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n e w e ng l a n d j o u r na l
of
m e dic i n e
Original Article
A BS T R AC T
BACKGROUND
From the Department of Medicine (G.T.,
A.L., D.B.-A.S., A.S.) and the Dr. Pinchas
Bornstein Talpiot Medical Leadership
Program (G.T., G.Y.), Sheba Medical Center, Tel Hashomer, the Israel Defense
Forces Medical Corps (G.T., G.Y., A.L.,
E.D., D.T.), Sackler School of Medicine,
Tel Aviv University, Tel Aviv (G.T., A.L.,
E.D., D.B.-A.S., A.A., A.S.), and Hebrew
UniversityHadassah School of Public
Health and Community Medicine (H.L.,
J.D.K.) and the Israel Ministry of Health
(N.G., A.A., Z.H.), Jerusalem all in Israel; and the Department of Medicine,
Mount Auburn Hospital, Harvard Medical School, Cambridge, MA (A.L.). Address reprint requests to Dr. Twig at the
Department of Medicine B, Sheba Medical Center, Tel Hashomer, Ramat Gan
52621, Israel, or at gilad.t wig@gmail.com.
This article was published on April 13,
2016, at NEJM.org.
N Engl J Med 2016;374:2430-40.
DOI: 10.1056/NEJMoa1503840
Copyright 2016 Massachusetts Medical Society.
In light of the worldwide increase in childhood obesity, we examined the association between body-mass index (BMI) in late adolescence and death from cardiovascular causes in adulthood.
METHODS
We grouped data on BMI, as measured from 1967 through 2010 in 2.3 million
Israeli adolescents (mean age, 17.30.4 years), according to age- and sex-specific
percentiles from the U.S. Centers for Disease Control and Prevention. Primary outcomes were the number of deaths attributed to coronary heart disease, stroke, sudden death from an unknown cause, or a combination of all three categories (total
cardiovascular causes) by mid-2011. Cox proportional-hazards models were used.
RESULTS
A BMI in the 50th to 74th percentiles, within the accepted normal range, during
adolescence was associated with increased cardiovascular and all-cause mortality
during 40 years of follow-up. Overweight and obesity were strongly associated with
increased cardiovascular mortality in adulthood. (Funded by the Environment and
Health Fund.)
2430
verweight and obesity in adolescents have increased substantially in recent decades and affect a third of the
adolescent population in some developed countries.1 Obesity early in life is considered to be a
risk factor for death from cardiovascular disease
and from all causes in adulthood,2-5 although not
all investigators concur6; such obesity may limit
the increase in life expectancy that otherwise
would be achieved.7,8 Despite progress in prevention and treatment of cardiovascular disease,
cardiovascular mortality among young adults
either has not declined or the decline has slowed
over recent decades in several developed countries coincident with the obesity epidemic.9,10
Some,2,3,11 although not all,12 studies suggest that
a body-mass index (BMI, the weight in kilograms
divided by the square of the height in meters)
that falls within the upper-normal range in adolescence is associated with an increased risk of
death from cardiovascular causes, although a
determination of the BMI threshold that is associated with such an increased risk of remains
uncertain. Thus, our main objective was to assess the risk of fatal cardiovascular events in
adulthood according to the BMI range during
adolescence. We also estimated the predicted
proportion of cardiovascular deaths that could
be attributed to the increasing prevalence of
overweight and obesity among adolescents.
Our study was based on a national database
of 2.3 million Israeli adolescents in whom height
and weight were measured between 1967 and
2010. We assessed the association between the
BMI in late adolescence and death from coronary heart disease, stroke, and sudden death in
adulthood.
2431
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
16.8 (16.317.1)
26
Ethiopia
28
1
31
25
25
12
24
80
162.16.0
173.46.7
19.2121.00
19.7221.41
20.1 (19.720.6)
20.6 (20.221.0)
353,265 (59)
17.30.4
25th to 49th
(N=600,966)
<1
32
25
23
13
24
82
161.86.0
173.66.8
21.0123.51
21.4223.62
22.1 (21.522.8)
22.4 (21.923.0)
320,517 (56)
17.30.4
50th to 74th
(N=577,331)
<1
33
25
22
14
24
83
161.86.1
173.86.8
23.5225.33
23.6325.12
24.2 (23.924.8)
24.3 (23.924.7)
116,233 (54)
17.30.4
75th to 84th
(N=216,086)
BMI Percentile
<1
32
25
22
14
25
82
161.86.2
174.06.9
25.3429.81
25.1328.43
26.8 (26.027.9)
26.4 (25.727.3)
108,820 (56)
17.30.4
85th to 94th
(N=194,972)
<1
30
26
21
16
27
81
162.36.4
174.17.3
29.8247.32
28.4447.54
32.0 (30.834.1)
30.8 (29.432.9)
59,520 (69)
17.30.4
95th
(N=86,061)
31
24
25
13
24
80
162.16.1
173.56.9
12.5547.32
12.1147.54
21.1 (19.423.2)
21.1 (19.423.1)
1,370,020 (60)
17.30.4
All Percentiles
(N=2,298,130)
* Plusminus values are means SD. The BMI is the weight in kilograms divided by the square of the height in meters. IQR denotes interquartile range, and USSR Union of Soviet
Socialist Republics.
