Coffee, Caffeine, and Health Outcomes: An Umbrella Review

Abstract

To evaluate the associations between coffee and caffeine consumption and various health outcomes, we performed an umbrella review of the evidence from meta-analyses of observational studies and randomized controlled trials (RCTs). Of the 59 unique outcomes examined in the selected 112 meta-analyses of observational studies, coffee was associated with a probable decreased risk of breast, colorectal, colon, endometrial, and prostate cancers; cardiovascular disease and mortality; Parkinson's disease; and type-2 diabetes. Of the 14 unique outcomes examined in the 20 selected meta-analyses of observational studies, caffeine was associated with a probable decreased risk of Parkinson's disease and type-2 diabetes and an increased risk of pregnancy loss. Of the 12 unique acute outcomes examined in the selected 9 meta-analyses of RCTs, coffee was associated with a rise in serum lipids, but this result was affected by significant heterogeneity, and caffeine was associated with a rise in blood pressure. Given the spectrum of conditions studied and the robustness of many of the results, these findings indicate that coffee can be part of a healthful diet.

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Coffee, caffeine and health outcomes: an umbrella review
Giuseppe Grosso1,2, Justyna Godos1,3, Fabio Galvano3, Edward L Giovannucci4 5 6
1Integrated Cancer Registry of Catania-Messina-Siracusa-Enna, Catania, Italy;
2NNEdPro Global Centre for Nutrition and Health, St John’s Innovation Centre, Cambridge, UK;
3Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy;
4Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA;
5Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA;
6Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Emails
Giuseppe Grosso giuseppe.grosso@studium.unict.it
Justyna Godos justyna.godos@uj.edu.pl
Fabio Galvano fgalvano@unict.it
Edward L. Giovannucci egiovann@hsph.harvard.edu
Corresponding author: Giuseppe Grosso MD, PhD, Integrated Cancer Registry of Catania-Messina-Siracusa-Enna, Via S. Sofia 85, 95123
Catania, Italy. Phone: +39 0953782182; Fax: +39 0953782177; Email: giuseppe.grosso@studium.unict.it
Running title
Coffee and human health
Abstract
To evaluate the association between coffee and caffeine consumption with various health outcomes, we
performed an umbrella review of the evidence across meta-analyses of observational studies and
randomised controlled trials (RCTs). Out of the 60 unique outcomes examined in the selected 91 meta-
analyses of observational studies, coffee was associated with a probable decreased risk of breast,
colorectal, colon, endometrial, and prostate cancer, cardiovascular disease and mortality, Parkinson’s
disease, and type-2 diabetes; caffeine was associated with probable decreased risk of Parkinson’s disease
and type-2 diabetes and increased risk of pregnancy loss. Out of the 12 unique acute outcomes examined
in the selected 7 meta-analyses of RCTs, coffee was associated with rise in serum lipids but affected by
significant heterogeneity, and caffeine with rise in blood pressure. Given the spectrum of conditions studied
and the robustness of many of the results, these findings indicate that coffee can be part of a healthful diet.
Keywords
Coffee; caffeine; cardiovascular disease; cancer; diabetes; neurodegenerative disease.

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INTRODUCTION
Coffee, among the most consumed beverages worldwide, has been
demonstrated to exert a number of effects on human health (42).
The association between coffee consumption and a variety of
conditions and diseases has been examined extensively, often with
contrasting results. The main concerns regarding its safety regarded
its content in caffeine, the most widely consumed physiological
stimulant worldwide with side effects toward cardiovascular
outcomes (156). The caffeine content has been considered the main
responsible for such effects due to its blood pressure rising action as
a result of increase in total peripheral resistance. However, short
length of randomised controlled trials (RCTs) trials emphasized
mostly the acute effects of coffee consumption, while observational
studies often lacked adequate control for confounding factors (i.e.,
smoking status) contributing to the negative outcomes associated
with coffee consumption. Later on, improvements in analytic
techniques uncovered numerous potentially beneficial components
in coffee, including antioxidant polyphenols, to be highly
concentrated in coffee (83). This attracted a growing scientific
audience aimed to find potential beneficial effects of this beverage.
In the last 20 years, a number of studies on a broad range of
diseases besides cardiovascular-related conditions, such as cancer
and overall mortality, suggested that coffee may exert beneficial
effects on human health. These results are of great interest from a
public health point of view due to the high frequency of coffee
drinking.
There is a need to address the broad scope of benefits and issues
related to coffee consumption and health, and to describe the
present evidence comprehensively but concisely to decision makers.
Thus, we evaluated extensively the content and findings from meta-
analyses of observational studies and RCTs that examined
associations between coffee consumption or caffeine intake and any
clinical condition. We summarized the pooled results of
observational studies and RCTs, and evaluated consistency and
evidence of potential bias throughout the studies.
METHODS
Study selection
To execute the present umbrella review, a search of quantitative
reviews conducted on coffee consumption or administration and any
health outcome was performed through Medline and Embase
electronic databases from inception to August 2016. Search terms
were “coffee”, “caffeine”, and “meta-analysis”, only articles
conducted on humans and in English language were considered
eligible for review. The search was independently performed by two
authors (GG and JG) and any discrepancies were solved with
discussion. Inclusion criteria were the following: (i) meta-analyses of
observational studies considering coffee consumption/caffeine intake
as exposure variable of interest and any health outcome; (ii) meta-
analyses of RCTs assessing effects of coffee/caffeine administration
from any source and any clinical outcome. Exclusion criteria were: (i)
studies in which coffee consumption was part of the outcomes; (ii)
studies on genetic polymorphisms related to coffee consumption; (iii)
studies that evaluated the prevalence of coffee consumption; (iv)
RCTs that combined coffee administration with other treatments.
Data extraction
From each eligible meta-analysis, the following information was
abstracted: name of the first author and year of publication, outcome,
study design of included studies (including case-control/cross-
sectional and prospective), type of coffee (any/decaffeinated),
number of studies included, total population, number of cases,
measure of exposure [including highest versus lowest (reference)
category of exposure; second and third highest versus lowest
(reference) category of exposure; incremental cups/d [linear]; dose-
response per cup or fixed dose], effect sizes [risk ratio (RR), odds
ratio (OR), hazard ratio (HR), or standardized weighted difference
(SWD)]. Outcomes were categorized as follow: cancer,
cardiovascular, and “other”.
Data evaluation
Whenever more than one meta-analysis was conducted on the same
outcome, included the same study design, and the same type of
population, concordance for the main outcome of interest, including
direction and magnitude (overlapping confidence interval) of the
association was evaluated. For further analyses, the most
recent/exhaustive study was considered. When more than one study
design was evaluated, results were considered and reported in the
following order of importance: 1) meta-analyses of prospective
studies, 2) comprehensive of prospective and case-control studies,
or 3) case-control studies. The pooled analyses of the highest vs.
the lowest (reference) category of exposure and dose-response
analyses were evaluated. Direction, magnitude, and heterogeneity
(I2) were considered to have indication of level of evidence. When
meta-analyses reported subgroup analyses or stratified analyses,
potential confounding factors were investigated. The relation
between coffee consumption/caffeine intake and outcomes of
interest was finally categorized as following: convincing association,
probable association, suggestive association, or inconclusive
evidence. Criteria used for evidence categorization modified from the
Joint WHO/FAO Expert Consultation (1) are shown in Table 1. Given
the nature of the exposure, we took into special account the
following considerations: 1) smoking habits is a well-known
confounding factor when considering coffee drinking; thus evidence
(especially on outcomes that may be affected by smoking) should be
based on results adjustment by and, whether possible, stratified for
smoking status; 2) RCTs should be considered depending on time
scale, as acute effects may differ from chronic consumption of
coffee.
RESULTS
The search strategy yielded 241 articles, 24 of which were excluded
for the following reasons: 14 were narrative/systematic reviews; 6
were meta-analyses on the effects of a number of exposures,
including but not limited to coffee; 2 were meta-analyses of selected
group of cohorts; 1 was a meta-analysis of a non-randomized/non
controlled trial; 1 was a meta-analysis of coffee derivate (Figure 1).
In total, 127 articles (2; 4-9; 11; 13-19; 21-23; 26-36; 38-41; 44; 46;
48-59; 61-82; 84; 85; 87; 89; 90; 93; 95; 97-99; 102-105; 107; 109;
110; 112-122; 124; 125; 127-151; 153-155) including 112 meta-
analyses of observational studies on coffee (2; 4-9; 11; 14-17; 21;
23; 27-36; 38; 40; 41; 44; 46; 49-58; 61-80; 82; 84; 85; 87; 90; 93;
95; 97; 99; 102-105; 109; 112-122; 124; 125; 127-130; 132-151;
153; 154), 19 on caffeine (14; 15; 18; 19; 22; 23; 26; 29; 39; 40; 53;
54; 59; 67; 81; 104; 107; 110; 128; 153), 5 meta-analyses of RCTs
on coffee (13; 52; 98; 118; 155) and 4 on caffeine (48; 89; 98; 131)
were considered in this umbrella review. A total of 62 outcomes
related to coffee exposure and 14 related to caffeine have been
examined in observational studies and 6 related to coffee and 9
related to caffeine among RCTs (Figure 1).
Meta-analyses of observational studies on coffee/caffeine
intake and health outcomes
The characteristics and summary of risk estimates of 40 non-
overlapping meta-analyses for 62 unique outcomes related to coffee
consumption (5; 9; 11; 14; 23; 28; 30; 33; 35; 36; 40; 41; 44; 50; 53;
54; 61; 64; 65; 67; 69; 72-74; 80; 82; 84; 85; 103; 105; 112; 115;
118; 121; 134; 138; 140; 148; 150; 153) are showed in Figure 2,
while those of 11 non-overlapping meta-analyses for 11 unique
outcomes related to decaffeinated coffee consumption (14; 30; 35;
50; 53; 54; 65; 134; 140; 142; 153) and 9 non-overlapping meta-
analyses for 14 unique outcomes related to caffeine intake (14; 22;
23; 40; 54; 59; 67; 81; 107) are showed in Figure 3. A total of 38
(43.1%) of the non-overlapping meta-analyses reported statistically
significant associations between coffee/caffeine intake and health
outcomes.
Regarding coffee consumption, meta-analyses on endometrial (153),

