Lead Article

Coffee consumption and reduced risk of developing type 2

diabetes: a systematic review with meta-analysis
Mattias Carlström and Susanna C. Larsson

Downloaded from https://academic.oup.com/nutritionreviews/article/76/6/395/4954186 by Universiteit Maastricht user on 16 February 2021

Context: Type 2 diabetes (T2D) is a major health problem worldwide that is associ-
ated with increased morbidity and mortality. There is increased interest in the value
of different nutrition-based strategies for preventing the development of T2D.
Objective: This review aims to cover current knowledge regarding the effects of
coffee consumption on development of T2D or modulation of adverse complica-
tions. A meta-analysis on coffee consumption and the risk of T2D was conducted.
Moreover, bioactive components in coffee, polymorphisms, and potential underly-
ing mechanism(s) in relation to T2D and adverse complications are discussed.
Data sources: PubMed was searched up to December 1, 2017, and prospective co-
hort and nested case–control studies of the association between coffee consump-
tion and T2D risk were selected. Data extraction: Two investigators independently
extracted data from included studies. Results: A total of 30 prospective studies
with 1 185 210 participants and 53 018 incident T2D cases were included in the
meta-analysis. The pooled relative risk (RR) was 0.71 (95% confidence interval [CI],
0.67–0.76) for the highest category of coffee consumption (median consumption,
5 cups/d) vs the lowest category (median consumption, 0 cups/d). The risk of T2D
decreased by 6% (RR ¼ 0.94; 95%CI, 0.93–0.95) for each cup-per-day increase in
coffee consumption. Results were similar for caffeinated coffee consumption (per
additional cup of coffee per day: RR ¼ 0.93; 95%CI, 0.90–0.96) and decaffeinated
coffee consumption (corresponding RR ¼ 0.94; 95%CI, 0.90–0.98). Conclusions:
Available evidence indicates that coffee consumption is inversely associated with
risk of T2D. Possible mechanisms behind this association include thermogenic, anti-
oxidative, and anti-inflammatory effects; modulation of adenosine receptor signal-
ing; and microbiome content and diversity.

INTRODUCTION (WHO),2 an estimated 422 million adults worldwide

were living with diabetes (ie, a prevalence of 8.5%
Aging, physical inactivity, and obesity are closely linked among the adult population) in 2014, compared with
to type 2 diabetes (T2D), which has become a global 108 million in 1980. According to WHO, the number of
health problem.1 Type 2 diabetes is characterized by ab- people with T2D continues to rise, which reflects the in-
normal insulin secretion or insulin resistance, resulting crease in associated risk factors, such as being over-
in hyperglycemia. According to the Global Report on weight or obese. The World Health Organization
Diabetes from the World Health Organization estimated that the largest numbers of people with
Affiliation: M. Carlström is with the Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. S.C. Larsson is
with the Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Correspondence: M. Carlström, Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz V€ag 2, SE-17177
Stockholm, Sweden. E-mail: mattias.carlstrom@ki.se.
Key words: cardiovascular, coffee, diabetes, inflammation, metabolic syndrome, oxidative stress, renal, type 2.
C The Author(s) 2018. Published by Oxford University Press on behalf of the International Life Sciences Institute.
V
All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

doi: 10.1093/nutrit/nuy014
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395
diabetes live in the South-East Asia and Western Pacific
Regions, accounting for approximately half of the dia-
betes cases in the world.
Type 2 diabetes increases the risk of both renal and
cardiovascular diseases (eg, kidney failure due to ne-
phropathies, myocardial infarction, and stroke) and of
adverse complications (eg, retinopathy, lower limb am-
putation, neuropathy, hearing impairment). Although
renal disease is commonly described as a complication
of metabolic syndrome and diabetes, recent studies sug-
gest that compromised renal function may not only
contribute to hypertension but also antecede metabolic
dysfunction with abnormal insulin and glucose
regulation.1,3,4
Major benefits of early diagnosis and treatment of
hyperglycemia and cardiovascular risk factors in T2D
have been proposed.5 However, this might be difficult
because, in the early phase, there are often no obvious
symptoms. Although diabetes-associated severe compli-
cations affect many people, there are currently very lim-
ited global estimates of diabetes-related end-stage renal
disease and cardiovascular events, which can partly be
explained by variations in population characteristics
and methodological dissimilarities between studies.6
Further studies are urgently needed to better under-
stand the underlying mechanisms and to reduce mor-
bidity and mortality associated with this triad of
metabolic, cardiovascular, and renal disorders.
Given the substantial burden of diabetes, much at-
tention has been given to the development of new phar-
macological or nutritional approaches to prevent the
development of T2D or to alleviate its complications.
Several risk factors for T2D have been identified, in-
cluding age, sex, obesity, low physical activity, smoking,
diets with a low amount of fiber and high amount of
saturated fat, ethnicity, family history, history of gesta-
tional diabetes mellitus, elevated blood pressure, dysli-
pidemia, and different drug treatments (eg, diuretics,
nonselective b-blockers, statins, etc). There is also am-
ple evidence that T2D has a strong genetic basis. The
concordance of T2D in monozygotic twins is 70%,
compared with 20%–30% in dizygotic twins.7 Although
genetic factors have been associated with the etiology of
T2D,8 accumulating evidence demonstrates important
influence of modifiable lifestyle factors. It is well known
that increased physical activity and lowering of caloric
intake reduce the incidence of T2D,9–11 but more
knowledge is needed to understand how different die-
tary approaches or food constituents may contribute to
the prevention of T2D.
Coffee is among the most widely consumed bever-
ages worldwide and is a central and popular part of dif-
ferent cultures. According to the European Coffee
Federation, an estimated 3.5 billion cups of coffee are
396
consumed around the world every day.12 Due to the
broad consumption of coffee, numerous studies have
examined the potential link between coffee intake and
its affect on the modulation of metabolic functions and
the development of diabetes. Considering the high con-
sumption of and the many bioactive molecules in
brewed coffee, further knowledge on both the positive
and negative health effects of coffee is important. This
review aims to cover current knowledge regarding the
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effects of coffee consumption on the risk of T2D or
modulation of adverse complications.
In this meta-analysis, results obtained using caf-
feinated versus decaffeinated coffee and filtered versus
unfiltered coffee are discussed, along with potential dif-
ferences between the sexes and among geographical
regions. Moreover, bioactive components in coffee and
underlying mechanisms, as well as how coffee con-
sumption may impact on the triad of metabolic, cardio-
vascular, and renal disorders and associated morbidity
and mortality, are discussed.
CURRENT EVIDENCE FROM EPIDEMIOLOGICAL AND
CLINICAL STUDIES ON TYPE 2 DIABETES
Very early studies that investigated the potential effects
of coffee on metabolic regulation were published in the
late 1960s.13,14 In contrast with the early observation
made by Jankelson and colleagues11 in men with
maturity-onset diabetes, the study by Feinberg et al.14
clearly demonstrated that coffee ingestion considerably
improved glucose clearance following an oral glucose
tolerance test in healthy human participants. Since these
initial studies, numerous cohort studies and cross-
sectional studies, along with a few systematic reviews
and meta-analyses on coffee consumption and the risk
of T2D, have been published.15–19 As reported herein, a
new analysis of coffee consumption and risk of T2D
was conducted, which expands beyond previously pub-
lished systematic reviews and meta-analyses by also dis-
cussing potential underlying mechanisms.
RESEARCH DESIGNS AND METHODS
A flow-chart of study selection is shown in Figure 1.
The implementation and reporting of this meta-analysis
followed the Meta-analyses of Observational Studies in
Epidemiology (MOOSE) guidelines (Appendix S1).20
PubMed was used to identify studies that evaluated the
association between coffee consumption and risk of
T2D and were published between January 1966 and
December 1, 2017. No language or other restrictions
were imposed. The computer-based search included the
keyword “coffee” combined with “diabetes.” The refer-
ence lists of relevant articles were reviewed to search for
Nutrition ReviewsV Vol. 76(6):395–417
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Figure 1 Flow diagram of the literature search process
further studies. No contact was made with researchers
to search for unpublished data. The Participants,
Intervention Comparators, Outcomes, Study design
(PICOS) criteria are shown in Table 1. Criteria for in-
clusion in this meta-analysis were 1) the study had a
prospective cohort or nested case–control design; 2) ex-
posure was coffee consumption (including total, caf-
feinated, decaffeinated, filtered, or unfiltered coffee);
and 3) outcome was T2D incidence. Studies with a
case–control or cross-sectional design without informa-
tion on quantity of coffee consumption or with mortal-
ity from T2D or gestational diabetes as the outcome
were excluded from the analysis. No restrictions were
made with regard to study population. If results from 1
study population were reported in > 1 publication, the
study with the longest follow-up or the one that pro-
vided results separately for men and women (if same
follow-up) was included. Where results were reported
separately for caffeinated and decaffeinated coffee but
not for total coffee consumption, results for caffeinated
coffee in the main analysis were included.
Characteristics extracted from each study included
first author’s name, publication year, study location,
study name, sex and age of participants, sample size,
number of cases, follow-up time, assessment of T2D,
variables adjusted for in the full multivariable model,
and the most fully adjusted relative risk (RR) estimates
for each category of coffee consumption. Study quality
was evaluated using the 9-star Newcastle-Ottawa Scale
(NOS).21 The quality assessment was based on 3 broad
perspectives, including selection, comparability, and
outcome. The literature search, assessment of eligibility
for inclusion in the meta-analysis, data extraction, and
assessment of study quality were carried out
Nutrition ReviewsV Vol. 76(6):395–417
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independently by both authors, and any disagreements
were resolved by open discussion.
Results were combined using a random-effects
model, which takes into account both within-study and
between-study variance. In addition to combining
results for the highest versus lowest category of coffee
consumption, a dose–response meta-analysis was con-
ducted using the methods described previously.22–24 A
P value for nonlinearity was computed by testing the
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null hypothesis that the coefficient of the second spline
was equal to zero.24 Heterogeneity among studies was
tested with the Cochran Q and I2 statistics.25 To evalu-
ate sources of heterogeneity, stratified analyses were
performed according to sex (men vs women), geo-
graphic region, study quality (NOS score 6–7 [moderate
quality] vs 8–9 [high quality]), and type of coffee (caf-
feinated vs decaffeinated). Publication bias was evalu-
ated using Egger’s test.26 The P value for difference
across strata was obtained using meta-regression. The
statistical analyses were conducted with GraphPad
Prism 6 (Mac OS X, version 6.0 b, 2012, La Jolla, CA,
USA) and Stata (version 14.2, College Station, TX,
USA).
RESULTS
Twenty-nine articles with data from 30 prospective
cohorts (1 article presented results from 2 cohorts) or
nested case–control studies were included in the analy-
sis (38 studies if separated by sex),27–55 with a total of al-
most 1.2 million participants (n ¼ 1 185 210, including
53 018 incident T2D cases; incidence of 4.5%) (Figure 1
and Table 2). Most studies adjusted for major potential
confounders, including age, sex, body mass index, phys-
ical activity, and smoking, and the majority of studies
also adjusted for alcohol and dietary factors
(Table 2).27–55 Only 1 study adjusted for milk and sugar
consumed with coffee or separately.
Overall results
The pooled RR for incident T2D was 0.71 (95%CI,
0.67–0.76) for the highest category of coffee consump-
tion (median consumption, 5 cups/d) compared with
the lowest category (median consumption, 0 cups/d)
(Figure 2).27–55 There was heterogeneity among studies
(P < 0.001; I2 ¼ 57.9%), which was mainly explained by
the strength of the inverse association because all but 1
of the 38 RR estimates were < 1 and 20 were statistically
significant. No evidence of publication bias was
detected (Egger’s test: P ¼ 0.27).
In a dose–response meta-analysis, the risk of T2D
decreased by 6% (RR, 0.94; 95%CI, 0.93–0.95) for each
cup-per-day increase of coffee consumption
397
 Table 1 PICOS criteria for inclusion and exclusion of there was evidence that the association was stronger in
studies studies with moderate quality than in those with high
Parameter Inclusion criteria Exclusion criteria quality (P for difference ¼ 0.02), but this difference was
Participants Adults, without regard only observed in the analysis between the highest versus
to sex or ethnicity the lowest category of coffee intake (Table 3).
Intervention Coffee consumption Studies on caffeine
or exposure (including total, caf- intake only Heterogeneity among studies was observed in most sub-
feinated, decaffein- groups, except in men (dose–response analysis only)
ated, filtered, or and in studies conducted in Asia (Table 3).
unfiltered coffee)

