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The impact of ezetimibe and high-dose of statin treatment on LDL levels in patients with heterozygous familial hypercholesterolemia
280
Letters to the Editor
The impact of ezetimibe and high-dose of statin treatment on LDL levels in patients with heterozygous familial hypercholesterolemia Christos Pitsavos, Ioannis Skoumas, Dimitris Tousoulis ⁎, George Metalinos, Constantina Masoura, Christina Chrysohoou, Lambros Papadimitriou, Nikolaos Giotsas, Marina Toutouza, Charalambos Antoniades, Christodoulos Stefanadis 1st Department of Cardiology, University of Athens Medical School, Hippokration Hospital, Athens, Greece Received 23 October 2007; accepted 20 December 2007 Available online 18 March 2008
Abstract We evaluated the efficacy and the safety of combining high doses of statins and ezetimibe in heterozygous familial hypercholesterolemia (hFH) patients. Seventy patients with hFH, received 10 mg of ezetimibe, in addition to their current statin therapy and were followed up for twelve months. The co-administration of statins and ezetimibe improved total cholesterol ( p b 0.05), LDL-c( p b 0.05), triglycerides ( p b 0.05) and apolipoprotein-B ( p b 0.05) in comparison to statin monotherapy. There were no changes in high density lipoprotein cholesterol (HDL-c), apolipoprotein-A, lipoprotein (a), fibrinogen and C-reactive protein (CPR). In conclusion the combination of 10 mg of ezetimibe with high dose statin therapy is effective in hFH, offering a further reduction of LDL-c throughout the 12 months of follow up. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Ezetimibe; Statins; Heterozygous familial hypercholesterolemia
Heterozygous familial hypercholesterolemia (hFH) is an autosomal dominant inherited disorder of lipoprotein metabolism characterized by very high plasma concentrations of low density lipoprotein cholesterol (LDL-c), and increased risk of premature coronary heart disease (CHD) [1]. Hypolipidaemic agents, such as statins, safely and efficiently reduce LDL-c and decrease cardiovascular morbidity and mortality. The co-administration of statins with ezetimibe, a new lipid-lowering drug, that inhibits the absorption of dietary and biliary cholesterol offers a new therapeutic strategy in LDL-c reduction [2]. The purpose of this study was to evaluate the efficacy and the safety of combining high doses of statins and 10 mg of ezetimibe in hFH patients. The study population consisted of 70 patients (29 males/ 41 females mean age 48.6 ± 11.8 years) with hFH who had been referred to our lipid outpatient clinic in our Institution. In all participants a complete medical history was obtained and detailed physical examination was performed. Coronary artery disease was defined with coronary angiogram (stenosis of N50% of an epicardial vessel) or/and positive exercise test result. In all the patients a dose of 10 mg ezetimibe was administered for 12 months in addition to current treatment with high doses of statins (i.e. atorvastastin 80 mg, pravastatin 40 mg, rosuvastatin 40 mg, simvastatin 80 mg, fluvastatin 80 mg). ⁎ Corresponding author. Athens University Medical School, 69 S. Karagiorga, 16675, Glifada, Athens, Greece. Tel.: +30 210 7782446; fax: +30 210 7485039. E-mail address: [email protected] (D. Tousoulis).
Continuous variables are presented as the mean ± standard deviation (SD), while their distribution was evaluated graphically by histograms and statistically by the nonparametric Kolmogorov–Smirnov test. p-values b 0.05 were considered to represent statistical significance. Statistical analysis was performed with SPSS 11.5 for Windows (SPSS Inc, Chicago). All the patients completed the 12 month study period. After maximum statin therapy a significant reduction of total cholesterol, LDL-c and Apo-B was observed ( p b 0.05) (Table 1). Moreover HDL-c levels were significantly increased ( p b 0.05) (Table 1). The levels of Apo-A, Lp(a) and fibrinogen remained unchanged. Thirty seven patients were with documented CAD. After 3 months co-administration of ezetimibe and statins a significant further reduction of total cholesterol p b 0.05), LDL-c ( pb 0.05), triglycerides ( p b 0.05) and Apo-B ( p b 0.05) was observed. This beneficial effect persisted 12 months with the same treatment. There was no change in HDL-c, Apo-A, Lp(a), fibrinogen and hs-CRP values (Table 1). In CAD and the non CAD subgroups the reduction in LDL-c were 35.8 and 43% respectively. Additionally, no adverse events were reported, while no important elevations of hepatic enzymes, and creatine phosphokinase (CPK) were documented. Previous studies in different dyslipidemic groups, reported a further reduction of LDL-C levels from 12.1% to 26.1% after co-administration of ezetimibe to statins [2]. Ballantyne et al. [3] reported that 85% of patients with ezetimibe and atorvastatin achieved the LDL-c goal. Our findings indicate