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liver (9), prostate (76), pancreatic (105), colon cancer (35) and
gallstone disease (148) reported a statistically significant reduced
risk for the highest versus the lowest category of coffee
consumption; those on atrial fibrillation (22), Parkinson’s disease
(81), and type-2 diabetes (54) reported reduced risk for the highest
versus the lowest category of intake of caffeine intake; those on
childhood leukemia (21) and pregnancy loss (67) reported increased
risk for the highest versus the lowest category of coffee
consumption; finally those on low birth weight (including measures)
(21; 107) and pregnancy loss (67) reported increased risk for the
highest versus the lowest category of caffeine intake during
pregnancy; all analyses had no evidence of large heterogeneity
(Figure 2). In addition, meta-analyses on colorectal adenoma (36),
oral cancer (72), skin cancers (melanoma and non-melanoma) (14;
140), all-cause mortality (50), death after myocardial infarction (11),
Parkinson’s disease (41), Alzheimer’s disease (80), type-2 diabetes
(54), metabolic syndrome, urolithiasis (138), and depression (40),
reported significant reduced risk for the highest versus the lowest
category of coffee consumption, and those on all-cause mortality
(50) and type-2 diabetes (54) reported reduced risk for the highest
versus the lowest category of decaffeinated coffee consumption but
with limited number of studies (≤3) or significant heterogeneity (I2
>50%). All these studies, however, did not clearly reported an
exposure dose, thus interpretation of results has to be considered for
generic “high” coffee intake compared to low/no consumption.
The variation of the effects by dose of coffee/caffeine was evaluated
in 25 non-overlapping meta-analyses testing for linear association
with 39 outcomes (9; 19; 22; 26; 29; 33; 35; 39; 40; 50; 56; 69; 70;
77-80; 84; 85; 105; 128; 134; 151; 153) (Supplementary Figure 1)
and 16 using a non-linear dose-response meta-analysis on 24
outcomes (27; 30; 35; 40; 53; 54; 62; 68; 93; 104; 112; 121; 127;
130; 148; 154) (Figure 4). Meta-analyses on liver (9), breast (70),
endometrial (153), skin (melanoma) (79), colon (35), and prostate
cancer (151), all-cause (50) and CVD mortality (85), Parkinson’s
disease (26), depression, type-2 diabetes (29), cirrhosis (56) and
chronic liver disease (9) reported significant decreased risk for 1 to 4
cup/d increment intake of coffee (depending on the study reference)
and endometrial cancer (153), Parkinson’s disease (26), depression
(40), atrial fibrillation (22), and type-2 diabetes (29) for 100 to 300
ml/d increment intake of caffeine (depending on the study reference)
(Supplementary Figure 1). In contrast, pregnancy loss, stillbirth, low
birth weight, and small-for-gestational-age (39), lung cancer (33),
and fracture risk (78) was increased with increasing intake of
coffee/caffeine (Supplementary Figure 1). Meta-analyses calculating
the non-linear dose-response relation between coffee/caffeine and
several outcomes showed significant decreased risk of stroke (62),
heart failure (93), CVD and all-cause mortality (27) for up to 4 cups/d
coffee, while decreased risk of colorectal and colon cancer (35),
breast cancer (53), skin cancer (melanoma) (127), Parkinson’s
disease (both coffee and caffeine exposure) (104), type-2 diabetes
(54), metabolic syndrome (112), and gallstone disease (148) with a
linear-dose response (Figure 4). An increased risk of lung cancer
(130), childhood acute lymphoblastic and myeloid leukemia (121)
was found for increased intake of coffee, while an inverted u-shaped
increased risk for moderate coffee consumption was found for
bladder cancer (154) and childhood acute leukemia (121). Similarly,
non-overlapping meta-analyses on caffeine showed a linear dose-
response decreased risk of type-2 diabetes (54), Parkinson’s
disease (104) and depression (40) (Figure 4).
Evaluation of sub-group analyses to test potential source of
heterogeneity for all included non-overlapping meta-analyses
interested mostly gender, geographical area, and adjustment for
smoking status while a limited number of studies reported also
stratified analyses for specific subgroups of individuals, including
smokers and non-smokers (Supplementary Figure 2). Some
differences were found by gender, as coffee was associated with
bladder and lung cancer (increased risk), and fractures (decreased
risk) in men but not in women. In contrast, meta-analysis on
gallstone diseases, skin cancer (melanoma) and lung cancer
showed a significant reduced risk in women. Regarding geographical
localization, the association of coffee and health outcomes varied
and did not show a discernible pattern. Sub-group analyses
considering studies adjusted by smoking status were conducted only
in a limited number of meta-analyses and showed reduced risk of
prostate cancer and all-cause mortality and increased risk of low
birth weight in studies adjusting for smoking while no significant
results were found in studies not adjusting; in contrast, significant
increased risk was found in meta-analyses on oral (72), laryngeal,
and lung cancer (33) only when considering studies not adjusting for
smoking status. Meta-analyses providing sub-group analyses
including results from studies stratifying by smokers and non-
smokers were even less and showed increased risk of adult glioma
(84) and childhood acute leukemia (121) among non-smokers while
no association was found for lung cancer risk (33).
General characteristics of meta-analyses for outcomes with more
than one meta-analysis published over time are presented in
Supplementary Table 1. Meta-analyses on atrial fibrillation (15; 61),
all-cause mortality (50; 85), childhood acute leukemia (21; 90; 121),
endometrial cancer (8; 49; 141; 153), liver cancer (6; 7; 9; 109; 141),
lung cancer (33; 119; 137), prostate cancer (16; 44; 76; 82; 102;
151), skin cancer (melanoma) (79; 127; 140), type-2 diabetes (29;
46; 54), metabolic syndrome (87; 112), Parkinson’s disease (caffeine
exposure) (26; 81), depression (40; 128), and low birth weight
(caffeine exposure) (18; 107) showed agreement over time in terms
of direction, magnitude, and statistical significance of the
association. In contrast, meta-analyses conducted on colorectal,
colon and rectal cancers (34-36; 51; 66; 141), breast cancer (53; 70;
120; 141), and pancreatic cancer (32; 97; 105; 124; 141) showed
differences in the statistical significance of the effect, but not in the
direction. Moreover, meta-analyses on oral/laryngeal cancer (17; 99;
125), atrial fibrillation (caffeine exposure) (15; 22), gastric cancer (4;
28; 68; 77; 113; 135; 136; 143), bladder cancer (44; 134; 141; 154),
and Alzheimer’s disease and cognitive disorders (caffeine exposure)
(59; 80; 110) showed increment in statistical significance or change
in the direction of the association (Supplementary Table 1).
Meta-analyses of RCTs on coffee consumption/caffeine intake
and health outcomes
Seven non-overlapping meta-analyses [5 including RCTs on coffee
(13; 52; 98; 118; 155) and 6 on caffeine (48; 60; 89; 98; 131; 155)]
explored cardiovascular (blood pressure and ventricular arrhythmia),
metabolic (blood lipids), respiratory (asthma), and pregnancy-related
outcomes (Table 2). The number of studies included ranged
between 1 and 12, the number of individuals ranged between 78 and
1488. All RCTs included in the meta-analyses investigated for acute
outcomes, as the length of the trials ranged between 180 min and 12
weeks. No meta-analysis was conducted to test the long-term
consumption of coffee or caffeine.
Among the non-overlapping meta-analyses of RCTs on coffee, a
significant increase in total cholesterol, LDL, and triglycerides was
found, despite with significant heterogeneity among studies included
(13), whereas no effects on blood pressure (118) and ventricular
fibrillation (including only one RCT) (155) were showed. Among the 6
non-overlapping meta-analyses of RCTs on caffeine, 2 studies (89;
98) demonstrated significant increment of blood pressure in both
healthy and hypertensive individuals after administration of caffeine
from coffee and one (including only one RCT) (48) reported
significant increase of serum insulin in newborns of mother
administered with caffeinated coffee compared with decaffeinated,
but no significant changes in birth weight and preterm birth and
small-for-gestational-age risk. In contrast, the other meta-analyses
showed significant increase in forced expiratory volume in one
second (131).
Three meta-analyses of RCTs on coffee explored the same
outcomes over time (Supplementary Table 2). Findings of meta-
analyses on SBP changed over time, varying from statistically
significant to non-significant results. Similarly, meta-analyses on
DBP showed differences in statistical significance, despite the most
recent two out of three meta-analyses reported same results.