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Comparison Highest vs lowest cate- Studies without in-
gory of coffee con- formation on
sumption; per 1-cup- quantity of
per-day increase in coffee
coffee consumption consumption
Outcome Incident T2D Mortality from
T2D, gestational
diabetes
Study design Prospective cohort and Case–control and
nested case–control cross-sectional
studies studies, case
reports
Abbreviation: T2D, type 2 diabetes.
(Figure 3),27–55 without evidence of departure from a
linear-response model (P ¼ 0.18). There was heteroge-
neity among studies (P < 0.001; I2 ¼ 66.5%). When con-
sumption of >8 cups of coffee per day was excluded,
the RR of T2D for each cup-per-day increase of coffee
consumption was 0.93 (95%CI, 0.92–0.95) with no evi-
dence of departure from a linear-response model
(P ¼ 0.56).
Although future prospective, well-designed clinical
studies are warranted, the existing knowledge from epi-
demiological studies emphasizes prevention of T2D de-
velopment with increasing intake of coffee. The
association between coffee consumption and T2D risk
appears to be linear, at least up to about 8–10 cups/day
of coffee. Data on the influence of very high coffee con-
sumption (>8–10 cups/d) on T2D risk are limited.
Stratified analyses by sex, geographical region, and
study quality
An inverse association between coffee consumption and
risk of T2D was observed in both men and women in
studies conducted in the United States, Europe, and
Asia, both in studies of moderate quality and those of
high quality (Table 3).27–55 There was indication of a
stronger association in women in the dose–response
analysis per additional cup per day of coffee (P for dif-
ference by sex ¼ 0.03) but not in the analysis comparing
high versus low coffee consumption (P ¼ 0.18)
(Table 3). A previous dose–response meta-analysis18
also showed a somewhat stronger inverse association
between coffee consumption and risk of T2D in women
than in men (Figure 4A). In the present meta-analysis,
The data show no clear differences in association
between coffee consumption and risk of T2D by sex,
geographic region, or study quality, although small dif-
ferences (eg, a possible stronger association in women)
cannot be ruled out.
Differences by age or body mass index
Given that aging and obesity are closely linked to the
development of T2D, it is of interest to distinguish po-
tential differences in the association between coffee
consumption and incident T2D in young versus old, as
well in lean versus obese people. Moreover, higher cof-
fee consumption has generally been associated with less
healthy lifestyle (eg, cigarette smoking, low level of
physical activity, less healthy diet).54 Thus, the true as-
sociation between coffee and diabetes risk might be
stronger than observed. Previously published meta-
regression analysis studies with obesity (BMI >25) or
increased age (>50 y) as independent variables found
similar association between coffee consumption and
risk of T2D.15,18
Caffeinated versus decaffeinated coffee
Results for both caffeinated and decaffeinated coffee
were available in 10 studies. Comparing the highest ver-
sus the lowest category, both caffeinated coffee con-
sumption (RR, 0.73; 95%CI, 0.64–0.83) and
decaffeinated coffee consumption (RR, 0.80; 95%CI,
0.69–0.94) were inversely associated with risk of T2D.
This association was dose-dependent, with no evidence
of departure from a linear-response model (P for non-
linearity ¼ 0.72 and 0.39, respectively, for caffeinated
and decaffeinated coffee). The risk of T2D decreased,
respectively, by 7% and 6% per cup-per-day increment
of caffeinated and decaffeinated coffee consumption (P
for difference ¼ 0.69) (Table 3). In agreement with a
previous study,18 this meta-analysis also shows that caf-
feinated and decaffeinated coffee consumption, as well
as caffeine intake, had similar inverse associations with
risk of T2D (Figure 4B).

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 Table 2 Studies included in the meta-analysis of coffee consumption and risk of type 2 diabetes
References Region (country) Study name Sex Age, y No. Cases Follow-up Assessment NOS Coffee, Adjusted RR (95%CI) Adjustments
years of T2D score cups/d
van Dam and Europe NA Both 30–60 17 111 306 7 SR 6 2 1.00 Age, sex, town, BMI, life-
Feskens (Netherlands) 3–4 0.79 (0.57–1.10) style, history of cardio-

R
(2002)24 5–6 0.73 (0.53–1.01) vascular disease, HT,
7 0.50 (0.35–0.72) hypercholesterolemia
Reunanen et al. Europe (Finland) Mobile Clinic Both 20–98 19 518 855 16 NR 7 2 1.00 Age, sex, BMI, PA,
(2003)25 Health 3–4 1.01 (0.81–1.27) smoking
Examination 5–6 0.98 (0.79–1.21)
Survey 7 0.92 (0.73–1.16)

