Maturitas 75 (2013) 7–21
Contents lists available at SciVerse ScienceDirect
Maturitas
journal homepage: www.elsevier.com/locate/maturitas
Review
The impact of coffee on health
A. Cano-Marquina a , J.J. Tarín b , A. Cano c,d,∗
a
Servicio de Radiología, Hospital Universitario General de Castellón, Avda Benicassim s/n, 12004 Castellon, Spain
Department of Functional Biology and Physical Anthropology, Facultad de Ciencias Biológicas, Campus Burjasot, University of Valencia, Valencia, Spain
c
Servicio de Obstetricia y Ginecología, Hospital Universitario Dr Peset, Av Gaspar Aguilar 90, 46017 Valencia, Spain
d
Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Av Blasco Ibáñez 15, 46010 Valencia, Spain
b
a r t i c l e
i n f o
Article history:
Received 31 January 2013
Received in revised form 4 February 2013
Accepted 7 February 2013
Keywords:
Coffee
Compounds
Health
Disease
Mortality
a b s t r a c t
Objective: Coffee is a beverage used worldwide. It includes a wide array of components that can have
potential implication on health. We have reviewed publications on the impact of coffee on a series of
health outcomes.
Methods: Articles published between January 1990 and December 2012 were selected after crossing coffee
or caffeine with a list of keywords representative of the most relevant health areas potentially affected
by coffee intake.
Results: Caffeine, chlorogenic acids and diterpenes are important components of coffee. Tolerance often
acts as a modulator of the biological actions of coffee. There is a significant impact of coffee on the
cardiovascular system, and on the metabolism of carbohydrates and lipids. Contrary to previous beliefs,
the various forms of arterial cardiovascular disease, arrhythmia or heart insufficiency seem unaffected by
coffee intake. Coffee is associated with a reduction in the incidence of diabetes and liver disease. Protection
seems to exist also for Parkinson’s disease among the neurological disorders, while its potential as an
osteoporosis risk factor is under debate. Its effect on cancer risk depends on the tissue concerned, although
it appears to favor risk reduction. Coffee consumption seems to reduce mortality.
Conclusion: The information gathered in recent years has generated a new concept of coffee, one which
does not match the common belief that coffee is mostly harmful. This view is further supported by the
discovery of a series of phyto-components with a beneficial profile. Reasonable optimism needs to be
tempered, however, by the insufficiency of the clinical data, which in most cases stem from observational
studies.
© 2013 Elsevier Ireland Ltd. All rights reserved.
Contents
1.
2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Bioactive compounds in coffee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Caffeine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Chlorogenic acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Diterpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The biological effect of coffee on organs and systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
Short and long-term effects. The point of tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.
Cardiovascular system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1.
Arterial wall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.2.
Blood pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.
Lipid metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4.
Homocysteine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Corresponding author at: Department of Pediatrics, Obstetrics and Gynecology, Facultad de Medicina, Av Blasco Ibáñez 15, 46010 Valencia, Spain. Tel.: +34 96 983087;
fax: +34 96 386 48 15.
E-mail addresses: AntonioJCano@hotmail.com (A. Cano-Marquina), Juan.J.Tarin@uv.es (J.J. Tarín), Antonio.Cano@uv.es (A. Cano).
0378-5122/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.maturitas.2013.02.002
8
A. Cano-Marquina et al. / Maturitas 75 (2013) 7–21
Carbohydrate metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5.1.
Caffeine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5.2.
Coffee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5.3.
Epidemiological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The impact of coffee on disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.
CVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.1.
CHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.2.
Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.3.
Arrhythmia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.4.
Heart insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.
Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.
Liver diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.
Neurological diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.1.
Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.2.
Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5.
Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.
Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Coffee and mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5.
5.
6.
7.
1. Introduction
Lifestyle characteristics are important determinants of healthy
aging. For example, there is consolidated evidence on the crucial
role of exercise as a preventive measure against cardiovascular disease (CVD), cancer, depression, or cognitive impairment, among
other ailments [1]. Nutrition is also a pivotal constituent of a
healthy lifestyle, and epidemiological evidence links diets rich in
fruits, vegetables and wine, such as the Mediterranean diet, with
healthy longevity [2]. In agreement with that evidence, there is
increasing interest in the so-called functional foods. Good quality
research has contributed to a better knowledge of the compounds
that are at the base of the attributed benefits of certain nutrients.
Flavonoids for instance, have been involved in much of the protective effects of distinct legumes and fruits, and even of chocolate.
Formerly associated with obesity or caries, more recent experimental and clinical studies favor the protective role of chocolate against
hypertension, glucose intolerance, or other cardiovascular risk
factors [3].
The case of coffee seems similar to that of chocolate in many
ways. Traditionally recommended as a beverage to reduce or
omit because of a risky global profile, coffee has progressively
moved to a less negative position due to its better known phytochemistry. Coffee includes a complex mixture of compounds,
where caffeine has been perhaps the most widely known; however, coffee is also rich in other bioactive substances with a
wide array of physiological effects. The list comprises up to 1000
described phytochemicals. Among them, are phenols, including
chlorogenic and caffeic acid, lactones, diterpenes, including cafestol
and kahweol, niacin, and the vitamin B3 precursor trigonelline.
Moreover, coffee is rich in vitamin B3, magnesium and potassium
[4,5].
The relevance of the overall impact of coffee on health derives
from its worldwide use, with a global consumption that, according
to FAO, reached approximately 7 million tons per year [6]. Coffee is
taken as a brewed beverage that is prepared from the roasted seeds
of a bush of the genus Coffea. The coffee seeds, or beans, are contained in berries that, once matured, are processed and dried. The
history of coffee begins in Ethiopia, where it was attributed with
energizing properties at some time prior to the turn of the 14th
century [7]. By the middle of the 15th century there is evidence of
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coffee drinking in the Yemeni Sufi monasteries, from where it disseminated into the rest of the Middle East and northern Africa. The
intense trade of the Venetian ships with the Middle East opened
the doors of Europe to coffee, from where it was subsequently
introduced to America [8].
2. Search strategy
We searched the PubMed database for basic and clinical articles published from 1990 up to December 6th 2012. The relevant
terms “coffee” or “caffeine” were paired with “cardiovascular”,
“blood pressure” “hypertension”, “lipids”, “homocysteine”, “renin”,
“angiotensin”, “stroke”, “coronary”, “arrhythmia”, “diabetes”, “glucose”, “carbohydrate”, “insulin”, “central nervous”, “Parkinson”,
“Alzheimer”, “osteoporosis” “cancer” or “mortality”. No language
restrictions were imposed. The search yielded 10,625 references
(Fig. 1). Two investigators (A.C.-M. and J.J.T.) read the title, or
title and abstract when the title raised doubt about the content of the article. The list was reduced to 2234 references,
which were further scrutinized by reading each abstract. Attention was then concentrated on 296 papers. Priority was given
to the conclusions from meta-analyses and systematic reviews
when available. When more than one of any of them with similar conclusions was available, the most recently published one
received priority. Supplementary searches included a manual
search of the reference lists of pertinent original articles and
selected review papers. After crossing-cleaning the reference lists,
318 articles were selected for detailed assessment. One hundred
and fifty nine of those papers were finally chosen for citation
(Fig. 1).
