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XXXIX Congresso Nazionale ANMCO Firenze, 30 maggio- 2 giugno 2008 Minimaster Cuore e diabete – Prevenzione delle recidive e aderenza alle terapie XXXIX.

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Presentation on theme: "XXXIX Congresso Nazionale ANMCO Firenze, 30 maggio- 2 giugno 2008 Minimaster Cuore e diabete – Prevenzione delle recidive e aderenza alle terapie XXXIX."— Presentation transcript:

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

2 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%) 0 mortality 25 p< MI 13 1 stroke 5 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

5 … the general impression is that pts with CAD and DM are inappropriately managed for several reasons… 1. 1.Cardiologists neglect o are inexperienced as regards GL treatments 2. A close collaboration between cardiologists and diabetologists is absent 3. 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

6 Dislipidemia nel diabetico: entità del problema

7 7LP High Incidence of Dyslipidemia in the Diabetic Population Modified from Jacobs MJ et al. Diabetes Res Clin Pract. 2005;70: LDL-C (mg/dL) Triglycerides (mg/dL) HDL-C (mg/dL) < <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 aged 18 years from NHANES

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

9 9LP 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. Turner RC et al. BMJ. 1998;316: VariableP-value 1. LDL-C < HDL-C HbA 1c Systolic BP Smoking *United Kingdom Prospective Diabetes Study.

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

11 11LP 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 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: limportanza di un approccio multidisciplinare

13 Gaede et al for the STENO-2 Investigators, NEJM 2003;348: 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. Effect of a multifactorial intervention on mortality in type 2 diabetes

14 Evidenze sullefficacia delle statine nel diabetico

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

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

17 17LP Goldberg RB et al. Circulation. 1998;98: CARE: CHD Event Reduction in Patients With Diabetes* *Post hoc analysis of an expanded CHD end point: CHD death, nonfatal MI, CABG, and PTCA. 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

18 18LP LIPID: CHD Event Reduction in Patients With Diabetes* Keech A et al. Diabetes Care. 2003;26: *Pre-specified diabetes subgroup primary endpoint: CHD death and nonfatal MI. 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

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

20 20LP HPS: Subgroup Evaluation Shows Consistent Benefit in Diabetic Patients Regardless of CVD HPS Collaborative Group. Lancet. 2003;361: Numbers in bars represent number of patients in category at baseline. 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

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

22 22LP 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 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:

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

32 32LP 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 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 33LP year follow-up CARDS: Primary Prevention of CVD With Atorvastatin in Type 2 Diabetes Atorvastatin 10 mg/day (n=1428) Placebo (n=1410) 2838 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: 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: Early 2005 Actual: Halted 2 years early due to significant results Study completion date Anticipated: Early 2005 Actual: Halted 2 years early due to significant results

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

35 35LP CARDS: Treatment Effect on the Primary End Point Colhoun HM et al. Lancet. 2004;364: Event Event rate, n (%)Hazard ratio (95% CI)RRR PlaceboAtorvastatin Event Event rate, n (%)Hazard ratio (95% CI)RRR PlaceboAtorvastatin Primary end point127 (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%) 31% revascularization Stroke39 (2.8%)21 (1.5%) 48% Placebo better Atorvastatin better

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

37 37LP CARDS: Treatment Effect on the Primary End Point By Median Baseline Lipid Level Colhoun HM et al. Lancet. 2004;364: Lipid parameter Event rate, n (%)Hazard ratio (95% CI)RRR PlaceboAtorvastatin Placebo better Atorvastatin better (9.5%)44 (6.1%)38% <12061 (8.5%)39 (5.6%)37% LDL-C (mg/dL) (9.5%)44 (6.1%)38% <12061 (8.5%)39 (5.6%)37% (8.5%)36 (5.2%)41% <5465 (9.6%)47 (6.4%)34% HDL-C (mg/dL) (8.5%)36 (5.2%)41% <5465 (9.6%)47 (6.4%)34% (9.6%)40 (5.5%)44% <15060 (8.4%)43 (6.1%)29% Triglycerides (mg/dL) (9.6%)40 (5.5%)44% <15060 (8.4%)43 (6.1%)29% (10.1%)44 (6.2%)41% <20956 (7.9%)39 (5.5%)33% Total-C (mg/dL) (10.1%)44 (6.2%)41% <20956 (7.9%)39 (5.5%)33% Tests of heterogeneity not significant for each lipid parameter.

