JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 67, NO. 4, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
Letters Statin Initiation During Childhood in Patients With Familial Hypercholesterolemia
information on CVD events. Detailed information on medical history and other cardiovascular risk factors was available from 194 young adult FH subjects. Lipid-lowering therapy was still used by 163 (84.0%) subjects, and mean treatment duration was 10.1 1.2 years (5). With respect to risk factors, 1 patient had developed diabetes, and 1 was treated for hyperten-
Consequences for Cardiovascular Risk
sion. Furthermore, 54 (27.8%) stated that they were current smokers.
Familial hypercholesterolemia (FH), a hereditary disorder of lipoprotein metabolism, results in lifelong increased cholesterol levels and predisposes to premature cardiovascular disease (CVD) (1). To prevent premature CVD in adult life, guidelines advocate initiation of statins in childhood (2). Since the introduction of statins in 1988, this treatment has proven highly effective in lowering low-density lipoprotein cholesterol levels for CVD prevention (3).
To determine the consequences of statins for the natural history of FH, we subsequently evaluated data of their affected parents in the first 30 years of their lives. The children originated from 156 different families, with 92 (59.0%) affected FH fathers and 64 (41.0%) affected FH mothers. Of these, 14 parents were already deceased. The mean age of the 142 remaining parents was 53.9 (6.4) years. On the basis of the assumption that statins were introduced in
Until now, no randomized or controlled data exist with regard to the primary prevention of CVD in FH
F I G U R E 1 Kaplan-Meier Curve of CVD-Free Survival
patients, because it was considered unethical to 100
withhold therapy. However, the natural history of the Cumulative Risk of CVD Event (%)
disease in the untreated parents can be compared with the history of their long-term treated FH children, at least until the age that the children reached at the end of follow-up. In this present study, we evaluated the consequences for cardiovascular outcomes of at least 10 years of statin treatment in young adults with FH and compared these outcomes in their affected parents for whom statins were available much later in life. In a long-term follow-up study, we determined the
95
90
85
80 FH children FH parents
incidence of cardiovascular events and mortality in FH patients who initiated statin therapy during childhood. Subjects were children with FH, random-
0
ized between 1997 and 1999 into a 2-year, doubleblind and placebo-controlled trial, evaluating pravastatin (4). After the trial, all children received pravastatin and were eligible for the current study after at least 10 years of follow-up. From the original
10
20
30
Age (Years) No. at risk FH children
214
214
193
3
FH parents
156
156
156
146
cohort of 214 FH children, 1 boy died after a traffic accident at the age of 15 years. Mean age (SD) of the remaining 213 now young adults was 24.0 3.2 years
Cumulative risk of cardiovascular disease (CVD) events in 213 young adults patients with familial hypercholesterolemia (FH) who started statin therapy in childhood (orange) and their 156
(range 18 to 30 years), and 100 (46.9%) were male.
affected FH parents (blue) for whom statins were available much
Statin therapy was initiated at a mean age of 14.0
later in life.
3.1 years. We contacted all 213 young adults to gain
456
JACC VOL. 67, NO. 4, 2016
Letters
FEBRUARY 2, 2016:455–61
1988, statin therapy was available for 43 (30.3%) of all FH parents before they were 30 years of age. For the remaining 99 (69.7%) parents, statins could have been initiated at the earliest after the age of 30 years. In the group of affected parents, 64 (41.6%) had a cardiovascular event during follow-up, mostly a myocardial infarction (n ¼ 43; 67.2%). At the age of 30 years, the cumulative CVD survival in the parental FH group was near 90% (Figure 1). None of the mothers had died before the age of 30, whereas the cumulative incidence of death due to CVD of the fathers was almost 5%. The youngest parent with a myocardial infarction was 20 years old and deceased from the consequences at the age of 23 years. Our findings that FH parents experiencing cardiovascular events at a younger age than those FH children treated from childhood onwards are in line with the results of Kusters et al. (5). They found in the same study population that long-term statin treat-
Achievement Award of the Dutch Heart Foundation (2010T082). Dr. Kastelein is a consultant to and receives honoraria from AstraZeneca, Eli Lilly and Company, Amgen, Sanofi, Regeneron, Genzyme, Isis, Aegerion, and KOWA. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Hutten and Wiegman are joint senior authors.
