Diabetes Slide Kit

1
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
Diagnosi di nuovi casi di diabete siamo
abbastanza attenti?
3
EuroHeart Survey n3940 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 plt0.002 1
MI 13
1 stroke
5
Anselmino et al, Eur Heart J 200829177-84
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 200829177-84
5

• 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 200829177-84
6
Dislipidemia nel diabetico entità del problema
7
High Incidence of Dyslipidemia in the Diabetic
Population
245 men with diabetes and 253 women with
diabetes aged ?18 years from NHANES 1999-2000.
Modified from Jacobs MJ et al. Diabetes Res Clin
Pract. 200570263-269.
8
MRFIT Cardiovascular Disease (CVD) Mortality 3
Times Greater in Men With Diabetes at All
Cholesterol Levels
Stamler J et al. Diabetes Care. 199316434-444.
Multiple Risk Factor Intervention Trial
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.
Turner RC et al. BMJ. 1998316823-828.
United Kingdom Prospective Diabetes Study.
10
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. 1998316823-828.
Age- and sex-adjusted.
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.
200326S83-S86.
12
Dislipidemia nel diabetico limportanza 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 2003348383-93
14
Evidenze sullefficacia delle statine nel
diabetico
15
Early Statin Secondary Prevention Trials Design
Overview
4S Study Group. Lancet. 19943341383-1389.
Primary end point All-cause mortality
Sacks F et al. N Engl J Med. 19963351001-1009.

• LIPID
• Age 31-75 years
• MI or unstable angina in previous3-36 months
• TC 155-271 mg/dL (4.0-7.0 mmol/L)
• Triglycerides lt445 mg/dL (lt5.0 mmol/L)

Primary end point CHD death
LIPID Study Group. N Engl J Med.
19983391349-1357.
16
4S Major CHD Event Reduction in Patients With
Diabetes
Patients without major CVD event ()
RRR32 P0.0001
RRR55 P0.002
Time (years)
Post-hoc analysis of the secondary end point
CHD death nonfatal MI.
Pyörälä K et al. Diabetes Care. 199720614-620.
17
CARE CHD Event Reduction in Patients With
Diabetes
Post hoc analysis of an expanded CHD end point
CHD death, nonfatal MI, CABG, and PTCA.
Goldberg RB et al. Circulation. 1998982513-2519.
18
LIPID CHD Event Reduction in Patients With
Diabetes
Pre-specified diabetes subgroup primary
endpoint CHD death and nonfatal MI.
Keech A et al. Diabetes Care. 2003262713-2721.
19
HPS Primary and Secondary Prevention of CVD in
Patients With Diabetes

• Pre-specified diabetes subgroup
• end points
• Major coronary events
• Major vascular events

• Patient population
• Age 40-80 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)

Mean follow-up 4.8 years
Simvastatin 40 mg/day (n1455)
Without CVD (n2912)
Placebo (n1457)
5963 patients with diabetes
Simvastatin 40 mg/day (n1523)
With CVD (n3051)
Placebo (n1528)
HPS Collaborative Group. Lancet.
20033612005-2016.
20
HPS Subgroup Evaluation Shows Consistent Benefit
in Diabetic Patients Regardless of CVD
Numbers in bars represent number of patients in
category at baseline.
HPS Collaborative Group. Lancet.
20033612005-2016.
21
HPS Consistent Benefit in Diabetic Patients
Regardless of Baseline LDL-C
Numbers in bars represent number of patients in
category at baseline.
HPS Collaborative Group. Lancet.
20033612005-2016.
22
HPS Implications

• Contributed to changes in treatment
  recommendations for diabetic patients
• 2003 European Guidelines for the Management of
  CVD
• total cholesterol lt175 mg/dL and LDL-C lt100 mg/dL
• 2004 ADA recommendations
• focus on LDL-C lowering as the primary lipid goal
  (lt100 mg/dL)
• statins recommended as the initial pharmacologic
  approach
• 2004 NCEP ATP update
• LDL-C goal of lt70 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 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
Atorvastatin 10 mg/day (n1428)

