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Fenofibrate lowers serum triglycerides and increases low density lipoprotein size in patients with type 2 diabetes
Posters 2. Diabetes - clinical research
52
lesions and/or less progression of existing lesions compared with more moderate lipid lowering with pravaatatin 40 mgday. REVERSAL is an 18-month, randomized, double-blind study that will enroll 600 patients from approximately 35 sites. Patients presenting for diagnostic coronary angiography are screened. Inclusion criteria include angiographic evidence of CHD (220% reduction in lumen diameter in a coronary artery). In addition, eligible patients must have <50% stenosis in the ‘target’ vessel for IVUS evaluation. Exclusion criteria include >50% reduction in lumen diameter of the left main coronary artery. Following a 2-week placebo run-in phase, patients are randomized to receive atorvastatin 80 mg/day or pravastatin 40 mg/day for 18 months. The primary efficacy measure is the % change from baseline in total plaque volume for all slices of anatomically comparable segments of the target coronary artery as measured by IVUS. REVERSAL, which is estimated to complete in 2002, is expected to demonstrate that an aggressive lipid-lowering regimen will result in formation of fewer new lesions or less progression of existing atherosclerosis compared with a more moderate lipid-lowering regimen. IP20 COMPARISON OF THE EFFECT OF ATORVASTATIN AND SIMVASTATIN ON LEVELS OF Lp(a) AND Ape(a) FRAGMENTS IN HYPERCHOLESTEROLEMIC PATIENTS AT HIGH CARDIOVASCULAR RISK S. Gonbert, C. Doucef H. Laouenan’, J. Chapman, J. Thillet. INSERM U321, Hopital de la Pitie Paris; ‘Pfier Courbevoie, France The effect of statins on Lp(a) levels is controversial, and there are no data concerning their effect on ape(a) fragmentation. We therefore determined the levels of Lp(a) and of ape(a) fragments in plasma of hypercholesterolemic patients before and after treatment (6 weeks) with Atorvastatin 10 mg/day (AlO) or Simvastatin 20 mg/day (S20). In a double blind study, 391 hypercholesterolemic patients at high cardiovascular risk (LDL-C = 4.13 mmol/l, TG < 2.24 mmol/l, 34% with documented CHD, 45% hypertensive, and 29% current smokers) were assigned to treatment with A10 (n = 199) or S20 (n = 192). Plasma Lp(a) and ape(a) fragment (n = 206) levels were measured prior and after treatment. At baseline, A10 and S20 groups did not differ in levels of lipids, Lp(a) (AlO: 0.45f0.48 mg/ml, S20: 0.46&0.5), and ape(a) fragments (AlO: 3.88~t5.22 ug/ml; S20: 3.25&3), and equally in ape(a) isofotm size (AlO: 26f5 kr, S20: 25.555.3). On treatment, A10 caused a sipPcant decrease in Lp(a) levels (0.42hO.47 mglml, 6% variation, p < O.OOl), whereas S20 caused a less signitlcant variation (0.45f0.53 mg/ml, 0.02% variation, p = 0.046). A10 and S20 did not significanly differ in their efficacy to lower Lp(a) levels. Plasma levels of ape(a) fragments were not modified by either statin. We therefore concluded that both A10 and S20 lowered Lp(a) with A10 tending to have a greater effect.
analyses (adjusted rr = 0.29 in FF group, adjusted ? = 0.28 in PL group). The association between the change in LPL activity and the change in TG in FF group was of borderline significance (r = -0.40, p = 0.055).
Baseline TG, mmovl
TC, mmolil
LDL size, nm
LPL activity, pmol FFAlmfi
***p
< 0.001, **p
IP22
J. Vakkilainen’, G. Steinerz, J.-C. Ansquer?, M.-R. Taskinen’. ‘Helsinki University Central Hospital, Helsinki, Finland; 2 University Health Network, Toronto, Canada; ‘Laboratories Fournier Da& Fmnce DAIS has reported that fenofibrate reduces the angiogmphic progression of coronary artery disease in patients with type 2 diabetes. The purpose of the study was to evaluate the effect of lowering triglycerides on LDL peak particle size in a Finnish subgroup of DAIS cohort. 45 patients with type 2 diabetes were randomized to receive 200 mg micronized fenofibrate (FF, n = 24) or placebo (PL, n = 21). The average treatment time was 3.8 years. Serum lipid concentrations, LDL peak particle diameter (LDL size), and post-heparin lipoprotein lipaae (LPL) activity were measured at baseline and at the end of treatment. At baseline the groups were matched for BMI, HbAlc, serum trigycerides (TG), total cholesterol (TC), HDL cholesterol (HDL), LDL size, and LPL activity. BMI, HbAlc, and HDL did not change significantly in either groups during the treatment. Baseline and end TG, TC, LDL size, and LPL activity are summarized in the Table. The change in TG was associated with the change in LDL size in FF (r = -0.57, p = 0.004) and PL (r = -0.45, p = 0.042) groups, and it was the only variable which explained the change in LDL size in regression
2.OYkO.6
1.3*0.7***
PL
2.2f0.9
2.2fl.O
FF
5.6ztO.5
4.6+0.8***
PL
5.51tO.6
5.4f0.7
FF
25.3fl.O
26.6iO.8’
PL
25.1fl.3
25.9il.2
FF
227f54
247f55’
PL
25lf64
211+49
< 0.01, *p < 0.05 FF “S PL.
