ORIGINAL RESEARCH
published: 20 Sep embe 2018
doi: 10.3389/ endo.2018.00547
F on ie s in Endoc inology | www. on ie sin.o g 1Sep embe 2018 | Volume 9 | A icle 547
Edi ed by:
Cha uma hi Sabanayagam,
Singapo e Eye Resea ch Ins i u e,
Singapo e
Re iewed by:
Ka i a Venka a aman,
Na ional Uni e si y o Singapo e,
Singapo e
Te su o Tsujimo o,
Na ional Cen e Fo Global Heal h and
Medicine, Japan
*Co espondence:
João Sé gio Ne es
[email p o ec ed]
Special y sec ion:
This a icle was submi ed o
Diabe es,
a sec ion o he jou nal
F on ie s in Endoc inology
Recei ed: 10 June 2018
Accep ed: 29 Augus 2018
Published: 20 Sep embe 2018
Ci a ion:
Ne es JS, Lei ão L, Mag iço R, Bigo e
Viei a M, Viegas Dias C, Oli ei a A,
Ca alho D and Clagge B (2018)
Ca eine Consump ion and Mo ali y in
Diabe es: An Analysis o NHANES
1999–2010. F on . Endoc inol. 9:547.
doi: 10.3389/ endo.2018.00547
Ca eine Consump ion and Mo ali y
in Diabe es: An Analysis o NHANES
1999–2010
João Sé gio Ne es1,2*, Lia Lei ão3, Ri a Mag iço4, Miguel Bigo e Viei a5,
Ca a ina Viegas Dias6, Ana Oli ei a1, Da ide Ca alho 1,7 and B ian Clagge 8
1Depa men o Endoc inology, Diabe es and Me abolism, São João Hospi al Cen e , Po o, Po ugal, 2Depa men o
Su ge y and Physiology, Facul y o Medicine, Ca dio ascula Resea ch Cen e , Uni e si y o Po o, Po o, Po ugal,
3Neu ology Depa men , Hospi al P o . Dou o Fe nando Fonseca, Amado a, Po ugal, 4Neph ology Depa men , Hospi al
Cu y Cab al, Lisbon, Po ugal, 5Neph ology and Renal T ansplan a ion Depa men , Cen o Hospi ala Lisboa No e, Lisbon,
Po ugal, 6NOVA Medical School, Lisbon, Po ugal, 7Facul y o Medicine, Ins i u o de In es igação e Ino ação em Saúde,
Uni e si y o Po o, Po o, Po ugal, 8Ca dio ascula Di ision, B igham and Women’s Hospi al, Ha a d Medical School,
Bos on, MA, Uni ed S a es
Aim: An in e se ela ionship be ween co ee consump ion and mo ali y has been
epo ed in he gene al popula ion. Howe e , he e ec o co ee consump ion in diabe es
emains unclea . We aimed o e alua e he associa ion o ca eine consump ion and
ca eine sou ce wi h mo ali y among pa ien s wi h diabe es.
Me hods: We examined he associa ion o ca eine consump ion wi h mo ali y among
1974 women and 1974 men wi h diabe es, using he Na ional Heal h and Nu i ion
Examina ion Su ey (NHANES) 1999–2010. Ca eine consump ion was assessed a
baseline using 24 h die a y ecalls. Cox p opo ional haza d models we e i ed o es ima e
haza d a ios (HR) o all-cause, ca dio ascula , and cance - ela ed mo ali y acco ding
o ca eine consump ion and i s sou ce, adjus ing o po en ial con ounde s.
Resul s: A dose-dependen in e se associa ion be ween ca eine and all-cause
mo ali y was obse ed in women wi h diabe es. Adjus ed HR o dea h among women
who consumed ca eine, as compa ed wi h non-consume s, we e: 0.57 (95% CI,
0.40–0.82) o <100 mg o ca eine/day, 0.50 (95% CI, 0.32–0.78) o 100 o <200 mg
o ca eine/day, and 0.39 (95% CI, 0.23–0.64) o ≥200 mg o ca eine/day (p=0.005
o end). This associa ion was no obse ed in men. The e was a signi ican in e ac ion
be ween sex and ca eine consump ion (p=0.015). No signi ican associa ion be ween
o al ca eine consump ion and ca dio ascula o cance mo ali y was obse ed. Women
who consumed mo e ca eine om co ee had educed isk o all-cause mo ali y
(p=0.004 o end).
Conclusion: Ou s udy showed a dose-dependen p o ec i e e ec o ca eine
consump ion on mo ali y among women wi h diabe es.
Keywo ds: ca eine, co ee, mo ali y, diabe es, na ional heal h and nu i ion examina ion su ey
Ne es e al. Ca eine and Mo ali y in Diabe es
INTRODUCTION
Diabe es is a majo public heal h p oblem wi h an inc easing
p e alence wo ldwide (1). Gi en i s signi ican bu den, i is
impo an o iden i y li es yle ac o s o imp o emen o
p ognosis. Ca eine is p o ided in di e en sou ces, mainly
co ee, ea, and so d inks. Co ee con ains mo e ca eine
han he majo i y o oods and cons i u es one o he mos
commonly consumed be e ages wo ldwide. The de ec ion o a
heal h- ela ed e ec associa ed wi h co ee consump ion may
ha e a po en ial g ea impac in public heal h (2). Co ee
has been e e ed as con aining se e al bioac i e compounds
including an ioxidan s wi h po en ially bene icial p ope ies.
An in e se associa ion be ween co ee consump ion and se um
bioma ke s o in lamma ion and insulin esis ance has been
desc ibed (3–5). A me a-analysis o p ospec i e s udies (6)
and a sys ema ic e iew (7) showed ha co ee consump ion
migh be associa ed wi h educ ion in he incidence o ype 2
diabe es.
A ecen dose- esponse sys ema ic e iew concluded ha
co ee consump ion was s ongly associa ed wi h a isk educ ion
in all-cause and ca dio ascula disease (CVD) mo ali y.