• 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

2838 patients
Placebo (n1410)
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 (n1428) Placebo (n1410)
Trial stopped early (median follow-up 3.9 years)
127 events
Cumulative incidence of events ( of patients)
83 events
RRR37 (95 CI 17-52) P0.001
Time (years)
Acute CHD event, coronary revascularization,
stroke.
Colhoun HM et al. Lancet. 2004364685-696.
35
CARDS Treatment Effect on the Primary End Point
Event Event rate, n
() Hazard ratio (95 CI) RRR Placebo Atorvastati
n
Primary end point 127 (9.0) 83
(5.8) 37 P0.001
Acute coronary 77 (5.5) 51 (3.6) 36events
Coronary 34 (2.4) 24 (1.7)
31revascularization
Stroke 39 (2.8) 21 (1.5) 48
Placebo better
Atorvastatin better
Colhoun HM et al. Lancet. 2004364685-696.
36
CARDS Atorvastatin Significantly Reduces Risk of
Stroke
Atorvastatin 10 mg (n1428) Placebo (n1410)
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) P0.016
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 Atorvastati
n
LDL-C (mg/dL) ?120 66 (9.5) 44 (6.1) 38
lt120 61 (8.5) 39 (5.6) 37
HDL-C (mg/dL) ?54 62 (8.5) 36 (5.2) 41
lt54 65 (9.6) 47 (6.4) 34
Triglycerides (mg/dL) ?150 67 (9.6) 40
(5.5) 44 lt150 60 (8.4) 43 (6.1) 29
Total-C (mg/dL) ?209 71 (10.1) 44
(6.2) 41 lt209 56 (7.9) 39 (5.5) 33
Placebo better
Atorvastatin better
Tests of heterogeneity not significant for each
lipid parameter.
Colhoun HM et al. Lancet. 2004364685-696.
38
CARDS 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 gt40 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 lt100 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
  lt70 mg/dL (1.8 mmol/L)

39
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 1478-85
40
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
41
Cosa consigliano le LLGG nel 2008
42

• Nel pz a basso rischio
• (LDLlt100, TGlt150, HDLgt50) controlli ogni 2 aa
• Nel pz con LDL gt 100
• CVD
• gt 40 aa con un fattore di rischio
  (retinopatia,
• nefropatia, ipertensione arteriosa, sindrome
  metabolica)
• aggiungere una statina con obiettivo LDLlt100
• (eventualmente lt70 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 -- 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
Non approvata per uso clinico
Roberts WC. Am J Cardiol. 199780106-107 Stein E
et al. J Cardiovasc Pharmacol Therapeut.
199727-16 Olsson A. Cardiovasc Drug Rev
200220303328
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
TNT Study Design Patients With Diabetes

• Patient population
• Age 35-75 years
• CHD
• LDL-C 130-250 mg/dL (3.4-6.5 mmol/L)
• Triglycerides ?600 mg/dL (?6.8 mmol/L)

• Primary end point
• Time to occurrence of a major CV event
• CHD death
• Nonfatal, nonprocedure-related MI
• Resuscitated cardiac arrest
• Fatal or nonfatal stroke

Baseline
Open-label run-in
Screening and wash-out
Double-blind periodn1501LDL-C lt130 mg/dL
(lt3.4 mmol/L)
n753
Atorvastatin 10 mg
Atorvastatin 10 mg LDL-C target 100 mg/dL (2.6
mmol/L)
n748
Atorvastatin 80 mg LDL-C target 75 mg/dL (1.9
mmol/L)
8 weeks
1-8 weeks
Median follow-up 4.9 years
Shepherd J et al. Diabetes Care.
2006291220-1226.
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)
Shepherd J et al. Diabetes Care.
2006291220-1226.
49
TNT Time to First Major Cardiovascular Event in
Patients With Diabetes
135 events
Atorvastatin 10 mg (n753) Atorvastatin 80 mg
(n748)
103 events
Cumulative incidence of events ( of patients)
RRR25 (95 CI 3-42) P0.026
Time (years)
CHD death, nonfatal nonprocedure-related MI,
resuscitated cardiac arrest, fatal or nonfatal
stroke.
Shepherd J et al. Diabetes Care.
2006291220-1226.
50
Hazard Ratios in Patients With and Without
Diabetes Secondary Efficacy Outcomes
Shepherd J et al. Diabetes Care.
2006291220-1226.
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
  (P0.026) 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 lt70 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 (gt 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 (gt65 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 20061142788-2797
56
Lowest Success Rates in Patients at Highest Risk

