Diabetes and Hyperlipidemiaassets.escardio.org/assets/Presentations/EHH2010/... · European guidelines: diabetes and cardiovascular disease Diabetes and Hyperlipidemia State of the

European guidelines: diabetes and cardiovascular disease

Diabetes and Hyperlipidemia

State of the art 2010

Lars RydénKarolinska InstitutetStockholm, Sweden


Diabetes and hyperlipidemia

http://se.youtube.com/watch?v=zbKRSYAuSNg


Treatment targets



Treatment targets

(Rydén, Standl et al Europ Heart J 2007; 28:88 )

Lipid category mmol/l mg/dl

Cholesterol

Total 4.5 <175

LDL ≤1.8 ≤70

HDL men >1.0 >40women >1.2 >46

Triglycerides <1.7 <150

Total/HDL cholesterol <3


Treatment targets

Epidemiology and cardiovascular risk



(Isomaa et al Diabetes Care 2001;24:683)

Dyslipidemia - common in diabetes

The BOTNIA studyn 4 483

age years 35–70

Glucose tolerance

Normal 1 988

IFG/IGT 7 98

Diabetes 1 697

DyslipidemiaTG ≥1.7 mmol/l

(≥ 66 mg/dl)

and/or

HDL

men/women <0.9 mmol/l

(35 mg/dl)

women <1.0 mmol/l

(39 mg/dl)

100

80

60

40

20

0

Glucose metabolism

Normal IFG/IGT Diabetes

Male

Female

Pre

vale

nce d

yslip

idem

ia(%

)29 16

45 31

54 56


Lipid profile in patients with and without diabetes (1)

(UKPDS Diabetes Care 1997; 20:1663)

DM

No

DM

No

DM DM

Total cholesterol

5.0 193

5.4 206

5.8 224

6.0 232

mmol/l mg/dl

5.6 216

5.2 201

Men Women

LDL-Cholesterol

DM

No

DM

No

DM DM

Men

3.0 116

3.2 124

3.4 131

4.0 154

3.8 147

3.6 139

Women

p<0.001

mmol/l mg/dl


Lipid profile in patients with and without diabetes (2)

1 89

1.2 106

1.4 124

1.6 142

1.8 159

2.0 177

Triglycerides

No

DMDM DM

No

DM1.0 39

1.2 46

1.4 54

1.6 62

HDL- Cholesterol

DM DM

No

DM

No

DM

Men

p<0.02

Women

p<0.001

Men

p<0.001

Women

p<0.001

(UKPDS Diabetes Care 1997; 20:1663)

mmol/l mg/dl mmol/l mg/dl


Risk factors and diabetes

(Stamler et al. Diabetes Care 1993;16:434)

80

60

40

30

10

5

Serum cholesterol (mmol/L)

No diabetes

Diabetes

4 5 6 7

Vulnerability to

hypercholesterolemia

by diabetic state

10 year CHD mortality

(per 103)

10 y

ear

CH

D m

ort

alit

y

Rate


(Turner et al. UKPDS 23. BMJ 1993;98:316)

LDL mmol/l HDL mmol/l Age (years)

0.1 mmol/l (4 mg/dl) increase in HDL

= 15% decrease in CVD endpoints

HbA1c (%) Syst BP (mm Hg) Smoking

Risk factors and diabetes

Estimated

Hazard Ratio

for coronary

artery disease

3 055 patients

with type 2

diabetes in UKPDS


Treatment targets


Statin therapy

Secondary and primary prevention



Heart Protection Study – subgroup with diabetes

(HPS Collaborative Group: Lancet 2003; 361: 2005)

Patients

Diabetes n = 5 963

Simvastatin 40 mg/day or placebo

Proportionate reduction %

Coronary mortality 20

Stroke 24

Revascularization 17

Major vascular events 22Simvastatin

Placebo

P<0.0001

Follow up (years)

Majo

r C

V e

vents

(%

)


(CTT Collaborators Lancet 2008; 371:117 )

Lancet 2008; 371:117

Risk reduction by LDL reduction and diabetic state

Diabetes (no) 18 686

Type 2 17 220

Events 3 247

Follow up (mean years) 4.3

Outcome measure

Effect of decreasing LDL by 1 mmol/l



Reduction by

1 mmol/l (39 mg/dl) decrease in LDL-cholesterol

Event Diabetes No diabetes

Total mortality 0.91 (0.82-1.01) 0.87 (0.82-0.92)

Major vascular 0.79 (0.72-0.86) 0.79 (0.76-0.82)

Major coronary 0.78 (0.69-0.87) 0.77 (0.73-0.81)

Overall reduction 20%




Reduction by

1 mmol/l (39 mg/dl) decrease in LDL-cholesterol

Subgroups with similar overall reduction

Diabetes type 1 or 2 BMI

Age and sex Smoking status

Blood pressure Other blood lipids

Hypertension Level of CV risk

Initial LDL level down to 2.6 mmol/l (100 mg/dl)



Statins in patients with and without diabetes

From the 4 S and CARE trials

(Kreisberg RA et al. Am J Cardiol 1998;82:67U)

Diabetes

LDL-Cholesterol

10

2.6100

20

30

40

Majo

r coro

nary

events

(%

) 60

70

3.9 150

5.2200

50

CARE - pravastatin

placebo

4S - simvastatin

statin

mmol/lmg/dl

No diabetes


Treating to New Targets – subgroup with diabetes

(Shephard et al: Diabetes care 2006; 29:1220)

Patients n= 1 501Diabetes + CAD + LDL <3.4 mmol/l (<130 mg/dl)

Atorvastatin 10 or 80 mg/day

Follow up (median) 4.9 years

EndpointFirst major CV-event

LDL cholesterol at end of treatmentAtorvastatin 10 2.5 mmol/l (99 mg/dl)