3. Bioactive compounds in coffee
An understanding of the physiological effects of coffee is drastically limited by the complexities deriving from two factors, the
vast array of components included in the brewed product, and the
varied effects of each compound. Nonetheless, the present state of
knowledge allows for a reasonable understanding of the actions
associated with the main constituents.
A. Cano-Marquina et al. / Maturitas 75 (2013) 7–21
9
10,625 overall results of PubMed searching
(produced in 1990 or later)
8,391 rejected aer reviewing tle or abstract
(topic out of field, poor quality, or other reasons)
2,234 abstracts reviewed
1,938 refused aer reading the abstract
296 final arcles with usable informaon
22 papers added by hand-search of reference
lists of original arcles and review papers
318 arcles retrieved in full text
for detailed assessment
159 Selected arcles for citaon
Fig. 1. Flowchart for identifying the selected articles.
3.1. Caffeine
Caffeine is the most investigated component in coffee. Originally isolated from coffee beans in 1820, it was then subjected
to intensive pharmacologic research and initial clinical application [9]. Caffeine, together with theobromine and theophylline,
is a methylxanthine, a methylated derivative of xanthine (Fig. 2).
Xanthines constitute a group of alkaloids commonly used for their
stimulant and bronchodilator actions.
Among dietary products, the concentration of this natural alkaloid is highest in coffee, although it is also detected in tea leaves and
other plants. The amount of caffeine in a cup of coffee is influenced
by the method of coffee preparation (e.g. boiled, filtered, espresso).
A sample of home-prepared cups of coffee in Canada has been
shown to contain from 30 to 175 mg [10]. The standard value for the
United States has been calculated to be 85 mg for ground roasted
coffee, 60 mg for instant and 3 mg for decaffeinated [11], whereas
the quantity of caffeine in one espresso may reach 200–300 mg [12].
Fig. 2. Molecular structures of principal compounds in coffee. Chlorogenic acid is represented by the 5-O-caffeoylquinic acid, the most frequent isomer.
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A. Cano-Marquina et al. / Maturitas 75 (2013) 7–21
Fig. 3. Phenolic acids are the most abundant polyphenols in coffee. Caffeic acid,
which is unrelated to caffeine, is the main phenolic acid in coffee. Caffeic acid may
be converted to ferulic acid, another type of phenolic acid by the intervention of
the enzyme catechol-O-methyltransferase (COMT). Both compounds may form an
ester bond with quinic acid, and generate any of the many isomers included in
the family of the chlorogenic acids. Nonetheless, the most frequent isomer is the
5-O-caffeoylquinic acid that, because of that, is commonly called chlorogenic acid.
Caffeine has a half-life of approximately 4–6 h. Its metabolism
occurs primarily in the liver, where the cytochrome P450 isoform CYP1A2 accounts for almost 95% of the primary metabolism.
Two to three cups of coffee can result in plasma caffeine levels of
20–40 ␮mol/L, a concentration in which the main action of caffeine is that of an antagonist of adenosine receptors. The picture
is complex because there are four different subtypes of adenosine
receptors, designated as adenosine A1 , A2A , A2B , and A3 [13]. Moreover, adenosine receptors are expressed in most tissues, such as
the central nervous system, the vascular endothelium, heart, liver,
adipose tissue, and muscle. As a consequence, there is a vast range
of potential responses to caffeine that, as will be commented on
later, is only a part of the physiological effects of coffee.
Pharmacologic studies confirm that adenosine receptors show
specialization for binding to Gi or Gs proteins, and consequently
decrease (A1 and A3 ) or increase (A2A and A2B ) the level of intracellular cyclic adenosine monophosphate (cAMP). Other intracellular
pathways associated with adenosine receptors include the modulation of phosphodiesterases and the mobilization of intracellular
calcium, but the concentrations required to achieve those effects
are far higher than those achieved by coffee consumption [14].
The physiological actions of caffeine concentration found in
human coffee drinkers include several primary and secondary
effects described in selective pharmacological experiments. However, some of them do not reproduce, or are counterbalanced
by actions at other targets, when caffeine is directly administered to humans. The main detected effects of caffeine in humans
affect the cardiovascular system and the central nervous system,
together with modifications in the metabolism of carbohydrates or
in inflammatory mechanisms. Other actions of caffeine include activation of the metabolic rate and diuresis (for a review see [15,16]).
Fig. 4. Main metabolic products of ingested chlorogenic acid, as obtained from highperformance chromatography in humans. The esterase activity in the small intestine
hydrolyzes the ester bond and generates caffeic acid, which is then conjugated.
Ferulic acid, resulting from either metabolism of caffeic acid or hydrolysis of ferulicbased chlorogenic acid, may be also detected. Therefore, the first wave of chlorogenic
acid metabolites in plasma corresponds to small bowel absorption, and is mainly
composed by the conjugates of caffeic acid (caffeic acid sulfate) and ferulic acid
(ferulic acid sulfate). The second wave, which attains a much higher concentration
in plasma, presents after approximately 4 h of ingestion. This later manifestation is
taken as an indication of absorption in the large intestine, where there is a crucial
role of the microbiota. At this stage, much of the present phenolic acid in the gut
has been metabolized by a reductase enzyme to dihydrocaffeic or dihydroferulic
acid, which may be also conjugated with sulfate groups. The order in which they
are listed and the thickness of the arrows in the figure correspond to the relative
quantitative importance. Based on data from citation 21. See text for further details.
Ch-A: chlorogenic acid; Caf-A: caffeic acid; Dihydrocaf-A: dihydrocaffeic acid.
acids (CQA), feruloylquinic acids (FQA) that may be found in several isomeric forms depending on the position of the ester link.
Additionally, there can be one or two phenolic acids per quinic
acid moiety thus creating a complex pattern. The most common
form of chlorogenic acid is 5-O-caffeoylquinic acid, which is often
called chlorogenic acid (Fig. 2). The particular profile of compounds
depends on coffee variety, roasting and processing (for a detailed
review, see [19]).
The metabolism of chlorogenic acids is still unclear, although
studies in humans have confirmed that it mainly occurs at two stations, small intestine and colon (for review, see [20]) (Fig. 4). The
first step is carried out by the active esterase enzymes, which generate the original phenolic acids in both the small and large bowel.
Absorption in the colon is probably the most quantitatively relevant, representing around two-thirds of the ingested chlorogenic
acid. The metabolism is carried out by the microbiota, which cleaves
the ester bond and provides esterases for further metabolism.
Different metabolites of chlorogenic acids are found in urine.
The 24-h excretion of the parent compounds and their metabolites
approximates 27–29% of intake [21].
3.3. Diterpenes
3.2. Chlorogenic acids
As are cocoa and other plant-derived products, coffee is rich
in polyphenols. These compounds are classified into flavonoids,
phenolic acids, lignans and stilbenes, which show a considerable
antioxidant potential [17]. The most common polyphenols in coffee
are phenolic acids, mainly caffeic acid, a type of trans-cinnamic acid,
and its derivative, chlorogenic acid (Fig. 3). A single serving of coffee
provides between 20 and 675 mg of chlorogenic acids depending
on the type of roast and the volume consumed [18].