VERSUS STANDARD IP23 THE EFFECT OF AGGRESSIVE DOSES OF ATORVASTATIN ON DIABETIC DYSLIPIDEMIA; THE DALI STUDY M.A. van de Reel, F.V van Venrooij*, I. Berk-Planket?, RF! Stolk2. On BehaIf of the Diabetes Atorvastatin Lipid Intervention Study (The DALI Study) Group: ‘Dept. of Gen. Internal Medicine, Leiden University Medical Center; 2Dept. of Vascular Medicine and the Julius Center for Patient On’ented Research, University Medical Center Utrecht; ‘Dept. of Internal Medicine, Erasmus Medical Center Rotterdam, The Netherlands Dyslipidemia constitutes an important modifiable risk factor contributing to angiopathy in type 2 diabetes mellitus. The DALI study is a double-blind, randomized, placebo-controlled, multicenter study in which aggressive lipid lowering by atorvastatin 80 mg (A80) was compared to standard 10 mg atorvastatin (AlO) and placebo (P) in type 2 diabetic patients for a period of 30 weeks. The primary endpoint was the change in fasting triglyceride (TG) level. Type 2 diabetes patients, HbAlc < lo%, without manifest coronary artery disease, aged 45-75 years, total cholesterol between 4.G8.0 mmol/L and fasting TG between 1.56.0 mmoYL were eligible for the study. The entry criteria were met by 217 patients of whom 197 patients completed the followup. Baseline TG levels were 2.67f0.98 mmol/L, total cholesterol (TC) 6.0+0.87 mmol/L, LDL-c 3.7f0.87 mmol/L, ApoB 1.24% 0.21 mg/lOO mL, HDL-c 1.04f0.24 mmol/L and TCHDL ratio 6.0&l .4.
Triglycerides,
FENOFIBRATE LOWERS SERUM TRIGLYCERIDES AND INCREASES LOW DENSITY LIPOPROTEIN SIZE IN PATIENTS WITH TYPE 2 DIABETES
FF
In conclusion, fenofibrate decreased significantly TG and TC concentrations in type 2 diabetes patients. The decrease of TG resulted in a shift of LDL size towards larger LDL particles. A possible mechanism responsible for the fenofibrate action is the increase of LPL activity.
30 weeks
On treatment,
2. Diabetes - clinical research
End
mmoVL
Total cholesteml, LDL-c, ApoB,
2.88il.68
mm&L
mmol/L
mg/l00 mL
(tO.5%)
3.6i0.8
(-2.7%)
1.25*0.2 1.04iO.2
TUHDL
6.Oztl.4
Mean +SD (Chmge);
(~10%)
6.0i0.9
HDL-c, mm&L ratio
arvaStatin
placebo
(-1.5%) (-0.9%) (+2.6%)
*p < O.OOJvw~w placebo:
10 mg
atomstdh
1.84ztO.86 (-25%)’
1.78ztl.21
4.110.8
(-30%)’
3.6fl.O
2.2f0.6
(41%)’
0.84iO.2 l.lOf0.3 3.9io.9
(-31%). (+6.0%)* (-34%).
sp < O.OOJ aforoasfafin
80 mg (-35%)*
(-39%)**$
1.7ztl.O (-52%)*.5 0.74zkO.2 (-4O%)*~$ 1.09~0.3 3.5fl.3
(+5.2%)* (-42%)‘rS
IO mg uersus 80 II@?
The difference in plasma triglyceride reduction between A10 and A80 mg was not significant (p > 0.5). Stratified analysis indicated that the treatment effect was independent of baseline triglyceride levels. A80 verus A10 improved significantly LDL-c and total cholesterol @ c 0.005 for both). LDL particle size and lipoprotein lipase activity dod not differ at 6 months. No differences between AlO, A80 and P were found in adverse events or safety parameters. In conclusion, atorvastatin 10 mg and 80 mg provide similar, significant reductions from baseline in triglycerides in patients with type 2 diabetes mellitus. A higher dose of atorvastatin improves cholesterol-related parameters. Both dosages were well tolerated in this patient population.
