- Email: [email protected]
Lipid altering efficacy of simvastatin in type III hyperlipidemia
71st EAS Meeting Abstracts accepted for presentation in the abstract book muhiexon 5 kb deletion of the LDL receptor gene was reported from St. Petersburg population previously, this mutation also unknown from other countries. Rapid tests for all the new mutations were developed based on PCR-restriction enzyme digestion assays or direct heteroduplex visualization in gels after electrophoresis of PCR products {mutations 347 delGCC and delta GI97). The enzymes used for mutation testing were as follows: Mva I for CI27W, Msp I for CI39G, Alu 1 for E397X. Mutations CI39G and deltaGI97 were recurrent, the latter responsible for 30% (7 out of 22) of independent FH cases in Jewish patients. According to our data spectra of the LDL receptor gene mutations in Russia has absolutely specific character. This research was supported by grant "Cholesterol reducers" MSGP #SRUS-01-98-SCH and by grants from Russian Fund of Basic Research. LIPID ALTERING EFFICACY O F SIMVASTATIN IN TYPE 111 HYPERLIPIDEMIA
191
Results: Baseline characteristics for diabetics (D) and non-diabetics (nonD) were similar. Median 6 week changes (% from baseline) in lipids were:
LDL-C D
VLDL-C
TG
HDL-C
non-D
D
non-D
D
non-D
D
non-D
PBO
5
I
-I
-5
-2
..-4
1
3
40 S 80
-29 -40
-31 -36
-.40 -49
-34 -43
-28 -33
-28 -33
9 13
12 16
S
Conclusions: Simvastatin is an effective lipid altering treatment in patients with type 2 diabetes and combined hyperlipidemia and provide qualitatively similar effects as in non-diabetic patients.
D. Hunninghake 1, D. Plotkin 2, G. Dujovne3. M. Stepanavage 2, L.M. Keilson4, M. Mereuri 2. For the Simvastatin in Combined
L A R G E AND DOSE DEPENDENT EFFECTS OF SIMVASTATIN 40 AND 80 MG/DAY IN COMBINED H Y P E R L I P I D E M I A
Hyperlipidemia Research Group: Ill:art Prevention Clinic, Minneapolis, MN: 2Merck Research Laboratories, Rahwgv, NJ; 3Midcontinent Clinical Trial Kansas Ci0,, KS; 4Center for Lipid and Cardiovascular Health, Portland, ME, USA
D.B. Hunninghake1 , D. Plotkin 2, M. Stepanavage2, H. Bays3, M.H. Davidson4, C.A. Dujovnes, L.M. Keilson°, S.G. Korenman7, D.G. Robertson 8, E.A. Stein9, S.R. Weiss1°, M. Mercuri 2. And the
Background: Type III hyperlipidemia or dysbetalipoproteinemia is a rare condition characterized by elevated remnant lipoproteins, and is associated with premature coronary and peripheral atherosclerosis. Patients have an apolipoprotein Ez/2 genotype which results in reduced apo E binding affinity to the low density lipoproten (LDL) receptor and delayed catabolism of lipoproteins. Effective lipid altering therapy is required to prevent atherosclerotic disease. Methods: Seven patients ( I black, 3 women, age 27-55 yrs), homozygous for the apo E2 gene and with a very low density lipoprotein (VLDL) to triglycerides (TG) ratio (VLDL/TG) > 2.5, were randomized to placebo, simvastatin 40 and 80 mg/day as part o f a larger (130 patients total) doubleblind, 3 period, 6 week, complete block crossover study. Results: Median baseline values [mg/dL, to convert to mmol/L, divide LDL and high density lipoproteio (HDL) by 38.6 and triglycerides (TG) by 88.6] and 6-week lipid effects (% change from baseline: A):
Simvastatin in Combined H),perli~idemia Research Group; I Heart Disease Prevention Clinic, Minneapolis; - Rahway: 3Louisville: 4Chicago; 5Kansas CiO,; 6portland; 7Los Angeles: 8Atlanta; 9Cincinnati; I°San Diego, USA to assess the lipid altering efficacy and safety o f simvastatin (S) 40and 80- mg/day in patients with combined hyperlipidemia (CHL, LDL-C > 130 mg/dL or (<4.2 mmol/L, and TG: 300-700 mg/dL or 3.4-7.9 retool/L). Methods: 130 patients (age: 53+10, women: 48%, type 2 diabetes: 16%) with CHL were recruited into a multicenter, double-blind, placebocontrolled, 3 period, 6 week, balanced cross-over study. Patients were randomized to one of 6 treatment sequences including placebo and S 40 and 80 mg/day. Results: The baseline values in mg/dL (mmol/L), and lipid changes (% change from baseline) are summarized below. Treatment with simvastatin was well tolerated.