Howe e , his sys ema ic e iew excluded s udies which analyzed
speci ic subpopula ions, such as hose including only people
wi h diabe es (8). Al hough ca eine consump ion appea s o be
associa ed wi h a dec eased isk o de eloping ype 2 diabe es,
i is unclea i i s p o ec i e e ec pe sis s in people wi h
es ablished diabe es. In a p ospec i e s udy including 4,365
pa ien s wi h a p io myoca dial in a c ion, d inking co ee
was associa ed wi h lowe isk o ca dio ascula mo ali y and
ischemic hea disease mo ali y (9). In his s udy, signi ican
in e se associa ions we e epo ed in pa ien s wi hou diabe es,
whe eas he associa ions we e weak and non-signi ican in he
smalle g oup wi h diabe es.
A e e iewing he li e a u e, we ound only h ee s udies
speci ic o pa ien s wi h diabe es. One p ospec i e coho o
7,170 emale egis e ed nu ses wi h diabe es ound ha habi ual
co ee consump ion was no associa ed wi h inc eased isk
o ca dio ascula diseases o p ema u e mo ali y (10). A
simila coho o 3,497 male heal h p o essionals wi h diabe es
ound no associa ion be ween ca eine consump ion and CVD
o all-cause mo ali y (11). Ano he s udy, es ic ed o a
Finnish popula ion (3,837 pa ien s), ound ha in pa ien s
wi h ype 2 diabe es, co ee d inking was associa ed wi h
educed all-cause, CVD, and co ona y hea disease mo ali y
(12). Howe e , in his s udy, no adjus men s we e made
o diabe es du a ion, complica ions o diabe es, and insulin
ea men .
Conside ing ha he e is limi ed and con lic ing e idence
ega ding he ela ionship be ween ca eine consump ion
and mo ali y in people wi h diabe es, we examined he
con inuous Na ional Heal h and Nu i ion Examina ion
Su ey (NHANES) 1999–2010 da abase o e alua e he e ec
o ca eine consump ion and ca eine sou ce on all-cause,
ca dio ascula , and cance mo ali y among pa ien s wi h
diabe es.
MATERIALS AND METHODS
S udy Design and Pa icipan s
We pe o med an analysis o he con inuous NHANES da abase.
The NHANES is a pe iodic su ey conduc ed by he Na ional
Cen e o Heal h S a is ics (NCHS) o he Cen e s o Disease
Con ol and P e en ion (CDC). NHANES is a s a i ied, mul i-
s age su ey using a na ionally ep esen a i e sample o he
non-ins i u ionalized ci ilian popula ion o he Uni ed S a es.
Pa icipan s a e selec ed a andom h ough a complex s a is ical
p ocess each yea , and hey comple e pe sonal s uc u ed
in e iews a home and hen pe o m a physical examina ion
a a mobile examina ion cen e ha includes heigh , weigh ,
and labo a o y measu emen s (13). We used da a om 1999 o
2010, ha includes 62,160 people. We es ic ed ou analysis
o indi iduals wi h ≥18-yea -old (35,379 subjec s) and wi h
diabe es (4,544 subjec s). Diabe es was de ined by a sel - epo ed
p e ious diagnosis, a hemoglobin A1c le el o ≥6.5%, o a as ing
plasma glucose le el o ≥126 mg/dL. Bo h pa ien s wi h ype 1
and ype 2 diabe es we e included. We excluded 596 subjec s
due o implausible alimen a y epo s (as de ined in p e ious
s udies: consump ion o <500 kcal/day o >3500 kcal/day)
(14) o missing in o ma ion on ca eine consump ion and/o
mo ali y. Finally, 3,948 subjec s we e included in ou p esen
analysis. The NCHS Resea ch E hics Re iew Boa d e iewed
and app o ed NHANES, and all pa icipan s p o ided w i en
in o med consen . This s udy was egis e ed a www.clinical ials.
go as NCT03367806.
Assessmen o Exposu e
In all cycles o NHANES 1999–2010, a 24-h die a y ecall
was collec ed. Using an au oma ed mul iple-pass me hod, all
ood i ems and quan i ies consumed in he 24 h p eceding
he in e iew we e eco ded. Fo pa icipan s in he 1999–
2002 NHANES, only one in-pe son 24-h die a y ecall was
adminis e ed. The cycles s a ing om 2003 onwa d included wo
ecalls, he i s one in-pe son and he second one ia elephone
collec ed 3 o 10 days ollowing he i s die a y in e iew bu no
on he same day o he week. To calcula e he ca eine, ene gy,
and nu ien in akes, o pa icipan s in he 1999–2002 NHANES,
we used he nu i ional in o ma ion om oods and be e ages
collec ed in he single 24-h die a y ecall. Fo pa icipan s in he
2003-2010 NHANES, he mean o he nu i ional in o ma ion
om bo h ecalls was used (15). NHANES includes in o ma ion
ega ding nu ien sou ce by ype o ood inges ed. This da a was
used o asce ain he quan i y o inges ed ca eine o igina ing in
co ee, ea, o so d ink o each pa ien . The impac o ca eine
consump ion ob ained om each o he h ee ypes o d ink on
di e en ou comes was e alua ed.
Conside ing he mean ca eine con en pe uni o ca eina ed
be e age (95 mg in 8 oz. o co ee, 48 mg in 8 oz. o ea, and 30 mg
in 12 oz. o cola) (16), we di ided he daily in ake o ca eine
om all sou ces and om co ee in o h ee ca ego ies (<100 mg,
100 o <200 mg, and 200 mg o mo e). Gi en he low numbe o
pa ien s wi h ca eine in ake om ea and om so d inks, and
he high a iabili y o ca eine in hese be e ages, hose pa ien s
F on ie s in Endoc inology | www. on ie sin.o g 2Sep embe 2018 | Volume 9 | A icle 547
Ne es e al. Ca eine and Mo ali y in Diabe es
we e di ided in o e iles o consump ion and a e p esen ed as
Supplemen a y Ma e ial.
Con inuous a iables a e p esen ed as means wi h s anda d
de ia ions excep o polyunsa u a ed o sa u a ed a y acids
a io, ibe s pe day, and yea s o diabe es which we e
summa ized using median (in e qua ile ange) due o hei
igh -skewed dis ibu ions. Ca ego ical a iables a e p esen ed as
pe cen wi h 95% con idence in e als.