Chlorogenic acids constitute a family of esters made up of transcinnamic acids, mainly caffeic acid and ferulic acid, and quinic
acid. The resulting forms of chlorogenic acids include caffeoylquinic
Cafestol and kahweol are two diterpenes found in coffee oil
(Fig. 2). Their interest resides in their being the main cholesterolraising compounds in coffee. They are retained in part by paper or
popular sock filters, but are preserved when coffee is directly prepared by boiling the ground beans, as is the case with Turkish or
Scandinavian coffee, with the French plunger, or with the South
European systems, where pressed ground coffee beans are used
directly, in either espresso or coffee pot so popular in Spanish or
Italian homes. It is unclear why the South-European espresso or
coffee pots, where boiled water is directly passed through pressed
coffee powder without any filtering, is considered to be a lower
source of cafestol and kahweol. It may be speculated that the short
A. Cano-Marquina et al. / Maturitas 75 (2013) 7–21
11
Table 1
Concentrations of cafestol and kahweol per coffee cup and predicted effects on serum cholesterol for consuming 5 cups daily. Different brewing methods are presented.
Cafestol (mg/cup)
Scandinavian (n = 14)
Turkish/Greek (n = 11)
French press (n = 5)
Espresso (n = 10)
Singapore (filtered sock) (n = 14)
0.64–9.68
0.4–8.0
1.84–4.4
0.16–2.32
0.02–0.23
Kahweol (mg/cup)
0.8–11.68
0.08–8.56
2.08–6.4
0.16–3.12
0.01–0.06
Cholesterol (mg/dL) (5 cups/d)
Triglycerides (mg/dL) (5 cups/d)
7.0
8.89
8.12
3.48
0.39
7.16
9.12
8.46
3.26
<0.65
Adapted from Ref. [22].
1 cup = 120 mL.
time of contact between water and coffee may be a possible explanation or alternatively, the lack of small particles in the systems that
decant the boiled fluid without filtration. The diterpene content of
each coffee preparation system is presented in Table 1 [22].
4. The biological effect of coffee on organs and systems
Adenosine receptors are ubiquitous, being detected in the heart
and endothelium, liver, nervous system, fat, and muscle. Since coffee also includes a mixture of substances in addition to caffeine, the
variety of potential targets where the beverage might exert significant biological effects is high. The following paragraphs review the
most significant known actions of coffee on the main organs and
systems, as a result of the conclusions obtained in either experimental or clinical studies. In most cases of the latter, randomized
controlled trials are available but were usually performed on small
groups of individuals for a maximum of a few weeks. Data from
large populations have been obtained in either cross-sectional or
longitudinal observational studies in most cases. When possible,
the separate effects of caffeine and whole coffee are presented.
4.1. Short and long-term effects. The point of tolerance
The analysis of the effects of coffee results not only from the
interaction of a considerable number of active substances with a
wide assortment of targets, but also from experimental and clinical
evidence confirming tolerance, which imposes a reduction in the
response as a consequence of previous exposure. Consequently, it
is possible that the effects observed after first exposure differ from
those observed after a series of repetitive coffee dosages. Accordingly, it is possible that the effects observed in clinical studies might
change depending on whether the population is totally naïve to
coffee or, as is more common, it is comprised of regular consumers.
Work performed some 30 years ago detected tolerance to the
effects of caffeine on blood pressure, heart rate, and plasma levels of catecholamines and renin after only 4 days of administration
[23]. A similar adaptation was found after 5 days of caffeinated
coffee intake [24]. Complexity, however, has increased as a result
of posterior studies that have presented a more heterogeneous
picture. There is data showing that tolerance may be detected in
some, but not all coffee drinkers, and debate has arisen on whether
this heterogeneity may be influenced by the particular pharmacokinetics of caffeine in each subject [25,26]. It is possible that the
inter-individual differences might be conditioned by genetic background, as suggested by a study comparing mono- and di-zygotic
twins [27].
It is also possible that tolerance does not necessarily affect
the whole range of biological responses to coffee ingestion.
This hypothesis was raised after a study in which participants
were stimulated with a triple espresso, with decaffeinated triple
espresso, with the intravenous administration of caffeine (250 mg)
or with placebo (saline) [28]. Muscle sympathetic nervous activity
significantly increased after intravenous caffeine or coffee intake
in both habitual and nonhabitual coffee drinkers. Also blood pressure increased in both categories after intravenous caffeine but,
interestingly, did not increase after coffee intake in regular coffee
drinkers. So, it seems that tolerance may be asymmetric at the different targets that are sensitive to coffee, both in its magnitude, as
well as in the intervals that are required between stimuli.
In order to gain in clarity, it is practical to distinguishing between
studies on pure naïve and on regular coffee drinkers. This may entail
difficulty, because most studies include habitual coffee consumers
given the difficulty in selecting individuals who do not drink coffee.
4.2. Cardiovascular system
4.2.1. Arterial wall
4.2.1.1. Caffeine. Much of the interest in the cardiovascular system
has focused on the specific actions of caffeine. The main pharmacologic action of caffeine at the concentration reached by coffee
ingestion consists of antagonism of the A1 and A2A adenosine receptors. The impact of caffeine on these receptor isoforms has been
investigated in different models, including isolated vessel preparations or anesthetized animals [14]. There are also direct experiences
in humans, in territories such as the isolated forearm, in an attempt
to investigate the direct effect on the vascular tone without potential interferences of central or reflex counter-regulations. One study
on non-habitual caffeine consumers found that 300 mg of caffeine,
which may be similar to the ingestion of 2–5 cups of coffee, did not
alter flow mediated dilation (FMD), but increased the endothelialmediated response subsequent to the use of acetylcholine, an
endothelium-dependent vasodilator. Interestingly, this protective
effect was abrogated when subjects were treated with a nitric oxide
synthase inhibitor, an indication in favor of an involvement of nitric
oxide production in the caffeine-mediated facilitation of the acetylcholine vasodilating effect [29].
Coffee, however, contains many substances in addition to caffeine. This is why interest has arisen on direct clinical studies in
humans who take either caffeinated or decaffeinated coffee in a
dose-range commonly used by most consumers.
4.2.1.2. Coffee. The impact of one caffeinated or decaffeinated
espresso coffee on endothelial function was examined in a doubleblind, crossover study on healthy subjects. Following caffeinated
coffee ingestion there was a slight, but significant decrease in FMD
[30]. This effect was opposite to that detected for decaffeinated
espresso, which promoted a dose-dependent increase in FMD in a
previous study by the same investigators [31]. The possibility of a
mediation of the antioxidant compounds in coffee, such as chlorogenic acid, was proposed as a hypothesis. Differences between
coffee and decaffeinated coffee were also detected in another randomized, single-blind study where the intake of one cup containing
80 mg of caffeine was followed by a reduction in FMD in non-heavy
coffee consumers; the decline was not reproduced with decaffeinated coffee [32] (Fig. 5). Of interest in this study, the effect was
acute and did not last for longer than 60 min.
Japanese investigators suggested that those differences
between caffeinated and decaffeinated coffee might be further
modulated by hydroxyhydroquinone, a compound generated by
the roasting of coffee beans. Hydroxyhydroquinone might interfere
12
A. Cano-Marquina et al. / Maturitas 75 (2013) 7–21
Fig. 5. Flow mediated dilation (FMD) of the brachial artery after intake of caffeinated
or decaffeinated coffee. Error bars represent S.E.M.
