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Rapid resolution of xanthelasmas after treatment with alirocumab
Journal of Clinical Lipidology (2016) 10, 1259–1261
Rapid resolution of xanthelasmas after treatment with alirocumab Fernando Civeira, MD*, Sofia Perez-Calahorra, MSc, Rocio Mateo-Gallego, PhD Lipid Unit, Hospital Universitario Miguel Servet, IIS Aragon, Zaragoza, Spain KEYWORDS: Xanthelasmas; Hypercholesterolemia; Alirocumab; PCSK9; Treatment
Abstract: Xanthelasmas are superficial fat deposits around the eyelids commonly present in different hyperlipidemias and associated with increased cardiovascular risk. Statins or other lipid-lowering treatments do not usually modify them. We present the case of a middle-age man with severe high levels of LDL cholesterol from youth due to a genetically defined heterozygous familiar hypercholesterolemia (HeFH). He presented large xanthelasmas of both inner eyelids in spite of long term treatment with statins and ezetimibe that disappeared after treatment with alirocumab75 mg every 2 weeks for 26 months. His LDL cholesterol went from 164 mg/dL to 47 mg/dL with alirocumab. Xanthelasma regression was not previously reported with lipid-lowering drugs in HeFH. This case demonstrates that regression of skin lipid lesions can be achieved with very low LDL cholesterol concentrations. Ó 2016 National Lipid Association. All rights reserved.
Introduction Xanthelasmas are yellowish deposits of fat underneath the skin around the eyelids, frequently associated with severe hypercholesterolemia and increased risk for atherosclerosis,1 although can be also present with normal cholesterol concentration as an isolated clinical sign, probably as result of a local lipid disorder. Microscopically, they are composed of lipid-laden macrophages located in the superficial dermis, often with surrounding fibrosis and other inflammatory cells, similar to atherosclerotic lesions. The ODYSSEY FH I clinical trial was funded by Sanofi and Regeneron Pharmaceuticals. Editorial assistance for the preparation of this letter was provided by Prime Medica Ltd., Knutsford, UK, funded by Sanofi and Regeneron Pharmaceuticals, Inc. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication. * Corresponding author. Lipid Unit, Hospital Universitario Miguel Servet, Avda Isabel La Cat olica 1-3, 50009, Zaragoza, Spain. E-mail address: [email protected] Submitted June 8, 2016. Accepted for publication July 20, 2016.
1933-2874/Ó 2016 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2016.07.007
Statins or other lipid-lowering treatments do not usually modify them.2
Materials and methods A 50-year-old man was seen in our lipid clinic for management of severe hypercholesterolemia initially diagnosed at 19 years (low-density lipoprotein cholesterol [LDL-C] . 300 mg/dL without treatment). He received treatment with several different statins over the last 20 years, with the addition of ezetimibe over the last 5 years. He was diagnosed with type 2 diabetes in 2012 and is a former smoker. His physical examination on June 2, 2009, was normal except for large xanthelasmas of both inner eyelids and bilateral Achilles tendon xanthomas. LDLR gene sequencing analysis showed a splicing mutation of intron 16. A diagnosis of heterozygous familial hypercholesterolemia (HeFH) was made and the patient has since been on atorvastatin 80 mg/d and ezetimibe 10 mg/d.
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Journal of Clinical Lipidology, Vol 10, No 5, October 2016
He was enrolled in the ODYSSEY FH I clinical trial (NCT01623115), a randomized, double-blind, placebocontrolled clinical trial to evaluate efficacy and safety of alirocumab in patients with HeFH not adequately controlled with a maximally tolerated stable daily dose of statin.3,4 The study was approved by the ethical institutional review board of our institution. Informed consent was obtained for participation in the study and use of facial photographs for publication. This work has been carried out in accordance with the Declaration of Helsinki for experiments involving humans.