Ou comes
The p ima y ou come was ime o dea h. As seconda y ou comes,
we selec ed ime o ca dio ascula dea h and ime o dea h by
TABLE 1 | Baseline cha ac e is ics o he s udy popula ion.
Baseline cha ac e is ics acco ding o ca eine consump ion among women (n=1974)
No consump ion
(n=219)
<100 mg/day
(n=979)
P- alue* 100 o <200
mg/day
(n=438)
P- alue* ≥200 mg/day
(n=338)
P- alue* P o end
Age, yea s 58.3 (15.8) 61.6 (15.0) 0.022 59.5 (14.3) 0.469 58.6 (13.2) 0.829 0.041
Non-Hispanic Whi e, % 34.7% 53.0% 0.001 59.2% <0.001 79.2% <0.001 <0.001
Annual amily income <$25000, % 51.4% 48.8% 0.399 39.1% 0.018 38.6% 0.010 0.004
Educa ion le el -Less han 9 h g ade, % 22.0% 15.9% 0.119 10.1% 0.002 9.1% <0.001 <0.001
Cu en smoke s, % 6.3% 8.4% 0.312 12.7% 0.029 25.9% <0.001 <0.001
Fo me smoke s, % 24.0% 26.5% 0.548 34.3% 0.053 33.2% 0.079 0.023
Alcohol consump ion >20 g ams/day, % 2.3% 2.9% 0.651 5.2% 0.172 4.9% 0.219 0.126
Ca bohyd a es pe day, g am/100 kcal 12.9 (3.0) 12.7 (2.3) 0.448 12.1 (2.3) 0.020 11.8 (2.5) 0.001 <0.001
Polyunsa u a ed/sa u a ed a y acids a io 0.73 (0.52–1.11) 0.70 (0.50–0.94) 0.061 0.67 (0.49–0.92) 0.056 0.65 (0.49–0.84) 0.001 0.001
Fibe pe day, g am/100 kcal 0.95 (0.54–1.27) 0.91 (0.65–1.16) 0.957 0.85 (0.64–1.09) 0.107 0.78 (0.59–1.03) 0.045 0.002
Low physical ac i i y le el, % 44.9% 37.2% 0.109 37.4% 0.201 41.9% 0.607 0.469
BMI, kg/m2 34.7 (8.9) 33.2 (8.3) 0.083 33.0 (6.9) 0.034 33.8 (7.8) 0.342 0.775
Hype ension, % 67.3% 67.2% 0.978 72.5% 0.266 67.0% 0.957 0.889
Dyslipidemia, % 53.1% 60.3% 0.188 61.3% 0.128 58.7% 0.283 0.926
Time since diagnosis o diabe es, yea s 3 (0–13) 5 (0–12) 0.100 5 (1–13) 0.415 7 (1–15) 0.092 0.592
Diabe ic e inopa hy, % 24.0% 21.7% 0.591 22.0% 0.722 25.4% 0.661 0.219
Diabe ic kidney disease, % 23.2% 26.4% 0.511 27.8% 0.477 16.8% 0.100 0.005
Mac o ascula complica ions, % 19.3% 18.1% 0.696 19.2% 0.988 19.5% 0.908 0.629
Insulin ea men , % 21.5% 18.6% 0.465 21.0% 0.876 27.6% 0.274 0.021
Baseline cha ac e is ics acco ding o ca eine consump ion among men (n=1974)
No consump ion
(n=186)
<100 mg/day
(n=739)
P- alue* 100 o <200
mg/day
(n=470)
P- alue* ≥200 mg/day
(n=579)
P- alue* P o end
Age, yea s 57.3 (14.6) 60.0 (14.0) 0.080 58.0 (14.0) 0.660 58.1 (12.4) 0.601 0.245
Non-Hispanic Whi e, % 41.4% 54.3% 0.013 70.4% <0.001 80.3% <0.001 <0.001
Annual amily income <$25000, % 35.2% 34.7% 0.871 27.6% 0.110 27.9% 0.123 0.029
Educa ion le el - Less han 9 h g ade, % 18.2% 16.3% 0.616 12.6% 0.126 10.2% 0.020 0.001
Cu en smoke s, % 16.0% 11.8% 0.300 14.8% 0.826 25.7% 0.097 <0.001
Fo me smoke s, % 39.7% 45.4% 0.247 46.7% 0.199 45.1% 0.366 0.834
Alcohol consump ion >20 g ams/day, % 15.9% 9.8% 0.073 11.4% 0.302 11.6% 0.169 0.867
Ca bohyd a es pe day, g am/100 kcal 11.9 (3.1) 11.8 (2.5) 0.958 11.7 (2.4) 0.573 11.3 (2.6) 0.124 0.006
Polyunsa u a ed/sa u a ed a y acids a io 0.70 (0.47–0.98) 0.68 (0.48–0.91) 0.306 0.70 (0.50–0.91) 0.249 0.64 (0.47–0.88) 0.133 0.216
Fibe pe day, g am/100 kcal 0.83 (0.55–1.10) 0.83 (0.61–1.14) 0.624 0.76 (0.55–1.09) 0.444 0.78 (0.57–0.99) 0.134 0.010
Low physical ac i i y le el, % 40.9% 30.0% 0.030 32.8% 0.157 33.4% 0.120 0.773
BMI, kg/m231.9 (8.1) 31.2 (6.1) 0.481 31.4 (6.0) 0.601 32.4 (7.3) 0.661 0.102
Hype ension, % 66.7% 60.5% 0.239 60.1% 0.278 55.1% 0.046 0.062
Dyslipidemia, % 55.6% 58.2% 0.666 60.0% 0.486 63.0% 0.207 0.166
Time since diagnosis o diabe es, yea s 3 (0–11) 4 (0–11) 0.882 3 (0–10) 0.539 5 (0–12) 0.966 0.779
Diabe ic e inopa hy, % 26.4% 26.1% 0.932 18.3% 0.223 18.6% 0.432 0.198
Diabe ic kidney disease, % 15.1% 25.0% 0.010 16.9% 0.639 20.1% 0.197 0.408
Mac o ascula complica ions, % 23.2% 24.8% 0.662 20.5% 0.551 26.2% 0.448 0.378
Insulin ea men , % 20.9% 21.8% 0.814 21.6% 0.888 23.2% 0.614 0.563
Baseline popula ion cha ac e is ics acco ding o ca eine consump ion among women and men. * s no consump ion g oup. Kcal, kilocalo ie; BMI, Body mass index. Signi ican P o
end alues a e shown in bold.
