46 Uno studio randomizzato
con statine ad alto dosaggio nei diabetici: lo studio TNT-diabete

47 TNT Study Design: Patients With Diabetes
Patient population: Age: years CHD LDL-C: mg/dL ( mmol/L) Triglycerides: 600 mg/dL (6.8 mmol/L) Primary end point: Time to occurrence of a major CV event: CHD death Nonfatal, non–procedure-related MI Resuscitated cardiac arrest Fatal or nonfatal stroke Baseline Screening and wash-out Open-label run-in Double-blind period n=1501 LDL-C: <130 mg/dL (<3.4 mmol/L) n=753 Atorvastatin 10 mg Atorvastatin 10 mg LDL-C target: 100 mg/dL (2.6 mmol/L) n=748 Atorvastatin 80 mg LDL-C target: 75 mg/dL (1.9 mmol/L) 1-8 weeks 8 weeks Median follow-up = 4.9 years Shepherd J et al. Diabetes Care. 2006;29:

48 TNT: Changes in LDL-C By Treatment Group in Patients With Diabetes
Baseline Final LDL-C = 98.6 mg/dL (2.5 mmol/L) Final LDL-C = 77.0 mg/dL (2.0 mmol/L) Final Screen 3 12 24 36 48 60 Shepherd J et al. Diabetes Care. 2006;29:

49 Cumulative incidence of events (% of patients)
TNT: Time to First Major Cardiovascular Event* in Patients With Diabetes 135 events Atorvastatin 10 mg (n=753) Atorvastatin 80 mg (n=748) 103 events Cumulative incidence of events (% of patients) RRR=25% (95% CI: 3%-42%) P=0.026 Time (years) *CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke. Shepherd J et al. Diabetes Care. 2006;29:

50 Hazard Ratios in Patients With and Without Diabetes: Secondary Efficacy Outcomes
Major CV event 17.9% 13.8% 9.7% 7.8% Any CV event 44.1% 39.8% 31.6% 26.1% Major coronary 12.9% 10.6% 7.5% 6.0% Any coronary 32.0% 29.3% 25.5% 20.2% Cerebrovascular 10.0% 7.0% 4.2% 3.4% CHF with hosp. 8.2% 7.2% 2.4% 1.6% PAD 8.9% 9.1% 5.1% 4.9% All-cause mortality 9.8% 10.8% 4.9% 4.8% Atorvastatin 80 mg better Atorvastatin 10 mg better Event rate (diabetes) Event rate (no diabetes) 10 mg 80 mg 10 mg 80 mg Shepherd J et al. Diabetes Care. 2006;29:

51 TNT: 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

52 Barriere all’aderenza all’utilizzo delle statine nel diabetico
Efficacia e sicurezza dell’alto dosaggio Anziani Insufficienza renale Donne

53 Statins for secondary prevention in elderly patients (> 65 yrs)
All cause mortality DM in 5-29% of pts Afilalo et al, JACC 2008; 51: 37-45

54 Statins for secondary prevention in elderly patients (>65 yrs)
Coronary artery disease mortality Afilalo et al, JACC 2008; 51: 37-45

55 Risk difference by FDA-approved statins
Kashani A et al, Circulation 2006;114:

56 Patients Achieving LDL-C Goal (%)
Lowest Success Rates in Patients at Highest Risk The high-risk paradox Patients Achieving LDL-C Goal (%) Low-risk (n=861) High-risk (n=1924) CHD (n=1352) Overall (n=4137) Pearson TA, et al. Arch Intern Med. 2000;160:

57 Barriere all’aderenza all’utilizzo delle statine nel diabetico
Efficacia e sicurezza dell’alto dosaggio Anziani Insufficienza renale Donne

58 DM in 18% of pts Sheperd J et al. JACC 2008; 51:

59 Statin therapy and mortality
in elderly and very elderly patients (> 80 yrs) statins not using statins 28% % % DM in 5-18% of pts statin prescription Allen Maycock CA et al, JACC 2002; 40:

60 Time to first CV event by treatment
in pts with kidney disease (eGFR <60) Sheperd J et al. JACC 2008; 51:

61 An assessment of statin safety by nephrologists
Kasiske BL et al. Am J Cardiol 2006;97:82C-85C

62 Barriere all’aderenza all’utilizzo delle statine nel diabetico
Efficacia e sicurezza dell’alto dosaggio Anziani Insufficienza renale Donne

63 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

64 Studies 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)

65 Gender 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 Annual eye exam 68.5 69.0 Annual foot exam 94.3 94.2 HbA1c < 8 mg/dl 65.8 66.7 BP <130/80 41.9 41.6

66 Gender 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 BP <130/80 35.0 35.4 NS

67 Gender differences in overall quality of diabetes care: UCI
Quality Measure Males Females P-value Annual HbA1c 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

68 Gender 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 KPG 67.3 65.3 34.4 24.7 UCI 100 61.7 51.8

69 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)

70 Come migliorare l’aderenza alla terapia farmacologica
(e alle raccomandazioni sullo stile di vita) nel paziente diabetico e dislipidemico

71 Long-term adherence with cardiovascular regimens
Basal prescription and discontinuation (gray bar) after 1 yr n= 1326 CAD pts, Duke University Kulkarni sp et al. Am Heart J 2006;151:

72 Cumulative probability to returning to treatment with statins
Brookhart MA et al. Arch Intern Med 2007; 167:847-52

73 Terapia con statine nel diabetico: come garantire l’aderenza
comunicare responsabilizzare gratificare

74 Helping pts with DM make treatment decision
Weymiller AJ et al, Arch intern Med 2007; 167:

75 Conclusions 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

76 Diapositive aggiuntive

77 Secondary Prevention of CVD With Statins in Patients With Diabetes

78 Primary Prevention of CVD With Statins in Patients With Diabetes

79

80 ASCOT-LLA: Primary Prevention in Patients at Modest Risk of CHD
Randomized -blocker ± diuretic CCB ± ACE inhibitor TC >250 mg/dL (>6.5 mmol/L) 2532 TC 250 mg/dL (6.5 mmol/L) TC >250 mg/dL (>6.5 mmol/L) Randomized Open lipid lowering 1258 Atorvastatin 10 mg 1274 Placebo Open lipid lowering Primary end point: Composite of fatal CHD and nonfatal MI Highlighted boxes indicate diabetes patients enrolled in lipid-lowering arm. Adapted from Sever PS et al. J Hypertens. 2001;19:

81 Cumulative incidence of events (% of patients)
ASCOT-LLA Post hoc Analysis: Total CV Events and Procedures in Patients With Diabetes RRR=23% P=0.036 151 events 116 events Trial stopped early (median follow-up 3.3 years) Cumulative incidence of events (% of patients) Time (years) Atorvastatin 10 mg Placebo Sever PS et al. Diabetes Care. 2005;28:

82 ASCOT-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

83 Cholesterol Treatment Trialists Collaboration: Major Vascular Events in Diabetes Patients
Baseline vascular disease/ Event rate, n (%) Hazard ratio (CI*) Relative risk hypertension Statin Control reduction Placebo better Statin better 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, 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% N=18,686 patients with diabetes * 95% CI 99% CI Cholesterol Treatment Trialists. Presentation at the American Diabetes Association 66th Scientific Sessions, 2006.

84 ESC on diabetes and pre-diabetes EHJ 2007; 28:88-136
In 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 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 pts DM fluva riduce 47% major coro events e rev GREACE 313 pts DM atorva riduce 58% major e stroke e rev Nell’alto dosaggio i vantaggi osservati enl PROVE IT e nel TNT sono stati simili anche per il pt con DM

85 ASCOT-LLA: Lack of Heterogeneity of Effect in Patients With or Without Diabetes
Hazard ratio (95% CI) Relative risk P value for reduction heterogeneity Placebo better Atorvastatin better Total CV events and procedures Diabetes % 0.82 No diabetes % Subtotal: 21% (P<0.001) Nonfatal MI + fatal CHD Diabetes 16% 0.14 No diabetes % Subtotal: 36% (P<0.001) Fatal and nonfatal stroke Diabetes 33% 0.66 No diabetes 24% Subtotal: 27% (P<0.024) Sever PS et al. Diabetes Care. 2005;28:

86 Lipid Treatment Guidelines: Which Diabetes Patients Should Be Treated?
Lipid targets in diabetes patients Treatment recommendations NCEP ATP III1 LDL-C <100 mg/dL (2.6 mmol/L) Optional LDL-C goal: <70 mg/dL (1.8 mmol/L) Intensity of therapy should be sufficient to achieve a 30-40% reduction in LDL-C ADA2 Patients without CVD LDL-C <100 mg/dL (2.6 mmol/L) Age >40 years: Statin therapy to achieve LDL-C reduction of 30-40%, irrespective of baseline LDL-C Patients with CVD Optional LDL-C goal: <70 mg/dL (1.8 mmol/L) All patients should be treated with a statin to achieve LDL-C reduction of 30-40% Joint European Societies3 TC <4.5 mmol/L (175 mg/dL) LDL-C <2.5 mmol/L (100 mg/dL) Joint British Societies4 TC <4.0 mmol/L (155 mg/dL) LDL-C <2.0 mmol/L (77 mg/dL) Treat to TC and LDL-C targets (or a 25% and a 30% reduction, respectively), using statins at doses whose efficacy and safety have been shown in trials In the US, NCEP ATP III guidelines1 recommend selection of lipid-lowering therapy based on a person’s risk status. Risk assessment requires measurement of LDL-C and identification of accompanying risk factors. The category of highest risk comprises patients with CHD or CHD risk equivalents (those with a risk for major coronary events equal to that of established CHD, ie, >20% per 10 years), including diabetes. In patients with CHD (or CHD risk equivalents), lipid-lowering drug therapy should be initiated at an LDL-C of 3.4 mmol/L, but can be considered at an LDL-C of mmol/L. These patients have the most aggressive LDL-C goal of <2.6 mmol/L. An optional LDL-C goal of <1.8 mmol/L in “very high-risk” patients was introduced in the 2004 update to NCEP ATP III.2 The second category comprises patients with multiple (2+) risk factors (eg, smoking, hypertension, low HDL-C, family history of premature CHD, age) in whom 10-year risk for CHD is 20%. The LDL-C goal for patients with multiple (2+) risk factors is <3.4 mmol/L. The third category comprises patients with 0-1 risk factor; these patients generally have a 10-year risk <10%. The LDL-C goal for patients with 0-1 risk factor is <4.1 mmol/L. 1. Grundy SM et al. Circulation. 2004;110: American Diabetes Association. Diabetes Care. 2006;29(suppl 1):S4-S42. De Backer G et al. Eur J Cardiovasc Prevent Rehabil. 2003;10(suppl 1):S1-S78. British Cardiac Society et al. Heart. 2005;91(suppl v):v1-v52. References 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285: 2. Grundy SM, et al. Circulation. 2004;110:


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