randomization, a picture of his xanthelasmas was taken (Figure 1A). The patient received alirocumab 75 mg (1-mL subcutaneous injection by prefilled pen) every 2 weeks (Q2W) for 78 weeks with 100% compliance and remained on atorvastatin and ezetimibe during the trial. After that period, he enrolled in an open-label extension to the study (NCT01954394) continuing with alirocumab 75-mg Q2W. The patient remained asymptomatic during the trials. After 9 more weeks of alirocumab therapy, a follow-up photograph illustrated dramatic reduction of his xanthelasmas (Figure 1B); his LDL-C value at this time was 23 mg/dL (TC 78 mg/dL; TG 115 mg/dL; and HDL-C 32 mg/dL). Twenty six weeks later, the xanthelasmas were no longer present (Figure 1C), and his LDL-C value was 47 mg/dL (TC 102 mg/dL; TG 110 mg/dL; and HDL-C 33 mg/dL).
Results Before randomization, the patient had a low-density lipoprotein cholesterol (LDL-C) level of 164 mg/dL; his other values were as follows: total cholesterol (TC) 224 mg/dL; triglycerides (TG) 155 mg/dL; and highdensity lipoprotein cholesterol (HDL-C) 29 mg/dL. At
Discussion This report illustrates the possibility for achievement of very low plasma levels of LDL-C with alirocumab in combination with high-dose statin and ezetimibe, with clinical evidence of reversal of physical findings associated with severe hypercholesterolemia. This suggests that ‘‘delipidation’’ of foam cells and regression of inflammatory lipid lesions may be occurring with treatment, at least in the visible manifestation of the disease we describe. Significant regression of xanthomas has been described after successful treatment of some secondary hypercholesterolemias as primary biliary cirrhosis5 and with lipoprotein-apheresis in homozygous FH.6 Regression of tendon xanthomas was described with probucol en HeFH7 and with intensive lipid-lowering treatment.8 However, xanthelasma regression was not previously reported with lipid-lowering drugs in HeFH.
Financial disclosure Dr Civeira received clinical research support to his institution from Sanofi for the conduct of the ODYSSEY FH I clinical trial; he has also received personal fees from Sanofi, Lilly, Synageva, Pfizer and Amgen outside of the submitted work; and grants and personal fees from Merck outside of the submitted work. Drs Perez-Calahorra and Mateo-Gallego report no conflicts of interest. All authors have approved the final article.
References Figure 1 Resolution of xanthelasmas with alirocumab treatment in a patient with heterozygous familial hypercholesterolemia. (A) Before treatment with alirocumab. (B) Dramatic reduction of xanthelasmas after 20 months of treatment with alirocumab 75 mg Q2W along with statin therapy and ezetimibe. (C) Complete visual resolution after just over 26 months of treatment.
1. Bergman R. Xanthelasmas palpebrarum and risk of atherosclerosis. Int J Dermatol. 1998;37:343–345. 2. Rohrich RJ, Janis JE, Pownell PH. Xanthelasmas palpebrarum: a review and current management principles. Plast Reconstr Surg. 2002;110: 1310–1314.
Civeira et al
Resolution of xanthelasmas with alirocumab
1261
3. Kastelein JJ, Robinson JG, Farnier M, et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies. Cardiovasc Drugs Ther. 2014;28:281–289. 4. Kastelein JJP, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36: 2996–3003. 5. Schmidt HH, Manns MP. Images in hepatology. Regression of xanthelasmas in a patient with primary biliary cirrhosis after liver transplantation. J Hepatol. 1998;28:1077.
6. Thompson GR, Kitano Y. The role of low density lipoprotein apheresis in the treatment of familial hypercholesterolemia. Ther Apher. 1997;1: 13–16. 7. Kajinami K, Nishitsuji M, Takeda Y, Shimizu M, Koizumi J, Mabuchi H. Long-term probucol treatment results in regression of xanthomas, but in progression of coronary atherosclerosis in a heterozygous patient with familial hypercholesterolemia. Atherosclerosis. 1996;120:181–187. 8. Lakey WC, Greyshock N, Guyton JR. Adverse reactions of Achilles tendon xanthomas in three hypercholesterolemic patients after treatment intensification with niacin and bile acid sequestrants. J Clin Lipidol. 2013; 7:178–181. Erratum in: J Clin Lipidol. 2013;7:384.