38 38LP 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) 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 Atorvastatin study in the prevention of CV endpoints in subjects with DM: the ASPEN study Knopp RH et al, Diabetes Care 2006; 29: Objective To evaluate atorvastatin 10 mg vs placebo in pts with DM and LDL cholesterol levels below the current guidelines cut-offs

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 Nel pz a basso rischio (LDL 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 * Non approvata per uso clinico AtorvaSimvaLovaPrava Fluva Rosuva LDL-C * Dose (mg) farmaco Riduzione% Efficacia comparata delle diverse statine 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 lutilizzo delle statine nei diabetici è ancora così basso?

45 Barriere alladerenza allutilizzo delle statine nel diabetico Efficacia e sicurezza dellalto dosaggio Anziani Insufficienza renale Donne

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

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

48 48LP267611FinalScreen Baseline TNT: Changes in LDL-C By Treatment Group in Patients With Diabetes Final LDL-C = 77.0 mg/dL (2.0 mmol/L) Final LDL-C = 98.6 mg/dL (2.5 mmol/L) Shepherd J et al. Diabetes Care. 2006;29:

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

50 50LP Hazard Ratios in Patients With and Without Diabetes: Secondary Efficacy Outcomes Major CV event17.9%13.8% 9.7%7.8% Major CV event17.9%13.8% 9.7%7.8% Any CV event44.1%39.8% 31.6%26.1% Any CV event44.1%39.8% 31.6%26.1% Major coronary12.9%10.6% 7.5%6.0% Major coronary12.9%10.6% 7.5%6.0% Any coronary32.0%29.3% 25.5%20.2% Any coronary32.0%29.3% 25.5%20.2% Cerebrovascular10.0%7.0% 4.2%3.4% Cerebrovascular10.0%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% PAD8.9%9.1% 5.1%4.9% PAD8.9%9.1% 5.1%4.9% All-cause mortality9.8%10.8% 4.9%4.8% All-cause mortality9.8%10.8% 4.9%4.8% Atorvastatin 80 mg better Atorvastatin 10 mg better Event rate (diabetes) Event rate (no diabetes) 10 mg80 mg10 mg80 mg Shepherd J et al. Diabetes Care. 2006;29:

51 51LP 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 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 alladerenza allutilizzo delle statine nel diabetico Efficacia e sicurezza dellalto dosaggio Anziani Insufficienza renale Donne

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

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

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

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

57 Barriere alladerenza allutilizzo delle statine nel diabetico Efficacia e sicurezza dellalto dosaggio Anziani Insufficienza renale Donne

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

59 Statin therapy and mortality in elderly and very elderly patients (> 80 yrs) Allen Maycock CA et al, JACC 2002; 40: statins not using statins statin prescription 28% 21% 20% DM in 5-18% of pts

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 alladerenza allutilizzo delle statine nel diabetico Efficacia e sicurezza dellalto dosaggio Anziani Insufficienza renale Donne

63 63LP 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 64LP 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) 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 65LP Gender differences in overall quality of diabetes care: PRP Quality MeasureMalesFemalesP-value Annual HbA1c NS Annual urine protein NS Annual eye exam NS Annual foot exam NS HbA1c < 8 mg/dl NS BP <130/ NS

66 66LP Gender differences in overall quality of diabetes care: KPG Quality MeasureMalesFemalesP-value Annual HbA1c <.001 Annual blood pressure <.01 HbA1c < 8 mg/dl <.001 BP <130/ NS

67 67LP Gender differences in overall quality of diabetes care: UCI Quality MeasureMalesFemalesP-value Annual HbA1c100 NS Annual foot exam <.01 HbA1c < 8 mg/dl <.001 BP <130/ NS

68 68LP Gender Differences in Lipid Monitoring and Control Quality Measure Sample MalesFemalesP-value Monitoring lipidsPRP NS LDL < 100mg/dl <.001 Monitoring lipidsKPG NS LDL < 100mg/dl <.001 Monitoring lipidsUCI100 NS LDL < 100mg/dl <.001

69 69LP 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)

70 Come migliorare laderenza 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 73LP Terapia con statine nel diabetico: come garantire laderenza - comunicare - responsabilizzare - gratificare