Nutrition ReviewsV Vol. 76(6):395–417

Saremi et al. North America (USA) Pima Indians Both 15 2680 824 11 OGTT 6 0 1.00 Age, sex, BMI
(2003)26 Study <1 1.09 (0.89–1.34)
1–2 0.92 (0.74–1.13)
3 1.01 (0.82–1.26)
Carlsson et al. Europe (Finland) Finnish Twin Both 30–60 10 652 408 20 CSR 6 2 1.00 Age, sex, education, BMI,
(2004)27 Cohort 3–4 0.70 (0.48–1.01) PA, smoking, alcohol
5–6 0.71 (0.50–1.01)
7 0.65 (0.44–0.96)
Rosengren Europe (Sweden) BEDA Study W 39–65 1361 74 18 CSR/NR 7 2 1.00 Age, education, BMI, PA,
et al. 3–4 0.56 (0.32–0.98) smoking, serum choles-
(2004)28 5–6 0.45 (0.23–0.90) terol, and triglycerides
>6 0.57 (0.26–1.29)
van Dam et al. Europe Hoorn Study Both 50–74 1312 128 6 OGTT 8 2 1.00 Age, sex, BMI, WHR, PA,
(2004)29 (Netherlands) 3–4 0.94 (0.56–1.55) smoking, alcohol, his-
5–6 0.92 (0.53–1.61) tory of cardiovascular
7 0.69 (0.31–1.51) disease, antihyperten-
sive medication use, di-
etary fiber, total
energy, saturated fat,
polyunsaturated fat
Greenberg North America (USA) NHANES-1 Both 32–60 7006 309 8.4 SR 7 0 1.00 Age, sex, race, education,
et al. <2 0.82 (0.55–1.23) income, BMI, PA, smok-
(2005)30 2–4 0.75 (0.50–1.13) ing, alcohol, type of
4 0.37 (0.22–0.64) diet
Iso et al. Asia (Japan) JACC Study Both 40–65 6727 200 5 SR 7 <1/wk 1.00 Age, BMI, PA, smoking, al-
(2006)31 1–6/wk 0.71 (0.46–1.07) cohol, FHDM, magne-
1–2 0.96 (0.68–1.36) sium, other beverages
3 0.54 (0.30–0.97)
Iso et al. Asia (Japan) JACC Study Both 40–65 10 686 185 5 SR 7 <1/wk 1.00 Age, BMI, PA, smoking, al-
(2006)31 1–6/wk 0.95 (0.63–1.44) cohol, FHDM, magne-
1–2 0.88 (0.61–1.25) sium, other beverages
3 0.61 (0.30–1.22)
(continued)

399
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 Table 2 Continued

400
References Region (country) Study name Sex Age, y No. Cases Follow-up Assessment NOS Coffee, Adjusted RR (95%CI) Adjustments
years of T2D score cups/d
Paynter et al. North America (USA) ARIC Study M 45–64 5414 718 9 FG, NFG, hy- 9 0 1.00 Age, race, education, BMI,
(2006)32 poglycemic <1 1.00 (0.78–1.27) WHR, PA, smoking, al-
medication 1 1.12 (0.90–1.39) cohol, HT, FHDM, total
use, or SR 2–3 0.88 (0.71–1.09) energy, dietary fiber,
4 0.84 (0.66–1.06) serum magnesium
Paynter et al. North America (USA) ARIC Study W 45–64 6790 719 12 FG, NFG, hy- 9 0 1.00 Age, race, education, BMI,
(2006)32 poglycemic <1 0.89 (0.70–1.14) WHR, PA, smoking, al-
medication 1 0.94 (0.77–1.15) cohol, HT, FHDM, total
use, or SR 2–3 0.89 (0.72–1.09) energy, dietary fiber,
4 0.88 (0.68–1.13) serum magnesium
Pereira et al. North America (USA) Iowa Women’s W 55–69 28 812 1418 11 SR 6 0 1.00 Age, education, BMI,
(2006)33 Health Study <1 0.95 (0.77–1.18) WHR, PA, smoking, al-
1–3 1.01 (0.85–1.19) cohol, HT, energy, total
4–5 0.85 (0.69–1.04) fat, Keys score, cereal
6 0.79 (0.61–1.02) fiber, tea, soda, magne-
sium, phytate
Smith et al. North America (USA) Rancho Bernardo Both 50 910 84 8.3 OGTT 7 0 1.00 Age, sex, BMI, PA, smok-
(2006)34 Study 1–2 0.66 (0.38–1.14) ing, alcohol, HT, fasting
3–4 0.53 (0.26–1.08) glucose
5 0.60 (0.26–1.40)
van Dam et al. North America (USA) Nurses’ Health W 26–46 88 259 1263 10 CSR 7 0 1.00 Age, BMI, PA, smoking, al-
(2006)35 Study II <1 0.93 (0.80–1.09) cohol, HRT, oral contra-
1 0.87 (0.73–1.03) ceptives, FHDM, HT,
2–3 0.58 (0.49–0.68) hypercholesterolemia,
4 0.53 (0.41–0.68) total energy, cereal fi-
ber, soft drinks, punch,
processed meat, poly-
unsaturated to satu-
rated fat ratio, glycemic
index
Bidel et al. Europe (Finland) NA M 35–74 10 665 483 Up to 21 NR 7 0–2 1.00 Age, BMI, PA, smoking, al-
(2008)36 3–4 0.93 (0.70–1.22) cohol, c-glutamyl-
5–6 0.91 (0.69–1.18) transferase
7 0.74 (0.55–0.99)
Bidel et al. Europe (Finland) NA W 35–74 11 161 379 Up to 21 NR 7 0–2 1.00 Age, BMI, PA, smoking, al-
(2008)36 3–4 0.78 (0.59–1.03) cohol, c-glutamyl-
5–6 0.66 (0.49–0.87) transferase
0.50 (0.34–0.72)

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7
(continued)

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 Table 2 Continued
References Region (country) Study name Sex Age, y No. Cases Follow-up Assessment NOS Coffee, Adjusted RR (95%CI) Adjustments
years of T2D score cups/d
Hamer et al. Europe (UK) Whitehall II Both 35–55 5823 387 11.7 OGTT 8 0 1.00 Age, sex, ethnicity, em-
(2008)37 Study 1 0.83 (0.60–1.14) ployment, BMI, WHR,

R
2–3 0.85 (0.60–1.20) PA, smoking, alcohol,
>3 0.80 (0.54–1.18) FHDM, HT, cholesterol,
total energy, diet pat-
tern, other beverage
types
Odegaard et al. Asia (Singapore) Singapore Both 45–74 36 908 1889 5.7 CSR 9 <1 1.00 Age, year of interview,

Nutrition ReviewsV Vol. 76(6):395–417

(2008)38 Chinese Healt 1 0.94 (0.81–1.09) sex, dialect, education,
Study 2–3 0.83 (0.68–1.01) BMI, PA, smoking, alco-
4 0.70 (0.53–0.93) hol, HT, dietary varia-
bles, magnesium
Fuhrman et al. Puerto Rico Puerto Rico M 35–79 4685 519 2.6 FG 8 1–2 1.00 Age, education, BMI, PA,
(2009)39 Heart Health 3 0.79 (0.69–1.00) smoking, alcohol,
Program 4 0.75 (0.58–0.97) FHDM, milk, and sugar
Kato et al. Asia (Japan) JPHC Study M 40–69 24 826 1601 10 CSR 7 0 1.00 Age, BMI, PA, smoking, al-
(2009)40 1–2/wk 0.93 (0.80–1.08) cohol, FHDM, HT, men-
3–4/wk 0.84 (0.71–1.01) tal stress, levels of type
1–2 0.84 (0.73–0.97) A behavior, hours of
3–4 0.83 (0.68–1.02) sleep
5 0.82 (0.60–1.11)
Kato et al. Asia (Japan) JPHC Study W 40–69 31 000 1093 10 CSR 7 0 1.00 Age, BMI, PA, smoking, al-
(2009)40 1–2/wk 0.90 (0.76–1.06) cohol, FHDM, HT, men-
3–4/wk 0.95 (0.77–1.17) tal stress, levels of type
1–2 0.81 (0.69–0.96) A behavior, hours of
3–4 0.62 (0.45–0.84) sleep
5 0.40 (0.20–0.78)
van Dieren Europe EPIC-NL Cohort Both 20–70 40 011 918 10 CSR 8 0–1 1.00 Age, sex, cohort, educa-
et al. (Netherlands) 1–2 0.88 (0.69–1.11) tion, BMI, PA, FHDM,
(2009)41 2–3 0.94 (0.75–1.17) smoking, alcohol, HT,
3–4 0.75 (0.60–0.92) hypercholesterolemia,
4–6 0.74 (0.61–0.91) energy, saturated fat,
>6 0.84 (0.65–1.08) fiber, vitamin C, and
tea
Oba et al. Asia (Japan) Takayama Study M 35 5897 278 11 SR 7 0 1.00 Age, education, BMI, PA,
(2010)42 <1 0.69 (0.50–0.97) smoking, alcohol, total
1 0.69 (0.49–0.98) energy, dietary fat
(continued)