Rapid resolution of xanthelasmas after treatment with alirocumab Fernando Civeira, MD*, Sofia Perez-Calahorra, MSc, Rocio Mateo-Gallego, PhD Lipid Unit, Hospital Universitario Miguel Servet, IIS Aragon, Zaragoza, Spain KEYWORDS: Xanthelasmas; Hypercholesterolemia; Alirocumab; PCSK9; Treatment
Abstract: Xanthelasmas are superficial fat deposits around the eyelids commonly present in different hyperlipidemias and associated with increased cardiovascular risk. Statins or other lipid-lowering treatments do not usually modify them. We present the case of a middle-age man with severe high levels of LDL cholesterol from youth due to a genetically defined heterozygous familiar hypercholesterolemia (HeFH). He presented large xanthelasmas of both inner eyelids in spite of long term treatment with statins and ezetimibe that disappeared after treatment with alirocumab75 mg every 2 weeks for 26 months. His LDL cholesterol went from 164 mg/dL to 47 mg/dL with alirocumab. Xanthelasma regression was not previously reported with lipid-lowering drugs in HeFH. This case demonstrates that regression of skin lipid lesions can be achieved with very low LDL cholesterol concentrations. Ó 2016 National Lipid Association. All rights reserved.
Introduction Xanthelasmas are yellowish deposits of fat underneath the skin around the eyelids, frequently associated with severe hypercholesterolemia and increased risk for atherosclerosis,1 although can be also present with normal cholesterol concentration as an isolated clinical sign, probably as result of a local lipid disorder. Microscopically, they are composed of lipid-laden macrophages located in the superficial dermis, often with surrounding fibrosis and other inflammatory cells, similar to atherosclerotic lesions. The ODYSSEY FH I clinical trial was funded by Sanofi and Regeneron Pharmaceuticals. Editorial assistance for the preparation of this letter was provided by Prime Medica Ltd., Knutsford, UK, funded by Sanofi and Regeneron Pharmaceuticals, Inc. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication. * Corresponding author. Lipid Unit, Hospital Universitario Miguel Servet, Avda Isabel La Cat olica 1-3, 50009, Zaragoza, Spain. E-mail address: [email protected] Submitted June 8, 2016. Accepted for publication July 20, 2016.
1933-2874/Ó 2016 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2016.07.007
Statins or other lipid-lowering treatments do not usually modify them.2
Materials and methods A 50-year-old man was seen in our lipid clinic for management of severe hypercholesterolemia initially diagnosed at 19 years (low-density lipoprotein cholesterol [LDL-C] . 300 mg/dL without treatment). He received treatment with several different statins over the last 20 years, with the addition of ezetimibe over the last 5 years. He was diagnosed with type 2 diabetes in 2012 and is a former smoker. His physical examination on June 2, 2009, was normal except for large xanthelasmas of both inner eyelids and bilateral Achilles tendon xanthomas. LDLR gene sequencing analysis showed a splicing mutation of intron 16. A diagnosis of heterozygous familial hypercholesterolemia (HeFH) was made and the patient has since been on atorvastatin 80 mg/d and ezetimibe 10 mg/d.
1260
Journal of Clinical Lipidology, Vol 10, No 5, October 2016
He was enrolled in the ODYSSEY FH I clinical trial (NCT01623115), a randomized, double-blind, placebocontrolled clinical trial to evaluate efficacy and safety of alirocumab in patients with HeFH not adequately controlled with a maximally tolerated stable daily dose of statin.3,4 The study was approved by the ethical institutional review board of our institution. Informed consent was obtained for participation in the study and use of facial photographs for publication. This work has been carried out in accordance with the Declaration of Helsinki for experiments involving humans.
