CHOLESTEROL CHOLESTEROL LOWERINGLOWERING

Lipids in T1D and T2DLipids in T1D and T2D

T1DT1D T2DT2D

TCTC N N

LDL-CLDL-C N N

HDL-CHDL-C N or

TGTG N or

Qualitative Qualitative changeschanges

?Small dense LDL particles

CHD mortality rises in line with total cholesterolCHD mortality rises in line with total cholesterol

1

10

100

3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0

Total cholesterol (mmol/l)

An

nu

al a

ge-

stan

dar

dis

ed C

HD

mo

rtal

ity

(%)

Stamler J, Wentworth D, Neaton JD. Stamler J, Wentworth D, Neaton JD. JAMAJAMA 1986;256(10):2823-2828 1986;256(10):2823-2828.

CHD mortality rises in line with total cholesterolCHD mortality rises in line with total cholesterol

1

10

100

3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0

Total cholesterol (mmol/l)

An

nu

al a

ge-

stan

dar

dis

ed C

HD

mo

rtal

ity

(%)

Stamler J, Wentworth D, Neaton JD. Stamler J, Wentworth D, Neaton JD. JAMAJAMA 1986;256(10):2823-2828 1986;256(10):2823-2828.

0.0%

0.2%

0.4%

0.6%

0.8%

1.0%

1.2%

1.4%

1.6%

1.8%

4 4.5 5 5.5 6 6.5 7 7.5

Total cholesterol (mmol/l)

An

nu

al C

HD

mo

rtal

ity

rate

Reducing cholesterol reduces CHD mortalityReducing cholesterol reduces CHD mortality

4S

HPSLIPID

CARE

POSCH

Helsinki

WOSCOPS LRC

AFCAPS/TexCAPS

High risk study groups

Low risk study groups

End of studyStart of study

MRC/BHF Heart Protection MRC/BHF Heart Protection StudyStudyMRC/BHF Heart Protection MRC/BHF Heart Protection StudyStudy• 20,000 subjects with Increased CHD risk due to 20,000 subjects with Increased CHD risk due to

prior disease :prior disease :

• Myocardial infarction or other CHD ;Myocardial infarction or other CHD ;• Occlusive disease of non-coronary arteries ; orOcclusive disease of non-coronary arteries ; or• Diabetes mellitus or treated hypertension.Diabetes mellitus or treated hypertension.

• Age 40-80 yearsAge 40-80 years• Total cholesterol >3.5 mmol/l ( >135mg/dl)Total cholesterol >3.5 mmol/l ( >135mg/dl)

• Randomised to simvastatin 40 mg or placeboRandomised to simvastatin 40 mg or placebo

• 20,000 subjects with Increased CHD risk due to 20,000 subjects with Increased CHD risk due to prior disease :prior disease :

• Myocardial infarction or other CHD ;Myocardial infarction or other CHD ;• Occlusive disease of non-coronary arteries ; orOcclusive disease of non-coronary arteries ; or• Diabetes mellitus or treated hypertension.Diabetes mellitus or treated hypertension.

• Age 40-80 yearsAge 40-80 years• Total cholesterol >3.5 mmol/l ( >135mg/dl)Total cholesterol >3.5 mmol/l ( >135mg/dl)

• Randomised to simvastatin 40 mg or placeboRandomised to simvastatin 40 mg or placebo

SIMVASTATIN: VASCULAR EVENT by PRIOR DISEASE

Risk ratio and 95% CISTATIN PLACEBOBaselinefeature (10269) (10267) STATIN better STATIN worse

S T A T IN w o rs e

Previous MI 1007 1255

Other CHD (not MI) 452 597

No prior CHD

CVD 182 215

PVD 332 427

Diabetes 279 369

ALL PATIENTS 2042 2606(19.9%) (25.4%)

24%SE 2.6reduction(2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

SIMVASTATIN: VASCULAR EVENT by PRIOR LIPID LEVELS

Risk ratio and 95% CISTATIN PLACEBOBaselinefeature (10269) (10267) STATIN better STATIN worse

LDL (mmol/l)

Hetc2

2 = 3.0

< 3.0 (116 mg/dl) 602 761³ 3.0 < 3.5 483 655³ 3.5 (135 mg/dl) 957 1190

Total cholesterol (mmol/l)

Hetc2

2 = 0.5

<5.0 (193 mg/dl) 361 476³ 5.0 < 6.0 746 965³ 6.0 (232 mg/dl) 935 1165

ALL PATIENTS 2042 2606(19.9%) (25.4%)