The high-risk paradox
Patients Achieving LDL-C Goal ()
Low-risk (n861)
CHD (n1352)
High-risk (n1924)
Overall (n4137)
Pearson TA, et al. Arch Intern Med.
2000160459-467.
57
Barriere alladerenza allutilizzo delle statine
nel diabetico

• Efficacia e sicurezza dellalto dosaggio
• Anziani
• Insufficienza renale
• Donne

58
DM in 18 of pts
Sheperd J et al. JACC 2008 51 1448-54
59
Statin therapy and mortality in elderly and very
elderly patients (gt 80 yrs)
statins
not using statins
28 21 20
DM in 5-18 of pts
statin prescription
Allen Maycock CA et al, JACC 2002 40 1777-85
60
Time to first CV event by treatment in pts with
kidney disease (eGFR lt60)

Sheperd J et al. JACC 2008 51 1448-54
61
An assessment of statin safety by nephrologists
Kasiske BL et al. Am J Cardiol 20069782C-85C
62
Barriere alladerenza allutilizzo delle statine
nel diabetico

• Efficacia e sicurezza dellalto 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 (n7364)
• Patients with diabetes at Kaiser Permanente
  Georgia (n14,671)
• Patients participating in the UCI Diabetes
  Coached Care Program (n272)

65
Gender differences in overall quality of diabetes
care PRP
66
Gender differences in overall quality of diabetes
care KPG
67
Gender differences in overall quality of diabetes
care UCI
68
Gender Differences in Lipid Monitoring and Control
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, plt 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 2006151 185-91
72
Cumulative probability to returning to treatment
with statins
Brookhart MA et al. Arch Intern Med 2007
167847-52
73
Terapia con statine nel diabeticocome
garantire laderenza

• comunicare
• responsabilizzare
• gratificare

74
Helping pts with DM make treatment decision
Weymiller AJ et al, Arch intern Med 2007 167
1076-82
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
• 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

• 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
(No Transcript)
80
ASCOT-LLA Primary Prevention in Patients at
Modest Risk of CHD
19,342 patients
Randomized
?-blocker diuretic
CCB ACE inhibitor
TC gt250 mg/dL (gt6.5 mmol/L)
2532 TC ?250 mg/dL(?6.5 mmol/L)
TC gt250 mg/dL (gt6.5 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.
2001191139-1147.
81
ASCOT-LLA Post hoc Analysis Total CV Events and
Procedures in Patients With Diabetes
Sever PS et al. Diabetes Care. 2005281151-1157.
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
riskhypertension Statin Control reduction
Diabetes vascular diseaseCoronary heart
disease 779 (30.3) 918 (36.2) 18
(Plt0.0001) Other vascular disease 127 (15.8) 156
(20.7) 22 (P0.02) Subtotal 906 (26.8) 1074
(32.6) 19
Diabetes, no vascular disease Hypertension 422
(10.0) 504 (12.0) 25 (P0.0003) No
hypertension 137 (7.7) 204 (11.2) 30
(Plt0.0001) Subtotal 559 (9.3) 708 (11.8) 27
All diabetes patients 1465 (15.6) 1782 (19.2) 21
Cholesterol Treatment Trialists. Presentation at
the American Diabetes Association 66th Scientific
Sessions, 2006.
84
ESC on diabetes and pre-diabetes EHJ 2007
2888-136 In prevenzione secondaria nessuno
studio ad hoc gt5000 pts in analisi post-hoc
4S 483 pts DM sim riduce 42 major coro events
Haffner Arch Int Med 991592661-7 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 rev Nellalto 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
Total CV events and proceduresDiabetes
23 0.82 No diabetes
20 Subtotal
21 (Plt0.001)
Nonfatal MI fatal CHD Diabetes 16 0.14 No
diabetes
44 Subtotal 36 (Plt0.001)
Fatal and nonfatal strokeDiabetes 33 0.66 No
diabetes 24 Subtotal 27 (Plt0.024)
Sever PS et al. Diabetes Care. 2005281151-1157.
86
Lipid Treatment Guidelines Which Diabetes
Patients Should Be Treated?

• 1. Grundy SM et al. Circulation. 2004110227-39.
• American Diabetes Association. Diabetes Care.
  200629(suppl 1)S4-S42.
• De Backer G et al. Eur J Cardiovasc Prevent
  Rehabil. 200310(suppl 1)S1-S78.
• British Cardiac Society et al. Heart.
  200591(suppl v)v1-v52.