Aim:
Tnglycerides ~
LDL-Cholesterof[ N
IDL + LDL-C Base A
IDL + VLDC-C apoE Base A Ba.~
(mg/dL)
(mg/dL)
Placebo $40 123 S 80
-8. I -49.8 -50. I
156
A
(mg/dL)
-3.8 -58.3 -59.5
72
TG Base
HDL-C Base A
A
(mg/dL)
9.5 -37.8 -50.4
411
Placebo 119
(m~dL)
3.5 -40.5 -38.2
31
- 1.6 6.7 6.7
Conclusions: Monotherapy with simvastatin is an effective lipid altering
treatment in patients with type 111 hyperlipidemia providing substantial lowering of total triglycerides and apo B containing lipoproteins rich in TG, while increasing HDL-C. SIMVASTATIN T R E A T M E N T IN PATIENTS W I T H TYPE 2 DIABETES AND C O M B I N E D H Y P E R L I P I D E M I A S.G. Korenman, E.A. Stein 2, D. Hunninghake3, M.H. Davidson4, LM. Keilson 5, M. Stepanavage 6, D. Plotkin 6, M. Mereuri 6. For the
Sinwastatin in Combined Hyperlipidemia Research Group; t UniversiO, of California, Los Angeles; :Metabolic and Atherosclerosis Research Center, Cincinnati; Heart Prevention Clinic, Minneapolis," 4Chicago Center for Clinical Research, Chicago; 5Center for Lipid and Cardiovascular Health, Portland; 6Endocrinology and Metabolism, Merck & Co. lnc, Rahway, USA Background: Diabetes is associated with a 2-4 increased risk o f coronary heart disease (CHD). In the Scandinavian Simvastatin Survival Study (4S), simvastatin reduced the risk of cardiovascular events in diabetics with CHD and hypercholesterolemia by 55%. Combined hyperlipidemia is a common lipid disorder in patients with diabetes and the use of statins in combination with other lipid lowering drugs often required. Availability of a new higher dose (80 mg) of simvastatin may provide effective monotherapy. Methods: A subset of 24 patients (11 women, mean age 54 yrs) with type 2 diabetes were randomized as part of a larger (total 130 patients) double-blind, 3 period, 6 week, complete block crossover study and treated with placebo, simvastatin (S) 40 and 80 rag/day.
S-40
120
A
N
Base
A
156 14.0) 156
2.1NS
120
389 14.4) 389
-3.5Ns 120
-28.9"* 120
(4.0) S-80
119
HDL-Cholasterol
Base
156
(4.0)
N
-27.8°° 120
14.4) -35.5""
121
391
(4.4)
Base
A
39.0 (1.0) 38.9
3.3" 13.1"°
(I.0) -33.0 °°
121
38.9
15.7 °"
(I.0)
t by ultracentnlegation.~Medianbaselineand % changereported.All ber,een treatmentcomparisor~ werestatisdca|lysignificantat p _<0.05.Withintreaunentcomparisons:NSnotsignificant;*p = 0.002; "'p < 0.001. Conclusions: Simvastatin is an effective treatment for CHL and exerts a beneficial effect across the lipoprotein profile. The reduction in TG was large, dose dependent and similar in magnitude to LDL-C. The effect on HDL-C was substantial and dose dependent.
