Plasma Lipids at diagnosis of Type 2 Diabetes

UKPDS study group, Diabetes Care 1997; 20: 1683-1687

1.4 (55)1.1 (43)1.1 (43)1.0 (39)HDL-C mmol/l (mg/dl)

1.8 (159)

3.9 (151)

5.8 (224)

1574

Type 2

WOMEN

1.2 (103)

3.4 (132)

5.3 (205)

52

Control

1.1 (95)

3.5 (135)

5.6 (217)

143

Control

1.8 (159)

3.6 (139)

5.5 (213)

2139

Type 2

MEN

TG mmol/l (mg/dl)

LDL-C mmol/l (mg/dl)

TC mmol/l (mg/dl)

N

UKPDS

MRFIT: DM type 2 and cardiovascular mortality

Stamler J et al. Diabetes Care 16(2): 434 - 444, 1993

0

20

40

60

80

100

120

140

160

< 4.7 4.7-5.1 5.2-5.7 5.8-6.2 6.3-6.7 6.8-7.2 ³ 7.3 mmol/L

CV

mo

rtal

ity

per

10.0

00 p

erso

n y

ears

DiabetesNo diabetes

total cholesterol

DiabetesLDL particles

‘Normal’ LDL-cholesterolhowever:

‘Normal’ LDL-cholesterol

No Diabetes LDL particles

LDL-apo BLDL-apo B/CELDL-CE/TG

Low CHD risk High

Diabetes and DyslipidemiaLDL- size and diabetes

M. Austin JAMA 1988; 269: 1916

LDL diameter vs plasma TG

R= -0.88

23

24

25

26

27

28

0 1 2 3 4 5 6

Plasma TG (mmol/L)

LDL diameter (nm)

Scheffer et al; Clin Chem 1997;43:1904-12

Atherosclerosis“The Overall Picture”

Clinical Trials of Lipid Therapy in Diabetic Subjects (subgroup analysis)

Haffner Diabetes Care; 1: 1998

Study journal N LDL-C Baseline CHD lowering LDL-C reduction

Primary preventionHelsinki HS Diabetes 135 -6 % 4,9 mmol/l -60 % (ns)

Care 1992 191 mg/dlAFCAPS/TEXCAPS JAMA 1998 264 -25% 3.9 mmol/l -43 % (ns)

150 mg/dl

Secondary preventionCARE NEJM 1996 586 -28 % 3,5 mmol/l -25 % (p=0.05)

137 mg/dl4S Diabetes 202 -36 % 4,8 mmol/l -55 % (p=0.002)

Care 1997 186 mg/dl

Risk Reduction 4 S trialEstimated CHD reduction after treating

100 CHD patients for 6 years

Expected fatal and non fatal Ml’s

Number of prevenedFatal and non fatal MI’s

patients with diabetes

patients without diabetes

49

29

24

9

Pyörälä K et al. Diabetes Care 20(4): 614 - 620, 1997

Management Of Lipids in Patients with Management Of Lipids in Patients with Diabetes Mellitus Type 2Diabetes Mellitus Type 2

Risk Factor Management General Rules

• Risk factor assessment• Setting goals for therapy

– Primary prevention– Secondary prevention

• Specific modalities of therapy based on impact and practicality– Lipid management– Asperin use– Blood pressure control– Smoking cessation– Glycemic control – Weight management

Suggested Risk Factor Target Levels

RISK FACTOR GOAL

Blood pressure 130/80 mm Hg

HbA1c <7.5%

BMI <25kg/m2

Waist circumferencemales <98 cmfemales <88 cm

Urinary albumin excretion <30 mg/day

Lipid Management Glycaemic Control

• Glucose lowering in untreated diabetics will

improve the lipidprofile

• Better glycaemic control, independent of mode of

therapy, further improves the lipidprofile

• Unfortunately target lipid levels are not achieved

with good glycaemic control in most patients

Lipid Targets for Patients with Type 2 Diabetes Mellitus

•Haffner SM. Management of dyslipidemia in adults withdiabetes [American Diabetes Association position state-ment].Diabetes Care. 1998;21:160-178.

•Garg A. Treatment of diabetic dyslipidemia. Am JCardiol. 1998;81(4A):47B-51B.

Target (mg/dl)Plasma Lipid Acceptable IdealTriglycerides 200 150

Total cholesterol 200 170

LDL-cholesterol 130 100

Non-HDL-cholesterol 160 130

HDL-cholesterol 35 45

ASAP Study Design

2 years

Simvastatin 40 mg

326patients

Atorvastatin 80 mg FH LDL-C >212 mg/dL TG <400 mg/dL

Patient populationB-mode US B-mode US

Patients are initiated on atorvastatin 40 mg or simvastatin 20 mg. Doses are doubled at Week 4

Primary efficacy parameter: Change in carotid and femoral IMT

B-mode US

Baseline Lipid Profile

Atorvastatinmmol/l mg/dl

TC 9.99 386

TG 1.86 165

HDL-C 1.17 45

LDL-C 8.00 309

Simvastatin mmol/l mg/dl

10.27 396

1.85 164

1.16 45

8.33 322

Cholesterol lowering (n=325)

Atorvastatin (80 mg)

TC - 42% 5.73 mmol/l 221 mg/dl

TG - 29% 1.23 mmol/l109 mg/dl

HDL +13% 1.32 mmol/l» mg/dl

LDL - 51% 3.88 mmol/l150 mg/dl

Simvastatin (40 mg) - 34% 6.71 mmol/l

259 mg/dl

-17 % 1.41 mmo/l125 mg/dl

+ 13 % 1.30 mmol/l

50 mg/dl

- 41 % 4.81 mmol/l186 mg/dl

Change in IMT after 1 and 2 years

-0.06

-0.05

-0.04

-0.03

-0.02

-0.01

0

0.01

0.02

0.03

0.04

0.05

year 0 year 1 year 2

atorva total

simva total

atorv male

simva male

atorva female

simva female

% patients with progression

AtorvastatinProgression

female 35.1 %

male 31.8 %

Regression

female 64.9 %

male 68.2 %

SimvastatinProgression

female 57.4 %

male 58.1 %

Regression

female 42.5 %

male 41.9 %

Priorities for Treatment Strategiesof Diabetic Dyslipidemia

• LDL-cholesterol lowering

• Triglyceride lowering

• HDL-cholesterol raising

• Other approaches

– Non-HDL cholesterol

– Apo B

– Remnants

Future Directions

Ongoing Trials with Lipid Lowering Focus

HPS Simvastatin

CARDS Atorvastatin

ASPEN Atorvastatin

LDS Cerivastatin / Fenofibrate

DAIS Fenofibrate

FIELD Fenofibrate