F on ie s in Endoc inology | www. on ie sin.o g 3Sep embe 2018 | Volume 9 | A icle 547
Ne es e al. Ca eine and Mo ali y in Diabe es
cance . Mo ali y s a us and cause o dea h we e de e mined
by NHANES linked Na ional Dea h Index public-access iles
h ough Decembe 31, 2011.
S a is ical Analysis
All calcula ions ook in o accoun he complex su ey design o
he NHANES da ase and we e analyzed acco ding o he CDC
analy ic ecommenda ions (17).
To assess he c ude associa ion be ween ca eine consump ion
and ime o dea h, we pe o med a Kaplan-Meie cu e and
log- ank es . We pe o med u he analysis using he Cox
p opo ional haza ds models o adjus o po en ial con ounde s.
We buil wo di e en Cox P opo ional Haza d models o
analyze he p ima y ou come: one model including age a
baseline, ace (Mexican Ame ican, o he Hispanic, non-Hispanic
whi e, non-Hispanic black, o he ace), annual amily income
(<$25000, $25000 o $75000, >$75000), smoking s a us (ne e
smoke , cu en smoke , o o me smoke ), and diabe ic
neph opa hy (glome ula il a ion a e <60 mL/min/1.73 m2o
u ine albumin/c ea inine a io ≥300 mg/g) (model 1); Model 2
including all model 1 co a ia es plus body mass index (BMI)
(<20.0, 20.0 o <25.0, 25.0 o <30.0, 30.0 o <35.0, 35.0 o
<40.0, ≥40.0 kg/m2), educa ion le el [less han 9 h g ade, 9-11 h
g ade, high-school g ade, some college o associa e’s (AA) deg ee,
college g adua e and abo e], daily ca bohyd a e consump ion
(g ams o ca bohyd a e pe 100 kcal), alcohol consump ion
(no alcohol consump ion, <20 g ams/day, ≥20 g ams/day),
yea s since diabe es diagnosis (undiagnosed, ≤5 yea s, 5 o
≤15 yea s, >15 yea s), diagnosis o hype ension, e inopa hy,
mac o ascula complica ions (co ona y a e y disease, his o y o
myoca dial in a c ion, o his o y o s oke), insulin ea men
and su ey cycle (yea s 1999–2000, 2001–2002, 2003–2004,
2005–2006, 2007–2008, o 2009–2010). Rega ding cause-speci ic
mo ali y, we only used he mo e es ic i e model (model 1), due
o he low numbe o ou come e en s. We es ed o in e ac ions
be ween ca eine consump ion and he o he 14 a iables in
model 2 o all-cause mo ali y.
We also conside ed physical ac i i y as an impo an po en ial
con ounde . Physical ac i i y was measu ed di e en ly along he
a ious NHANES cycles. The e o e, we chose o use a iables
ha allowed ca ego iza ion o physical ac i i y le el in o h ee
ca ego ies (low, in e media e, and high), o combine hem in o a
single a iable. F om 1999 o 2006 he physical ac i i y le el was
assessed wi h he ques ion “compa e ac i i y wi h o he s o he
same age” (pa icipan s we e classi ied in o app oxima e e iles
as low i “less ac i e,” as in e media e i “abou he same,” and
as high i “mo e ac i e,” wi h 31, 28, and 41% o pa icipan s,
espec i ely, alling in o hese ca ego ies). F om 2007 o 2010 he
weekly me abolic equi alen s (MET) minu es o physical ac i i y
(accoun ing o igo ous wo k- ela ed ac i i y, mode a e wo k-
ela ed ac i i y, walking o bicycling o anspo a ion, igo ous
leisu e- ime physical ac i i y, and mode a e leisu e- ime physical
ac i i y) was di ided in o e iles (pa icipan s we e classi ied as
low i included in he lowe MET-minu e e ile, as in e media e
i in he middle MET-minu e e ile, and as high i in he highe
MET-minu e e ile). The esul s o mo ali y associa ed wi h
ca eine consump ion adjus ed o physical ac i i y a e p esen ed
in he Supplemen a y Ma e ial.
As sensi i i y analysis, we addi ionally pe o med he Cox
p opo ional haza ds models using daily in ake o ca eine ( om
all sou ces and om co ee, ea, o so d inks) as a con inuous
a iable.
Mul iple impu a ion by chained equa ions was used o
dealing wi h missing da a ega ding co a ia es. Twen y
impu a ions pe missing obse a ion we e pe o med and
analyzed. A es o end o e inc easing ca eine consump ion
ca ego ies was pe o med whe e each ca ego y median was
modeled as a con inuous a iable in he eg ession. A wo-sided
p- alue o <0.05 was conside ed s a is ically signi ican . Analyses
we e pe o med wi h S a a ( e sion 14.2).
RESULTS
Associa ion o Ca eine Consump ion Wi h
Die a y and Li es yle Fac o s
Ca eine consump ion a baseline was associa ed wi h se e al
o he die a y and li es yle ac o s, wi h some di e ences
acco ding o sex (Table 1). In bo h men and women, compa ed
wi h people who did no d ink ca eine-con aining be e ages,
ca eine consume s we e mo e likely o be non-Hispanic whi e
and cu en smoke s, o ha e a highe le el o educa ion, o ha e
an annual amily income highe han $25000, and o consume less
ca bohyd a es and less ibe s pe kilocalo ie inges ed. Women
ha consumed ca eine we e mo e likely o be ea ed wi h
insulin, had less diabe ic kidney disease, and a lowe a io o
polyunsa u a ed/sa u a ed a y acids in ake.