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 Table 2 Continued

402
References Region (country) Study name Sex Age, y No. Cases Follow-up Assessment NOS Coffee, Adjusted RR (95%CI) Adjustments
years of T2D score cups/d
Oba et al. Asia (Japan) Takayama Study W 35 7643 175 11 SR 7 0 1.00 Age, education, BMI, PA,
(2010)42 <1 1.08 (0.74–1.60) smoking, alcohol, total
1 0.70 (0.44–1.12) energy, dietary fat,
menopausal status
Boggs et al. North America (USA) Black Women’s W 30–69 46 906 3671 12 SR 7 0 1.00 Age, education, BMI, PA,
(2010)43 Health Study <1 0.94 (0.86–1.04) smoking, alcohol,
1 0.90 (0.81–1.01) FHDM, HT, cholesterol,
2–3 0.82 (0.72–0.93) tea, energy, glycemic
4 0.83 (0.69–1.01) index, cereal fiber, soft
drinks
Sartorelli et al. Europe (France) E3N/EPIC W 41–72 69 532 1415 11 CSR 8 0 1.00 Age, education, BMI, PA,
(2010)44 1 1.04 (0.87–1.26) smoking, alcohol, HT,
1.1–2.9 0.86 (0.73–1.02) hypercholesterolemia,
3 0.73 (0.61–0.87) FHDM, menopausal sta-
tus, HRT, oral contra-
ceptives, energy,
dietary fiber, saturated
fat, magnesium
Zhang et al. North America (USA) Strong Heart Both 45–74 1141 188 7.6 OGGT/FG 8 0 1.00 Age, sex, BMI, PA, smok-
(2011)45 Study 1–2 0.93 (0.55–1.57) ing, alcohol, FHDM
3–4 0.87 (0.53–1.44)
5–7 0.72 (0.43–1.23)
8–11 0.78 (0.44–1.37)
12 0.33 (0.12–0.81)
Goto et al. North America (USA) Women’s Health W 45 718 359 10 CSR 7 0 1.00 Age, BMI, PA, smoking, al-
(2011)46 Study 1 0.92 (0.46–1.84) cohol, FHDM, sex hor-
2–3 0.96 (0.48–1.94) mone-binding globulin,
4 0.71 (0.31–1.61) total energy
Hjellvik et al. Europe (Norway) NA M 40–45 171 414 5917 Up to 20 Oral antidia- 7 <1 1.00 Age, education, BMI, PA,
(2011)47 betic drug 1–4 0.86 (0.79–0.93) smoking
use 5–8 0.69 (0.64–0.76)
>9 0.67 (0.60–0.74)
Hjellvik et al. Europe (Norway) NA W 40–45 190 631 3969 Up to 20 Oral antidia- 7 <1 1.00 Age, education, BMI, PA,
(2011)47 betic drug 1–4 0.80 (0.73–0.88) smoking
use 5–8 0.60 (0.54–0.66)
>9 0.58 (0.51–0.67)
(continued)

R
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 Table 2 Continued
References Region (country) Study name Sex Age, y No. Cases Follow-up Assessment NOS Coffee, Adjusted RR (95%CI) Adjustments
years of T2D score cups/d
Floegel et al. Europe (Germany) EPIC-Germany Both 35–65 42 659 1432 8.9 CSR 8 <1 1.00 Age, sex, education, em-
(2012)48 1–2 0.89 (0.69–1.16) ployment, BMI, WHR,

R
2–3 0.92 (0.76–1.13) PA, smoking, alcohol,
3–4 0.82 (0.65–1.02) HT, vitamin and min-
4 0.77 (0.63–0.94) eral supplement use,
total energy, tea
Bhupathiraju North America (USA) Health M 40–75 39 059 2865 22 CSR 7 <1 1.00 Age, BMI, weight change,
et al. Professionals 1–3 0.95 (0.88–1.03) PA, smoking, alcohol,

Nutrition ReviewsV Vol. 76(6):395–417

(2013)49 Follow-up 4–5 0.92 (0.82–1.05) FHDM, HT, hypercho-
Study 6 0.65 (0.49–0.85) lesterolemia, tea, fruit
punch, sweetened bev-
erage, AHEI, low-calorie
diet, total energy
Bhupathiraju North America (USA) Nurses Health W 30–55 74 749 7370 24 CSR 7 <1 1.00 Age, BMI, weight change,
et al. Study 1–3 0.91 (0.86–0.95) PA, smoking, alcohol,
(2013)49 4–5 0.78 (0.72–0.85) FHDM, HT, hypercho-
6 0.65 (0.58–0.73) lesterolemia, tea, fruit
punch, sweetened bev-
erage, AHEI, low-calorie
diet, total energy, HRT
Doo et al. North America (USA) Multiethnic M 45–75 36 120 4541 14 CSR 8 0 1.00 Age, ethnicity, education,
(2014)50 Cohort <1 1.12 (1.01–1.24) BMI, PA, smoking, alco-
1 1.06 (0.97–1.17) hol, HT, energy, soda,
2 1.05 (0.95–1.16) dietary fiber, processed
3 0.95 (0.84–1.08) meat
Doo et al. North America (USA) Multiethnic W 45–75 39 020 4041 14 CSR 8 0 1.00 Age, ethnicity, education,
(2014)50 Cohort <1 1.08 (0.98–1.19) BMI, PA, smoking, alco-
1 0.96 (0.87–1.05) hol, HT, energy, soda,
2 0.82 (0.74–0.91) dietary fiber, processed
3 0.69 (0.59–0.81) meat
Nordestgaard Europe (Denmark) Copenhagen Both 42–71 83 436 789 NA NR 6 0 1.00 Age, sex, PA, smoking,
et al. General <1 0.70 (0.54–0.91) use of antihyperten-
(2015)51 Population 1–2 0.66 (0.51–0.86) sive, and lipid-lowering
Study 2–3 0.72 (0.56–0.93) medication
3–4 0.52 (0.38–0.71)
4–5 0.48 (0.35–0.67)
>5 0.57 (0.42–0.78)
Lee et al. Asia (Korea) Korean M 40–69 1961 652 4 OGTT 8 0 1.00 Age, residential area, BMI,
(2015)52 Association <1 0.80 (0.58–1.10) PA, smoking, alcohol,
Resource 1–2 1.01 (0.74–1.39) total energy, fruit, veg-
Study 2 0.75 (0.56–1.02) etables, red meat, dairy
foods
(continued)

403
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 Unfiltered versus filtered coffee

Age, residential area, BMI,

etables, red meat, dairy

total energy, fruit, veg-

Health and Nutrition Examination Survey; NOS, Newcastle-Ottawa Scale; NR, national register; OGTT, oral glucose tolerance test; PA, physical activity; RR, relative risk; SR, self-report in follow-
PA, smoking, alcohol,

Abbreviations: AHEI, Alternative Healthy Eating Index; ARIC, Atherosclerosis Risk in Communities Study; BMI, body mass index; CI, confidence interval; CSR, confirmed self-report; E3N/EPIC,
European Prospective Investigation into Cancer and Nutrition; FG, fasting glucose; FHDM, family history of diabetes mellitus; HRT, hormone replacement therapy; HT, hyptertension; JACC,
Unfiltered coffee, such as Scandinavian boiled, French

Journal of the American College of Cardiology; JPHC, Japan Public Health Center–Based Prospective Study; M, men; NA, not available; NFG, non-fasting glucose; NHANES-1, first National
Adjustments
press, and Turkish/Greek coffees, contains diterpenes,
which raise blood cholesterol and triglycerides levels.56
Lipid levels have been shown to be inversely associated

foods
with risk of T2D.57 Espresso coffee, which is often the
base for other drinks such as latte and cappuccino, con-
tains intermediate amounts of diterpenes.56,58 Filtered

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Adjusted RR (95%CI)

coffee (also known as drip-brewed coffee) and instant

0.90 (0.68–1.20)
0.99 (0.75–1.30)
0.87 (0.65–1.18)

coffee contain negligible amounts of diterpenes.58 Few

studies have examined whether the association between
coffee consumption and risk of T2D differs for unfil-
1.00

tered versus filtered coffee. A Norwegian cohort study

showed an approximately 35% decreased risk of T2D
Coffee,
cups/d

associated with high (vs low) consumption of both

1–2

boiled coffee and other types of coffee.50 Likewise,

<1

2
0

results from a Finnish cohort study showed that both

score
NOS

consumption of boiled coffee and consumption of fil-

8

tered coffee were inversely associated with T2D.59

Assessment

These findings suggest that the observed inverse associ-

of T2D

ation between coffee consumption and T2D is not likely

OGTT

explained by diterpenes and raised lipid levels, but fur-

ther studies on type of brewing method are needed to
confirm this.
Cases Follow-up
years

RANDOMIZED CONTROLLED TRIALS OF COFFEE AND

4

RISK OF TYPE 2 DIABETES AND CARDIOMETABOLIC

596

FACTORS
2116

The causality of the association between coffee con-

No.

sumption and the risk of incident T2D cannot be estab-

lished solely based on observational studies. Therefore,
up questionnaires; T2D, type 2 diabetes; W, women; WHR, waist-to-hip ratio.
Age, y

40–69

long-term, randomized, placebo-controlled trials are

warranted to confirm the observed protective associa-
tion and to elucidate the underlying mechanisms.
Sex

Currently, no such interventional studies have been

published. However, a recent prospective study, based
Study name

Association

on 3 large cohorts of men and women in the United

Resource

States, investigated how a 4-year change in coffee con-

Study
Korean

sumption influenced the risk of incident T2D in the

subsequent 4 years.60 In this novel study (with > 1.6
million person-years of follow-up), Bhupathiraju and
Region (country)

associates demonstrated that increased coffee intake by

> 1 cup/day lowered the risk of T2D by 11% (RR, 0.89;
Asia (Korea)

95%CI, 0.82–0.87), whereas participants who decreased

their coffee intake by > 1 cup/day had a higher risk of
developing T2D (RR, 1.17; 95% CI, 1.08–1.26). In the
Table 2 Continued

same study, changes in tea consumption over the same

4-year period were not associated with any differences
in the risk of T2D development.
References

(2015)52
Lee et al.

