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UKPDS. MEN. WOMEN. Type 2. Control. Type 2. Control. N. 2139. 52. 1574. 143. TC mmol/l (mg/dl). 5.5 (213). 5.3 (205). 5.8 (224). 5.6 (217). LDL-C mmol/l (mg/dl). 3.6 (139). 3.4 (132). 3.9 (151). 3.5 (135). HDL-C mmol/l (mg/dl). 1.0 (39). 1.1 (43). 1.1 (43). 1.4 (55). - PowerPoint PPT Presentation
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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