Ca eine Consump ion and Mo ali y
Du ing a median 57 mon hs o ollow-up ( o al pe son-yea s,
21,606), 407 men and 351 women died. The e was a signi ican
in e ac ion be ween sex and ca eine consump ion wi h espec
o mo ali y (p=0.015 o in e ac ion in model 2). In
he unadjus ed analysis (Figu e 1), and also a e mul i a ia e
analysis, ca eine consump ion was associa ed wi h a dec ease
in all-cause mo ali y in women (p=0.005 o end ac oss
FIGURE 1 | Kaplan-Meie cu es o all-cause mo ali y by ca eine
consump ion among women.
F on ie s in Endoc inology | www. on ie sin.o g 4Sep embe 2018 | Volume 9 | A icle 547
Ne es e al. Ca eine and Mo ali y in Diabe es
ca ego ies, in model 2). A dose-dependen in e se associa ion
be ween ca eine and all-cause mo ali y was obse ed. Haza d
a ios (HR) o dea h among women who consumed ca eine, as
compa ed wi h women who did no consume ca eine, we e as
ollows: 0.57 (95% con idence in e al [CI], 0.40 o 0.82) o less
han 100 mg o ca eine pe day, 0.50 (95% CI, 0.32 o 0.78) o
100 o less han 200 mg o ca eine, and 0.39 (95% CI, 0.23 o 0.64)
o 200 mg o mo e o ca eine pe day (Table 2). In con as , his
associa ion was no obse ed among men (Figu e 2), e en a e
adjus men o po en ial con ounde s (Table 2).
Speci ic causes o dea h we e also examined. The e we e 199
dea hs om CVD and 133 dea hs due o cance du ing he
ollow-up. A e mul i a ia e adjus men , he e was no signi ican
associa ion be ween ca eine consump ion and dea hs om CVD
o cance , bo h in men and women (Table 2).
Sou ce o Ca eine Consump ion and
Mo ali y
An analysis o ca eine consump ion acco ding o i s o igin on
co ee, ea, o so d inks was also pe o med. In he unadjus ed
analysis, and also a e mul i a ia e analysis, a educed isk in
all-cause mo ali y was obse ed in women wi h diabe es who
consumed ca eine om co ee (Table 3). The adjus ed haza d
a ios we e as ollows: 0.74 (95% CI, 0.53 o 1.02) o less han
100 mg o ca eine pe day, 0.71 (95% CI, 0.46 o 1.09) o 100 mg
TABLE 2 | Associa ion o ca eine consump ion wi h mo ali y.
Associa ion o ca eine consump ion wi h mo ali y among women
No consump ion
(n=219)
<100 mg/day
(n=979)
100 o <200
mg/day
(n=438)
≥200 mg/day
(n=338)
P o
end
Con inuous
analysisa
All-cause mo ali y
No. o dea hs (%) 59 (26.9%) 170 (17.4%) 73 (16.7%) 49 (14.5%) 351 (17.8%)
Unadjus ed HR – 0.71 (0.51–1.00) 0.63 (0.42–0.96) 0.46 (0.27–0.78) 0.010 0.86 (0.76–0.96)
Model 1 HR – 0.60 (0.43–0.83) 0.52 (0.34–0.80) 0.42 (0.25–0.71) 0.020 0.88 (0.77–0.99)
Model 2 HR – 0.57 (0.40–0.82) 0.50 (0.32–0.78) 0.39 (0.23–0.64) 0.005 0.86 (0.76–0.96)
CVD mo ali y
No. o dea hs (%) 16 (7.3%) 40 (4.1%) 15 (3.4%) 8 (2.4%) 79 (4.0%)
Unadjus ed HR – 0.66 (0.33–1.30) 0.45 (0.22–0.93) 0.40 (0.15–1.08) 0.118 0.82 (0.68–0.99)
Model 1 HR – 0.52 (0.26–1.02) 0.37 (0.18–0.76) 0.38 (0.14–1.00) 0.208 0.86 (0.70–1.06)
Cance mo ali y
No. o dea hs (%) 9 (4.1%) 26 (2.7%) 11 (2.5%) 8 (2.4%) 54 (2.7%)
Unadjus ed HR – 0.87 (0.34–2.22) 0.70 (0.24–2.02) 0.49 (0.13–1.80) 0.204 0.88 (0.65–1.19)
Model 1 HR – 0.71 (0.27–1.89) 0.52 (0.17–1.59) 0.35 (0.08–1.53) 0.126 0.84 (0.59–1.20)
Associa ion o ca eine consump ion wi h mo ali y among men
No consump ion
(n=186)
<100 mg/day
(=739)
100 o <200
mg/day
(n=470)
≥200 mg/day
(n=579)
P o
end
Con inuous
analysis a
All-cause mo ali y
No. o dea hs (%) 50 (26.9%) 159 (21.5%) 82 (17.5%) 116 (20.0%) 407 (20.6%)
Unadjus ed HR – 1.24 (0.81–1.91) 1.00 (0.64–1.57) 1.21 (0.81–1.82) 0.739 1.03 (0.97–1.09)
Model 1 HR – 0.94 (0.62–1.41) 0.77 (0.49–1.23) 0.91 (0.60–1.39) 0.925 1.04 (0.98–1.10)
Model 2 HR – 1.09 (0.70–1.69) 0.90 (0.55–1.47) 1.01 (0.65–1.56) 0.783 1.03 (0.97–1.10)
CVD mo ali y
No. o dea hs (%) 11 (5.9%) 50 (6.8%) 23 (4.9%) 36 (6.2%) 120 (6.1%)
Unadjus ed HR – 2.09 (0.99–4.39) 1.59 (0.58–4.33) 1.92 (0.85–4.31) 0.749 1.07 (0.98–1.18)
Model 1 HR – 1.47 (0.70–3.12) 1.13 (0.41–3.10) 1.18 (0.54–2.58) 0.517 1.07 (0.98–1.16)
Cance mo ali y
No. o dea hs (%) 12 (6.5%) 28 (3.8%) 18 (3.8%) 21 (3.6%) 79 (4.0%)
Unadjus ed HR – 1.15 (0.51–2.63) 0.96 (0.37–2.47) 1.17 (0.52–2.62) 0.830 1.09 (0.97–1.22)
Model 1 HR – 1.03 (0.42–2.54) 0.78 (0.28–2.13) 0.90 (0.37–2.18) 0.777 1.07 (0.95–1.22)
Model 1: Adjus ed o age, ace, annual amily income, smoking s a us, and diabe ic kidney disease. Model 2: Adjus ed o co a ia es in Model 1 and body mass index, educa ion
le el, daily ca bohyd a e consump ion, alcohol consump ion, yea s since diabe es diagnosis, diagnosis o hype ension, e inopa hy, mac o ascula complica ions, insulin ea men and
su ey cycle.