From citation 32, with permission. © Portland Press.
with the protective function promoted by chlorogenic acid at the
vascular endothelium [33].
There is also work on the effect of coffee on large arteries. Parameters such as pulse wave analysis or radial artery tonometry are
widely used in hemodynamic investigation assessing cardiovascular risk profile [34]. In a study on subjects who drank caffeinated
and decaffeinated coffee in random order, both the carotid femoral
pulse wave and the arterial wave reflection at the aorta, two indicators of arterial stiffness, increased after caffeinated coffee intake
[35]. Similar results were found by other groups, when investigating coffee alone [36] or its synergy with smoking [37].
4.2.2. Blood pressure
4.2.2.1. Caffeine. Pharmacologic studies have confirmed that the
activation of adenosine receptors has a series of cardiovascular
effects affecting heart rate and blood pressure, through separate
effects on the myocardium, the vascular tone, the activity of the
sympathetic nervous system, and the renin–angiotensin system
(reviewed in [14]).
The association of a slight increase, in the order of 10–20 mm Hg,
in blood pressure at approximately 1 h after caffeine ingestion was
already confirmed some decades ago in a small study with healthy
subjects who were not regular coffee drinkers [38]. There was a
concomitant increase of renin and catecholamines and a decrease,
which might be followed by an ulterior increase, in heart rate. The
increase in blood pressure was corroborated in another study in
which caffeine was administered to subjects who had abstained
from coffee the week prior to the study [39]. The pressor effect did
not seem to be due to an increase in cardiac output or myocardial
contractility, but to an increased systemic vascular resistance, most
probably influenced by the above mentioned changes in renin and
amines, together with the direct effect of caffeine. According to a
more recent study, this mechanism might be different in women,
who undergo an elevation in cardiac output and stroke volume, but
no changes in peripheral resistance [40].
The elevation of blood pressure in association with the intake
of caffeine (200–300 mg) in already hypertensive individuals has
been investigated in several trials, which are unanimous in detecting slight increases in both systolic and diastolic pressure for up to
3 h after caffeine ingestion, according to a recent systematic review
and meta-analysis [41].
Tolerance to the pressor effects of caffeine, which has been found
in clinical studies, may be heterogeneous and depend on the personal idiosyncrasy of each subject, as shown in a placebo-controlled
study [42] (Fig. 6). In agreement with that finding, a recent study has
shown that, genetic traits linked to polymorphisms in the adenosine A2A receptors and in the ␣(2)-adrenergic receptors might
modify the response in certain individuals [43].
4.2.2.2. Coffee. Apart from the pressor effects of caffeine, the question has arisen on whether the response may be mitigated, or even
reversed, after the ingestion of coffee. Chlorogenic acid, for example, has been assigned an antioxidant effect, which associates with
improved endothelial function and a limiting action against the
increase of blood pressure (reviewed in [44]). The proof of concept derives from studies using decaffeinated coffee, which had a
mitigated effect in one study [45] but, in turn, reproduced the same
pressor effect as caffeinated coffee in another study [28]. The reason for the divergence is unclear, but the previously mentioned
hypothesis about the possible generation of hydroxyhydroquinone
and its interference with chlorogenic acid might be operative [33].
In agreement with findings for caffeine, tolerance to the pressor effect of coffee has been found in some studies. Contrary to
nonhabitual coffee drinkers, blood pressure remained unchanged
despite similar changes in sympathetic activity in an above cited
study [28]. Moreover, two systematic reviews and meta-analyses
support a neutral effect of chronic coffee intake on blood pressure in
either unselected [46] or already hypertensive subjects [41]. Other
investigators have found that the circulating level of caffeine resulting from previous coffee intake has a modulating influence because
it is inversely correlated with blood pressure response [25].
4.3. Lipid metabolism
There are two distinct reasons for finding alterations in circulating lipids after coffee intake. One of them is that unfiltered coffee
is rich in the cholesterol-raising diterpenes kahweol and cafestol.
The other is that the antioxidants included in coffee might reduce
lipid oxidation.
A small observational study detected an 8.2% increase in total
cholesterol in men consuming two small cups per day of boiled
Turkish coffee [47]. The most consolidated and updated evidence comes from a recent meta-analysis that, including only
randomized controlled trials, has found that the intake of coffee,
especially the unfiltered modality, contributes significantly to the
increase in total cholesterol, low-density lipoprotein-cholesterol
(LDL-C) and triglycerides [48]. The lipid changes are also detected
in non-habitual drinkers, as confirmed by a study that examined the effect in subjects who refrained from drinking coffee
in the previous month [49]. The details of this study are important because the investigators showed that the ratio of LDL to
high-density lipoprotein-cholesterol (HDL) and of apolipoprotein
B to apolipoprotein A-I decreased significantly by 8% and 9%,
respectively. Therefore, the increase in total cholesterol might
offer a beneficial face thanks to the induction of a protective
balance between the detrimental LDL and the favorable HDL, or
their respectively related apolipoprotein B- and apolipoprotein AI
(Fig. 7).
One interesting point regarding the persistence of the lipid
changes, a controlled Scandinavian study found that the effect vanished after 3 weeks of coffee abstinence [50].
There has been debate on whether the antioxidants present in
coffee might protect low-density lipoprotein (LDL) particles from
oxidation. The topic has been insufficiently investigated, with two
small studies reporting protective (boiled coffee for 1 week) [51]
and neutral (filtered coffee for 3 weeks) [52] effects.
4.4. Homocysteine
Elevated homocysteine in plasma has been associated with
increased cardiovascular risk in observational studies [53,54]. The
elevation of homocysteine may result from genetic defects, for
example, mutation in the methylenetetrahydrofolate reductase
enzyme or by insufficiency in vitamin B12, folate, or vitamin B6. There is controversy, however, on whether the amino acid acts
A. Cano-Marquina et al. / Maturitas 75 (2013) 7–21
13
Fig. 6. The upper panel presents mean/SEM change in systolic and diastolic blood pressure at 40–60 min after placebo or caffeine challenge on a test day after 5 days of no
caffeine in the diet compared with caffeine 300 or 600 mg/day in the diet. The lower panel shows different response when participants were divided into those presenting
high or low tolerance. * Indicates highly significant differences, oscillating between p < 0.0001 and p < 0.009. BP: blood pressure; PP: placebo–placebo: PC: placebo–caffeine;
C300: caffeine 300 mg/day; C600: caffeine 600 mg/day.
From citation 42, © Elsevier, with permission.
only as an indirect indicator, or instead, has a role in the pathophysiology of CVD. Against the latter, the reduction of homocysteine
with folic acid and vitamin B3 did not modify cardiovascular
risk [55].
There is some literature on the homocysteine increasing effects
of coffee. Elevations in plasma homocysteine in the range of 10–20%
were found in trials on healthy individuals who drank 1 L/day
of unfiltered coffee for 2–4 weeks [56,57]. This effect seems to
result from the independent contribution of both caffeine and
coffee itself [58]. The ATTICA Study, a larger, population-based
study, which included 2282 participants in Greece, concluded
similarly [59]. The coffee-induced increase in homocysteine may
be controlled by treatment with folic acid [60], but given
the inconsistencies about the implication of homocysteine in
the pathogenesis of CVD, this observation seems of low relevance.