Letters to the Editor
281
Table 1 Effects of treatment on serum lipids during the follow-up period. Baseline
Total cholesterol (mg/dl) Triglycerides (mg/dl) HDL (mg/dl) LDL (mg/dl) APO-A (mg/dl) APO-B (mg/dl) LPA (mg/dl) CRP (mg/ml) Fibrinogen (mg/ml) SGOT (IU/L) SGPT (IU/L) CPK (IU/L) LDL-Target achieved(%)
354.3 ± 83.9 125.0 ± 59.5 48.8 ± 10.8 278.0 ± 81.9 152.2 ± 29.7 204.2 ± 66.0 42.7 ± 39.6 – 316.5 ± 64.5 22.9 ± 12.0 20.6 ± 13.6 91.0 ± 39.4 –
Statins
238.4 ± 51.0 96.6 ± 43.2 55.7 ± 13.7 † 163.5 ± 44.4 † 147.4 ± 28.3 117.8 ± 26.0 † 36.2 ± 40.7 0.89 ± 1.04 294.5 ± 66.7 23.3 ± 9.0 25.2 ± 13.7 110.6 ± 51.7 20%
Statins + ezetimibe
Statins + ezetimibe
(3 months)
(12 months)
193.5 ± 40.8†⁎ 84.0 ± 35.8†⁎ 53.5 ± 11.6† 122.5 ± 34.9†⁎ 144.4 ± 30.7 99.4 ± 23.7†⁎ 33.8 ± 39.6 0.89 ± 1.42 304.8 ± 83.7 26.8 ± 11.4 27.8 ± 13.8† 121.5 ± 68.1† 55.7%
192.5 ± 34.7†⁎ 84.2 ± 32.0†⁎ 55.0 ± 12.9† 121.6 ± 36.0†⁎ 145.7 ± 36.6 99.2 ± 26.5†⁎ 35.0 ± 43.6 1.14 ± 1.36 323.5 ± 76.7 24.5 ± 8.5 28.1 ± 12.4† 115.7 ± 53.9† 60%
HDL: High density lipoprotein; LDL: low density lipoprotein; Apo-A: Apolipoprotein A; Apo-B: Apolipoprotein B; LPA: Lipoprotein a; CRP: C-reactive protein; SGOT: Glutamate oxaloacetate transaminase; SGPT: Glutamate pyruvate transaminase; CPK: Creatine phosphokinase; †p b 0.05 vs baseline; ⁎p b 0.05 vs statins.
that the addition of ezetimibe to high dose of statins, enhanced the achievement of LDL-c goal by 35.8% and 43% in CAD and non CAD subgroups respectively. Furthermore we observed an important additional reduction of triglycerides (∼13%) and Apo-B (∼16%) after 3 months of combined therapy, which remained unchanged through the 12 months of follow up. On the other hand, after 3 and 12 months, no change of HDL and Apo-A plasma levels was noticed. This is consistent with the findings of recent study [2] reported an incremental reduction of 7.5% in triglycerides values and 10.9% in Apo-B values in the simvastatin plus ezetimibe group compared to simvastatin monotherapy, without significant changes in HDL and Apo-A values. Regarding the impact of combined treatment on hs-CRP and fibrinogen levels, in our study we did not find any statistically significant difference during the 12 months period. This is in agreement with the findings of Gaudiani et al. [4], showed that despite the absolute lower values of hsCRP in the statin plus ezetimibe group, there were no significant variations, neither for hs-CRP, nor for fibrinogen. On contrary, another study [5] showed that hs-CRP, was reduced by 18.2% with simvastatin monotherapy and 34.8% with the co administration of ezetimibe. 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.12.065
In conclusion, the addition of ezetimibe to the current hypolipidemic therapy with high dose of statins, offers a further reduction of LDL-c, and provides an important potential for reducing the LDL-c near the target in the majority of hFH patients. Both statins and ezetimibe exert a constant and safe beneficial effect on lipidemic profile throughout the 12 month follow up. References [1] Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic basis of inherited disease, vol. 120. New York: McGraw-Hill; 2001. p. 2863–913. [2] Davidson MH, McGarry T, Bettis R, et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002;40:2125–34. [3] Ballantyne Ch, Houri J, Notarbartolo A, et al. Circulation 2003;107: 2409–15. [4] Gaudiani LM, Lewin A, Meneghini L, et al. Efficacy and safety of ezetimibe co-administered with simvastatin in thiazolinedione-treated type 2 diabetic patients. Diabetes Obes Metab 2005;7:88–97. [5] Sager Ph, Melani L, Lipka L, et al. Effect of co-administration of ezetimibe and simvastatin on high-sensitivity C-reactive protein. Am J Cardiol 2003;92:1414–8.