aHR o he con inuous analysis a e p esen ed o each 100 mg inc ease in ca eine consump ion. HR, Haza d Ra io; CVD, Ca dio ascula disease. Signi ican P o end alues and
signi ican haza d a ios in he con inuous analysis a e shown in bold.
F on ie s in Endoc inology | www. on ie sin.o g 5Sep embe 2018 | Volume 9 | A icle 547

Ne es e al. Ca eine and Mo ali y in Diabe es
FIGURE 2 | Kaplan-Meie cu es o all-cause mo ali y by ca eine
consump ion among men.
o less han 200 mg o ca eine, and 0.53 (95% CI, 0.35 o 0.80) o
200 mg o mo e o ca eine pe day (p=0.004 o end ac oss
ca ego ies, in model 2). The e we e no signi ican associa ions o
ca eine consump ion om co ee wi h ca dio ascula o cance
mo ali y.
Rega ding ca eine consump ion om ea and om so
d inks, he e we e no signi ican associa ions wi h all-cause o
cause-speci ic mo ali y (Supplemen a y Tables 1,2).
Among men, he e we e no signi ican associa ions
be ween sou ce o ca eine and mo ali y (Table 3,
Supplemen a y Table 2).
Sensi i i y Analysis
The analysis o he associa ion be ween sou ce o ca eine and
mo ali y using daily in ake o ca eine as a con inuous a iable
showed simila esul s (Table 2,Supplemen a y Table 3).
Among women, he HR o each 100 mg inc ease in ca eine
consump ion o all-cause mo ali y was 0.86 (95% CI,
0.76–0.96; p=0.009) o unadjus ed analysis and 0.86
(95% CI, 0.76–0.96; p=0.011) o adjus ed analysis. The
e ec o ca eine consump ion acco ding o ca eine sou ce
on all-cause, ca dio ascula , and cance mo ali y among
women and men we e also conco dan wi h he main
analysis (Table 2,Supplemen a y Table 3). Fu he mo e,
he associa ion o ca eine consump ion wi h mo ali y adjus ing
o physical ac i i y was also consis en wi h ou main analysis
(Supplemen a y Table 4).
DISCUSSION
Ou s udy showed a dose-dependen p o ec i e e ec o
ca eine consump ion on all-cause mo ali y among women
wi h diabe es. The e was no signi ican associa ion be ween
ca eine consump ion and mo ali y among men wi h diabe es.
Al hough ca eine consump ion in women was associa ed wi h
lowe all-cause mo ali y, no associa ion was ound be ween
ca eine consump ion and ca dio ascula o cance mo ali y.
When compa ing ca eine consump ion acco ding o i s o igin on
co ee, ea, o so d inks, women wi h diabe es who consumed
mo e ca eine om co ee also had educed isk o all-cause
dea h. No di e ences on mo ali y we e obse ed on he adjus ed
analysis o consump ion o ca eine om ea o so d inks.
Howe e , hese esul s should be in e p e ed cau iously as he
numbe o e en s in each sou ce o ca eine ca ego y was low.
P e ious s udies had al eady shown a p o ec i e e ec o
co ee consump ion in he gene al popula ion. Lo ield e al.,
o example, showed a dec eased isk o all-cause mo ali y in
people wi h highe co ee consump ion (18). Speci ically, an
in e se associa ion was ound be ween co ee consump ion and
diabe es- ela ed dea h. In he subg oup o pa icipan s wi h sel -
epo ed diabe es, his associa ion seemed s onge . Rega ding
s udies in people wi h diabe es, a s udy in he Finnish popula ion
in 3,837 pa ien s, ound an in e se ela ionship be ween co ee
d inking and all-cause and ca dio ascula -associa ed mo ali y
(12). On he o he hand, wo p e ious s udies ha e ob ained
neu al esul s in pa ien s o bo h sexes. In a s udy including
only emale nu ses wi h diabe es, habi ual co ee consump ion
was no associa ed wi h ca dio ascula diseases o p ema u e
mo ali y (10). Fu he mo e, no signi ican associa ion be ween
co ee consump ion and mo ali y was obse ed in a p ospec i e
coho o male heal h p o essionals wi h diabe es (11). Al hough
he Finnish popula ion s udy esul s a e no consis en wi h
hese wo s udies, hei esul s also sugges a p o ec i e e ec o
ca eine-con aining be e ages as obse ed in ou s udy. Possible
explana ions o hese di e ences be ween s udies migh be he
use o di e en endpoin s, di e en du a ion o ollow-up and
di e ences in he popula ion’s cha ac e is ics.
Ou esul s sugges ha biological di e ences may
exis be ween men and women ega ding he e ec s o
ca eine consump ion. Conside ing he pa hophysiology and
complica ions o diabe es, se e al s udies ha e highligh ed
di e ences be ween sexes (19). Gene ic and epigene ic
mechanisms, nu i ional ac o s, and seden a y li es yle
ha e been shown o di e en ly a ec diabe es complica ions
acco ding o sex (19). Fu he mo e, ca eine may induce di e en
hemodynamic e ec s in men and women. In a double-blind
ial compa ing age-ma ched women and men, women showed
an inc ease in ca diac ou pu , whe eas men showed inc eased
ascula esis ance a e a die a y dose o ca eine (20). These
di e ences may pa ially explain why ca eine in ake is associa ed
wi h educed mo ali y in women wi h diabe es whe eas he
e ec s in mo ali y a e neu al in men wi h diabe es. In he
gene al popula ion, some s udies ha e also sugges ed di e ences
in he esponse o co ee be ween sexes. The in e se associa ion
o co ee d inking wi h o al mo ali y has been shown o be
educed in men compa ing o women (21–23).