These findings bring further support to the meta-

analysis demonstrating that higher coffee consumption
is associated with a lower risk of developing T2D.

404 Nutrition ReviewsV Vol. 76(6):395–417

R
 %
Reference RR (95% CI) Weight
27
van Dam and Feskens28(2002) 0.50 (0.35−0.72) 2.18
Reunanen et al (2003) 29
0.92 (0.73−1.16) 3.43
Saremi et al (2003) 30 1.01 (0.82−1.26) 3.63
Carlsson et al (2004) 31 0.65 (0.44−0.96) 1.97
Rosengren et al (2004) 32
0.57 (0.26−1.29) 0.63
van Dam et al (2004) 33 0.69 (0.31−1.51) 0.65
Greenberg et al (2005) 34
0.37 (0.22−0.64) 1.25
Iso et al (2006) (M) 34 0.54 (0.30−0.97) 1.08
Iso et al (2006) (W) 35
0.61 (0.30−1.22) 0.80
Paynter et al (2006) (M) 35 0.84 (0.66−1.06) 3.37

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Paynter et al (2006)36(W) 0.88 (0.68−1.13) 3.17
Pereira et al (2006) 37
0.79 (0.61−1.02) 3.14
Smith et al (2006) 38 0.60 (0.26−1.40) 0.58
van Dam et al (2006)39 0.53 (0.41−0.68) 3.18
Bidel et al (2008) (M) 39 0.74 (0.55−0.99) 2.75
Bidel et al (2008) (W) 40
0.50 (0.34−0.72) 2.07
Hamer et al (2008) 41 0.80 (0.54−1.18) 1.97
Odegaard et al (2008)42 0.70 (0.53−0.93) 2.88
Fuhrman et al (2009)43 0.75 (0.58−0.97) 3.14
Kato et al (2009) (M) 43 0.82 (0.60−1.11) 2.62
Kato et al (2009) (W) 44 0.40 (0.20−0.78) 0.84
van Dieren et al (2009) 45
0.84 (0.65−1.08) 3.17
Oba et al (2010) (M) 45 0.69 (0.49−0.98) 2.29
Oba et al (2010) (W) 46
0.70 (0.44−1.12) 1.53
Boggs et al (2010) 47
0.83 (0.69−1.01) 3.94
Sarotorelli et al (2010)
48
0.73 (0.61−0.87) 4.11
Zhang et al (2011) 49
0.33 (0.12−0.81) 0.46
Goto et al (2011) 50
0.71 (0.31−1.61) 0.60
Hjellvik et al (2011) (M) 50 0.67 (0.60−0.74) 5.05
Hjellvik et al (2011) 51(W) 0.58 (0.51−0.67) 4.65
Floegel et al (2012) 52
0.77 (0.63−0.94) 3.82
Bhupathiraju et al (2013) (M) 52 0.65 (0.49−0.85) 2.94
Bhupathiraju et al (2013) 53
(W) 0.65 (0.58−0.73) 4.92
Doo et al (2014) (M) 53 0.95 (0.84−1.08) 4.79
Doo et al (2014) (W) 54
0.69 (0.59−0.81) 4.37
Nordestgaard et al (2015) 55
0.57 (0.42−0.78) 2.60
Lee et al (2015) (M) 55 0.75 (0.56−1.02) 2.70
Lee et al (2015)
2
(W) 0.87 (0.65−1.18) 2.71
Overall (I = 57.9%, P <0.001) 0.71 (0.67−0.76) 100.00

0.2 0.4 0.7 1 1.5

RR (95% CI) of T2D for the highest versus lowest category of coffee consumption

Figure 2 Forest plot of the associations between total coffee consumption (highest vs lowest category) and risk of type 2 diabetes.
Squares indicate study-specific relative risks (size of the square reflects the study-specific statistical weight; that is, the inverse of the variance);
horizontal lines indicate 95% confidence intervals; diamond indicates the summary relative risk with its 95% confidence interval.
Abbreviations: CI, confidence interval; RR, relative risk; T2D, type 2 diabetes.

Changes in habitual coffee consumption in a rela-
tively short amount of time appear to affect diabetes,
but mechanistic knowledge from controlled interven-
tion studies is limited. A randomized controlled trial
in overweight men with mild-to-moderate elevation
of fasting plasma glucose demonstrated that 16 weeks
of consumption of caffeinated coffee (5 cups/d) mod-
estly improved glucose tolerance and decreased waist
circumference.61 These favorable effects were not ob-
served in the groups that consumed decaffeinated
coffee or no coffee at all. In another randomized con-
trolled trial (8-wk intervention), consumption of caf-
feinated coffee was associated with improvements in
adipocyte and liver function, as indicated by changes
in adiponectin and fetuin-A concentrations, but did
not change measures of glycemia or insulin sensitiv-
ity.62 A recent intervention (3 mo) cross-over design
study investigated the cardiometabolic effects of 2
different coffee blends in overweight adults.63 Dark
roasted caffeinated coffee rich in N-methylpyridi-
nium (a metabolite from degradation of trigonel-
line) was associated with a reduction in systolic
blood pressure and increased low-density lipopro-
tein cholesterol, whereas consumption of the mild
roasted caffeinated coffee rich in chlorogenic acids
(CGA) increased adiponectin and high-density lipo-
protein cholesterol levels. In the same trial with
overweight participants, no effects on body weight
were found, although the authors observed greater
weight loss in participants with higher serum levels
of N-methylpyridinium after coffee consumption.
Further intervention studies of health effects in rela-
tion to coffee consumption and type of coffee are
warranted.

Nutrition ReviewsV Vol. 76(6):395–417

R
405
 %
Reference RR (95% CI) Weight
27
van Dam and Feskens28(2002) 0.91 (0.86−0.96) 2.70
Reunanen et al (2003) 29
0.99 (0.95−1.02) 4.04
Saremi et al (2003) 30 0.99 (0.94−1.05) 2.44
Carlsson et al (2004) 31 0.94 (0.89, 0.99) 2.49
Rosengren et al (2004) 32
0.87 (0.77−0.98) 0.78
van Dam et al (2004) 33 0.96 (0.87−1.07) 1.03
Greenberg et al (2005) 34
0.85 (0.78−0.93) 1.19
Iso et al (2006) (M) 34 0.90 (0.77−1.04) 0.52
Iso et al (2006) (W) 35
0.89 (0.75−1.05) 0.42
Paynter et al (2006) (M) 35 0.95 (0.91−1.00) 2.98

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Paynter et al (2006)36(W) 0.97 (0.93−1.02) 2.73
Pereira et al (2006) 37
0.96 (0.94−0.99) 4.26
Smith et al (2006) 38 0.89 (0.78−1.02) 0.64
van Dam et al (2006)39 0.84 (0.81−0.88) 3.11
Bidel et al (2008) (M) 39 0.96 (0.92−1.00) 3.30
Bidel et al (2008) (W) 40
0.90 (0.86−0.95) 2.78
Hamer et al (2008) 41 0.97 (0.89−1.06) 1.28
Odegaard et al (2008)42 0.93 (0.88−0.98) 2.70
Fuhrman et al (2009)43 0.89 (0.83−0.97) 1.52
Kato et al (2009) (M) 43 0.96 (0.92−1.00) 3.46
Kato et al (2009) (W) 44 0.87 (0.82−0.93) 2.04
van Dieren et al (2009) 45
0.96 (0.93−0.99) 4.07
Oba et al (2010) (M) 45 0.90 (0.77−1.06) 0.44
Oba et al (2010) (W) 46
0.75 (0.58−0.97) 0.19
Boggs et al (2010) 47
0.94 (0.91−0.98) 3.97
Sarotorelli et al (2010)
48
0.92 (0.88−0.95) 3.56
Zhang et al (2011) 49
0.95 (0.91−1.00) 3.20
Goto et al (2011) 50
0.94 (0.79−1.11) 0.41
Hjellvik et al (2011) (M) 50 0.96 (0.95−0.97) 5.94
Hjellvik et al (2011) 51(W) 0.95 (0.94−0.96) 5.82
Floegel et al (2012) 52
0.94 (0.90−0.98) 2.97
Bhupathiraju et al (2013) (M) 52 0.96 (0.94−0.99) 4.63
Bhupathiraju et al (2013) 53
(W) 0.93 (0.91−0.95) 5.38
Doo et al (2014) (M) 53 0.98 (0.95−1.01) 4.20
Doo et al (2014) (W) 54
0.88 (0.85−0.92) 3.67
Nordestgaard et al (2015) 55
0.91 (0.87−0.95) 3.22
Lee et al (2015) (M) 55 0.93 (0.84−1.03) 1.00
Lee et al (2015)
2
(W) 0.97 (0.87−1.08) 0.91
Overall (I = 66.5%, P <0.001) 0.94 (0.93−0.95) 100.00

0.7 0.8 0.9 1 1.12

RR (95% CI) of T2D per 1 cup/day increase in coffee consumption

Figure 3 Forest plot of the associations between total coffee consumption (per 1 cup/d) and risk of type 2 diabetes. Squares indicate
study-specific relative risks (size of the square reflects the study-specific statistical weight; that is, the inverse of the variance); horizontal lines
indicate 95% confidence intervals; diamond indicates the summary relative risk with its 95% confidence interval. Abbreviations: CI, confidence
interval; RR, relative risk; T2D, type 2 diabetes.