4.5. Carbohydrate metabolism
As mentioned for the impact on previous targets, caffeine and
coffee are two different challenges and, consequently, do not
necessarily have the same impact on carbohydrate metabolism.
The acute effects of both caffeine and coffee on carbohydrate
metabolism have been examined with two techniques, the
euglycemic–hyperinsulinemic clamp, which explores the peripheral tissue response to insulin, and the oral glucose tolerance test
(OGTT), which is influenced by the response of the gut, pancreatic
␤ cells and the liver.
4.5.1. Caffeine
A series of trials during the last 10–12 years has been unanimous
in that caffeine increases insulin resistance by 15–30%, and that the
14
A. Cano-Marquina et al. / Maturitas 75 (2013) 7–21
Fig. 7. There is not a clear conclusion on whether the balance of coffee
on lipids favors protection or harm. There is a consistent consensus in that
coffee increases total cholesterol and low-density lipoprotein cholesterol (LDLcholesterol), although the magnitude of the effect seems to decrease in modalities
of coffee preparation that use any form of filter. Data from investigators that
have studied other parameters associated with lipid metabolism suggest that
coffee may reduce the LDL-cholesterol/HDL-cholesterol ratio, the apolipoprotein
B/apolipoprotein AI ratio, and the LDL-cholesterol sensitivity to oxidation. LDLC: LDL-cholesterol; HDL-C: HDL-cholesterol; Apo B: apolipoprotein B; Apo AI:
apolipoprotein AI; oxLDL-C: oxidized LDL.
most important reason is impaired glucose disposal in the skeletal
muscle (reviewed in [16]).
Studies on regular coffee drinkers further confirm that caffeine
effect. A trial on subjects who received 200 mg of caffeine or placebo
during 7 days confirmed that caffeine significantly impaired insulin
sensitivity, although it did not alter glucose levels [61]. Findings in
the same direction have been obtained when subjects with diabetes
have been investigated. In a small group of habitual coffee drinkers
with type 2 diabetes mellitus, the addition of 250 mg of caffeine to
decaffeinated coffee was followed by a significant increase in the
glucose and insulin response in the course of a mixed-meal tolerance test (MMTT), in comparison with decaffeinated coffee alone
[62]. The responsibility of caffeine in subjects with type II diabetes
has been further confirmed by investigators who have detected
increased glucose response after meals [63].
4.5.2. Coffee
The acute ingestion of caffeinated coffee follows a pattern similar to that of caffeine, with a detrimental effect on glucose tolerance
and insulin sensitivity (reviewed in [16]). As for other clinical targets formerly mentioned, interest has arisen on whether other
substances in coffee, like polyphenols, might modulate carbohydrate metabolism and, should that be the case, in which sense.
Comparisons between caffeinated coffee and decaffeinated coffee
in clinical studies may help to clarify that point. Moreover, comparisons between placebo and decaffeinated data may help answer
whether coffee substances distinct from caffeine are not only neutral, but even protective.
There is not enough information to clearly resolve those important questions, but one study on 11 non-caffeine user males
detected that the area under the curve for glucose and insulin
was lower for decaffeinated coffee than for caffeine in the course
of a 2-h OGTT [64] (Fig. 8). Interestingly, the ingestion of decaffeinated coffee resulted in a 50% lower glucose response than
placebo in this study. Another small, well-designed study found
that decaffeinated coffee had a slight antagonistic effect on intestinal glucose absorption [65]. Other investigators directly compared
decaffeinated coffee with chlorogenic acid and trigonelline and
found no difference in the insulin or glucose area under the curve
during an OGTT when compared with placebo [66].
Whether the response is different on people with diabetes mellitus was explored in a study on habitual coffee drinkers. Following
a cross-over design, the investigators detected that the glucose
Fig. 8. Time course for serum insulin (A) and whole blood glucose (B) concentrations before and through an oral glucose tolerance test for placebo (PL), caffeine
(CAF), chronic coffee ingestion (RCOF) or decaffeinated coffee (DECAF). Values are
means ± SEM.
From citation 64, © American Society for Nutrition, with permission.
response to an OGTT was marginally higher after ingesting caffeinated coffee than after either hot water or decaffeinated coffee
[67].
The above data, although still sparse, may be used to support
the hypothesis that, should tolerance develop to the effects of
caffeine and not, or in a lower magnitude, to those of protective
substances in coffee, either polyphenols or other agents, the balance of the effects of coffee on carbohydrate metabolism might
turn into protection. In fact, recent work has found a protective
balance when examining the effect of long term coffee consumption on modulators of carbohydrate metabolism. One study has
examined the effect of increasing filtered coffee dosages, up to
8 cups (1200 ml)/day for 2 months, on interleukin-18 (IL-18), 8isoprostane, and adiponectin. The interest in each molecule resides
in the predictive potential of IL-18 on type 2 diabetes development
[68], in the recognized value of 8-isoprostane as a marker of oxidative stress [69], and in the insulin sensitizing ability of adiponectin
[70]. The consumption of 8 cups/day of coffee is associated with
a decrease in IL-18 and in 8-isoprostane, and with an increase
in adiponectin [49]. A subsequent study in which regular coffee
drinkers were randomized to 5 cups/day of caffeinated coffee,
decaffeinated coffee or no coffee for 8 weeks confirmed the increase
in adiponectin [71]. Decaffeinated coffee, in turn, decreased the
concentration of fetuin-A, a hepatic glycoprotein associated with
insulin resistance and risk for type 2 diabetes.
A. Cano-Marquina et al. / Maturitas 75 (2013) 7–21
4.5.3. Epidemiological studies
The hypothesis of a favorable balance of habitual coffee consumption on insulin sensitivity has been further suggested by
epidemiological studies. A cross-sectional study on 954 nondiabetic adults from the Insulin Resistance Atherosclerosis Study
(IRAS) found that the regular consumption of caffeinated coffee, as
assessed by a food frequency questionnaire, was positively associated with insulin sensitivity and inversely related to 2 h post-load
glucose [72]. In agreement with those data, a cross-sectional and
prospective study on Dutch men and women followed during a
mean period of 6.4 years detected that regular coffee drinking
favored post-load rather than fasting glucose [73]. Two more studies, one on 2434 Finnish men and women and the other on 3224
Japanese men found that coffee consumption was significantly and
inversely associated with both fasting glucose and insulin, as well
as with the response to a 2-h OGTT [74,75].
Focusing the point from a different perspective, another study
has examined the effect of coffee on the levels of sex hormonebinding globulin (SHBG). The rationale for the study derived from
the known inverse association between circulating levels of SHBG
and insulin resistance, and of higher interest, on the risk for developing type 2 diabetes [76]. A direct relationship between coffee
consumption and circulating levels of SHBG was found in a group of
postmenopausal women from the Nurses’ Health Study (NHS) and
NHSII [77]. A subsequent case–control study nested in the prospective Women’s Health Study found that the multivariable-adjusted
mean levels of SHBG were significantly higher (26.6 nmol/l, p = 0.01)
in women consuming ≥4 cups/day of caffeinated coffee than in
nondrinkers (23.0 nmol/l) [78].