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

75 75LP 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 CARDSthe first prospective statin trial in patients with diabeteswas 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 CARDSthe first prospective statin trial in patients with diabeteswas 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 76LP Diapositive aggiuntive

77 77LP Secondary Prevention of CVD With Statins in Patients With Diabetes

78 78LP Primary Prevention of CVD With Statins in Patients With Diabetes

79 79LP267611

80 80LP ASCOT-LLA: Primary Prevention in Patients at Modest Risk of CHD Highlighted boxes indicate diabetes patients enrolled in lipid-lowering arm. -blocker ± diuretic -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) Open lipid lowering 1258 Atorvastatin 10 mg 1274 Placebo Open lipid lowering 19,342 patients Randomized Primary end point: Composite of fatal CHD and nonfatal MI Adapted from Sever PS et al. J Hypertens. 2001;19:

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

82 82LP 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 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 83LP Diabetes + vascular disease Coronary heart disease779 (30.3)918 (36.2)18% ( P <0.0001) Other vascular disease127 (15.8)156 (20.7)22% ( P =0.02) Subtotal906 (26.8)1074 (32.6)19% Diabetes + vascular disease Coronary heart disease779 (30.3)918 (36.2)18% ( P <0.0001) Other vascular disease127 (15.8)156 (20.7)22% ( P =0.02) Subtotal906 (26.8)1074 (32.6)19% Cholesterol Treatment Trialists Collaboration: Major Vascular Events in Diabetes Patients Baseline vascular disease/ Event rate, n (%)Hazard ratio (CI*)Relative risk hypertensionStatinControlreduction Diabetes, no vascular disease Hypertension422 (10.0)504 (12.0)25% ( P =0.0003) No hypertension137 (7.7)204 (11.2)30% ( P <0.0001) Subtotal559 (9.3)708 (11.8)27% Diabetes, no vascular disease Hypertension422 (10.0)504 (12.0)25% ( P =0.0003) No hypertension137 (7.7)204 (11.2)30% ( P <0.0001) Subtotal559 (9.3)708 (11.8)27% All diabetes patients1465 (15.6)1782 (19.2)21% Placebo better Statin better N=18,686 patients with diabetes *95% CI99% CI Cholesterol Treatment Trialists. Presentation at the American Diabetes Association 66 th Scientific Sessions, 2006.

84 ESC on diabetes and pre-diabetes EHJ 2007; 28: In prevenzione secondaria nessuno studio ad hoc >5000 pts in analisi post-hoc 4S483 pts DMsim riduce 42% major coro events Haffner Arch Int Med 99;159: HPS 3050 pts DMsim riduce 18% major coro, stroke, rev CARE 586 pts DM prava riduce 25% major coro events LIPID 782 pts DMprava riduce 19% major coro events e rev LIPS 202 pts DMfluva riduce 47% major coro events e rev GREACE 313 pts DM atorva riduce 58% major e stroke e rev Nellalto dosaggio i vantaggi osservati enl PROVE IT e nel TNT sono stati simili anche per il pt con DM

85 85LP 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 Diabetes Hazard ratio (95% CI)Relative riskP value for reductionheterogeneity Sever PS et al. Diabetes Care. 2005;28: 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 Diabetes33%0.66 No diabetes24% Subtotal:27% (P<0.024) Fatal and nonfatal stroke Diabetes33%0.66 No diabetes24% Subtotal:27% (P<0.024) Placebo better Atorvastatin better

86 86LP Lipid Treatment Guidelines: Which Diabetes Patients Should Be Treated? GuidelinesLipid targets in diabetes patientsTreatment recommendations NCEP ATP III 1 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 ADA 2 LDL-C <100 mg/dL (2.6 mmol/L) 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 Optional LDL-C goal: <70 mg/dL (1.8 mmol/L) 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 Societies 3 TC <4.5 mmol/L (175 mg/dL) LDL-C <2.5 mmol/L (100 mg/dL) Joint British Societies 4 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 1.Grundy SM et al. Circulation. 2004;110: American Diabetes Association. Diabetes Care. 2006;29(suppl 1):S4-S42. 3.De Backer G et al. Eur J Cardiovasc Prevent Rehabil. 2003;10(suppl 1):S1-S78. 4.British Cardiac Society et al. Heart. 2005;91(suppl v):v1-v52.


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