TYPE 2 DIABETES, CARDIOVASCULAR DISEASE, AND
RENAL DYSFUNCTION AND ASSOCIATED MORTALITY
There is no doubt that T2D is associated with in-
creased risk of developing cardiovascular and renal
disease or having adverse complications. Therefore it
is not surprising that early diagnosis and treatment of
T2D have been suggested to reduce cardiovascular
morbidity and mortality.5 Recent studies have sug-
gested a triad of disorders because renal disease and
hypertension may antecede or increase the risk of met-
abolic syndrome and T2D.1,3,4 Because accumulating
data from experimental, epidemiological, and clinical
studies suggest an inverse association between coffee
consumption and the risk of T2D, it is also possible
that high intake of coffee may have favorable effects on
the triad of renal, cardiovascular, and metabolic
disorders.
The relation between coffee consumption and risk
of cardiovascular disease has been examined in many
studies, but the issue remains controversial. However,
the overall evidence from epidemiological studies indi-
cates nonlinear relationships between coffee consump-
tion and risk of total cardiovascular disease, coronary
heart disease, and stroke.64 In a meta-analysis of 36 pro-
spective cohort studies with almost 1.3 million individ-
uals and 36 352 cases of cardiovascular disease,
compared with the lowest category of coffee consump-
tion (median, 0 cups/d), the RR estimates were 0.89
(95%CI, 0.84–0.94) for a median intake of 1.5 cups/day,
0.85 (95%CI, 0.80–0.90) for a median intake of 3.5
cups/day, and 0.95 (95%CI, 0.87–1.03) for a median in-
take of 5 cups/day.64
In a recent large prospective study that included 3
cohorts from the United States, Ding et al.65 examined
the associations of consumption of total, caffeinated,

406 Nutrition ReviewsV Vol. 76(6):395–417

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 Table 3 Association between total coffee consumption and risk of type 2 diabetes according to sex, geographic region,
study quality, and type of coffee
Comparisons No.a Highest vs lowest category Dose–response (per 1 cup/d)
RR (95%CI) I2 (P value) RR (95%CI) I2 (P value)
Sex
Men 10 0.76 (0.67–0.85) 58.1% (0.01) 0.94 (0.92–0.96) 0% (0.73)
Women 15 0.68 (0.62–0.75) 49.0% (0.02) 0.92 (0.90–0.94) 73.5% (<0.001)
Both sexes 13 0.71 (0.61–0.82) 59.7% (0.003) 0.96 (0.95–0.97) 46.0% (0.04)
P value for difference (men vs women) 0.18 0.03

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Region
USA 14 0.74 (0.65–0.84) 73.8% (<0.001) 0.94 (0.92–0.96) 77.2% (<0.001)
Europe 14 0.69 (0.62–0.75) 46.8% (0.03) 0.94 (0.93–0.96) 59.8% (0.002)
Asia 9 0.73 (0.64–0.82) 0% (0.60) 0.92 (0.90–0.95) 17.3% (0.28)
P value for difference (US vs. Europe) 0.35 0.82
P value for difference (Europe vs Asia) 0.59 0.27
Study quality (NOS)
Moderate (6–7) 24 0.67 (0.61–0.73) 55.3% (0.001) 0.94 (0.92–0.95) 72.8% (<0.001)
High (8–9) 14 0.79 (0.74–0.86) 26.0% (0.18) 0.94 (0.92–0.96) 46.8% (0.003)
P value for difference 0.02 0.51
Type of coffee
Caffeinated 10 0.73 (0.64–0.83) 73.3% (<0.001) 0.93 (0.90–0.96) 88.1% (<0.001)
Decaffeinated 10 0.80 (0.69–0.94) 70.2% (<0.001) 0.94 (0.90– 0.98) 72.8% (<0.001)
P-value for difference 0.35 0.69
Abbreviations: CI, confidence interval; NOS, Newcastle-Ottawa Scale (ranges from 1 to 9, with higher score indicating higher quality);
RR, relative risk.
a
Number of studies (separated by sex) included in the analysis. The study conducted in Puerto Rico was not included in the region-
stratified analysis.

Figure 4 Dose–response analysis of the association between coffee consumption and risk of type 2 diabetes. Comparisons are made
between the sexes (A) and also for intake of regular caffeinated coffee, decaffeinated coffee, or caffeine (B) and the incidence of type 2 diabe-
tes. The data originate from that originally described in a meta-analysis of prospective studies by Jiang and colleagues.16 Data presented in
panel A involved 148 06 men and 21 754 women. Data in panel B included 46 722 individuals who consumed caffeinated coffee, 23 781 indi-
viduals who consumed decaffeinated coffee, and 8711 individuals with only caffeine intake.

and decaffeinated coffee with risk of subsequent total
and cause-specific mortality in both men (n ¼ 40 557)
and women (n ¼ 167 944). Consumption of total, caf-
feinated, and decaffeinated coffee were inversely associ-
ated with mortality, with hazard ratios of 0.94 (95%CI,
0.89–0.99) for 1 cup, 0.92 (95%CI, 0.87–0.97) for 1–3 or
more cups, 0.85 (95%CI, 0.79–0.92) for 3–5 or
more cups, and 0.88 (95%CI, 0.78–0.99) for 5 or more
cups/day (P value for trend < 0.001). The inverse associ-
ation was stronger and with a dose–response relation-
ship in never smokers. Analysis of cause-specific
mortality in the total population demonstrated inverse
associations between coffee consumption and cardio-
vascular disease mortality, as well as diabetes-associated
mortality. Likewise, results from the European
Prospective Investigation into Cancer and Nutrition