5. The impact of coffee on disease
The association of coffee consumption with clinical events has
been investigated through observational studies only. In addition
to this limitation, the small size of the sample has further restricted
the weight of the conclusions in some studies. However, those
weaknesses of the literature are partially balanced by the frequent
availability of numerous studies that, as presented in the following
sections, allow the use of more powerful analytical methods, such
as meta-analyses.
5.1. CVD
Due to a series of experimental or clinical data associating coffee
with changes in blood pressure, lipid profile, or insulin resistance,
there has been an interest in investigating the link between coffee
consumption and arterial CVD, either coronary heart disease (CHD)
or stroke. Precise knowledge of the acute effects of caffeine and
coffee on pharmacologic models, together with the acute effects on
blood pressure, has led to a widespread belief among the general
public that coffee is harmful.
5.1.1. CHD
Studies reviewing the evidence gathered in case–control studies
performed several years ago have suggested an increase in coronary
risk associated with coffee intake [79,80]. The results of cohort studies have been more varied. The balance has been well established
by a group of investigators that, using meta-analysis as a tool, has
examined the clinical studies published up to January 2008 [81].
Against the premises advocating for a harmful effect, the investigators could not find a deleterious effect of coffee on CHD risk (Fig. 9).
Of interest, a separate analysis by gender detected a slight beneficial effect with relative risk of 0.82 [95% confidence intervals (CI),
0.73–0.92] (p < 0.001) in women for moderate coffee consumption.
The potential susceptibility associated with previous pathology
has been examined as well. Coffee consumption was not associated
15
Fig. 9. A composition of the pooled relative risks (95% confidence intervals) for the
association between different categories of coffee drinking and risk for coronary
heart disease for all cohort studies. RR: relative risk; CI: confidence interval.
Modified from citation 81, © Elsevier, with permission.
with elevated risk in postmyocardial infarction patients [82]. Previous hypertension does not seem to confer risk either since a recent
meta-analysis, which included data from 7 cohort studies, found
no evidence of an association between regular coffee consumption
and any form of CVD [41].
Given the acute effects of coffee on several targets affecting
the cardiovascular system, particularly among infrequent drinkers,
the hypothesis has been raised that, apart from the apparent benefit detected in clinical studies, a higher risk might arise in the
time immediate to coffee ingestion or in more susceptible subjects. Indeed, a case–control study has detected an increased risk for
myocardial infarction in the hour following coffee intake, particularly in non-habitual coffee drinkers or in subjects with risk factors
[83].
5.1.2. Stroke
The effect of coffee on the risk of stroke has been investigated
less. Two recent meta-analyses, which have examined studies published up to 2011, have concluded that a weak inverse association
(around 10–20% risk reduction) may exist between coffee consumption and the risk of stroke [84,85].
As for CHD, the risk of ischemic stroke also appears to increase in
the hour subsequent to the ingestion of coffee among non-habitual
coffee drinkers according to a meta-analysis [86] (Table 2).
5.1.3. Arrhythmia
The association of coffee consumption and arrhythmia is a common belief, which arises from experimental studies with animal
models or from isolated clinical cases reports. A recent review of
both the experimental and the clinical evidence shows that, in
the case of experimental models, most, but not all studies, show
that high dosages of caffeine increase the frequency of ventricular arrhythmia. This effect seems mediated by the triggering of
catecholamines [87]. The dosages used in experimental studies,
Table 2
Risk for acute ischemic stroke in the hour after consuming coffee, tea, or cola.
Type of beverage
RR (95% CI)
Significance (p)
Coffee
Tea
Cola
2.0 (1.4–2.9)
0.9 (0.4–2.0)
1.0 (0.4–2.4)
<0.001
0.85
0.95
Data from citation 86.
RR: relative risk; CI: confidence intervals.
16
A. Cano-Marquina et al. / Maturitas 75 (2013) 7–21
however, are far from those achieved by the intake of coffee in
humans. Moreover, those studies with only caffeine ignore the
potential effects of substances like the antioxidants present in coffee.
As for other diseases, there are no randomized trials available,
but the observational studies are almost unanimous in showing
that the ingestion of coffee does not relate to higher risk for either
atrial or ventricular arrhythmia (reviewed in [87]). Subsequent to
the publication of that review, the association of coffee drinking and
the incidence of any form of cardiac arrhythmia leading to hospitalization were studied in 3137 persons. When taking non-coffee
drinkers as the referent, there was a slight, but significant inverse
relation between coffee intake and hospitalization for arrhythmia [88]. Moreover, the Framingham Heart Study has shown that
there is no association between diet caffeine consumption and risk
for atrial fibrillation [89]. Finally, the association between coffee
intake and QT interval duration, which has been associated with an
increased risk of ventricular arrhythmias and sudden cardiac death,
has not been confirmed in the Third National Health and Nutrition
Survey (NHANES III, 1988–1994) [90].
In summary, it may be concluded that the available evidence,
although limited, allows stating that there is not a clinical basis for
associating coffee intake and risk for cardiac arrhythmia. However,
the discrepancy brought by the experimental data imposes caution,
particularly in cases in which a catecholamine involvement is suspected or, simply, when there is a clear association between coffee
intake and the incidence of arrhythmia in a particular subject.
5.1.4. Heart insufficiency
The interest in heart insufficiency resides in the impact of heart
failure as a determinant of death. American statistics confirm that
heart failure is found in one out of every 9 diagnoses in death certificates [91]. A recent meta-analysis examining prospective studies
up to December 2011 found that moderate, but not high coffee consumption, is inversely related with risk of heart failure [92]. This
J-shaped dose–effect relationship suggests that components of coffee determining protection might reduce their effect with dosage,
although there is an absolute lack of knowledge of either the agents
or their mechanism.
5.2. Diabetes
The inverse association between coffee consumption and the
incidence of diabetes mellitus has been repeatedly observed by different investigators. A systematic review identified 9 cohort studies
of coffee consumption and risk of type 2 diabetes, including 193,473
participants and 8394 incident cases of type 2 diabetes. The relative
risk of type 2 diabetes was 0.65 (95% CI, 0.54–0.78) for the highest
(≥6 or ≥7 cups/day) and 0.72 (95% CI, 0.62–0.83) for the second
highest (4–6 cups/day) category of coffee consumption compared
with the lowest consumption category (0 or ≤2 cups/day) [93]. A
subsequent meta-analysis assessing 18 studies with information on
457,922 participants found a log-linear relationship and, of interest, was able to establish that every additional cup of coffee was
associated with a 7% reduction in the risk of incident diabetes [94].
A similar level of protection was found for decaffeinated coffee.
The protective effect of coffee has been also detected in particularly susceptible populations. The Strong Heart Study followed a
cohort of 1141 Native American subjects, a group known to present
a high incidence and prevalence of diabetes, over a period of 7.6
years. A high level (12 cups/day) of coffee consumption reduced
the risk of developing diabetes by 67% (hazard ratio: 0.33, 95% CI,
0.13–0.81) [95] (Fig. 10). The requirement of a moderate or high
intake to achieve protection was also found in another prospective
observational study, the Puerto Rico Heart Health Program. It found
Fig. 10. Crude incidence of diabetes by daily coffee consumption categories.
From citation 95, © Elsevier, with permission.
a significant, 25%, reduction in risk, only in individuals reporting an
intake of ≥4 servings/day [96].