The di ec ion and s eng h o he associa ion be ween ca eine
consump ion and mo ali y has a ied be ween s udies in he
gene al popula ion. In a s udy including Japanese pa icipan s
wi hou a his o y o cance , myoca dial in a c ion, o s oke
a baseline, co ee consump ion was s ongly associa ed wi h
educed all-cause and ca dio ascula mo ali y among women
[HR o 0.48 (0.29–0.80) o 1–2 cups o co ee pe day and
F on ie s in Endoc inology | www. on ie sin.o g 6Sep embe 2018 | Volume 9 | A icle 547
Ne es e al. Ca eine and Mo ali y in Diabe es
TABLE 3 | Associa ion o ca eine consump ion om co ee wi h mo ali y.
Associa ion o ca eine consump ion om co ee wi h mo ali y among women
No consump ion
(n=734)
<100 mg/day
(n=707)
100 o <200 mg/day
(n=316)
≥200 mg/day
(n=217)
P o
end
Con inuous analysisa
All-cause mo ali y
No. o dea hs (%) 127 (17.3%) 130 (18.4%) 58 (18.4%) 36 (16.6%) 351 (17.8%)
Unadjus ed HR – 1.25 (0.94–1.66) 1.09 (0.75–1.60) 0.73 (0.50–1.09) 0.077 0.91 (0.83–0.99)
Model 1 HR – 0.79 (0.60–1.04) 0.74 (0.47–1.15) 0.57 (0.38–0.85) 0.009 0.87 (0.78–0.98)
Model 2 HR – 0.74 (0.53–1.02) 0.71 (0.46–1.09) 0.53 (0.35–0.80) 0.004 0.85 (0.76–0.95)
CVD mo ali y
No. o dea hs (%) 31 (4.2%) 32 (4.5%) 11 (3.5%) 5 (2.3%) 79 (4.0%)
Unadjus ed HR – 1.51 (0.86–2.66) 0.98 (0.42–2.26) 0.50 (0.18–1.41) 0.123 0.83 (0.69–0.99)
Model 1 HR – 0.96 (0.56–1.66) 0.72 (0.28–1.85) 0.42 (0.14–1.25) 0.110 0.81 (0.64–1.02)
Cance mo ali y
No. o dea hs (%) 19 (2.6%) 18 (2.6%) 12 (3.8%) 5 (2.3%) 54 (2.7%)
Unadjus ed HR – 1.66 (0.80–3.42) 1.81 (0.74–4.38) 0.89 (0.23–3.41) 0.905 0.99 (0.76–1.29)
Model 1 HR – 1.16 (0.54–2.48) 1.24 (0.47–3.23) 0.59 (0.15–2.39) 0.392 0.91 (0.64–1.29)
Associa ion o ca eine consump ion om co ee wi h mo ali y among men
No consump ion
(n=656)
<100 mg/day
(n=572)
100 o <200 mg/day
(n=358)
≥200 mg/day
(n=388)
P o
end
Con inuous
analysisa
All-cause mo ali y
No. o dea hs (%) 132 (20.1%) 126 (22.0%) 70 (19.6%) 79 (20.4%) 407 (20.6%)
Unadjus ed HR – 1.59 (1.19–2.13) 1.13 (0.77–1.66) 1.42 (0.93–2.08) 0.282 1.06 (1.00–1.12)
Model 1 HR – 1.05 (0.76–1.45) 0.80 (0.57–1.11) 1.07 (0.74–1.55) 0.922 1.03 (0.96–1.11)
Model 2 HR – 1.04 (0.74–1.47) 0.76 (0.53–1.08) 1.09 (0.76–1.56) 0.873 1.03 (0.96–1.11)
CVD mo ali y
No. o dea hs (%) 34 (5.2%) 45 (7.9%) 18 (5.0%) 23 (5.9%) 120 (6.1%)
Unadjus ed HR – 2.13 (1.35–3.38) 1.15 (0.55–2.42) 1.48 (0.64–3.40) 0.791 1.09 (0.99–1.20)
Model 1 HR – 1.33 (0.79–2.26) 0.70 (0.35–1.41) 0.97 (0.44–2.15) 0.563 1.06 (0.94–1.19)
Cance mo ali y
No. o dea hs (%) 17 (3.5%) 23 (3.5%) 19 (5.3%) 14 (3.6%) 79 (4.0%)
Unadjus ed HR – 3.34 (1.58–7.05) 2.85 (1.39–5.84) 3.12 (1.79–5.42) 0.022 1.09 (1.00–1.19)
Model 1 HR – 2.51 (1.10–5.71) 2.19 (1.00–4.81) 2.24 (1.10–4.56) 0.270 1.06 (0.93–1.20)
Model 1: Adjus ed o age, ace, annual amily income, smoking s a us, and diabe ic kidney disease. Model 2: Adjus ed o co a ia es in Model 1 and body mass index, educa ion le el,
daily ca bohyd a e consump ion, alcohol consump ion, yea s since diabe es diagnosis, diagnosis o hype ension, e inopa hy, mac o ascula complica ions, insulin ea men , and
su ey cycle. aHR o he con inuous analysis a e p esen ed o each 100 mg inc ease in ca eine consump ion om co ee. HR, Haza d Ra io; CVD, Ca dio ascula disease. Signi ican
P o end alues and signi ican haza d a ios in he con inuous analysis a e shown in bold.