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Summary evidence from observational studies and RCTs
Only blood pressure and pregnancy-related outcomes have been
examined in both meta-analyses of observational studies and of
RCTs. Meta-analyses of observational studies on blood pressure
showed substantial no effects of coffee drinking on hypertension risk
whereas RCTs on caffeine showed significant increase of both SBP
and DBP, suggesting that caffeine itself, rather than coffee, exert
blood pressure-rising effect while coffee has a probable no
significant effect. Meta-analyses on pregnancy-related outcomes
showed disagreement on relation between caffeine intake during
pregnancy and birth weight, as well as risk of preterm birth and
small-for-gestational-age; however, a probable evidence of
increased risk of pregnancy loss related to caffeine intake and
possible increased risk of low birth weight subsisted in the studies
conducted in the US. Among other meta-analyses of RCTs, the
acute effects of coffee on serum lipids resulted probable, despite no
evidence is available for long-term consumption.
The summary evidence from meta-analyses of observational studies
on coffee/caffeine and various outcomes is showed in Table 3. The
details of the process for evidence evaluation are presented in
Supplementary Figure 3. Coffee was associated with a probable
decreased risk of breast, colorectal and colon, endometrial, prostate
cancers, CVD related outcomes considered as a whole (including
CHD, stroke, heart failure, and mortality), Parkinson’s disease, and
type-2 diabetes and with probable no effect on pancreatic and rectal
cancer risk. Notably, a high possible decreased risk of liver cancer,
chronic liver disease, stroke and Alzheimer’s disease was found.
Possible increased risk of childhood acute leukemia and gastric
cancer was found. Contrasting results on lung cancer were due to
different association in men and women, only relying on studies not
adjusting for smoking status, and not significant when conducted
only among non-smokers. Caffeine was associated with probable
decreased risk of Parkinson’s disease and type-2 diabetes. Several
other associations were retrieved but often affected by heterogeneity
or potential confounding factors.
DISCUSSION
In this study, the findings of 128 meta-analyses on coffee/caffeine
exposure comprising 62 outcomes including cancer, cardiovascular,
and other outcomes were reviewed. Most of the evidence relied on
meta-analyses of observational studies while fewer meta-analyses
included RCTs. Comparisons of pooled analyses of observational
studies and RCTs were possible only on blood
pressure/hypertension and low birth-weight with inconclusive
findings. On the basis of these results, there is probable evidence of
beneficial effect of coffee consumption for a number of chronic
diseases, including some cancers (endometrial, prostate, colorectal,
and liver cancer), CVD and metabolic-related outcomes (such as
type-2 diabetes and metabolic syndrome), and neurological
conditions (such as Parkinson’s disease, Alzheimer’s disease, and
depression). The risk estimates relations in most of meta-analyses
were calculated on high versus low consumption, thus not allowing
to define a clear reference exposure; among the studies providing
dose-response analyses, some relations were linear while others
showed the lowest risk at about 4-5 cups/d. Adverse effects were
limited mainly on pregnancy-related outcomes following caffeine
intake rather than other components in coffee, as controls used for
the studies were administered decaffeinated coffee.
Antioxidant properties of coffee
Most of the potential beneficial effects of coffee rely on the
assumption that coffee may have an antioxidant and anti-
inflammatory action that, over long time, could induce protection
against subclinical inflammation and inflammatory-triggered chronic
diseases (86). Experimental models and studies on humans
demonstrated, albeit with some contrasting results, the attenuation
of inflammatory markers, such as interleukin 6, tumor necrosis factor
alpha, interferon-gamma, and tumor growth factor beta, after
administration of coffee (86). The main components of coffee
described to exert such effects are phenolic compounds, caffeine,
coffee diterpenes, trigonelline, and melanoidins.
The phenolic component of coffee is mostly characterized by
chlorogenic acids, a family of esters of hydroxycinnamic acids
(mostly caffeic acid and ferulic acid) with D-(-)-quinic acid. These
compounds represent the highest phenolic component of green
coffee seeds, together with tannis, lignans and anthocyanins, and
significantly determine coffee quality, aroma and flavor. Chlorogenic
acids have been demonstrated to induce antioxidant effect
decreasing the production of inflammatory mediators through several
mechanisms, including (i) inhibition of protein tyrosine phosphatase
1B, (ii) inhibition of expression of pro-inflammatory cytokine genes,
and (iii) modulation of inflammatory nuclear factor kappa-light-chain-
enhancer of activated B cells (NF-kB) activation via the redox-related
tyrosine-protein kinase/extracellular signal-regulated kinase and NF-
kB-inducing kinase/IkappaB kinase pathways via the reduction of
oxidative stress (37).
Caffeine has been by far the most studies coffee component due to
its effects on adenosine receptors in brain, as well as in the
cardiovascular, respiratory, renal, gastrointestinal systems, and in
adipose tissue. However, caffeine has been reported to have the
ability to inhibit induced NF-kB activation though similar mechanisms
described for chlorogenic acids (156).
Cafestol and kahweol are two diterpenes that naturally occurs in
coffee beans. It is unclear whether coffee diterpens may exert direct
antioxidant properties, but it has been shown that (i) they may
increase the expression of NAD(P)H:quinone oxidoreductase 1, an
enzyme implicated in the synthesis of endogenous antioxidants
through nuclear factor erythroid-2-like 2 factor (Nrf2) pathway, and
(ii) they increase the production of glutathione and gamma-
glutamylcysteine synthase, the limiting enzyme for glutathione
synthesis, which is an important endogenous antioxidant and
cofactor of detoxifying metabolism (43).
Trigonelline is a plant alkaloid derivate of vitamin B6 contained in
coffee beans and one of the main components that contributes to
undue bitterness in coffee. Animal studies have shown that
trigonelline decrease malonaldehyde and nitric oxide contents, and
increase superoxide dismutase, catalase, glutathione, and inducible
nitric oxide synthase activities in the pancreas, suggesting that also
trigonelline may exert antioxidant effects by up-regulating antioxidant
enzyme activities and decreasing lipid peroxidation (152).
Melanoidins are defined as high molecular weight nitrogenous brown
colored polymers that may exert antioxidant and anti-inflammatory
activity based on their radical scavenging activity and or their metal
chelating capacity, despite depending on the degree of coffee
roasting level (it seems that coffee antioxidant activity may decrease
with roasting degree) (92).
Coffee and microbiota
The anti-inflammatory effects of coffee may be also mediated by
alteration of gut microbiota. There is evidence from cellular, animal
and human studies that administration of coffee would induce
changes in the structure and function of the gut microbiota modifying
the ratio among major phyla (Proteobacteria, Actinobacteria,
Bacteroidetes, and Firmicutes) in favour of an anti-obese profile (i.e.,
decreased Firmicutes:Bacteroidetes ratio) (101). Increase of
Bifidobacteria has been associated with anti-inflammatory effects,
which in turn may mitigate local inflammation, decrease pro-
carcinogenetic processes and lower misfolding rates of α-synuclein
in the enteric nervous system, reducing the risk of Parkinson’s