72nd EAS Congress
52
lesions and/or less progression of existing lesions compared with more moderate lipid lowering with pravaatatin 40 mgday. REVERSAL is an 18-month, randomized, double-blind study that will enroll 600 patients from approximately 35 sites. Patients presenting for diagnostic coronary angiography are screened. Inclusion criteria include angiographic evidence of CHD (220% reduction in lumen diameter in a coronary artery). In addition, eligible patients must have <50% stenosis in the ‘target’ vessel for IVUS evaluation. Exclusion criteria include >50% reduction in lumen diameter of the left main coronary artery. Following a 2-week placebo run-in phase, patients are randomized to receive atorvastatin 80 mg/day or pravastatin 40 mg/day for 18 months. The primary efficacy measure is the % change from baseline in total plaque volume for all slices of anatomically comparable segments of the target coronary artery as measured by IVUS. REVERSAL, which is estimated to complete in 2002, is expected to demonstrate that an aggressive lipid-lowering regimen will result in formation of fewer new lesions or less progression of existing atherosclerosis compared with a more moderate lipid-lowering regimen. IP20 COMPARISON OF THE EFFECT OF ATORVASTATIN AND SIMVASTATIN ON LEVELS OF Lp(a) AND Ape(a) FRAGMENTS IN HYPERCHOLESTEROLEMIC PATIENTS AT HIGH CARDIOVASCULAR RISK S. Gonbert, C. Doucef H. Laouenan’, J. Chapman, J. Thillet. INSERM U321, Hopital de la Pitie Paris; ‘Pfier Courbevoie, France The effect of statins on Lp(a) levels is controversial, and there are no data concerning their effect on ape(a) fragmentation. We therefore determined the levels of Lp(a) and of ape(a) fragments in plasma of hypercholesterolemic patients before and after treatment (6 weeks) with Atorvastatin 10 mg/day (AlO) or Simvastatin 20 mg/day (S20). In a double blind study, 391 hypercholesterolemic patients at high cardiovascular risk (LDL-C = 4.13 mmol/l, TG < 2.24 mmol/l, 34% with documented CHD, 45% hypertensive, and 29% current smokers) were assigned to treatment with A10 (n = 199) or S20 (n = 192). Plasma Lp(a) and ape(a) fragment (n = 206) levels were measured prior and after treatment. At baseline, A10 and S20 groups did not differ in levels of lipids, Lp(a) (AlO: 0.45f0.48 mg/ml, S20: 0.46&0.5), and ape(a) fragments (AlO: 3.88~t5.22 ug/ml; S20: 3.25&3), and equally in ape(a) isofotm size (AlO: 26f5 kr, S20: 25.555.3). On treatment, A10 caused a sipPcant decrease in Lp(a) levels (0.42hO.47 mglml, 6% variation, p < O.OOl), whereas S20 caused a less signitlcant variation (0.45f0.53 mg/ml, 0.02% variation, p = 0.046). A10 and S20 did not significanly differ in their efficacy to lower Lp(a) levels. Plasma levels of ape(a) fragments were not modified by either statin. We therefore concluded that both A10 and S20 lowered Lp(a) with A10 tending to have a greater effect.
analyses (adjusted rr = 0.29 in FF group, adjusted ? = 0.28 in PL group). The association between the change in LPL activity and the change in TG in FF group was of borderline significance (r = -0.40, p = 0.055).
Baseline TG, mmovl
TC, mmolil
LDL size, nm
LPL activity, pmol FFAlmfi
***p
< 0.001, **p
IP22
J. Vakkilainen’, G. Steinerz, J.-C. Ansquer?, M.-R. Taskinen’. ‘Helsinki University Central Hospital, Helsinki, Finland; 2 University Health Network, Toronto, Canada; ‘Laboratories Fournier Da& Fmnce DAIS has reported that fenofibrate reduces the angiogmphic progression of coronary artery disease in patients with type 2 diabetes. The purpose of the study was to evaluate the effect of lowering triglycerides on LDL peak particle size in a Finnish subgroup of DAIS cohort. 45 patients with type 2 diabetes were randomized to receive 200 mg micronized fenofibrate (FF, n = 24) or placebo (PL, n = 21). The average treatment time was 3.8 years. Serum lipid concentrations, LDL peak particle diameter (LDL size), and post-heparin lipoprotein lipaae (LPL) activity were measured at baseline and at the end of treatment. At baseline the groups were matched for BMI, HbAlc, serum trigycerides (TG), total cholesterol (TC), HDL cholesterol (HDL), LDL size, and LPL activity. BMI, HbAlc, and HDL did not change significantly in either groups during the treatment. Baseline and end TG, TC, LDL size, and LPL activity are summarized in the Table. The change in TG was associated with the change in LDL size in FF (r = -0.57, p = 0.004) and PL (r = -0.45, p = 0.042) groups, and it was the only variable which explained the change in LDL size in regression
2.OYkO.6
1.3*0.7***
PL
2.2f0.9
2.2fl.O
FF
5.6ztO.5
4.6+0.8***
PL
5.51tO.6
5.4f0.7
FF
25.3fl.O
26.6iO.8’
PL
25.1fl.3
25.9il.2
FF
227f54
247f55’
PL
25lf64
211+49
< 0.01, *p < 0.05 FF “S PL.