REFERENCES 1. Goldstein JL, Hobbs HH, Brown MS. PART 12: LIPIDS chapter 120: familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. 8th edition. New York, NY: McGraw-Hill Professional, 2001:2863–913. 2. Wiegman A, Gidding SS, Watts GF, et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 2015;36:2425–37. 3. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterollowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78. 4. Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA 2004;292:331–7. 5. Kusters DM, Avis HJ, de Groot E, et al. Ten-year follow-up after initiation of statin therapy in children with familial hypercholesterolemia. JAMA 2014;312: 1055–7.
ment initiated during childhood was associated with normalization of carotid intima–media thickness (IMT) progression in FH subjects. Furthermore, earlier initiation of statin therapy was associated with thinner carotid IMT at follow-up. Because carotid IMT is an established marker of early atherosclerosis, these results support the pivotal role of statins in the inhibition of the development of early atherosclerotic lesions in FH children. Altogether, our results suggest that initiation of statin therapy in childhood may be effective in the
Association of Hemoglobin A1c Levels With Cardiovascular Disease and Mortality in Chinese Patients With Diabetes
prevention of very premature CVD and cardiovascular mortality. These findings underline the importance of early diagnosis and treatment of FH patients that should include initiation of statin treatment as well as modulation of other major CVD risk factors, particularly smoking.
Among diabetic patients, hemoglobin A1c (HbA1c) is an important indicator of glycemic control and, together with blood pressure and cholesterol, is an indicator for risk of complications, including cardiovascular disease (CVD) and mortality. At present,
*Marjet J.A.M. Braamskamp, MD, PhD John J.P. Kastelein, MD, PhD D. Meeike Kusters, MD Barbara A. Hutten, MD, PhD Albert Wiegman, MD, PhD
there is no universal consensus on the optimal HbA1c
*Department of Vascular Medicine and
and CVD incidence and all-cause mortality, but
Department of Pediatrics
such a relationship has not yet been confirmed in a
level. Despite this, most international guidelines include a recommended HbA1c target range or level as a treatment goal. Several studies have identified a J-shaped curvilinear relationship between HbA1c
Academic Medical Center
Chinese population (1). There are substantial dif-
Meibergdreef 9, Room F4-136
ferences in disease risks across racial and ethnic
Amsterdam 1105 AZ
groups due to genetic and environmental factors
the Netherlands
including life-style and health behaviors, and thus,
E-mail: [email protected]
previous results from Western studies may not be
http://dx.doi.org/10.1016/j.jacc.2015.11.021
transferable to a Chinese population (2). We sought
Please note: The current study is supported by a grant from the Dutch Heart Foundation (2009B059). The Dutch Heart Foundation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Dr. Kastelein is a recipient of the Lifetime
to examine the association among mean HbA1c, CVD events, and mortality among Chinese primary care patients with type 2 diabetes mellitus (T2DM) in Hong Kong.
VOL. 67, NO. 4, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
Letters Statin Initiation During Childhood in Patients With Familial Hypercholesterolemia
information on CVD events. Detailed information on medical history and other cardiovascular risk factors was available from 194 young adult FH subjects. Lipid-lowering therapy was still used by 163 (84.0%) subjects, and mean treatment duration was 10.1 1.2 years (5). With respect to risk factors, 1 patient had developed diabetes, and 1 was treated for hyperten-
Consequences for Cardiovascular Risk
sion. Furthermore, 54 (27.8%) stated that they were current smokers.
Familial hypercholesterolemia (FH), a hereditary disorder of lipoprotein metabolism, results in lifelong increased cholesterol levels and predisposes to premature cardiovascular disease (CVD) (1). To prevent premature CVD in adult life, guidelines advocate initiation of statins in childhood (2). Since the introduction of statins in 1988, this treatment has proven highly effective in lowering low-density lipoprotein cholesterol levels for CVD prevention (3).
To determine the consequences of statins for the natural history of FH, we subsequently evaluated data of their affected parents in the first 30 years of their lives. The children originated from 156 different families, with 92 (59.0%) affected FH fathers and 64 (41.0%) affected FH mothers. Of these, 14 parents were already deceased. The mean age of the 142 remaining parents was 53.9 (6.4) years. On the basis of the assumption that statins were introduced in
Until now, no randomized or controlled data exist with regard to the primary prevention of CVD in FH
F I G U R E 1 Kaplan-Meier Curve of CVD-Free Survival
patients, because it was considered unethical to 100
withhold therapy. However, the natural history of the Cumulative Risk of CVD Event (%)
disease in the untreated parents can be compared with the history of their long-term treated FH children, at least until the age that the children reached at the end of follow-up. In this present study, we evaluated the consequences for cardiovascular outcomes of at least 10 years of statin treatment in young adults with FH and compared these outcomes in their affected parents for whom statins were available much later in life. In a long-term follow-up study, we determined the
95
90
85
80 FH children FH parents
incidence of cardiovascular events and mortality in FH patients who initiated statin therapy during childhood. Subjects were children with FH, random-
0
ized between 1997 and 1999 into a 2-year, doubleblind and placebo-controlled trial, evaluating pravastatin (4). After the trial, all children received pravastatin and were eligible for the current study after at least 10 years of follow-up. From the original
10
20
30
Age (Years) No. at risk FH children
214
214
193
3
FH parents
156
156
156
146
cohort of 214 FH children, 1 boy died after a traffic accident at the age of 15 years. Mean age (SD) of the remaining 213 now young adults was 24.0 3.2 years
Cumulative risk of cardiovascular disease (CVD) events in 213 young adults patients with familial hypercholesterolemia (FH) who started statin therapy in childhood (orange) and their 156
(range 18 to 30 years), and 100 (46.9%) were male.
affected FH parents (blue) for whom statins were available much
Statin therapy was initiated at a mean age of 14.0
later in life.