Nutrition ReviewsV Vol. 76(6):395–417

R
407
cohort, which was comprised of > 5000 000 individuals
from 10 European countries, showed inverse associa-
tions of coffee consumption with mortality due to circu-
latory diseases and all-cause mortality, with a stronger
inverse association observed in never smokers.66
Furthermore, high coffee consumption (6 cups/d) was
associated with a 12%–28% lower risk of coronary heart
disease mortality, a 40%–43% lower risk of T2D mortal-
ity, and a 10%–15% lower risk of all-cause mortality
among 229 119 men and 173 141 women in the
National Institutes of Health–AARP Diet and Health
Study.67
Diabetes and kidney disease are closely associated
and share many risk factors.68 Therefore it is tempting
to speculate that coffee consumption may protect
against progressive decline in renal function (ie, esti-
mated glomerular filtration rate [eGFR]). However,
results from relatively short-term clinical studies with
coffee have not been conclusive, and long-term inter-
vention studies in individuals at increased risk for T2D
and renal disease have not been conducted. Two weeks
of coffee consumption in young adults in Japan in-
creased eGFR.69 Moreover, in 2 studies in adults in
Japan, higher eGFR was observed in habitual coffee
consumers compared with coffee restrainers.70,71 In a
study in women in Korea, coffee consumption was asso-
ciated with a decreased risk of kidney function impair-
ment in participants with diabetes.72 Several of the
conducted studies used a cross-sectional design, and the
evidence of a temporal relation between exposure and
outcome is thus limited. In addition to the studies men-
tioned above, which were conducted in Asian popula-
tions, a recent study investigated the prospective
association of coffee and changes in eGFR in a Western
population.73 Both men and women were included, and
repeated measurements of coffee consumption and
eGFR were conducted every 5 years for 15 years. Higher
coffee consumption was associated with a slightly
higher eGFR, which could not be explained by differen-
ces in sex, education, lifestyle, diet, biological risk fac-
tors, or coffee constituents. The authors concluded that
the absence of an association with subsequent annual
changes in or risk of a rapid decline in eGFR suggests
that the higher eGFR among coffee consumers is un-
likely to be a result of glomerular hyperfiltration.
Therefore, low to moderate coffee consumption is not
expected to be a concern for kidney health in the gen-
eral population. The observed increase in eGFR associ-
ated with coffee consumption may be linked with
caffeine-mediated modulation of adenosine receptor
signaling in the kidney (see “Modulation of adenosine
receptor signaling”) that modulates renal autoregulatory
mechanisms.74
408
In conclusion, T2D, cardiovascular disease, and re-
nal dysfunction are interrelated and associated with in-
creased morbidity and mortality. Although the
underlying mechanisms require further investigations,
several epidemiological and prospective studies have
found that coffee consumption is inversely associated
with total mortality, cardiovascular disease mortality,
and T2D mortality. Higher intake of coffee has been
demonstrated to increase eGFR, but long-term inter-
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vention studies in individuals with T2D and renal dis-
ease are still missing.
BIOACTIVE COMPONENTS IN COFFEE
Coffee is a complex mixture of chemical compounds,
and its composition varies according to the coffee bean
species, the roasting process (speed, time, and tempera-
ture), and the grinding and brewing process (water/cof-
fee grounds ratio, coffee grind size, water temperature,
duration, and methods). In healthy volunteers, con-
sumption of dark roast coffee blends was related to
stronger activation of antioxidant defense and repair
enzymes (eg, tocopherol [vitamin E], glutathione sys-
tems, nuclear factor erythroid 2-related factor 2 [Nrf2])
compared with consumption of light roast coffee.75–77
However, the maximum antioxidant capacity was ob-
served for medium roast coffee.78,79 Numerous bioac-
tive components in coffee have been proposed to
contribute to the associated favorable metabolic effects,
including caffeine, phenolics (eg, chlorogenic acid
[CGA]), lignans, trigonelline, N-methylpyridinium,
minerals and vitamins (eg, magnesium, potassium, nia-
cin), proteins, and lipids in special diterpenes (eg, cafes-
tol and kahweol).80–84 Many of these compounds may
play a role in regulation of insulin and glucose and thus
influence the development or progression of T2D.
Among the many bioactive substances found in coffee,
caffeine and CGA are among the most reviewed and
discussed compounds.
GENETIC POLYMORPHISMS
It should be noted that some of the discrepancies re-
garding the effects of caffeinated coffee consumption
and metabolic functions in humans could be linked
with pharmacokinetic and pharmacodynamic polymor-
phisms.85 More than 90% of caffeine is metabolized by
CYP1A2, and caffeine is an inducer of the enzyme.86
Individuals homozygous for the CYP1A2 *1 A/*1 A ge-
notype are fast caffeine metabolizers, whereas carriers
of the slow *1 F allele are more exposed to the effects of
caffeine.87,88 Results from a recent meta-analysis indi-
cated that sex and ethnicity could also modify the asso-
ciation between the CYP1A2 polymorphism and
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R
habitual coffee intake.89 Comparison of consumers of
high amounts and consumers of low amounts of coffee
demonstrated that a high caffeine intake was associated
with the genotype conferring fast metabolism. In sub-
group analyses this association was found in males,
younger individuals, and those with Caucasian ethnic-
ity, but not in females, older individuals, and those with
Asian ethnicity. Variable responses may also occur at
the receptor level (pharmacodynamic and pharmacoki-
netic polymorphisms), and human studies have sug-
gested that polymorphisms in the adenosine A2A
receptor may contribute to different degrees of caffeine-
induced anxiety or arousal effects.85 Several experimen-
tal studies have demonstrated a link between impaired
A2 receptors signaling and development of metabolic
syndrome90; however, there is currently lack of knowl-
edge regarding A2 receptor polymorphism(s) and T2D.
Genome-wide association studies have identified associ-
ations of genetic variants near CYP1A2 and aryl hydro-
carbon receptor (AHR) with habitual caffeine and
coffee intake,91 but those variants have not been found
to be associated with T2D.54 In conclusion, future long-
term randomized prospective studies should consider
genetic polymorphisms (eg, CYP1A2 genotype) when
investigating the effects of coffee/caffeine consumption
and the risk of T2D and associated comorbidities.
POSSIBLE MECHANISMS OF ACTION
The possibility that part of the beneficial effect of coffee
consumption is that it reduces the amount of soft drinks
consumed should not be overlooked. The magnitude of
such an effect has not been quantified. However, it
seems likely that there are also direct effects of > 1 com-
ponents in coffee. Given the many bioactive compo-
nents in coffee, several different mechanisms have been
suggested to contribute to the proposed favorable meta-
bolic effects associated with coffee. The reported effects
of caffeine and CGA on insulin and glucose homeosta-
sis have been reviewed in detail previously80–84,92; they
include modulation of adenosine receptor signaling, in-
hibition of intestinal glucose absorption (via increased
production of gastric inhibitory peptide-1 [GIP-1] and
glucagon-like-peptide-1 [GLP-1] or inhibition of
glucose-6-phosphate translocase 1), reduction of hepatic
glucose output (via inhibition of glucose-6-
phosphatase), and improvement of pancreatic islet insu-
lin secretion or peripheral insulin sensitivity and glu-
cose uptake (via stimulation of glucose transporter type
4 [GLUT4] and modulation of intracellular signaling
pathways, including Akt, AMPK, MAPK activation).
Many of the described favorable metabolic effects may
be linked to thermogenic effects, modulation of
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adenosine receptor signaling, reduction of oxidative
stress, and modulation of immune cell function(s).
Thermogenic effects
Coffee consumption has been proposed to stimulate
thermogenesis and thus induce weight loss and reduce
the risk of T2D.93 It has been estimated that daily intake
of coffee (6 cups/d) increases energy expenditure by ap-
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proximately 100 kcal/day, which clearly may reduce the
risk of developing overweight and obesity. Accumulated
mechanistic knowledge suggests that caffeine likely is
the main ingredient that contributes to the thermogenic
effects of coffee, but current evidence from human stud-
ies is limited.93 The target organ(s) and the specific
mechanism(s) whereby caffeinated coffee mediates
these metabolic effects have yet to be clarified, but caf-
feine has been shown to increase thermogenesis of
brown adipose tissue partly by upregulating the expres-
sion of an uncoupling protein in rodents94 and to in-
crease energy expenditure and stimulate lipid oxidation
in humans.95 Some studies in humans demonstrated
that ingestion of caffeinated coffee96 and instant caffein-
ated coffee95,97 increased lipolysis. No increase in lipoly-
sis was found after ingestion of decaffeinated coffee or
instant decaffeinated coffee.96 In contrast, other studies
concluded that neither caffeine, caffeinated coffee, or
decaffeinated coffee altered fat metabolism in human
skeletal muscle during exercise.98,99
An alternative mechanism that may contribute to
reduced body weight is that caffeine or other com-
pounds in coffee may enhance satiety.93 In an epidemi-
ological study, Lopez-Garcia and colleagues100 showed
that increases in caffeine intake may lead to a small re-
duction in long-term weight gain. In a recent double-
blind, randomized, crossover intervention study in
healthy participants (n ¼ 84), consumption of caffein-
ated coffee was associated with a decrease in body fat
over the whole study period.101 Interestingly, the ob-
served changes in food intake and body fat were to
some extent linked to coffee-associated regulation of sa-
tiety biomarkers (eg, increased serotonin and reduced
ghrelin levels in plasma).
The activation of energy metabolism by caffeinated
coffee could also be promoted by inhibition of adeno-
sine receptor signaling (discussed below) or by induc-
tion of catecholamine release.92,93,102,103 Although most
studies have focused on the role of caffeine as the pri-
mary component in coffee, some studies suggest that
phenolic compounds such as CGA might have an effect
on weight control. For example, supplementation with
coffee polyphenols reduced high-fat diet–induced obe-
sity and fat accumulation in mice.104 Moreover, in over-
weight persons, supplementation with CGA (estimated
409
to 0.5–1 g/d) reduced body weight compared with pla-