24%SE 2.6reduction(2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

CARDSCARDSCollaborative Atorvastatin Diabetes Study

Helen Colhoun, John Betteridge, Paul Durrington, Graham Hitman, Andrew Neil, Shona Livingstone, Margaret Thomason, Michael Mackness, Valentine Menys, John Fuller on behalf of the CARDS Investigators

Primary prevention diabetes patients with one other risk factor (hypertension, smoker, micro-albuminuria, retinopathy)

Atorvastatin 10mg

Placebo

2838patients

CARDS Design

Placebo

Treatment effect on the primary endpointTreatment effect on the primary endpoint

21 (1.5%)

24 (1.7%)

51 (3.6%)

83 (5.8%)

Atorva*

48% (11- 69)39 (2.8%)Stroke

31% (16- 59)34 (2.4%)Coronary revascularisation

36% (9- 55)77 (5.5%)Acute coronary events

37% (17- 52)

p=0.001127 (9.0%)Primary endpoint**

Hazard Ratio Risk Reduction (CI)

Placebo*Event

.2 .4 .6 .8 1 1.2** Fatal MI, other acute CHD death, non fatal MI, unstable angina, CABG, fatal stroke, non fatal stroke

Subgroup* Placebo** Atorva**Hazard Ratio Risk Reduction

(CI)

LDL-C ≥ 3.06 66 (9.5) 44 (6.1) 38% (9-58)

LDL-C < 3.06 61 (8.5) 39 (5.6) 37% (6-58)

p=0.96

HDL-C ≥ 1.35 62 (8.4) 36 (5.2) 41% (11-61)

HDL-C < 1.35 65 (9.6) 47 (6.4) 35% (5-55)

p=0.71

Trig. ≥ 1.7 67 (9.6) 40 (5.5) 44% (18-62)

Trig. < 1.7 60 (8.4) 43 (6.1) 29% (-5-52)p=0.40

Treatment effect on the primary endpoint by lipid levelsTreatment effect on the primary endpoint by lipid levels

.2 .4 .6 .8 1 1.2

JBS 2 : indications for statin therapy in JBS 2 : indications for statin therapy in type 1 or type 2 diabetestype 1 or type 2 diabetes

• Age > 40 yearsAge > 40 years

• Retinopathy of greater than background Retinopathy of greater than background severityseverity

• Nephropathy, including microalbuminuriaNephropathy, including microalbuminuria

• Poor glycaemic control (HbAPoor glycaemic control (HbA11c > 9%)c > 9%)

• Hypertension requiring treatmentHypertension requiring treatment

• Elevated total cholesterol ( > 6.0 mmol/l)Elevated total cholesterol ( > 6.0 mmol/l)

• Metabolic syndromeMetabolic syndrome

• Family history of premature CHD in a first Family history of premature CHD in a first degree relativedegree relative

• Age > 40 yearsAge > 40 years

• Retinopathy of greater than background Retinopathy of greater than background severityseverity

• Nephropathy, including microalbuminuriaNephropathy, including microalbuminuria

• Poor glycaemic control (HbAPoor glycaemic control (HbA11c > 9%)c > 9%)

• Hypertension requiring treatmentHypertension requiring treatment

• Elevated total cholesterol ( > 6.0 mmol/l)Elevated total cholesterol ( > 6.0 mmol/l)

• Metabolic syndromeMetabolic syndrome

• Family history of premature CHD in a first Family history of premature CHD in a first degree relativedegree relative

Total cholesterol still > 4 ?Total cholesterol still > 4 ?Total cholesterol still > 4 ?Total cholesterol still > 4 ?

• Use a more potent statin ?Use a more potent statin ?

• Add cholesterol absorption Add cholesterol absorption inhibitor : ezetimibe ?inhibitor : ezetimibe ?

• Role of fibrate or nicotinic acid ?Role of fibrate or nicotinic acid ?

• Use a more potent statin ?Use a more potent statin ?

• Add cholesterol absorption Add cholesterol absorption inhibitor : ezetimibe ?inhibitor : ezetimibe ?

• Role of fibrate or nicotinic acid ?Role of fibrate or nicotinic acid ?