Letters to the Editor
The impact of ezetimibe and high-dose of statin treatment on LDL levels in patients with heterozygous familial hypercholesterolemia Christos Pitsavos, Ioannis Skoumas, Dimitris Tousoulis ⁎, George Metalinos, Constantina Masoura, Christina Chrysohoou, Lambros Papadimitriou, Nikolaos Giotsas, Marina Toutouza, Charalambos Antoniades, Christodoulos Stefanadis 1st Department of Cardiology, University of Athens Medical School, Hippokration Hospital, Athens, Greece Received 23 October 2007; accepted 20 December 2007 Available online 18 March 2008
Abstract We evaluated the efficacy and the safety of combining high doses of statins and ezetimibe in heterozygous familial hypercholesterolemia (hFH) patients. Seventy patients with hFH, received 10 mg of ezetimibe, in addition to their current statin therapy and were followed up for twelve months. The co-administration of statins and ezetimibe improved total cholesterol ( p b 0.05), LDL-c( p b 0.05), triglycerides ( p b 0.05) and apolipoprotein-B ( p b 0.05) in comparison to statin monotherapy. There were no changes in high density lipoprotein cholesterol (HDL-c), apolipoprotein-A, lipoprotein (a), fibrinogen and C-reactive protein (CPR). In conclusion the combination of 10 mg of ezetimibe with high dose statin therapy is effective in hFH, offering a further reduction of LDL-c throughout the 12 months of follow up. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Ezetimibe; Statins; Heterozygous familial hypercholesterolemia
Heterozygous familial hypercholesterolemia (hFH) is an autosomal dominant inherited disorder of lipoprotein metabolism characterized by very high plasma concentrations of low density lipoprotein cholesterol (LDL-c), and increased risk of premature coronary heart disease (CHD) [1]. Hypolipidaemic agents, such as statins, safely and efficiently reduce LDL-c and decrease cardiovascular morbidity and mortality. The co-administration of statins with ezetimibe, a new lipid-lowering drug, that inhibits the absorption of dietary and biliary cholesterol offers a new therapeutic strategy in LDL-c reduction [2]. The purpose of this study was to evaluate the efficacy and the safety of combining high doses of statins and 10 mg of ezetimibe in hFH patients. The study population consisted of 70 patients (29 males/ 41 females mean age 48.6 ± 11.8 years) with hFH who had been referred to our lipid outpatient clinic in our Institution. In all participants a complete medical history was obtained and detailed physical examination was performed. Coronary artery disease was defined with coronary angiogram (stenosis of N50% of an epicardial vessel) or/and positive exercise test result. In all the patients a dose of 10 mg ezetimibe was administered for 12 months in addition to current treatment with high doses of statins (i.e. atorvastastin 80 mg, pravastatin 40 mg, rosuvastatin 40 mg, simvastatin 80 mg, fluvastatin 80 mg). ⁎ Corresponding author. Athens University Medical School, 69 S. Karagiorga, 16675, Glifada, Athens, Greece. Tel.: +30 210 7782446; fax: +30 210 7485039. E-mail address: [email protected] (D. Tousoulis).
Continuous variables are presented as the mean ± standard deviation (SD), while their distribution was evaluated graphically by histograms and statistically by the nonparametric Kolmogorov–Smirnov test. p-values b 0.05 were considered to represent statistical significance. Statistical analysis was performed with SPSS 11.5 for Windows (SPSS Inc, Chicago). All the patients completed the 12 month study period. After maximum statin therapy a significant reduction of total cholesterol, LDL-c and Apo-B was observed ( p b 0.05) (Table 1). Moreover HDL-c levels were significantly increased ( p b 0.05) (Table 1). The levels of Apo-A, Lp(a) and fibrinogen remained unchanged. Thirty seven patients were with documented CAD. After 3 months co-administration of ezetimibe and statins a significant further reduction of total cholesterol p b 0.05), LDL-c ( pb 0.05), triglycerides ( p b 0.05) and Apo-B ( p b 0.05) was observed. This beneficial effect persisted 12 months with the same treatment. There was no change in HDL-c, Apo-A, Lp(a), fibrinogen and hs-CRP values (Table 1). In CAD and the non CAD subgroups the reduction in LDL-c were 35.8 and 43% respectively. Additionally, no adverse events were reported, while no important elevations of hepatic enzymes, and creatine phosphokinase (CPK) were documented. Previous studies in different dyslipidemic groups, reported a further reduction of LDL-C levels from 12.1% to 26.1% after co-administration of ezetimibe to statins [2]. Ballantyne et al. [3] reported that 85% of patients with ezetimibe and atorvastatin achieved the LDL-c goal. Our findings indicate