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disease by minimizing propagation of the protein to the central
nervous system (94). Besides the direct effects of gut microbiota
itself on metabolism (lower energy expenditure, higher energy
harvest, fat deposition and weight gain), microbiota alterations may
play an important role in the biotransformation of polyphenols, which
in turn may exert collateral benefits associated with coffee
consumption, such as rise in polyphenol metabolites with anti-
oxidant properties (91).
Coffee and cancer
A number of plausible mechanisms may explain the observed
associations between coffee and cancer risk. Phytochemical
compounds contained in coffee (diterpens, melanoidins, and
polyphenols) may exert beneficial effects, including inhibition of
oxidative stress and oxidative damage irrespectively of the site
involved. These actions may play a role especially in the early
process of transformation of a normal cell into a malignant tumor.
Coffee has demonstrated to play a role in the defense mechanisms,
including regulation of DNA repair, phase II enzymatic activity, and
apoptosis as well as having anti-proliferative, anti-angiogenetic
effects and anti-metastatic effects; the expression of antioxidant
defense and detoxification genes depends on transcription factors,
such as the complex of Nrf2 and Kelch-like ECH-associated protein
1, activator protein 1, or aryl hydrocarbon receptor that can be
regulated by coffee (3).
Besides the general effects at cellular level, coffee consumption may
exert specific benefits toward individual cancer sites. High intake of
caffeine has been positively associated with increase in sex
hormone binding globulin and inversely associated with bioavailable
testosterone, which may influence risk of endometrial and breast
cancer (47). Regarding colorectal cancer, effects of coffee
consumption are related to excretion of bile acids and neutral sterols
into the colon, alteration of microbiota composition, and increase of
bowel mobility in the rectum region (126). Coffee consumption also
increases the detoxification capacity and anti-mutagenic properties
in the colorectal mucosa through an increase in glutathione
concentration (45). A key role is played by coffee diterpenes that
have been found to reduce mutagenesis by strongly metabolizing
carcinogenic compounds and to induce glutathione-S-transferase
and inhibit N-acetyltransferase, both mechanisms resulting beneficial
in preventing cancer (45).
Coffee and liver health
Coffee is also associated with improved serum gamma
glutamyltransferase, aspartate aminotransferase and alanine
aminotransferase concentrations in a dose dependent manner,
severity of steatohepatitis in patients with non-alcoholic
fatty liver disease, and decreased liver fibrosis, which are chronic
alterations preceding hepatocellular carcinoma. The main
mechanisms proposed for the hepatoprotection of coffee involve
caffeine, phenolic compounds, and melanoidins. Caffeine may
counteract hepatic fibrinogenesis pathway by down-regulating
transforming growth factor beta-1-induced connective tissue growth
factor production, by up-regulating the PPAR-gamma receptor, and
by inhibiting focal adhesion kinase and actin synthesis (108).
Phenolic compounds, melanoidins, and caffeine are responsible for
antioxidant effects at hepatic level preventing free radical tissue
damage by reducing reactive oxygen species, which in turn play a
central role in the inflammation processes characterizing non-
alcoholic fatty liver disease, steatohepatitis, and ultimately liver
fibrosis (20).
Coffee and metabolic health
Coffee consumption and caffeine intake have been also associated
with decreased risk of a number of metabolic outcomes. Consistent
evidence demonstrated beneficial effects of coffee compounds
toward insulin and glucose metabolism. Consumption of chlorogenic
acids has been demonstrated to reduce fasting plasma glucose,
increase sensitivity to insulin, and slow the appearance of glucose in
circulation after glucose load (88). The mechanisms underlining
these actions include (i) competitive inhibition of the glucose-6-
phosphate translocase, an enzyme involved in the regulation of
homeostasis of blood glucose levels; (ii) activation of adenosine
monophosphate-activated protein kinase, a sensor and regulator of
cellular energy balance, which may induce inhibition of fatty acid
synthesis and hepatic glucose production; (iii) reduction of sodium-
dependent glucose transport in brush border membrane vesicles of
small intestine; and (iv) inhibition of α-amylase and α-glucosidase
activity, two key enzymes responsible for digestion of dietary
carbohydrates, resulting in a reduction of intestinal absorption of
glucose (12).
Coffee and cardiovascular health
The association between coffee consumption and cardiovascular
outcomes may be the result of the aforementioned beneficial effects
of coffee toward cardiometabolic health. Most of the effects are
supposed to be related to the antioxidant effects of coffee,
specifically (i) reduction of LDL oxidation susceptibility, which is a
key step of atherosclerosis development and progression; and (ii)
ability of methyltetrahydrofolate, the main circulating metabolite of
folate, and caffeine to increase nitric oxide production and scavenge
superoxide radicals (106).
Coffee and lithiasis
Coffee also demonstrated decreased risk of gallstone disease,
possibly, urolithiasis. In various experimental studies, coffee
stimulates cholecystokinin release, enhances gallbladder
contractility, improves gall-bladder mucosal function, and decreases
cholesterol crystallization in the bile, which may result from its
caffeine content (111). Insulin resistance has also been associated
with gallstone risk. Moreover, caffeine also increases urinary calcium
and oxalate excretion (24). Finally, anti-inflammatory effects of
coffee are postulated to be related with lithiasis sues.
Coffee and mental health
The potential beneficial effects of coffee on Parkinson’s and, more in
general, mental health may rely on a neuroprotective action that can
be coffered by (i) caffeine acting as an adenosine receptor
antagonist, which result in activating the release of mainly excitatory
transmitters, including dopamine; (ii) trigonelline, N-
methylpyridinium, chlorogenic acid, catechol, pyrogallol and 5-
hydroxytryptamides, that have been demonstrated to increase
calcium signaling and dopamine release; and (iii) local antioxidant
effects of chlorogenic acids, which have been associated to
neurogenesis (the process by which neurons are generated) (96).
Potential de trimental effects of coffee and caffeine
consumption
The only potentially adverse outcomes related to coffee consumption
have been found to be increased risk of lung and gastric cancers
and alteration of serum lipids. The former outcomes are highly
sensitive to the potential modifying effect of smoking habit over
coffee drinking. In fact, in both cases a subgroup analysis revealed
that the association was significant only in studies not adjusting for
smoking status and no increased risk of lung was observed in a
subgroup analysis of studies conducted on non-smokers. Regarding
the potential serum lipid increasing effect of coffee, it has been
documented that unfiltered coffee may contain significant quantity of
diterpenes that may affect the LDL receptor, which is responsible for