5.3. Liver diseases
Some studies have suggested that habitual coffee consumption
may defend hepatocytes from damage, regardless of whether the
aggressive agent is a virus, alcohol, drugs, or other aggressors. This
protection translates into clinical data that suggest a reduced risk
against abnormal liver function tests, cirrhosis or hepatocellular
carcinoma (reviewed in [97]). In favor of this protection, studies
in both unselected and at risk population have found that coffee
consumption is associated with reduced levels of aspartate aminotransferases (AST) [98], gamma-glutamyltransferase (GGT) [99]
and alanine aminotransferase (ALN) [100]. There are also studies
suggesting that coffee reduces the risk of cirrhosis, a fibrotic hepatic
status that results from frequent tissue remodeling (reviewed in
[97]). Frequent or chronic inflammation following some types of
hepatitis is the most frequent cause.
The mechanism associated with the protective effect of coffee on
the liver is still unclear. In fact, caffeine antagonizes A2 adenosine
receptors at the concentration determined by the range of coffee
ingested by most consumers, as previously mentioned. The blockade of A2 receptors in immune cells leads to exacerbation, and not
protection, of acute inflammation (reviewed in [15]). Again, the
potential counterbalancing actions of other substances in coffee
should be considered to explain the contrast between this detrimental action and the protection consistently reported in clinical
studies.
5.4. Neurological diseases
5.4.1. Parkinson’s disease
Both case–control and cohort studies suggest a protective effect
against Parkinson’s disease that, according to data from a recent
meta-analysis, yields a 33% reduction in risk (RR: 0.67, 95% CI,
0.58–0.76) [101]. Another study published in the same year has
prospectively examined the effect of caffeine on 304,980 participants in the National Institutes of Health-AARP Diet and Health
Study. The odds ratio comparing the highest quintile of caffeine
intake with the lowest was 0.75 (95% CI, 0.60–0.94) for men and
0.60 (95% CI, 0.39–0.91) for women [102]. The protective effect of
caffeine was further confirmed by a meta-analysis on prospective
studies carried forward by authors in the same paper. The mechanism for the protection is unknown, although one study using
genome wide-based technology has proposed a link between coffee
and the glutamate receptor gene (GRIN2A) [103].
A. Cano-Marquina et al. / Maturitas 75 (2013) 7–21
It is interesting that one group of investigators has found that
hormone therapy in postmenopausal women may shift the balance
and convert caffeine into a risk factor for Parkinson disease in two
different cohorts [104–106].
5.4.2. Alzheimer’s disease
This outcome is under debate. Some favorable data from
experimental studies has nourished the hypothesis that caffeine
[107,108] chlorogenic acid [109] or their combination [110] may
protect against the cognitive deterioration or biological features of
Alzheimer’s disease in the central nervous system. Epidemiological
studies in humans, however, are sparse and controversial. A review
suggests that the balance of evidence favors protection [111], something further suggested by two subsequent studies. One of these
is an epidemiological study on 3494 men in the Honolulu-Asia
Aging Study, which investigated the association between coffee
consumption in midlife and subsequent disease. Neither coffee nor
caffeine intake could be associated with any form of cognitive deterioration, although high caffeine intake could be linked with a lower
risk of having any form of lesion types at autopsy in the 418 decedents in the group [112]. The other study has found, based in a
case–control design, that progression to dementia was reduced in
mild cognitive impairment subjects who had a higher concentration of caffeine in blood [113].
5.5. Osteoporosis
The association of coffee intake with bone metabolism, bone
density or bone fracture has been a matter of debate for years. The
background supporting association resides in initial findings that
the intake of coffee increased urinary calcium output, most probably as a result of the acidic load favored by coffee. Because bone
provides a large reservoir of buffering capacity from the content
of calcium salts, mobilization of this reservoir is a physiological
counterbalance against acidosis [114].
This concept has received subsequent indirect clinical support
[115]. Initial work, such as the Framingham study or others, did
detect an association between coffee intake and hip [116] or hip
and forearm [117] fracture. The finding, however, was not found by
other coetaneous studies [118,119]. In any case, there was agreement that harm occurred only in drinkers exceeding 2–3 cups/day
[116,120] and/or in subjects at particular risk, such as women with
impaired calcium metabolism because of low intake or because
of elderly age [118,121]. Successive studies, such as the Mediterranean Osteoporosis Study (MEDOS) and others, were unable to
detect any association between coffee intake and fracture [122] or
bone status [123,124].
The debate is still active, with some more recent studies suggesting that coffee intake, again in high volumes and in at risk
individuals, may be associated with bone loss [125], lower bone
density [126] or fracture [127,128]. Other studies have been unable
to identify the beverage as a risk factor [129–131] or a determinant
of bone loss in experimental studies [132].
The inconclusive debate has weakened interest in coffee as a
risk factor for osteoporosis. This position has been reinforced by
the absence of coffee on the list of risk factors contemplated in the
World Health Organization’s predictive scale for fracture (FRAX)
[133].
5.6. Cancer
Recent years have witnessed a considerable amount of epidemiological studies on the association of coffee with cancer, which due
to similar methodological limitations as other health outcomes, are
sometimes unsatisfactory. Therefore, interest has focused on metaanalyses or pooled analyses that have tried to by-pass the shortages
17
of individual studies. Different groups of investigators have used
that strategy to clarify a potential association of coffee with cancer in the ovary [134,135], pancreas [136,137], bladder [138,140],
prostate [141], colon or rectum [142–144], lung [145], stomach
[146] and breast [147]. Most analyses give a neutral effect, although
some discrepancy may be found. This is the case of pancreatic cancer, for which coffee has been concluded to be neutral [136.] or
protective [137], or of bladder cancer, for which the most recent
meta-analysis supports an inconclusive balance [140] against the
increased risk found previously [139].
There is data suggesting protection against liver cancer, as
brought up by two meta-analyses [148,149] and subsequent clinical
studies [150–152]. In addition, but with less consistency, protection has been suggested against oral cavity-pharynx cancer by
one meta-analysis [153], which has been further confirmed by
a subsequent study [154]. The meta-analysis also included the
effect on larynx cancer, esophageal squamous cell carcinoma, and
esophageal adenocarcinoma, with a neutral result in all three. Protection has been detected against endometrial cancer [155,156]
and against total cancer [157]. The magnitude of the effect of coffee intake on the risk for different types of cancer is presented in
Table 3.
There is not a clear explanation of how coffee may protect
against cancer, but the hypothesis of an implication of the proinflammatory actions of caffeine has been raised as a potential
mechanism. Caffeine acts as an antagonist of the A2 receptors
at the concentration range achieved during normal coffee intake
in humans. Consequently, caffeine does not operate as a phosphodiesterase inhibitor, a pharmacologic effect of the alkaloid
when acting at higher concentrations. This lack of stimulation may
reduce the intracellular availability of cAMP, which is an antiinflammatory agent in T lymphocytes (reviewed in [15]). Caffeine
might then act as a pro-inflammatory agent. In this way, the alkaloid might behave similarly to immunotherapy in the treatment of
tumors. The achievement of an inflammatory response is the objective of the modern approach that uses cancer vaccines, genetically
designed antitumor T cells, etc.