C L I N I C A L IMPORTANCE O F SOME LIPID P A R A M E T E R S IN PRIMARY P R E V E N T I O N OF A T H E R O S C L E R O S I S IN YOUNG PEOPLE L.L. Faleiro 1, A. Forts:ca 2, M.O. Rodrignes2, M.C. Martins 2.
l Departamento de Cardiologia, IPR, Lisboa; 21nstituto Nacional de Safade, Lisboa, Portugal Cardiovascular diseases (CVD) have their origin in childhood when starts the atherosclerosis pathogen:sis under the influence of genetic and environment factors. Among these factors hyperlipidemia is one of the most important. So high total and LDL cholesterol, low HDL cholesterol concentrations in children and youngsters can be relevant for predicting men and v ~ m e n who will develop CVD being the clifiical follow up of those at risk extremely important at individual and public health levels through their treatment and monitoring. The authors decided so to screen a total o f 153 children and adolescents, both sexes, 4-19 years old by measuring total, LDL and HDL cholesterol. The laboratory methods for these parameters were: CHOD-PAP for total
71st EAS Congress and Satellite Symposia
191
Results: Baseline characteristics for diabetics (D) and non-diabetics (nonD) were similar. Median 6 week changes (% from baseline) in lipids were:
LDL-C D
VLDL-C
TG
HDL-C
non-D
D
non-D
D
non-D
D
non-D
PBO
5
I
-I
-5
-2
..-4
1
3
40 S 80
-29 -40
-31 -36
-.40 -49
-34 -43
-28 -33
-28 -33
9 13
12 16
S
Conclusions: Simvastatin is an effective lipid altering treatment in patients with type 2 diabetes and combined hyperlipidemia and provide qualitatively similar effects as in non-diabetic patients.
D. Hunninghake 1, D. Plotkin 2, G. Dujovne3. M. Stepanavage 2, L.M. Keilson4, M. Mereuri 2. For the Simvastatin in Combined
L A R G E AND DOSE DEPENDENT EFFECTS OF SIMVASTATIN 40 AND 80 MG/DAY IN COMBINED H Y P E R L I P I D E M I A
Hyperlipidemia Research Group: Ill:art Prevention Clinic, Minneapolis, MN: 2Merck Research Laboratories, Rahwgv, NJ; 3Midcontinent Clinical Trial Kansas Ci0,, KS; 4Center for Lipid and Cardiovascular Health, Portland, ME, USA
D.B. Hunninghake1 , D. Plotkin 2, M. Stepanavage2, H. Bays3, M.H. Davidson4, C.A. Dujovnes, L.M. Keilson°, S.G. Korenman7, D.G. Robertson 8, E.A. Stein9, S.R. Weiss1°, M. Mercuri 2. And the
Background: Type III hyperlipidemia or dysbetalipoproteinemia is a rare condition characterized by elevated remnant lipoproteins, and is associated with premature coronary and peripheral atherosclerosis. Patients have an apolipoprotein Ez/2 genotype which results in reduced apo E binding affinity to the low density lipoproten (LDL) receptor and delayed catabolism of lipoproteins. Effective lipid altering therapy is required to prevent atherosclerotic disease. Methods: Seven patients ( I black, 3 women, age 27-55 yrs), homozygous for the apo E2 gene and with a very low density lipoprotein (VLDL) to triglycerides (TG) ratio (VLDL/TG) > 2.5, were randomized to placebo, simvastatin 40 and 80 mg/day as part o f a larger (130 patients total) doubleblind, 3 period, 6 week, complete block crossover study. Results: Median baseline values [mg/dL, to convert to mmol/L, divide LDL and high density lipoproteio (HDL) by 38.6 and triglycerides (TG) by 88.6] and 6-week lipid effects (% change from baseline: A):
Simvastatin in Combined H),perli~idemia Research Group; I Heart Disease Prevention Clinic, Minneapolis; - Rahway: 3Louisville: 4Chicago; 5Kansas CiO,; 6portland; 7Los Angeles: 8Atlanta; 9Cincinnati; I°San Diego, USA to assess the lipid altering efficacy and safety o f simvastatin (S) 40and 80- mg/day in patients with combined hyperlipidemia (CHL, LDL-C > 130 mg/dL or (<4.2 mmol/L, and TG: 300-700 mg/dL or 3.4-7.9 retool/L). Methods: 130 patients (age: 53+10, women: 48%, type 2 diabetes: 16%) with CHL were recruited into a multicenter, double-blind, placebocontrolled, 3 period, 6 week, balanced cross-over study. Patients were randomized to one of 6 treatment sequences including placebo and S 40 and 80 mg/day. Results: The baseline values in mg/dL (mmol/L), and lipid changes (% change from baseline) are summarized below. Treatment with simvastatin was well tolerated.