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the endocytic process of apoB- and apoE- containing lipoproteins
and, consequently, leading to extracellular accumulation of
cholesterol (37). However, there is no evidence that long-term coffee
consumption would be associated with increased risk of
dyslipidaemia or other outcomes related to rise in serum lipids.
Caffeine has been associated with acute rise in blood pressure.
There is no definitive consensus on the mechanism explaining the
weaker effects demonstrated in long-term habitual drinkers. It is
biologically plausible that chronic administration of coffee could
induce tolerance and, thus, lack of significant effects at level of
vessels. Moreover, the antioxidant compounds contained into coffee
may somehow counteract the blood pressure rising effects of
caffeine. The adverse associations for caffeine were mostly related
to pregnancy-related outcomes (including low birth weight,
pregnancy loss, and childhood leukemia). Caffeine passes through
placental barriers and cytochrome P450 1A2 activity during
pregnancy is reduced, thus potentially exposing the fetus to caffeine
for a long period of time, which may affect fetal growth (10).
Moreover, caffeine may act as an inhibitor for DNA topoisomerase II
and DNA repairing systems, which in turn may induce chromosomal
aberrations and translocations, such as abnormalities related to
leukemia (123). Some other evidence suggests that caffeine may
influence DNA methylation through alteration of responsible genes,
resulting in a notable increase in total methylation as well as
increased methylation frequency (123). However, the studies
included in the meta-analyses did not stratify by smoking status,
which is known risk factor itself for the aforementioned outcomes.
LIMITATIONS OF THE STUDY
The present umbrella review should be considered in light of two
major limitations. The first one regards the lack of available and
consistent data (between studies) of a clear and univocal exposure
dose to which the associations refer. Indeed, most of the evidence
gathered relies on effect sizes referring to "the highest compared to
the lowest" category of exposure. Although we may arbitrarily
hypothesize what high, moderate, and low coffee consumption are
referring to (>6 cups/d, 3-5 cups/d, and <3 cups/d respectively), this
is not sufficient to draft adequate dietary guidelines with scientific
accuracy. However, several meta-analyses presented dose-
response analyses on numerous outcomes, straightening the
evidence of a potential effect and resolving, at least in part, the
aforementioned limitation. The second major issue regards the
ubiquitous lack of information on potentially important concerns
relative to genetic polymorphisms. Although out of the scope of the
present umbrella review, it is noteworthy to mention that
polymorphisms of the cytochrome P450 1A2 have been
demonstrated to affect caffeine metabolism, which in turn may result
in potentially different risk estimates depending on its activity
(especially regarding cardiovascular outcomes) (25; 100). Thus, the
possibility that the association of coffee consumption with health
benefits may not be reproducible in individuals with specific genetic
profiles should be taken into account and further investigated in
future studies. Other limitations regard lack of consistent information
on methods of coffee preparation [filtered, boiled, drying method (for
soluble coffee)], roasting characteristics, as well as coffee add-ins
(sugar, dairy products).
IMPLICATIONS FOR PUBLIC HEALTH EXPERTS AND FUTURE
RESEARCH
Essentially all of the data on chronic conditions, for which long-term
consumption of coffee may be required for any effect, is based on
observational studies. Available RCTs data considered presumed
intermediate biomarkers (e.g. lipids) or physiologic effects (e.g.,
blood pressure) but not direct estimation of long-term effects of
coffee have been explored yet. Although it cannot definitively prove
causality, observational data as a whole includes a number of
strengths: overall coffee consumption is reasonably well measured;
the findings for many of the conditions were based on large
numbers, in diverse populations, covered long-term intake, over
multiple time periods, in some cases with regular and decaffeinated
coffee; little heterogeneity observed in some cases would reinforce
the evidence of the finding. However, coffee is generally not
considered a health conscious behaviour and in fact, in many
populations high coffee consumes tended to smoke more, and were
more likely to consume alcohol excessively. Thus, uncontrolled or
residual confounding cannot be excluded definitively. In fact, as
studies better controlled for confounding factors over time,
particularly tobacco use, inverse associations emerged or
strengthened. Based on an examination of characteristics of
individuals who consume more coffee in numerous studies, we could
not identify an obvious candidate confounding factor that could
plausibly explain the potential beneficial effect of coffee consumption
toward human health, while in some cases (i.e., lung and gastric
cancer) the role of tobacco use as effect modifier appeared quite
evident.
To date, the broad research on beneficial effects of coffee on cancer,
CVD, metabolic and neurological disorders from observational
studies is promising. The main limitation in making strong
conclusions regarding causal associations is the lack of long-term
RCTs. Nonetheless, given the fact that coffee consumption is a wide
spread behavior in numerous populations, these results are largely
reassuring against adverse effects (except in the context of
pregnancy) and, if anything, are suggestive of potential benefits. A
consumption of 4-5 cups/d seems to exert benefits toward many of
the outcomes examined, higher intakes could require caution
especially regarding pregnancy- and CVD-related conditions, though
this can be due potentially to residual confounding by smoking.
Given the lack of RCTs, the extensive study from observational data
to date, the robustness of the findings, which have generally
strengthened with better study design and control for confounding, it
is unlikely that the level of evidence will change appreciably in the
foreseeable future. In any case, our findings indicate that coffee can
be part of a healthful diet.
Acknowledgements
Contributors: GG conceived the study. GG and JG performed the
systematic review and extracted the data; GG, FG and ELG wrote
the manuscript. All authors reviewed the manuscript. All authors
equally contributed to the paper.
Funding: No specific funding.
Competing interests: All authors had no support from any
organisation for the submitted work; no financial relationships with
any organisations that might have an interest in the submitted work
in the previous three years; no other relationships or activities that
could appear to have influenced the submitted work.
Ethical approval: Not needed.