randomization, a picture of his xanthelasmas was taken (Figure 1A). The patient received alirocumab 75 mg (1-mL subcutaneous injection by prefilled pen) every 2 weeks (Q2W) for 78 weeks with 100% compliance and remained on atorvastatin and ezetimibe during the trial. After that period, he enrolled in an open-label extension to the study (NCT01954394) continuing with alirocumab 75-mg Q2W. The patient remained asymptomatic during the trials. After 9 more weeks of alirocumab therapy, a follow-up photograph illustrated dramatic reduction of his xanthelasmas (Figure 1B); his LDL-C value at this time was 23 mg/dL (TC 78 mg/dL; TG 115 mg/dL; and HDL-C 32 mg/dL). Twenty six weeks later, the xanthelasmas were no longer present (Figure 1C), and his LDL-C value was 47 mg/dL (TC 102 mg/dL; TG 110 mg/dL; and HDL-C 33 mg/dL).
Results Before randomization, the patient had a low-density lipoprotein cholesterol (LDL-C) level of 164 mg/dL; his other values were as follows: total cholesterol (TC) 224 mg/dL; triglycerides (TG) 155 mg/dL; and highdensity lipoprotein cholesterol (HDL-C) 29 mg/dL. At
Discussion This report illustrates the possibility for achievement of very low plasma levels of LDL-C with alirocumab in combination with high-dose statin and ezetimibe, with clinical evidence of reversal of physical findings associated with severe hypercholesterolemia. This suggests that ‘‘delipidation’’ of foam cells and regression of inflammatory lipid lesions may be occurring with treatment, at least in the visible manifestation of the disease we describe. Significant regression of xanthomas has been described after successful treatment of some secondary hypercholesterolemias as primary biliary cirrhosis5 and with lipoprotein-apheresis in homozygous FH.6 Regression of tendon xanthomas was described with probucol en HeFH7 and with intensive lipid-lowering treatment.8 However, xanthelasma regression was not previously reported with lipid-lowering drugs in HeFH.
Financial disclosure Dr Civeira received clinical research support to his institution from Sanofi for the conduct of the ODYSSEY FH I clinical trial; he has also received personal fees from Sanofi, Lilly, Synageva, Pfizer and Amgen outside of the submitted work; and grants and personal fees from Merck outside of the submitted work. Drs Perez-Calahorra and Mateo-Gallego report no conflicts of interest. All authors have approved the final article.
References Figure 1 Resolution of xanthelasmas with alirocumab treatment in a patient with heterozygous familial hypercholesterolemia. (A) Before treatment with alirocumab. (B) Dramatic reduction of xanthelasmas after 20 months of treatment with alirocumab 75 mg Q2W along with statin therapy and ezetimibe. (C) Complete visual resolution after just over 26 months of treatment.
1. Bergman R. Xanthelasmas palpebrarum and risk of atherosclerosis. Int J Dermatol. 1998;37:343–345. 2. Rohrich RJ, Janis JE, Pownell PH. Xanthelasmas palpebrarum: a review and current management principles. Plast Reconstr Surg. 2002;110: 1310–1314.
Civeira et al
Resolution of xanthelasmas with alirocumab
1261
3. Kastelein JJ, Robinson JG, Farnier M, et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies. Cardiovasc Drugs Ther. 2014;28:281–289. 4. Kastelein JJP, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36: 2996–3003. 5. Schmidt HH, Manns MP. Images in hepatology. Regression of xanthelasmas in a patient with primary biliary cirrhosis after liver transplantation. J Hepatol. 1998;28:1077.
6. Thompson GR, Kitano Y. The role of low density lipoprotein apheresis in the treatment of familial hypercholesterolemia. Ther Apher. 1997;1: 13–16. 7. Kajinami K, Nishitsuji M, Takeda Y, Shimizu M, Koizumi J, Mabuchi H. Long-term probucol treatment results in regression of xanthomas, but in progression of coronary atherosclerosis in a heterozygous patient with familial hypercholesterolemia. Atherosclerosis. 1996;120:181–187. 8. Lakey WC, Greyshock N, Guyton JR. Adverse reactions of Achilles tendon xanthomas in three hypercholesterolemic patients after treatment intensification with niacin and bile acid sequestrants. J Clin Lipidol. 2013; 7:178–181. Erratum in: J Clin Lipidol. 2013;7:384.