Cost EffectivenessCost Effectiveness

InterventionIntervention

Substitute Substitute rosuvastatinrosuvastatin Add ezetimibeAdd ezetimibe

CostCost10 mg £18.0310 mg £18.03

20 mg £26.0220 mg £26.02£1.31 + £26.31 £1.31 + £26.31 = £27.62= £27.62

Expected TC Expected TC reductionreduction 10%10% 25%25%

British National Formulary 2008

Patients not on target on simvastatin 40 mgPatients not on target on simvastatin 40 mg

Total Total cholesterolcholesterol

TargetTarget

<< 5.0 5.0 < 4.0< 4.0

ActionAction

> 5.5> 5.5 Add ezetimibeAdd ezetimibe

Add ezetimibeAdd ezetimibe5.5 – 5.05.5 – 5.0 RosuvastatinRosuvastatin

5.0 – 4.55.0 – 4.5

On targetOn target4.5 – 4.04.5 – 4.0 RosuvastatinRosuvastatin

<< 4.0 4.0 On targetOn target

Fibrates : FIELD StudyFibrates : FIELD Study

• 9795 subjects with T2D : 7664 no CVD9795 subjects with T2D : 7664 no CVD

• Fenofibrate 200 mg versus placeboFenofibrate 200 mg versus placebo

• Average 5 year follow upAverage 5 year follow up

• 36% of placebo group and 19% of fenofibrate 36% of placebo group and 19% of fenofibrate group given statinsgroup given statins

• Fenofibrate : TC Fenofibrate : TC 11%, LDL 11%, LDL 12%, HDL 12%, HDL 5% , 5% , TG TG 29% 29%

• Primary endpoint Primary endpoint 11% (NS) 11% (NS)

• Reduction in laser therapy / progression of Reduction in laser therapy / progression of albuminuria in fenofibrate groupalbuminuria in fenofibrate group

• Myositis / rhabdomyolysis < 1%Myositis / rhabdomyolysis < 1%

• 9795 subjects with T2D : 7664 no CVD9795 subjects with T2D : 7664 no CVD

• Fenofibrate 200 mg versus placeboFenofibrate 200 mg versus placebo

• Average 5 year follow upAverage 5 year follow up

• 36% of placebo group and 19% of fenofibrate 36% of placebo group and 19% of fenofibrate group given statinsgroup given statins

• Fenofibrate : TC Fenofibrate : TC 11%, LDL 11%, LDL 12%, HDL 12%, HDL 5% , 5% , TG TG 29% 29%

• Primary endpoint Primary endpoint 11% (NS) 11% (NS)

• Reduction in laser therapy / progression of Reduction in laser therapy / progression of albuminuria in fenofibrate groupalbuminuria in fenofibrate group

• Myositis / rhabdomyolysis < 1%Myositis / rhabdomyolysis < 1%

FIELD Study Investigators, Lancet 2005; 366; 1849-1861

The Alphabet StrategyThe Alphabet StrategyThe Alphabet StrategyThe Alphabet Strategy

• AAdvicedvice Smoking , diet , exerciseSmoking , diet , exercise

• BBlood pressure lood pressure << 140/80 140/80

• CCholesterol holesterol TC TC << 4.0 mmol/l , LDL ≤ 2.0 mmol/l 4.0 mmol/l , LDL ≤ 2.0 mmol/lHDL > 1.0 mmol/l, TGs HDL > 1.0 mmol/l, TGs << 1.7 mmol/l 1.7 mmol/l

• DDiabetes control iabetes control HbA1c ≤ 7%HbA1c ≤ 7%

• EEye examination ye examination Annual examinationAnnual examination

• FFeet examination eet examination Annual examinationAnnual examination

• GGuardian drugs uardian drugs Aspirin, ACEI, ARB, statinsAspirin, ACEI, ARB, statins

• AAdvicedvice Smoking , diet , exerciseSmoking , diet , exercise

• BBlood pressure lood pressure << 140/80 140/80

• CCholesterol holesterol TC TC << 4.0 mmol/l , LDL ≤ 2.0 mmol/l 4.0 mmol/l , LDL ≤ 2.0 mmol/lHDL > 1.0 mmol/l, TGs HDL > 1.0 mmol/l, TGs << 1.7 mmol/l 1.7 mmol/l

• DDiabetes control iabetes control HbA1c ≤ 7%HbA1c ≤ 7%

• EEye examination ye examination Annual examinationAnnual examination

• FFeet examination eet examination Annual examinationAnnual examination

• GGuardian drugs uardian drugs Aspirin, ACEI, ARB, statinsAspirin, ACEI, ARB, statins