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Summary points list:
There is probable evidence of beneficial effects of coffee
consumption for a number of chronic diseases, including cancers,
cardiovascular, metabolic, and neurological conditions.
The dose-response effect in most of meta-analyses was linear or
with the lowest risk reached at about 4-5 cups/d.
Adverse effects were mainly limited to pregnancy-related outcomes
following caffeine intake rather than other components in coffee.
Evidence retrieved for other potential adverse effects, such as lung
and gastric cancer, seems to be rather affected by the confounding
effect of smoking.
Future issues list:
Future studies should include stratification by smoking status, to
most definitively exclude confounding, and to better characterize the
dose-response relation.
Taking genetic variation in caffeine metabolism into account could
strengthen associations and conclusions.
Interventions with endpoints based on physiologic parameters,
hormones and metabolomics can potentially offer mechanistic
insights, and thereby strengthen the conclusions.
Separating regular and decaffeinated coffee would be critical in
determining whether any benefits are due to caffeine or other
components, such as chlorogenic acid.
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Table 1. Criteria used to define the level of evidence, modified from the Joint WHO/FAO Expert
Consultation.
Definition
Level of evidencea
Convincing
Level 1a (high): concordance between meta-analyses of RCT and meta-analyses of
observational studies (any).
Level 1b (low): meta-analyses of RCT with contrary results from meta-analyses of
observational studies (any).
Probable
Level 2a (high): meta-analyses of prospective studies with no heterogeneity, no
potential confounding factors identified, and agreement of results over time and
between meta-analyses including studies with different study design.
Level 2b (medium): meta-analyses of prospective studies with no heterogeneity and
no potential confounding factors identified.
Level 2c (low): meta-analyses of prospective + case-control studies with no
heterogeneity and no potential confounding factors identified.
Possible
Level 3a (high): meta-analysis of prospective studies with lack of information on
heterogeneity and potential confounding factors.
Level 3b (medium): meta-analysis of prospective + case-control studies with lack of
information on heterogeneity and potential confounding factors.
Level 3c (low): meta-analyses of case-control studies or meta-analyses of any other
study design with significant heterogeneity (I2 >50%) and potential confounding
factors.
Limited/contrasting
Level 4: Limited studies included in meta-analyses (n ≤3) or evident contrasting
results from meta-analyses with the same level of evidence.
aAll the associations should be biologically plausible; potential confounding factors should be taken into
account.

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Table 2. Characteristics of non-overlapping meta-analyses of randomized controlled trial on coffee consumption/caffeine intake reporting unique
outcomes.
Outcome
Intervention
Type of placebo
No. of
studies
Total
participa
nts
Duration
(range)
Exposure
(range)
Type of
metric
Effect size
I2
Ref.
Coffee
TC
Regular,
decaffeinated,
filtered, instant
None/tea
12
1,017
2-11 w
2.4-8
cups/d
WMD
8.05 (4.48,
11.62)
67%
(13)
LDL
Regular,
decaffeinated,
filtered, instant
None/tea
8
686
2-11 w
(range)
2.4-8
cups/d
WMD
5.44 (1.38, 9.51)
58%
(13)
HDL
Regular,
decaffeinated,
filtered, instant
None/tea
9
830
2-11 w
(range)
2.4-8
cups/d
WMD
-0.12 (-0.62,
0.38)
21%
(13)
TG
Regular,
decaffeinated,
filtered, instant
None/tea
7
697
2-11 w
(range)
2.4-8
cups/d
WMD
12.55 (3.47,
21.64)
66%
(13)
SBP
Filtered, boiled,
instant,
decaffeinated
NA
10
1,488
6-14 w
(range)
2-6 cups/d
WMD
-0.55 (-2.46,
1.36)
72%
(118)
DBP
Filtered, boiled,
instant,
decaffeinated
NA
10
1,488
6-14 w
(range)
2-6 cups/d
WMD
-0.45 (-1.52,
0.61)
41%
(118)
Ventricular
arithmia
Instant coffee
Decaffeinated
coffee
1
52
5 d
4.7 cups/d
(mean)
RR
0.98 (0.93, 1.03)
NA
(155)
Caffeine
SBP
Filtered, boiled,
instant
No coffee,
decaffeinated
coffee
5
1,010
1-12 w
(range)
295-750
mg
WMD
(mmHg)
4.16 (2.13, 6.20)
NA
(98)
DBP
Filtered, boiled,
instant
No coffee,
decaffeinated
coffee
5
1,010
1-12 w
(range)
295-750
mg
WMD
(mmHg)
0.41 (0.98, 3.84)
NA
(98)
Asthma
Various sources
Decaffeinated
coffee
6
78
1-2 w
5-450 mg
SMD
(change in
FEV1)
0.72 (0.25, 1.20)
0%
(131)
SBP (in
hypertensive
individuals)
NA
NA
5
207
180 min
200-300
mg
WMD
(mmHg)
8.14 (5.68,
10.61)
0%
(89)

