The Journal of Nutrition. First published ahead of print June 4, 2014 as doi: 10.3945/jn.114.191775. The Journal of Nutrition Nutrition and Disease
Serum Lipid Responses to Weight Loss Differ between Overweight Adults with Familial Hypercholesterolemia and Those with Familial Combined Hyperlipidemia1–3 Roc´ıo Mateo-Gallego,4* Sof´ıa Perez-Calahorra,4 Montserrat Cofan, ´ 5,6 Luc´ıa Baila-Rueda,4 Ana Cenarro,4 5,6 7 4 Emilio Ros, Jos´e Puzo, and Fernando Civeira 4
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Unidad de L´ıpidos and Laboratorio de Investigacion ´ Molecular, Hospital Universitario Miguel Servet, Instituto Aragon´es de Ciencias de la Salud, Zaragoza, Spain; 5Lipid Clinic, Endocrinology and Nutrition Service, Institut dÕInvestigacions Biome`diques August Pi Sunyer, Hospital Cl´ınic, Barcelona, Spain; 6CIBER Fisiopatolog´ıa de la Obesidad y Nutricion, ´ Instituto de Salud Carlos III, Madrid, Spain; and 7 Unidad de L´ıpidos, Bioqu´ımica Cl´ınica, Hospital San Jorge, Huesca, Spain
Abstract The effect of weight loss on lipids differs among individuals, although whether it can modify the management of hereditary hyperlipidemias has not yet been explored. The objective of this study was to examine the effect of weight loss on cholesterol metabolism, assessed by circulating noncholesterol sterols, in overweight adults with familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCHL). We conducted a 6-mo weight loss intervention in untreated individuals (FH: n = 28; FCHL: n = 50) with a body mass index of >25 kg/m2 and mean age of 46.9 6 11.3 y, of whom 53.8% were men. A hypocaloric diet was implemented and serum lipid analyses, including noncholesterol sterols, were assessed. Global significant mean weight losses of 5.7 kg (26.6%) and 6.6 kg (27.6%) were achieved after 3 and 6 mo, respectively. Mean non-HDL cholesterol and triglyceride (TG) changes at 3 and 6 mo compared with baseline were 25.8% (P = 0.004) and 27.1% (P = 0.014), and 230.1% (P < 0.001) and 231.4% (P < 0.001), respectively. Among participants who lost >5% weight, only significant changes in TGs and non-HDL cholesterol were observed in FCHL participants. Sterol precursors of cholesterol synthesis decreased significantly by 10.4% at 6 mo in FCHL participants, mostly because of a 23.9% lathosterol reduction. Baseline synthesis precursors were associated with TG reduction in FCHL participants (P = 0.039; R2 = 0.20), and intestinally derived sterols were inversely associated with non-HDL cholesterol changes in FH participants (P = 0.036; R2 = 0.21). Thus, FCHL participants had better lipid-lowering response to weight loss than FH participants. This response was positively associated with baseline cholesterol synthesis, which was reduced by weight loss. Our results confirm the cholesterol overproduction mechanism of FCHL and its interaction with fat mass, while also supporting the differential management of familial hyperlipidemias if obesity coexists. This trial was registered at clinicaltrials.gov as NCT01995149. J. Nutr. doi: 10.3945/jn.114.191775.
Introduction Hereditary hypercholesterolemias are a heterogeneous group of lipid disorders that are usually associated with high cardiovascular risk (1–3). Among them, familial combined hyperlipidemia (FCHL)8 and different familial forms of severe isolated hypercholesterolemia, generically referred to as familial hypercholes1 Supported by grants from the Spanish Ministry of Health (FIS PI12/01087) and ´ RETIC (RIC RD12/0042/0055). CIBER Fisiopatolog´ıa de la Obesidad y Nutricion (CIBERobn) is an initiative of the Instituto de Salud Carlos III, Spain. 2 Author disclosures: R. Mateo-Gallego, S. Perez-Calahorra, M. Cof´an, L. Baila-Rueda, A. Cenarro, E. Ros, J. Puzo, and F. Civeira, no conflicts of interest. 3 Supplemental Tables 1 and 2 are available from the ‘‘Online Supporting Material’’ link in the online posting of the article and from the same link in the online table of contents at http://jn.nutrition.org. 8 Abbreviations used: CRP, C-reactive protein; FCHL, familial combined hyperlipidemia; FH, familial hypercholesterolemia; TC, total cholesterol. * To whom correspondence should be addressed. E-mail: rmateo.iacs@aragon. es.