0.45 (0.20–1.03) o 3 o mo e cups pe day compa ing wi h
no consump ion) bu no in men (24). O he s udies ha e also
shown in e se associa ions be ween consump ion o ca eine-
con aining be e ages and mo ali y among women, albei wi h
weake associa ions (22,25). Al hough some s udies sugges
g ea e bene i s o consump ion o ca eine o co ee among
women, hese indings a e no consis en ac oss s udies. Se e al
s udies ha e shown simila in e se associa ions be ween co ee
consump ion and mo ali y in women and men (26–28). The ype
o ca eine-con aining be e age, he popula ion’s isk ac o s o
he du a ion o ollow-up may explain he di e ences be ween
s udies.
The bene i s o co ee may be di ec ly ela ed o ca eine
o o o he componen s p esen in co ee, including mine als,
phy ochemicals, and an ioxidan s (25,29). The an ioxidan
capaci y o hese d inks may con ibu e o he heal h-p o ec i e
e ec desc ibed wi h deca eina ed co ee consump ion (7). The
lack o signi ican di e ences on mo ali y ega ding ca eine
consump ion om ea on ou s udy may be explained by
insu icien powe . A ecen me a-analysis ound a signi ican
associa ion be ween ea consump ion and educ ion o all-cause
mo ali y; u he mo e, black ea was in e sely associa ed wi h
cance mo ali y (30).
Tsujimo o e al. also used NHANES da a o e alua e he e ec s
o ca eine consump ion in he gene al popula ion (31). In hei
main analysis, ca eine in ake was associa ed wi h a dec eased isk
o all-cause mo ali y. Al hough i was no hei main objec i e,
he au ho s also pe o med an addi ional analysis limi ed o he
F on ie s in Endoc inology | www. on ie sin.o g 7Sep embe 2018 | Volume 9 | A icle 547
Ne es e al. Ca eine and Mo ali y in Diabe es
pa icipan s wi h diabe es. Con a y o ou esul s, hey epo ed
a non-signi ican associa ion be ween ca eine consump ion and
mo ali y among pa icipan s wi h diabe es. In he s udy by
Tsujimo o e al., no adjus men s we e made o diabe es-speci ic
pa ame e s, including diabe es du a ion, ype o ea men and
complica ions o diabe es. Pa icipan s wi h diabe es we e no
s a i ied acco ding o sex and no adjus men was pe o med
o he p esence o kidney disease. Fu he mo e, in he s udy
by Tsujimo o e al., pa icipan s wi h missing in o ma ion
on any o he po en ial con ounde s we e excluded, whe eas
we included hese pa ien s using mul iple impu a ion. The
di e ences in pa icipan s’ selec ion and in he s a is ical analyses
echniques used p obably accoun o he di e ences be ween
he s udies.
Ou s udy has se e al s eng hs, including he e alua ion o
a coho o pa icipan s om a la ge da abase ep esen a i e
o he Ame ican popula ion. Da a was p ospec i ely collec ed
and included ha d ou come measu es such as dea h and cause-
speci ic mo ali y. The p esence o de ailed in o ma ion abou
he pa icipan s allowed o adjus men o he main biologically
plausible con ounde s.
As o limi a ions, i should be no ed ha ca eine
consump ion was e alua ed by 24-h die a y ecalls. I
canno be excluded ha da a gene a ed using his me hod
may no ep esen long- e m die a y habi s. We conside
ha he inclusion o da a om non-consecu i e ecalls o
es ima e usual die a y in ake dis ibu ions minimizes his
isk. Al hough we p esen addi ional in o ma ion ega ding
die in he s udied popula ion (such as consump ion o
ca bohyd a e, sa u a ed a , o ibe ), no adjus men was
pe o med o addi i es p esen in ca eine-con aining be e ages.
None heless, o he s udies showed signi ican associa ion
be ween co ee consump ion and dec eased isk o dea h e en
a e adjus men o co ee addi i es, such as c eam, milk,
suga , o honey (32). E en hough we ha e ound a signi ican
associa ion be ween ca eine consump ion and mo ali y
in women wi h diabe es, i is possible ha he di e ences
ound a e due o chance, unmeasu ed con ounde s, o he
possibili y ha ca eine consume s also pe o m o he p o ec i e
beha io s, con ibu ing o a heal hy use e ec . To minimize
his possibili y, we ha e conside ed die a y ac o s and physical
ac i i y as po en ial con ounde s. As he numbe o dea hs
in ou s udy was low, hese es ima es should be cau iously
in e p e ed.
In conclusion, his la ge obse a ional s udy showed a
signi ican in e se associa ion be ween ca eine consump ion
and dea h om all causes in women wi h diabe es. These
esul s sugges ha ad ising women wi h diabe es o d ink
mo e ca eine may educe hei mo ali y. This would
ep esen a simple, clinically bene icial, and inexpensi e
op ion in emale pa ien s. Fu he s udies, ideally andomized
clinical ials, a e needed o con i m his bene i . New
esea ch should also ocus on he di e en e ec s o
ca eine consump ion in men and women and on he
bene i s o o he compounds p esen in ca eine-con aining
be e ages.
DATA AVAILABILITY STATEMENT
The da ase analyzed o his s udy can be ound in: h ps://www.
cdc.go /nchs/nhanes/index.h m.
AUTHOR CONTRIBUTIONS
JSN, LL, RM, MBV, and CVD join ly designed and conduc ed
esea ch, de eloped he analy ical s a egy and did he s a is ical
analysis. BC e iewed he analy ic s a egy and s a is ical analysis.
JSN, LL, RM, MBV, and CVD join ly con ibu ed o he i s d a .
All au ho s con ibu ed o in e p e a ion o da a o he wo k,
c i ically e ised he wo k, and app o ed he inal e sion o he
manusc ip .
ACKNOWLEDGMENTS
We hank he pa icipan s and s a o NHANES.
Pa s o his s udy we e p esen ed in abs ac o m a he 47 h
Eu opean Associa ion o he S udy o Diabe es Annual Mee ing,
Lisbon, Po ugal 11–15 Sep embe 2017.
SUPPLEMENTARY MATERIAL
The Supplemen a y Ma e ial o his a icle can be ound
online a : h ps://www. on ie sin.o g/a icles/10.3389/ endo.
2018.00547/ ull#supplemen a y-ma e ial
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