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DBP (in
hypertensive
individuals)
NA
NA
6
207
180 min
200-300
mg
WMD
(mmHg)
5.75 (4.09, 7.41)
0%
(89)
Birthweight
Instant caffeinated
coffee
Instant
decaffeinated
coffee
1
1,207
Up to 4 w
after
delivery
62 mg/d
(mean)
WMD (g)
20.00 (-48.68,
88.68)
NA
(48)
Preterm birth
Instant caffeinated
coffee
Instant
decaffeinated
coffee
1
1,207
Up to 4 w
after
delivery
62 mg/d
(mean)
RR
0.81 (0.48, 1.37)
NA
(48)
Small-for-
gestational-age
Instant caffeinated
coffee
Instant
decaffeinated
coffee
1
1,207
Up to 4 w
after
delivery
62 mg/d
(mean)
RR
0.97 (0.57, 1.64)
NA
(48)
Serum insulin
Instant caffeinated
coffee
Instant
decaffeinated
coffee
1
1,207
Up to 4 w
after
delivery
62 mg/d
(mean)
WMD
(pmol/L)
38.8 (13.57,
64.03)
NA
(48)
DBP, diastolic blood pressure; FEV1, forced expiratory volume in one second; NA, not applicable; SBP, systolic blood pressure; SMD, standardized mean
difference; WMD, weighted mean difference.

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Table 3. Evidence of association between coffee/caffeine intake and health outcomes from observational studies.
Level of evidence
Outcome
Coffee
Decaffeinated coffee
Caffeine
Probable
Decreased risk of breast cancer, colorectal cancer, colon cancer,
endometrial cancer, prostate cancer, cardiovascular disease,
cardiovascular disease mortality, Parkinson’s disease, and type-2
diabetes.
Decreased risk of Parkinson’s
disease and type-2 diabetes.
Increased risk of pregnancy loss.
Possible
Decreased risk of liver cancer, oral/laryngeal cancer, melanoma,
coronary heart disease, all-cause mortality, chronic liver
disease/cirrhosis, Alzheimer’s disease, and gallstone disease.
Decreased risk of all-cause mortality
and endometrial cancer.
Decreased risk of cognitive
disorders.
Increased risk of childhood acute leukaemia (myeloid and
lymphoblastic), gastric cancer, and pregnancy loss.
Increased risk of low birth weight.
No conclusions
No association with adult glioma, bladder cancer, cancer
mortality, esophageal cancer, ovarian cancer, pancreatic cancer,
renal cancer, atrial fibrillation, hypertension, stroke, hip fractures,
peptic ulcer, rectal cancer, and cognitive disorders (including
cognitive decline, impairment, dementia).
No association with breast cancer,
coronary heart disease, and
melanoma.
No association with breast
cancer, and cognitive disorders.
Limited
Decreased risk of colorectal adenoma, non-melanoma skin
cancer, death after myocardial infarction, venous
thromboembolism, depression, gout, metabolic syndrome, and
urolithiasis.
Decreased risk of colorectal cancer.
Decreased risk of depression.
No association with gastroesophageal reflux, duodenal and
gastric ulcer, endometriosis, neural tube defects and spina bifida
in offsprings, and rheumatoid arthritis.
No association with bladder cancer,
urinary tract cancer, rheumatoid
arthritis, and non-melanoma skin
cancer.
No association with Alzheimer’s
disease, cognitive impairment,
endometriosis, and non-
melanoma skin cancer.
Contrasting
Risk of lung cancer and fractures.
Risk of atrial fibrillation.

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Figure captions
Figure 1. Flowchart of study selection.
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Figure 2. Findings from non-overlapping meta-analyses of observational studies on coffee presenting effect size for highest versus lowest
(reference) category of exposure.
Outcome
No. of
studies
No. of
subjects
No. of
cases
RR (95% CI) I2 Ref.
Coffee
Cancer
Hepatocellular carcinoma
11 P
2,266,671
2,942
0.50 (0.43, 0.58)
13%
(9)
Colorectal adenoma
1 P, 2 CC
NA
NA
0.57 (0.44, 0.72)
NA
(36)
Oral cancer
4 P
2,331,316
1,758
0.66 (0.45, 0.98)
79%
(72)
Pancreatic cancer
20 P
1,341,876
2,872
0.75 (0.63, 0.86)
38%
(105)
Skin cancer (melanoma)
9 P
925,484
3,327
0.76 (0.64, 0.91)
NA
(140)
Endometrial cancer
13 P
1,534,039
10,100
0.80 (0.74, 0.86)
31%
(153)
Skin cancer (non-melanoma)
3 P, 1 CC
NA
33,352
0.82 (0.75, 0.89)
48%
(14)
Esophageal cancer
4 P
NA
NA
0.88 (0.65, 1.19)
31%
(150)
Proximal colon cancer
4 P
NA
NA
0.90 (0.78, 1.04)
65%
(35)
Prostate cancer
13 P
539,577
34,105
0.90 (0.85, 0.95)
17%
(76)
Colon cancer
16 P
NA
NA
0.91 (0.84, 0.98)
30%
(35)
Distal colon cancer
4 P
NA
NA
0.92 (0.79, 1.07)
0%
(35)
Adult glioma
4 P
1,322,407
1,486
0.98 (0.79, 1.23)
6%
(84)
Colorectal cancer
19 P
2,046,575
22,629
0.98 (0.90, 1.06)
41%
(35)
Breast cancer
17 P
NA
30,931
0.98 (0.95, 1.02)
0%
(53)
Renal cancer
4 P
310,625
366
0.99 (0.52, 1.89)
45%
(44)
Bladder cancer
5 P
236,343
753
0.99 (0.70, 1.39)
63%
(134)
Cancer mortality
10 P
NA
NA
1.03 (0.97, 1.09)
Yes
(85)
Rectal cancer
15 P
NA
NA
1.07 (0.97, 1.18)
13%
(35)
Lung cancer
8 P, 13 CC
623,645
19,892
1.09 (1.00, 1.19)
84%
(33)
Ovarian cancer
6 P
644,044
3,236
1.13 (0.89, 1.43)
50%
(5)
Gastric cancer
13 P
1,324,559
3,484
1.16 (1.03, 1.32)
27%
(28)
CALL
6 CC
4,869
2,483
1.43 (1.22, 1.68)
0%
(121)
CAL
6 CC
3,989
2,417
1.57 (1.16, 2.11)
55%
(121)
CAML
4 CC
4,041
387
1.81 (0.93, 3.53)
54%
(121)
Cardiovascular outcomes
Death after acute MI
2 P
3,271
604
0.54 (0.45, 0.65)
13%
(11)
CVD mortality
17 P
NA
NA
0.89 (0.77, 1.02)
75%
(85)
Coronary heart disease
30 P
NA
NA
0.93 (0.84, 1.02)
52%
(30)
Stroke
22P
NA
NA
0.95 (0.84, 1.07)
54%
(30)
CVD
35 P
NA
NA
0.95 (0.87, 1.03)
No
(30)
Atrial fibrillation
6 P
248,910
10,406
0.96 (0.84, 1.08)
60%
(61)
Venous thromboembolism
1 P, 2 CC
67,754
NA
0.97 (0.88, 1.08)
NA
(74)
Hypertension
4 P
1,467,361
36,178
1.03 (0.98, 1.08)
73%
(118)
Other
Chronic liver disease
5 P
386,049
1,410
0.35 (0.22, 0.56)
16%
(9)
Gout
2 P
135,302
1,653
0.50 (0.36, 0.70)
36%
(103)
Parkinson’s disease
4 P
187,740
459
0.70 (0.56, 0.88)
NA
(41)
Type-2 diabetes
26 P
1,096,647
50,595
0.71 (0.67, 0.76)
54%
(54)
Alzheimer’s disease
4 P
15,761
396
0.73 (0.55, 0.97)
0%
(80)
Cognitive impairment
3 P
6,649
NA
0.78 (0.48, 1.26)
49%
(80)
Gallstone disease
5 P
226,627
11,282
0.83 (0.76, 0.89)
35%
(148)
Neural tube defects
1 RP, 6 CC
NA
2,077
0.86 (0.51, 1.45)
86%
(73)
All-cause mortality
20 P
973,904
129,538
0.86 (0.80, 0.92)
69%
(50)
Gastric ulcer
3 P, 2 CC
9,517
633
0.88 (0.49, 1.60)
79%
(115)
Depression
3 P
316,894
4,656
0.88 (0.79, 0.99)
43%
(40)
Urolithiasis
3 P
NA
NA
0.90 (0.82, 0.98)
51%
(138)
Metabolic syndrome
3 P
106,855
31,770
0.91 (0.87, 0.96)
0%
(112)
Cognitive disorders
10 P
29,155
NA
0.97 (0.84, 1.11)
25%
(80)
Peptic ulcer
5 P, 3 CC
NA
1,824
0.99 (0.75, 1.32)
77%
(115)
Fractures
9 P
NA
NA
0.99 (0.86, 1.14)
69%
(64)
Cognitive decline
4 P
9,254
NA
1.02 (0.88, 1.18)
0%
(80)
Gastroesophageal reflux
15 CC
89,608
12,816
1.06 (0.94, 1.19)
66%
(58)
Dementia
5 P
12,607
NA
1.08 (0.81, 1.44)
28%
(80)
Pregnancy loss
13 P
NA
NA
1.10 (1.01, 1.19)
50%
(67)
Endometriosis
2 P, 1 CC
772
387
1.13 (0.46, 2.76)
70%
(23)
Hip fracture
9 P
205,930
5,408
1.13 (0.86, 1.48)
79%
(69)
Duodenal ulcer
3 P, 5 CC
NA
966
1.17 (0.79, 1.73)
59%
(115)
Spina bifida
4 CC
NA
1,496
1.30 (0.67, 2.52)
87%
(73)
Rheumatoid arthritis
2 P
114,460
638
1.31 (0.96, 1.77)
0%
(65)
Vascular dementia
1 P
3,734
80
1.96 (0.76, 5.04)
NA
(80)
CAL, childhood acute leukemia; CALL, childhood acute lymphoblastic leukemia; CAML, childhood acute myeloid leukemia; CC, case-control; CI, confidence interval; CVD,
cardiovascular disease; MI, myocardial infarction; NA, not applicable; P, prospective; RP, retrospective study; RR, relative risk.