terolemia (FH), confer the highest vascular risk (2,4,5). FCHL is a complex genetic disease with an important interaction with environmental factors, particularly overweight, obesity, and insulin resistance, with variable penetrance and phenotype among affected individuals (6,7). FHs are monogenic diseases caused by mutations in the gene coding for the LDL receptor; its apo ligand within the LDL particle, apoB; or proprotein convertase subtilisin/kexin type 9, a serine protease involved in the recycling control of the LDL receptor. In contrast with FCHL, the penetrance in genetically confirmed FH is almost 100% (8). However, because as many as 25% of heterozygous FH patients present a combined hyperlipidemia phenotype (9), there is a large clinical presentation overlapping between hereditary hypercholesterolemias (10). Obesity in and of itself is a risk factor for cardiovascular disease but is also an important factor in hyperlipidemias that
ã 2014 American Society for Nutrition. Manuscript received February 7, 2014. Initial review completed March 19, 2014. Revision accepted May 7, 2014. doi: 10.3945/jn.114.191775.
Copyright (C) 2014 by the American Society for Nutrition
1 of 8
Participants and Methods Study population. From June 2010 to September 2012, consecutive patients aged $18 y with the diagnosis of FCHL and FH attending 2 lipid clinics in northern Spain were recruited to participate in a weight loss trial. FH was diagnosed in individuals with off-treatment serum LDL cholesterol concentrations above the age- and sex-specific 95th percentiles of a Spanish reference population (19), serum TGs 25 kg/m2, steady weight (63 kg in the last 3 mo), and absence of lipid-lowering drugs including plant sterol/stanol supplements in the previous 5 wk. Patients with alcohol consumption >30 g/d, uncontrolled type 2 diabetes (glycated hemoglobin >8%), or any other disease that could interfere with the ability to comply with the study protocol were excluded. Individuals with prior cardiovascular disease, very high risk as defined by the presence of $2 major risk factors, or TC $350 mg/dL were excluded because hypolipidemic drug treatment was considered indispensable. The pro2 of 8
Mateo-Gallego et al.
tocol was approved by the ethical committee of our institution (Comit´e de Investigacion ´ Cl´ınica de Aragon) ´ and complied with the Helsinki Declaration as revised in 1986. All participants provided written informed consent. Dietary intervention. The weight loss intervention had a total duration of 6 mo. Each participantÕs caloric prescription represented a deficit of 600 kcal/d as calculated from energy intakes estimated by multiplying the activity factor by resting energy expenditure calculated by the HarrisBenedict equation. In general, prescribed energy intake was between 1200 kcal and 1600 kcal/d. Dietary composition consisted of 50–55% carbohydrates, 15–20% protein, and 30% fat (#7% saturated fat and
Serum Lipid Responses to Weight Loss Differ between Overweight Adults with Familial Hypercholesterolemia and Those with Familial Combined Hyperlipidemia1–3 Roc´ıo Mateo-Gallego,4* Sof´ıa Perez-Calahorra,4 Montserrat Cofan, ´ 5,6 Luc´ıa Baila-Rueda,4 Ana Cenarro,4 5,6 7 4 Emilio Ros, Jos´e Puzo, and Fernando Civeira 4
Downloaded from jn.nutrition.org at WEST VIRGINIA UNIVERSITY on June 25, 2014
Unidad de L´ıpidos and Laboratorio de Investigacion ´ Molecular, Hospital Universitario Miguel Servet, Instituto Aragon´es de Ciencias de la Salud, Zaragoza, Spain; 5Lipid Clinic, Endocrinology and Nutrition Service, Institut dÕInvestigacions Biome`diques August Pi Sunyer, Hospital Cl´ınic, Barcelona, Spain; 6CIBER Fisiopatolog´ıa de la Obesidad y Nutricion, ´ Instituto de Salud Carlos III, Madrid, Spain; and 7 Unidad de L´ıpidos, Bioqu´ımica Cl´ınica, Hospital San Jorge, Huesca, Spain
Abstract The effect of weight loss on lipids differs among individuals, although whether it can modify the management of hereditary hyperlipidemias has not yet been explored. The objective of this study was to examine the effect of weight loss on cholesterol metabolism, assessed by circulating noncholesterol sterols, in overweight adults with familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCHL). We conducted a 6-mo weight loss intervention in untreated individuals (FH: n = 28; FCHL: n = 50) with a body mass index of >25 kg/m2 and mean age of 46.9 6 11.3 y, of whom 53.8% were men. A hypocaloric diet was implemented and serum lipid analyses, including noncholesterol sterols, were assessed. Global significant mean weight losses of 5.7 kg (26.6%) and 6.6 kg (27.6%) were achieved after 3 and 6 mo, respectively. Mean non-HDL cholesterol and triglyceride (TG) changes at 3 and 6 mo compared with baseline were 25.8% (P = 0.004) and 27.1% (P = 0.014), and 230.1% (P < 0.001) and 231.4% (P < 0.001), respectively. Among participants who lost >5% weight, only significant changes in TGs and non-HDL cholesterol were observed in FCHL participants. Sterol precursors of cholesterol synthesis decreased significantly by 10.4% at 6 mo in FCHL participants, mostly because of a 23.9% lathosterol reduction. Baseline synthesis precursors were associated with TG reduction in FCHL participants (P = 0.039; R2 = 0.20), and intestinally derived sterols were inversely associated with non-HDL cholesterol changes in FH participants (P = 0.036; R2 = 0.21). Thus, FCHL participants had better lipid-lowering response to weight loss than FH participants. This response was positively associated with baseline cholesterol synthesis, which was reduced by weight loss. Our results confirm the cholesterol overproduction mechanism of FCHL and its interaction with fat mass, while also supporting the differential management of familial hyperlipidemias if obesity coexists. This trial was registered at clinicaltrials.gov as NCT01995149. J. Nutr. doi: 10.3945/jn.114.191775.