Listed are the BMI ranges of the participants at a mean age of 17.3 years. For each of the 48 months between the ages of 16.0 years and 19.99 years, there is a different age- and sexspecific BMI range that determines the percentile of BMI, as measured by the U.S. Centers for Disease Control and Prevention (a total of 96 in this study).
25
Europe
24
28
32
22
Asia
12
North Africa
12
Israel
25
Former USSR
78
162.56.1
163.26.5
75
173.36.8
Women
Men
17.3219.20
17.8519.71
18.4 (18.018.9)
18.9 (18.519.4)
302,527 (64)
17.40.5
5th to 24th
(N=472,226)
173.17.1
12.5517.31
Women
Height cm
12.1117.84
Men
BMI range
17.2 (16.717.6)
Men
109,138 (73)
17.40.5
<5th
(N=150,488)
Women
Age yr
Variable
Table 1. Characteristics of the Participants at Baseline, According to Percentile of Body-Mass Index (BMI).*
2433
2434
No. of deaths
Noncardiovascular causes
2059
0.637
6147
0.591
44.610.2
44.210.4
530
496 (94)
177
0.206
168 (95)
No. of deaths
0.266
177 (96)
40.410.5
70 (95)
41.410.4
7574
0.567
45.19.9
586 (90)
652
0.186
41.410.9
197 (92)
214
7193
0.675
46.29.5
639 (88)
728
0.199
42.910.7
187 (87)
215
0.130
46.89.4
111 (79)
140
0.346
47.88.2
341 (91)
373
10,782,122
18.9 (10.029.9)
50th to 74th
(N=577,331)
2725
0.824
45.29.7
270 (85)
317
0.223
41.010.6
75 (87)
86
0.143
46.69.6
34 (62)
55
0.457
46.88.7
161 (91)
176
3,848,492
17.7 (9.128.3)
75th to 84th
(N=216,086)
2397
1.019
45.59.8
300 (91)
329
0.232
40.011.7
67 (89)
75
0.170
46.410.0
46 (84)
55
0.616
47.38.0
187 (94)
199
3,229,523
15.8 (8.025.5)
85th to 94th
(N=194,972)
1114
1.545
45.29.7
174 (94)
185
0.367
39.010.2
41 (93)
44
0.217
49.38.6
25 (96)
26
0.960
46.78.7
108 (94)
115
1,197,403
12.0 (6.020.5)
95th
(N=86,061)
29,209
0.690
45.39.8
2,633 (90)
2,918
0.211
41.310.8
814 (91)
893
0.125
46.010.4
418 (79)
528
0.354
47.48.2
1,401 (94)
1,497
42,297,007
18.4 (9.929.3)
All Percentiles
(N=2,298,130)
of
185
74
0.099
45.011.2
85 (75)
114
0.282
47.57.8
304 (94)
324
11,494,064
19.5 (10.630.5)
25th to 49th
(N=600,966)
n e w e ng l a n d j o u r na l
No. of deaths
Sudden death
0.112
0.119
45.411.2
44.211.9
107
87 (81)
31
0.265
30 (97)
No. of deaths
Stroke
0.259
47.58.2
232 (97)
68 (94)
47.08.9
238
8,967,197
19.2 (10.729.8)
5th to 24th
(N=472,226)
72
2,778,207
18.4 (10.428.5)
<5th
(N=150,488)
No. of deaths
Cause of death
Cumulative duration
person-yr
Study follow-up
Variable
Table 2. Duration of Follow-up and Cause of Death, According to Percentile of BMI during Adolescence.*
The
m e dic i n e
* Plusminus values are means SD. Person-years of follow-up were calculated from 1981 through 2011.
Included in this category are 1662 deaths for which the cause was missing. Excluded are 3991 deaths from 1967 through 1980 for which the official underlying cause of death was not
available. Such exclusion was designed to be consistent with the numbers of deaths from cardiovascular causes that were determined from 1981 through 2011.
