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
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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.