Introduction Hereditary hypercholesterolemias are a heterogeneous group of lipid disorders that are usually associated with high cardiovascular risk (1–3). Among them, familial combined hyperlipidemia (FCHL)8 and different familial forms of severe isolated hypercholesterolemia, generically referred to as familial hypercholes1 Supported by grants from the Spanish Ministry of Health (FIS PI12/01087) and ´ RETIC (RIC RD12/0042/0055). CIBER Fisiopatolog´ıa de la Obesidad y Nutricion (CIBERobn) is an initiative of the Instituto de Salud Carlos III, Spain. 2 Author disclosures: R. Mateo-Gallego, S. Perez-Calahorra, M. Cof´an, L. Baila-Rueda, A. Cenarro, E. Ros, J. Puzo, and F. Civeira, no conflicts of interest. 3 Supplemental Tables 1 and 2 are available from the ‘‘Online Supporting Material’’ link in the online posting of the article and from the same link in the online table of contents at http://jn.nutrition.org. 8 Abbreviations used: CRP, C-reactive protein; FCHL, familial combined hyperlipidemia; FH, familial hypercholesterolemia; TC, total cholesterol. * To whom correspondence should be addressed. E-mail: rmateo.iacs@aragon. es.
terolemia (FH), confer the highest vascular risk (2,4,5). FCHL is a complex genetic disease with an important interaction with environmental factors, particularly overweight, obesity, and insulin resistance, with variable penetrance and phenotype among affected individuals (6,7). FHs are monogenic diseases caused by mutations in the gene coding for the LDL receptor; its apo ligand within the LDL particle, apoB; or proprotein convertase subtilisin/kexin type 9, a serine protease involved in the recycling control of the LDL receptor. In contrast with FCHL, the penetrance in genetically confirmed FH is almost 100% (8). However, because as many as 25% of heterozygous FH patients present a combined hyperlipidemia phenotype (9), there is a large clinical presentation overlapping between hereditary hypercholesterolemias (10). Obesity in and of itself is a risk factor for cardiovascular disease but is also an important factor in hyperlipidemias that
ã 2014 American Society for Nutrition. Manuscript received February 7, 2014. Initial review completed March 19, 2014. Revision accepted May 7, 2014. doi: 10.3945/jn.114.191775.
Copyright (C) 2014 by the American Society for Nutrition
1 of 8
Participants and Methods Study population. From June 2010 to September 2012, consecutive patients aged $18 y with the diagnosis of FCHL and FH attending 2 lipid clinics in northern Spain were recruited to participate in a weight loss trial. FH was diagnosed in individuals with off-treatment serum LDL cholesterol concentrations above the age- and sex-specific 95th percentiles of a Spanish reference population (19), serum TGs 25 kg/m2, steady weight (63 kg in the last 3 mo), and absence of lipid-lowering drugs including plant sterol/stanol supplements in the previous 5 wk. Patients with alcohol consumption >30 g/d, uncontrolled type 2 diabetes (glycated hemoglobin >8%), or any other disease that could interfere with the ability to comply with the study protocol were excluded. Individuals with prior cardiovascular disease, very high risk as defined by the presence of $2 major risk factors, or TC $350 mg/dL were excluded because hypolipidemic drug treatment was considered indispensable. The pro2 of 8
Mateo-Gallego et al.
tocol was approved by the ethical committee of our institution (Comit´e de Investigacion ´ Cl´ınica de Aragon) ´ and complied with the Helsinki Declaration as revised in 1986. All participants provided written informed consent. Dietary intervention. The weight loss intervention had a total duration of 6 mo. Each participantÕs caloric prescription represented a deficit of 600 kcal/d as calculated from energy intakes estimated by multiplying the activity factor by resting energy expenditure calculated by the HarrisBenedict equation. In general, prescribed energy intake was between 1200 kcal and 1600 kcal/d. Dietary composition consisted of 50–55% carbohydrates, 15–20% protein, and 30% fat (#7% saturated fat and