7.596
38.912.4
8.441
10.848
40.312.3
7.904
7.157
7.346
38.512.4
8.048
7.446
Age at death yr
37.812.1
38.012.3
39.212.4
39.812.5
39.612.1
25,441 (79)
32,127
1299
1116 (86)
2726
2078 (76)
3042
7921
5928 (75)
8226
6496 (79)
2236
6677
No. of deaths
1983 (89)
5575 (83)
6.671
6.589
7.411
Incidence rate per 10,000
person-yr)
6.855
2265 (74)
9.303
7.422
7.081
6.906
38.212.4
22,808 (78)
942 (85)
38.712.3
1778 (74)
39.612.5
1995 (73)
5289 (74)
5910 (78)
37.912.5
5079 (83)
1815 (88)
37.212.0
37.412.3
38.512.4
39.212.6
95th
(N=86,061)
85th to 94th
(N=194,972)
75th to 84th
(N=216,086)
50th to 74th
(N=577,331)
25th to 49th
(N=600,966)
5th to 24th
(N=472,226)
<5th
(N=150,488)
Variable
All Percentiles
(N=2,298,130)
R e sult s
Participants
2435
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
0.039
1.05 (1.001.11)
0.04
1.05 (1.001.11)
0.79
1.02 (0.861.21)
0.33
1.15 (0.881.50)
0.77
0.94 (0.631.41)
0.72
0.95 (0.731.24)
<5th
1.00 (reference)
1.00 (reference)
1.00 (reference)
1.00 (reference)
1.00 (reference)
1.00 (reference)
5th to 24th
0.45
0.99 (0.961.02)
0.37
0.99 (0.951.02)
0.81
1.01 (0.901.14)
0.91
0.99 (0.811.20)
0.21
0.84 (0.651.10)
0.23
1.11 (0.941.31)
25th to 49th
<0.001
1.06 (1.031.10)
0.019
1.04 (1.011.08)
<0.001
1.32 (1.181.48)
0.12
1.17 (0.961.42)
0.19
1.18 (0.921.53)
<0.001
1.49 (1.271.76)
50th to 74th
<0.001
1.20 (1.151.26)
<0.001
1.16 (1.111.21)
<0.001
1.76 (1.532.03)
0.009
1.41 (1.091.82)
0.034
1.42 (1.031.97)
<0.001
2.17 (1.782.64)
75th to 84th
<0.001
1.30 (1.241.36)
<0.001
1.23 (1.171.29)
<0.001
2.25 (1.962.58)
0.006
1.46 (1.111.91)
<0.001
1.81 (1.302.51)
<0.001
3.02 (2.503.65)
85th to 94th
<0.001
1.68 (1.581.78)
<0.001
1.54 (1.441.64)
<0.001
3.46 (2.934.10)
<0.001
2.09 (1.502.91)
<0.001
2.64 (1.724.08)
<0.001
4.89 (3.916.12)
95th
* A total of 2918 participants died from cardiovascular causes (including 1497 from coronary heart disease, 528 from stroke, and 893 from sudden death of unknown cause), 29,209 died
from noncardiovascular causes, and 32,127 died from all causes. Hazard ratios were calculated with the use of the Cox proportional-hazards method among 2,298,130 participants between the ages of 16 and 19 years at the time of examination with 42,297,007 person-years of follow-up; the hazard ratios were adjusted for age, birth year, sex, socioeconomic status,
country of origin, educational level, and height. In these analyses, we accounted for competing risk (deaths from other causes). In tests for trend for all comparisons, P<0.001 for linear
terms and P0.004 for quadratic terms.
The hazard ratio in this category was essentially unchanged when socioeconomic status and height were excluded from the seven-covariate model.
P value
All causes
P value
Noncardiovascular causes
P value
P value
Sudden death
P value
Stroke
P value
Cause of death
Variable
Table 3. Hazard Ratios for Cause of Death, According to Percentile of BMI during Adolescence.*
2437
Cumulative
Cumulative Mortality
from Cardiovascular
Cardiovascular
Disease
Disease
(%) Mortality
The
n e w e ng l a n d j o u r na l
BMI Percentile
1.4
1.2
95th
1.0
0.8
85th94th
0.6
75th84th
0.4
50th74th
25th49th
5th24th
<5th
0.2
0.0
10
20
30
1,042,018
30,718,320
609
540,636
38,472,521
1,577
160,145
41,926,636
2,676
Discussion
No. at Risk
1,712,018
17,201,301
185
m e dic i n e
40
Yr of Follow-up
Participants at risk
Cumulative person-yr
Cumulative cardiovascular deaths
of
2439
2440
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Copyright 2016 Massachusetts Medical Society.