3.1 years. We contacted all 213 young adults to gain
456
JACC VOL. 67, NO. 4, 2016
Letters
FEBRUARY 2, 2016:455–61
1988, statin therapy was available for 43 (30.3%) of all FH parents before they were 30 years of age. For the remaining 99 (69.7%) parents, statins could have been initiated at the earliest after the age of 30 years. In the group of affected parents, 64 (41.6%) had a cardiovascular event during follow-up, mostly a myocardial infarction (n ¼ 43; 67.2%). At the age of 30 years, the cumulative CVD survival in the parental FH group was near 90% (Figure 1). None of the mothers had died before the age of 30, whereas the cumulative incidence of death due to CVD of the fathers was almost 5%. The youngest parent with a myocardial infarction was 20 years old and deceased from the consequences at the age of 23 years. Our findings that FH parents experiencing cardiovascular events at a younger age than those FH children treated from childhood onwards are in line with the results of Kusters et al. (5). They found in the same study population that long-term statin treat-
Achievement Award of the Dutch Heart Foundation (2010T082). Dr. Kastelein is a consultant to and receives honoraria from AstraZeneca, Eli Lilly and Company, Amgen, Sanofi, Regeneron, Genzyme, Isis, Aegerion, and KOWA. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Hutten and Wiegman are joint senior authors.
REFERENCES 1. Goldstein JL, Hobbs HH, Brown MS. PART 12: LIPIDS chapter 120: familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. 8th edition. New York, NY: McGraw-Hill Professional, 2001:2863–913. 2. Wiegman A, Gidding SS, Watts GF, et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 2015;36:2425–37. 3. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterollowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78. 4. Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA 2004;292:331–7. 5. Kusters DM, Avis HJ, de Groot E, et al. Ten-year follow-up after initiation of statin therapy in children with familial hypercholesterolemia. JAMA 2014;312: 1055–7.
ment initiated during childhood was associated with normalization of carotid intima–media thickness (IMT) progression in FH subjects. Furthermore, earlier initiation of statin therapy was associated with thinner carotid IMT at follow-up. Because carotid IMT is an established marker of early atherosclerosis, these results support the pivotal role of statins in the inhibition of the development of early atherosclerotic lesions in FH children. Altogether, our results suggest that initiation of statin therapy in childhood may be effective in the
Association of Hemoglobin A1c Levels With Cardiovascular Disease and Mortality in Chinese Patients With Diabetes
prevention of very premature CVD and cardiovascular mortality. These findings underline the importance of early diagnosis and treatment of FH patients that should include initiation of statin treatment as well as modulation of other major CVD risk factors, particularly smoking.
Among diabetic patients, hemoglobin A1c (HbA1c) is an important indicator of glycemic control and, together with blood pressure and cholesterol, is an indicator for risk of complications, including cardiovascular disease (CVD) and mortality. At present,
*Marjet J.A.M. Braamskamp, MD, PhD John J.P. Kastelein, MD, PhD D. Meeike Kusters, MD Barbara A. Hutten, MD, PhD Albert Wiegman, MD, PhD
there is no universal consensus on the optimal HbA1c
*Department of Vascular Medicine and
and CVD incidence and all-cause mortality, but
Department of Pediatrics
such a relationship has not yet been confirmed in a
level. Despite this, most international guidelines include a recommended HbA1c target range or level as a treatment goal. Several studies have identified a J-shaped curvilinear relationship between HbA1c
Academic Medical Center
Chinese population (1). There are substantial dif-
Meibergdreef 9, Room F4-136
ferences in disease risks across racial and ethnic
Amsterdam 1105 AZ
groups due to genetic and environmental factors
the Netherlands
including life-style and health behaviors, and thus,
E-mail: [email protected]
previous results from Western studies may not be
http://dx.doi.org/10.1016/j.jacc.2015.11.021
transferable to a Chinese population (2). We sought
Please note: The current study is supported by a grant from the Dutch Heart Foundation (2009B059). The Dutch Heart Foundation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Dr. Kastelein is a recipient of the Lifetime
to examine the association among mean HbA1c, CVD events, and mortality among Chinese primary care patients with type 2 diabetes mellitus (T2DM) in Hong Kong.