Letters to the Editor
281
Table 1 Effects of treatment on serum lipids during the follow-up period. Baseline
Total cholesterol (mg/dl) Triglycerides (mg/dl) HDL (mg/dl) LDL (mg/dl) APO-A (mg/dl) APO-B (mg/dl) LPA (mg/dl) CRP (mg/ml) Fibrinogen (mg/ml) SGOT (IU/L) SGPT (IU/L) CPK (IU/L) LDL-Target achieved(%)
354.3 ± 83.9 125.0 ± 59.5 48.8 ± 10.8 278.0 ± 81.9 152.2 ± 29.7 204.2 ± 66.0 42.7 ± 39.6 – 316.5 ± 64.5 22.9 ± 12.0 20.6 ± 13.6 91.0 ± 39.4 –
Statins
238.4 ± 51.0 96.6 ± 43.2 55.7 ± 13.7 † 163.5 ± 44.4 † 147.4 ± 28.3 117.8 ± 26.0 † 36.2 ± 40.7 0.89 ± 1.04 294.5 ± 66.7 23.3 ± 9.0 25.2 ± 13.7 110.6 ± 51.7 20%
Statins + ezetimibe
Statins + ezetimibe
(3 months)
(12 months)
193.5 ± 40.8†⁎ 84.0 ± 35.8†⁎ 53.5 ± 11.6† 122.5 ± 34.9†⁎ 144.4 ± 30.7 99.4 ± 23.7†⁎ 33.8 ± 39.6 0.89 ± 1.42 304.8 ± 83.7 26.8 ± 11.4 27.8 ± 13.8† 121.5 ± 68.1† 55.7%
192.5 ± 34.7†⁎ 84.2 ± 32.0†⁎ 55.0 ± 12.9† 121.6 ± 36.0†⁎ 145.7 ± 36.6 99.2 ± 26.5†⁎ 35.0 ± 43.6 1.14 ± 1.36 323.5 ± 76.7 24.5 ± 8.5 28.1 ± 12.4† 115.7 ± 53.9† 60%
HDL: High density lipoprotein; LDL: low density lipoprotein; Apo-A: Apolipoprotein A; Apo-B: Apolipoprotein B; LPA: Lipoprotein a; CRP: C-reactive protein; SGOT: Glutamate oxaloacetate transaminase; SGPT: Glutamate pyruvate transaminase; CPK: Creatine phosphokinase; †p b 0.05 vs baseline; ⁎p b 0.05 vs statins.
that the addition of ezetimibe to high dose of statins, enhanced the achievement of LDL-c goal by 35.8% and 43% in CAD and non CAD subgroups respectively. Furthermore we observed an important additional reduction of triglycerides (∼13%) and Apo-B (∼16%) after 3 months of combined therapy, which remained unchanged through the 12 months of follow up. On the other hand, after 3 and 12 months, no change of HDL and Apo-A plasma levels was noticed. This is consistent with the findings of recent study [2] reported an incremental reduction of 7.5% in triglycerides values and 10.9% in Apo-B values in the simvastatin plus ezetimibe group compared to simvastatin monotherapy, without significant changes in HDL and Apo-A values. Regarding the impact of combined treatment on hs-CRP and fibrinogen levels, in our study we did not find any statistically significant difference during the 12 months period. This is in agreement with the findings of Gaudiani et al. [4], showed that despite the absolute lower values of hsCRP in the statin plus ezetimibe group, there were no significant variations, neither for hs-CRP, nor for fibrinogen. On contrary, another study [5] showed that hs-CRP, was reduced by 18.2% with simvastatin monotherapy and 34.8% with the co administration of ezetimibe. 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.12.065
In conclusion, the addition of ezetimibe to the current hypolipidemic therapy with high dose of statins, offers a further reduction of LDL-c, and provides an important potential for reducing the LDL-c near the target in the majority of hFH patients. Both statins and ezetimibe exert a constant and safe beneficial effect on lipidemic profile throughout the 12 month follow up. References [1] Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic basis of inherited disease, vol. 120. New York: McGraw-Hill; 2001. p. 2863–913. [2] Davidson MH, McGarry T, Bettis R, et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002;40:2125–34. [3] Ballantyne Ch, Houri J, Notarbartolo A, et al. Circulation 2003;107: 2409–15. [4] Gaudiani LM, Lewin A, Meneghini L, et al. Efficacy and safety of ezetimibe co-administered with simvastatin in thiazolinedione-treated type 2 diabetic patients. Diabetes Obes Metab 2005;7:88–97. [5] Sager Ph, Melani L, Lipka L, et al. Effect of co-administration of ezetimibe and simvastatin on high-sensitivity C-reactive protein. Am J Cardiol 2003;92:1414–8.