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Figure 3. Findings from non-overlapping meta-analyses of observational studies on decaffeinated coffee and caffeine presenting effect size for
highest versus lowest (reference) category of exposure.
Outcome
No. of
studies
No. of
subjects
No. of
cases
RR (95% CI) I2 Ref.
Decaffeinated coffee
Endometrial cancer
4 P
NA
NA
0.77 (0.63, 0.94)
0%
(153)
Type-2 diabetes
10 P
491,485
29,165
0.79 (0.69, 0.91)
65%
(54)
All-cause mortality
5 P
NA
NA
0.86 (0.80, 0.92)
NA
(50)
Colorectal cancer
3 P
NA
NA
0.89 (0.80, 0.99)
2%
(35)
Skin cancer (melanoma)
5 P, 1 CC
718,231
3,269
0.92 (0.82, 1.05)
NA
(140)
Breast cancer
4 P, 8 CC
NA
31,790
0.97 (0.89, 1.06)
29%
(53)
Coronary heart disease
5 P
NA
NA
1.00 (0.88, 1.14)
NA
(30)
Skin cancer (non-melanoma)
3 P
NA
32,975
1.01 (0.85, 1.21)
0%
(14)
Rheumatoid arthritis
2 P
NA
NA
1.05 (0.78, 1.42)
0%
(65)
Urinary tract cancer
4 P+CC
NA
NA
1.18 (0.99, 1.40)
NA
(142)
Bladder cancer
5 P+CC
NA
NA
1.29 (0.88, 1.89)
62%
(134)
Caffeine
Parkinson’s disease
9 P
NA
NA
0.67 (0.57, 0.80)
46%
(81)
Type-2 diabetes
6 P
321,960
9,302
0.70 (0.65, 0.75)
49%
(54)
Dementia
3 P, 2 CC
NA
NA
0.72 (0.34, 1.51)
76%
(59)
Alzheimer’s disease
2 P, 3 CC
NA
NA
0.78 (0.50, 1.22)
71%
(59)
Cognitive impairment
5 CS
NA
NA
0.79 (0.61, 1.04)
21%
(59)
Cognitive disorders
19 P+CC
31,479
NA
0.82 (0.67, 1.01)
63%
(59)
Depression
3 P
58,756
2,656
0.84 (0.75, 0.93)
0%
(40)
Skin cancer (non-melanoma)
2 P, 2 CC
NA
25,993
0.86 (0.80, 0.91)
48%
(14)
Atrial fibrillation
6 P
228,465
4,261
0.88 (0.78, 0.99)
41%
(22)
Cognitive decline
4 P
NA
NA
0.99 (0.70, 1.39)
62%
(59)
Breast cancer
9 P+CC
NA
15,775
0.99 (0.94, 1.04)
0%
(53)
Pregnancy loss
13 P
NA
NA
1.21 (1.08, 1.37)
21%
(67)
Endometriosis
1 P, 4 CC
3,441
1,020
1.26 (0.95, 1.66)
68%
(23)
Low birth weight
8 P
74,885
3,887
1.43 (1.14, 1.79)
49%
(107)
CC, case-control; CI, confidence interval; NA, not applicable; P, prospective; RR, relative risk.

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Figure 4. Findings from dose-response meta-analyses of observational studies on coffee/caffeine using relative risk as type of metric.

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Supplementary Figure 1. Findings from non-overlapping meta-analyses of observational studies on coffee/caffeine presenting effect size for linear
increased or category of exposure.
Supplementary Figure 2. Sub-group analyses in non-overlapping meta-analyses of observational studies on coffee consumption reporting unique
outcomes.
Supplementary Figure 3. Detailed findings of this umbrella review and level of evidence for coffee/caffeine intake and health outcomes from
observational studies.
Acronyms and Definitions list:
Umbrella review. An umbrella review aims to systematically examine existing research syntheses of different outcomes for the same intervention or
phenomena of interest. (to be inserted next to the first sentence of the methods)