6. Coffee and mortality
Given the multiple links between coffee consumption and
chronic diseases, it is important to discern whether there is
any association between coffee intake and any cause mortality.
Reduced mortality has been found in studies in which the population has been segmented, as for example, individuals suffering type
2 diabetes mellitus [158]. More conclusive has been a recent study
in which the huge population size conferred ample power to either
detect modest associations or develop subgroup analyses according to important baseline factors, such as cigarette smoking status
or others. The study examined 229,119 men and 173,141 women in
the National Institutes of Health-AARP Diet and Health Study. Coffee consumption was assessed once at baseline. After adjustment
for tobacco-smoking status and other potential confounders there
was a significant inverse association between coffee consumption
and total mortality. The magnitude of the effect was not dramatic
and seemed to stabilize after 2 or 3 cups consumption, since the
adjusted hazard ratios for death among coffee drinkers was 0.90
(95% CI, 0.86–0.93) for 2 or 3 cups, 0.88 (95% CI, 0.84–0.93) for 4 or
5 cups, and 0.90 (95% CI, 0.85–0.96) for 6 or more cups in the case
of men (p < 0.001 for the trend), while the respective figures for
women were 0.87 (95% CI, 0.83–0.92), 0.84 (95% CI, 0.79–0.90), and
0.85 (95% CI, 0.78–0.93) (p < 0.001 for trend) [159]. It is of interest
that the cause-specific mortality detected inverse associations for
death due to heart disease, respiratory disease, stroke, injuries and
accidents, diabetes, and infections, but not for death due to cancer.
18
A. Cano-Marquina et al. / Maturitas 75 (2013) 7–21
Table 3
Results obtained by meta-analyses on published data about coffee consumption and risk for different types of cancer.
Type of cancer
Risk [RR (95% CI)]
Ref.
Ovary
↔ [1.18 (0.97–1.44)]
↔ [1.13 (0.89–1.43)]
[134]
[135]
Pancreas
↔ [1.08 (0.94–1.25)]
[136]
↓ [0.82 (0.69–0.95)]a
[137]
Bladder
↔ [1.0 (0.8–1.3)]
↑ [1.18 (1.01–1.38)]
↑ [1.49 (1.27–1.75)]b
↔ [1.15 (0.88–1.52)]c
[138]
[139]
[140]
[140]
Case–control studiesb
Cohort studiesc
Prostate
↑ [1.16 (1.01–1.33)]d
[141]
Discrepancy between adjusted case–control studies, which
show harm [1.21 (1.03–1.43)] and cohort studies, which show
neutrality [1.06 (0.83–1.35)]d
Colon-rectum
↓ [0.76 (0.66–0.89)]e
↔ [1.07 (0.89–1.30)]
↔ [0.91 (0.81–1.02)]
[142]
[143]
[144]
Discrepancy between case–control studies, which show
protection [0.72 (0.61–0.84)] and cohort studies, which show
neutrality [0.97 (0.73–1.29)]e
Lung
↑ [1.27 (1.04–1.54)]f
[145]
Confounding by smoking not totally preventedf
Stomach
↔ [0.97 (0.86–1.09)]
[146]
Breast
↔ [0.95(0.90–1.00)]
[147]
Liverg
↓ [0.59 (0.49–0.72)]g
[148]
↓ [0.57 (0.49–0.67)]h
[149]
↓ [0.64 (0.51–0.80)]i
[153]
i
Oral cavity-pharynx
Comments
Association found in men but not in women in subgroup
analysisa
Further confirmation of protection by 3 clinical studies
(150–152) subsequent to the publication of the meta-analysisg
For an increase in consumption of 2 cups of coffee per dayh
Protection further confirmed by a prospective cohort study
(Hildebrand)i
Larynx
↔ [1.56 (0.60–4.02)]
[153]
Esophagus
↔ [0.87 (0.65–1.17)]j
↔ [1.18 (CI 0.81–1.71)]k
[153]
Squamous cell carcinomaj
adenocarcinomak
Endometrium
↓ [0.80 (0.68–0.94)]l
[155]
↓ [0.71 (0.62–0.81)]m
[156]
Dose-dependent protection [RR: 0.87 (95% CI: 0.78–0.97) for
low to moderate coffee drinkers], and [RR: 0.64 (95% CI:
0.48–0.86) for heavy coffee drinkers]. Summary RR for an
increase in 1 cup/day: 0.93 (95% CI: 0.39–0.97)l
Summary RR for an increase in 1 cup/day: 0.92 (95% CI:
0.90–0.93)m
↓ [0.87 (0.82–0.92)]n
[157]
All cancers
Data for regular coffee drinkers. RR, 95% CI for low to moderate
drinkers: 0.89, 0.84–0.93, and for heavy drinkers: 0.82,
0.74–0.89n
RR: relative risk; CI: confidence intervals; Ref: reference; ↑: coffee increases risk; ↔: coffee is neutral; ↓: coffee decreases risk.
7. Conclusion
Coffee is a beverage consumed worldwide, and whose health
implications are, consequently, of highest interest. The global view
on the impact of coffee on health has been displaced from a mostly
harmful balance toward a likely beneficial profile. The data in favor
of this optimistic perspective derive from the rather clear benefit
deriving from liver protection, diabetes and Parkinson’s risk reduction or recent observations on global mortality. Data on cancer seem
mostly balanced toward benefit as well. Moreover, the traditional
adscription of coffee as a risk factor for hypertension, osteoporosis or cardiovascular disease seems to vanish. Much of the contrast
between the former prevention and the present view may be influenced by the past association of coffee effects to caffeine in the
presence of an insufficient number of clinical studies. The subsequent arrival of more and better quality clinical data, together with
the improvement in the knowledge of such coffee components as
phenolic acids, has contributed to the change. It may be concluded,
therefore, that the labeling of coffee as a mostly harmful beverage
lacks support in the light of present knowledge.
Despite the good news, it must be stressed that much still
needs to be known. Most clinical studies, particularly those with
high numbers of participants, are only observational. Additionally,
the response relative to certain targets may be modified according to each personal profile, either because of genetic background
or because of a special vulnerability derived from risk factors, as
detailed above. This calls for caution in cases where there are prejudicial outcomes in terms of blood pressure, arrhythmia and the like,
persistently associated with coffee intake. Finally, coffee should not
be taken as a substitute, but only as a one more partner in a general strategy to promote health, where exercise and healthy diet
continue to play key and irreplaceable roles.
Contributors
Dr. Antonio Cano-Marquina and Prof. Juan J. Tarín have made
the systematic review of the literature and have made a first selection of articles. Moreover, they have been involved in analysis and
interpretation of data, revising the article critically for important
intellectual content and final approval of the version to be published.
Prof. Antonio Cano has been the leading author. He has been
involved in analysis and interpretation of data. Moreover, he has
written the manuscript and has decided its main contents.
Competing interest
All author authors declared that they have nothing to disclose.
A. Cano-Marquina et al. / Maturitas 75 (2013) 7–21
Funding
This manuscript has been supported by the Grant PS09/01687
from Instituto de Salud Carlos III, Fondo de Investigación Sanitaria,
Ministerio de Sanidad y Consumo, Madrid, Spain.
Provenance and peer review
Commissioned and externally peer reviewed.
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