Atorvastatin 80 2.0 mmol/l (77 mg/dl)


Treating to New Targets – subgroup with diabetes

(Shephard et al: Diabetes care 2006; 29:1220)

Follow up (years)

Pro

port

ion w

ith m

ajo

r C

V e

vents

(%

)

Atorvastatin 10 mg 18%

Atorvastatin 80 mg 14%

HR 0.75 (95% CI 0.58-0.97)

p = 0.026


Guideline recommendations

Secondary prevention Class Level

Elevated LDL- and low HDL are important risk I A

factors in patients with diabetes mellitus

Statins are first line agents for lowering LDL-

cholesterol in diabetic patients I A

In diabetic patients with CVD statin therapy should be I B

initiated regardless of baseline LDL-cholesterol with

a treatment target of ≤1.8-2.0 mmol/l (70-77 mg/dl)



Patients with type 2 diabetes

Age (years) 40-75

Baseline LDL mmol/l (mg/dl) 3.0 (116)

CVD-manifestation None

Risk factor for CVD ≥1

retinopathy or albuminuria or smoker or hypertension

Randomised treatment

Atorvastatin 10 mg/day n=1 428

Placebo n=1 410

(Colhoun HM et al. Lancet 2004;364:685)

Primary prevention with statins in diabetesThe Collaborative Atorvastatin Diabetes Study (CARDS)


Primary prevention with statins in diabetesThe Collaborative Atorvastatin Diabetes Study (CARDS)


0

5

10

15

0 1 2 3 4 4.75

Atorvastatin

Placebo

Follow up (years)

Majo

r coro

nary

events

(%

)

Primary endpoint - major coronary event

-37% (95 CI: -52 to -17; p=0.001)


Primary prevention with statins in diabetesThe CARDS trial


Primary

ACS

Coron revasc

Stroke

Mortality

Any CVE

Treatment effects

primary and secondary endpoints

Major CVE

All cause mortality

Any CVE



Primary prevention Class Level

Given the high lifetime risk of CVD, it is suggested IIb C

that all type 1 patients above age 40 years should

be considered for statin therapy.

In patients 18-39 years (type 1 or 2), statin therapy

should be considered when other risk factors are

present (e.g. microvasc complications, poor glycemic

control, hypertension, family history….)




Primary prevention Class Level

Statin therapy should be considered in adult patients IIb B

with type 2 diabetes without CVD if total

cholesterol is >3.5 mmol/l (>135 mg/dl)

targeting a LDL-cholesterol reduction of 30-40%



Treatment targets


Statin therapy


Fibrates



Atheroprotective effects of HDL

(After Barter et al 1999;Harwood Acad Publ)

Promotion of cholesterol efflux

Inhibition of adhesion molecule expression

Inhibition of LDLoxidation


Proportionate risk reduction in major fibrate trialsSecondary prevention in patients with diabetes

RR: 68% - MI or sudden death (ns)

GemfibrozilHelsinki Heart Study

RR 23% - combined cardiac endpoints (ns)

DAIS

RR: 70% - definite CHD events (p=0.01)

SENDCAP

Clinical OutcomesFibrateStudy

VA-HIT RR: 32% - composite endpoint (p=0.004)

Patients no

135

Bezafibrate

Gemfibrozil 769

164

Fenofibrate 418

(Koskinen et al. Diabetes Care 1992;15:820. Elkeles et al. Diabetes Care 1998;21:64.

Rubins et al. Arch Int Med 2002;162:2597. DAIS Investigators. Lancet 2001;357:905)


Fenofibrate Intervention and Event Lowering in DiabetesThe FIELD trial

PatientsDiabetes ± CVDn = 9 795No statins at entryFenofibrate 200 mg/dayPlacebo

(The FIELD Study Investigators. Lancet 2005; 366:1849)

Coronary deaths or

myocardial infarction

Cum

ula

tive r

isk (

%)


Patientsn = 5,518 type 2 diabetes

Simvastatin +Fenofibrate 200 mg/day

PlaceboMean follow up 4.7 years

Endpoint CV death or nonfatal MI or stroke

Accord Study group. New Engl J Med 2010; 362: 1563

The effect of combination lipid therapy in T2 DMThe ACCORD trial


Accord Study group. New Engl J Med 2010; 362: 1563

The effect of combination lipid therapy in T2 DMThe ACCORD trial



Secondary prevention Class Level

In diabetic patients with hypercholesterolaemia IIb B

>2mmol/l (177 mg/dl) after having reached the

LDL target with statin therapy, statin therapy

should be increased to reduce the secondary target

of non-HDL cholesterol.

In some cases, combination therapy with the

addition of ezetemibe, nicotinic acid or fibrates

may be considered



Treatment targets


Statin therapy


Fibrates

Multifactorial management



Statins in patients with and without diabetes

From the 4 S and CARE trials

(Kreisberg RA et al. Am J Cardiol 1998;82:67U)

Diabetes

LDL-Cholesterol

10

2.6100

20

30

40

Majo

r coro

nary

events

(%

) 60

70

3.9 150

5.2200

50

CARE - pravastatin

placebo

4S - simvastatin

statin

mmol/lmg/dl

No diabetes



Concluding remarks


common combination

with special characteristics

statin treatment rewarding

need for HDL-increasing drugs

Treatment

part of a multifactorial management

present practice far from satisfactory



State of the art

Thanks for the attention!

Documents

Diabetes and Hyperlipidemiaassets.escardio.org/assets/Presentations/EHH2010/... · European guidelines: diabetes and cardiovascular disease Diabetes and Hyperlipidemia State of the