Aim:
Tnglycerides ~
LDL-Cholesterof[ N
IDL + LDL-C Base A
IDL + VLDC-C apoE Base A Ba.~
(mg/dL)
(mg/dL)
Placebo $40 123 S 80
-8. I -49.8 -50. I
156
A
(mg/dL)
-3.8 -58.3 -59.5
72
TG Base
HDL-C Base A
A
(mg/dL)
9.5 -37.8 -50.4
411
Placebo 119
(m~dL)
3.5 -40.5 -38.2
31
- 1.6 6.7 6.7
Conclusions: Monotherapy with simvastatin is an effective lipid altering
treatment in patients with type 111 hyperlipidemia providing substantial lowering of total triglycerides and apo B containing lipoproteins rich in TG, while increasing HDL-C. SIMVASTATIN T R E A T M E N T IN PATIENTS W I T H TYPE 2 DIABETES AND C O M B I N E D H Y P E R L I P I D E M I A S.G. Korenman, E.A. Stein 2, D. Hunninghake3, M.H. Davidson4, LM. Keilson 5, M. Stepanavage 6, D. Plotkin 6, M. Mereuri 6. For the
Sinwastatin in Combined Hyperlipidemia Research Group; t UniversiO, of California, Los Angeles; :Metabolic and Atherosclerosis Research Center, Cincinnati; Heart Prevention Clinic, Minneapolis," 4Chicago Center for Clinical Research, Chicago; 5Center for Lipid and Cardiovascular Health, Portland; 6Endocrinology and Metabolism, Merck & Co. lnc, Rahway, USA Background: Diabetes is associated with a 2-4 increased risk o f coronary heart disease (CHD). In the Scandinavian Simvastatin Survival Study (4S), simvastatin reduced the risk of cardiovascular events in diabetics with CHD and hypercholesterolemia by 55%. Combined hyperlipidemia is a common lipid disorder in patients with diabetes and the use of statins in combination with other lipid lowering drugs often required. Availability of a new higher dose (80 mg) of simvastatin may provide effective monotherapy. Methods: A subset of 24 patients (11 women, mean age 54 yrs) with type 2 diabetes were randomized as part of a larger (total 130 patients) double-blind, 3 period, 6 week, complete block crossover study and treated with placebo, simvastatin (S) 40 and 80 rag/day.
S-40
120
A
N
Base
A
156 14.0) 156
2.1NS
120
389 14.4) 389
-3.5Ns 120
-28.9"* 120
(4.0) S-80
119
HDL-Cholasterol
Base
156
(4.0)
N
-27.8°° 120
14.4) -35.5""
121
391
(4.4)
Base
A
39.0 (1.0) 38.9
3.3" 13.1"°
(I.0) -33.0 °°
121
38.9
15.7 °"
(I.0)
t by ultracentnlegation.~Medianbaselineand % changereported.All ber,een treatmentcomparisor~ werestatisdca|lysignificantat p _<0.05.Withintreaunentcomparisons:NSnotsignificant;*p = 0.002; "'p < 0.001. Conclusions: Simvastatin is an effective treatment for CHL and exerts a beneficial effect across the lipoprotein profile. The reduction in TG was large, dose dependent and similar in magnitude to LDL-C. The effect on HDL-C was substantial and dose dependent.
C L I N I C A L IMPORTANCE O F SOME LIPID P A R A M E T E R S IN PRIMARY P R E V E N T I O N OF A T H E R O S C L E R O S I S IN YOUNG PEOPLE L.L. Faleiro 1, A. Forts:ca 2, M.O. Rodrignes2, M.C. Martins 2.
l Departamento de Cardiologia, IPR, Lisboa; 21nstituto Nacional de Safade, Lisboa, Portugal Cardiovascular diseases (CVD) have their origin in childhood when starts the atherosclerosis pathogen:sis under the influence of genetic and environment factors. Among these factors hyperlipidemia is one of the most important. So high total and LDL cholesterol, low HDL cholesterol concentrations in children and youngsters can be relevant for predicting men and v ~ m e n who will develop CVD being the clifiical follow up of those at risk extremely important at individual and public health levels through their treatment and monitoring. The authors decided so to screen a total o f 153 children and adolescents, both sexes, 4-19 years old by measuring total, LDL and HDL cholesterol. The laboratory methods for these parameters were: CHOD-PAP for total
71st EAS Congress and Satellite Symposia