VERSUS STANDARD IP23 THE EFFECT OF AGGRESSIVE DOSES OF ATORVASTATIN ON DIABETIC DYSLIPIDEMIA; THE DALI STUDY M.A. van de Reel, F.V van Venrooij*, I. Berk-Planket?, RF! Stolk2. On BehaIf of the Diabetes Atorvastatin Lipid Intervention Study (The DALI Study) Group: ‘Dept. of Gen. Internal Medicine, Leiden University Medical Center; 2Dept. of Vascular Medicine and the Julius Center for Patient On’ented Research, University Medical Center Utrecht; ‘Dept. of Internal Medicine, Erasmus Medical Center Rotterdam, The Netherlands Dyslipidemia constitutes an important modifiable risk factor contributing to angiopathy in type 2 diabetes mellitus. The DALI study is a double-blind, randomized, placebo-controlled, multicenter study in which aggressive lipid lowering by atorvastatin 80 mg (A80) was compared to standard 10 mg atorvastatin (AlO) and placebo (P) in type 2 diabetic patients for a period of 30 weeks. The primary endpoint was the change in fasting triglyceride (TG) level. Type 2 diabetes patients, HbAlc < lo%, without manifest coronary artery disease, aged 45-75 years, total cholesterol between 4.G8.0 mmol/L and fasting TG between 1.56.0 mmoYL were eligible for the study. The entry criteria were met by 217 patients of whom 197 patients completed the followup. Baseline TG levels were 2.67f0.98 mmol/L, total cholesterol (TC) 6.0+0.87 mmol/L, LDL-c 3.7f0.87 mmol/L, ApoB 1.24% 0.21 mg/lOO mL, HDL-c 1.04f0.24 mmol/L and TCHDL ratio 6.0&l .4.
Triglycerides,
FENOFIBRATE LOWERS SERUM TRIGLYCERIDES AND INCREASES LOW DENSITY LIPOPROTEIN SIZE IN PATIENTS WITH TYPE 2 DIABETES
FF
In conclusion, fenofibrate decreased significantly TG and TC concentrations in type 2 diabetes patients. The decrease of TG resulted in a shift of LDL size towards larger LDL particles. A possible mechanism responsible for the fenofibrate action is the increase of LPL activity.
30 weeks
On treatment,
2. Diabetes - clinical research
End
mmoVL
Total cholesteml, LDL-c, ApoB,
2.88il.68
mm&L
mmol/L
mg/l00 mL
(tO.5%)
3.6i0.8
(-2.7%)
1.25*0.2 1.04iO.2
TUHDL
6.Oztl.4
Mean +SD (Chmge);
(~10%)
6.0i0.9
HDL-c, mm&L ratio
arvaStatin
placebo
(-1.5%) (-0.9%) (+2.6%)
*p < O.OOJvw~w placebo:
10 mg
atomstdh
1.84ztO.86 (-25%)’
1.78ztl.21
4.110.8
(-30%)’
3.6fl.O
2.2f0.6
(41%)’
0.84iO.2 l.lOf0.3 3.9io.9
(-31%). (+6.0%)* (-34%).
sp < O.OOJ aforoasfafin
80 mg (-35%)*
(-39%)**$
1.7ztl.O (-52%)*.5 0.74zkO.2 (-4O%)*~$ 1.09~0.3 3.5fl.3
(+5.2%)* (-42%)‘rS
IO mg uersus 80 II@?
The difference in plasma triglyceride reduction between A10 and A80 mg was not significant (p > 0.5). Stratified analysis indicated that the treatment effect was independent of baseline triglyceride levels. A80 verus A10 improved significantly LDL-c and total cholesterol @ c 0.005 for both). LDL particle size and lipoprotein lipase activity dod not differ at 6 months. No differences between AlO, A80 and P were found in adverse events or safety parameters. In conclusion, atorvastatin 10 mg and 80 mg provide similar, significant reductions from baseline in triglycerides in patients with type 2 diabetes mellitus. A higher dose of atorvastatin improves cholesterol-related parameters. Both dosages were well tolerated in this patient population.
72nd EAS Congress