cebo,105 and consumption of CGA-enriched instant cof-
fee for 3 months (amount of added CGA: 450–500 mg/d)
reduced body weight and fat mass more than consump-
tion of normal instant coffee.106 The average losses in
mass in the CGA-enriched and normal instant coffee
groups were 5.4 and 1.7 kg, respectively, and the different
response between groups was partly ascribed to CGA-
induced reduction in glucose absorption.106
Modulation of adenosine receptor signaling
After consumption of 1 regular cup of coffee, which
normally equals 80–120 mg of caffeine), the plasma con-
centration of caffeine ranges from 5 to 10 mM. Among
the 4 different adenosine receptors (A1, A2A, A2B, A3),
this concentration of caffeine is an antagonist of A1
(Kd ¼ 20 mM in rat and 12 mM in human), A2A
(Kd ¼ 8.1 mM in rat and 2.4 mM in human), and A2B
(Kd ¼ 17 mM in rat and 13 mM in human) but should
not be sufficient to inhibit the A3 receptor (Kd
¼ 190 mM in rat and 80 mM in human).103,107
Comparisons of tissue-specific expression of the adeno-
sine receptors have been reviewed previously.107,108
Moreover, a recent comprehensive review discussed the
effects of adenosine signaling in T2D and associated
cardiovascular and renal complications.90
In tissues where the receptors are abundant, nor-
mal levels of adenosine are sufficient to activate A1,
A2A, and A3, but less likely A2B.107,108 Therefore, the tar-
gets for caffeine after normal coffee consumption are
likely the A1 and A2A receptors, but antagonism of the
A3 receptor would also be possible after high intake of
caffeinated coffee. Adenosine is an important regulator
of metabolic functions that may be exerted by multiple
sites, including the gastrointestinal tract, liver, pancreas,
skeletal muscle, and adipose tissue.90,92 In addition to
its peripheral actions, adenosine acts in the brain to reg-
ulate sleep–wakefulness, food intake, and body temper-
ature.92 Adenosine modulates visceral adipose tissue
function through inhibition of lipolysis and increased
lipogenesis.92,109 Adenosine mediates metabolically in-
duced vasodilation in several tissues,110,111 including is-
let blood flow in response to glucose.112 Adenosine can
also affect the endocrine pancreas per se113 and may
therefore modulate insulin and glucagon secretion.114
However, the precise roles of the specific receptors in
metabolism are still somewhat unclear, which can partly
be explained by the limited availability of potent and se-
lective adenosine receptor antagonists for in vivo use.
Studies using gene-modified mice also suggested that
the A1 receptor interacts with insulin and glucagon sig-
naling114,115 or secretion.116 A recent study in mice
demonstrated that abrogation of A1 receptor signaling
410
ameliorated age-related metabolic abnormalities, in-
cluding accumulation of visceral adipose tissue and in-
sulin resistance.117 The underlying mechanisms of
adenosine A1–mediated actions are multifactorial, and
in addition to the the known effects on adenosine A1 on
lipolysis and lipogenesis,92,109 Yang et al demonstrated
modulation of the islet microvasculature and actions on
peripheral insulin signaling via attenuation of nicotin-
amide adenine dinucleotide phosphate (NADPH)
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oxidase–derived oxidative stress, as well as modulation
of inflammatory pathways.117
Adenosine A2A and A2B receptors also play a role
in modulating glucose homeostasis and obesity, which
may be explained by modulation of vascular and im-
mune cell functions, respectively.118–120 Finally, in a
chronic mouse model of renal and cardiovascular dis-
ease associated with metabolic dysfunction, abrogation
of A3 receptor signaling reduced abdominal fat content,
improved glucose disposal, reduced plasma insulin and
leptin levels, and increased plasma adiponectin levels.3
These favorable effects could be linked to reduced
NADPH oxidase–derived oxidative stress and modula-
tion of the immune system.3,117
Considering that caffeinated coffee can influence
adenosine receptor signaling (in particular inhibition of
A1), future studies are needed to determine to what ex-
tent modulation of the different adenosine receptor
subtypes contributes to the reduced risk of T2D follow-
ing coffee consumption. Numerous studies have dem-
onstrated that adenosine, apart from modulating
metabolic function, influences via its different receptors
both cardiovascular and renal functions in health and
disease.74,121,122
Antioxidative effects
Oxidative stress implies increased production or de-
creased scavenging or metabolism of reactive oxygen
species (ROS). NADPH oxidase–derived superoxide is a
major source of renal and vascular ROS, and increased
NADPH oxidase activity has been reported in T2D, car-
diovascular disease, and renal disease.74,123 Elevated lev-
els of superoxide and interaction with nitric oxide (NO)
can lead to NO deficiency and hypertension, which is a
main risk factor for renal complications. Previous stud-
ies indicate that microvascular oxidative stress plays a
fundamental role in the triad of cardiovascular, meta-
bolic, and renal disorders, partly by impairment of renal
autoregulatory mechanisms.74 This may disrupt
glomerular-tubular balance and lead to hypertensive
and diabetic nephropathies with progressive inflamma-
tion and oxidative stress. Moreover, oxidative stress in
pancreatic islets and peripheral metabolically active tis-
sues, induced by chronic hyperglycemia and
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dyslipidemia, may impair insulin release from B cells of
pancreatic islets and also attenuate insulin sensitivity,
respectively, thus contributing to impaired metabolic
function.124–129
Coffee contains several antioxidants (eg, caffeine,
CGA, lignan, flavonoids, caffeic acid, and melanoidins),
which may antagonize oxidative stress, and acute intake
and long-term intake of coffee have been demonstrated
to lower oxidative stress in both experimental animal
studies and humans.130–135 Phenolic compounds in cof-
fee have been suggested as the main contributors to the
antioxidant properties, but several studies have demon-
strated that caffeine also exerts potent antioxidant prop-
erties.136–139 Interestingly, brewed coffee is, together
with fruit and vegetables, one of the major contributors
to the antioxidant capacity of the diet in many coun-
tries.82,140–143 Coffee antioxidants are bioavailable, as
demonstrated by increased plasma antioxidant capacity
following coffee consumption in animal and human
studies.82,130 Considering the demonstrated antioxida-
tive effects associated with caffeinated coffee, it should
be noted that inhibition of both adenosine A1 and A3
receptor signaling prevented metabolic dysfunctions in
2 different experimental disease models by reducing
NADPH oxidase–derived oxidative stress. The underly-
ing mechanisms explaining the antioxidative properties
of caffeinated coffee require further investigations, but
it is possible that antagonism of A1 and A3 receptors
can inhibit function of NADPH oxidases.74
Apart from NADPH oxidase–derived ROS, mito-
chondrial dysfunction with increased superoxide gener-
ation has been proposed to contribute to insulin
resistance.144,145 In addition, lower mitochondrial
uncoupling and thermogenesis may contribute to accu-
mulation of visceral adipose tissue and obesity.146 There
is little knowledge about the specific effects of coffee
consumption and modulation of mitochondrial func-
tion in the context of metabolism, but experimental
studies indicate that caffeine-mediated inhibition of A1
may have favorable metabolic effects (reduce superox-
ide and prevent weight gain), whereas opposite effects
have been observed with A2 inhibition, which was
partly explained by decreased mitochondrial uncou-
pling and lower caloric expenditure.119 Finally, cell cul-
ture studies indicate that coffee may attenuate oxidative
stress by modulating different antioxidant systems (eg,
glutathione/glutathione disulfide equilibrium, NADPH/
quinone oxidoreductase)147 and by induction of Nrf2
gene transcription.148 Crossover intervention studies in
humans demonstrated that 4 weeks of coffee consump-
tion increased antioxidant capacity (elevated glutathi-
one and glutathione reductase activity), reduced
oxidative stress, reduced body fat mass and energy/nu-
trient uptake, and protected DNA integrity.76,101,149
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Oxidative stress is considered a pathological state
in the triad of metabolic, cardiovascular, and renal dis-
orders. In T2D, oxidative stress has been linked with
adiposity, dyslipidemia, and insulin resistance. Coffee
contains several antioxidants or components that may
attenuate enzymatic or mitochondrial production of
ROS. Accumulating studies suggest that regular coffee
consumption may provide health benefits by reducing
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oxidative damage, body fat mass, and caloric intake,
thus contributing to better metabolic control.
Anti-inflammatory effects
A growing body of evidence suggests that chronic low-
grade inflammation has an important role in cardiovas-
cular and metabolic disorders (eg, obesity, metabolic
syndrome, and T2D).150–152 Several components of the
immune system are altered in T2D, with changes occur-
ring in the adipose tissue, liver, pancreatic islets, vascu-
lature, and circulating leukocytes.150 Glucotoxicity and
lipotoxicity in T2D have been associated with activation
of proinflammatory signaling pathways, such as nuclear
factor kappa B (NF-jB), and oxidative stress in pancre-
atic islets and peripheral insulin-sensitive organs (ie, ad-
ipose tissue, liver, and muscle), which may trigger the
production and release of various pro-inflammatory
cytokines (eg, interleukin 1-beta [IL-1b], interleukin 6
[IL-6], tumor necrosis factor alpha [TNF-a]) and che-
mokines that can promote inflammation in other tis-
sues.150,153 Together these observations clearly indicate
that inflammation participates in the pathogenesis of
T2D and suggest that anti-inflammatory strategies may
be therapeutically useful in preventing the development
of cardiovascular disease and T2D and their complica-
tions. Indeed, the concept of inflammation contributing
to the disease is supported by the results of both pre-
clinical studies and new clinical trials using anti-
inflammatory approaches.150
Several different components in coffee have been
described to have anti-inflammatory properties (eg, caf-
feine, CGA, cafestol, trigonelline, kahweol, caffeic acid,
and ferulic acid).80,82–84,154 As reviewed previously, ex-
perimental, epidemiological, and clinical studies have
shown that regular coffee consumption may reduce the
levels of proinflammatory biomarkers (eg, IL-1b, IL-6,
TNF-a, C-reactive protein, monocyte chemotactic pro-
tein 1, vascular cell adhesion molecule 1, C-peptides,
endothelial-leukocyte adhesion molecule 1, and inter-
leukin 18 [IL-18]) in healthy individuals, obese individ-
uals, and individuals with T2D, whereas levels of
anti-inflammatory adiponectin, interleukin 4, and inter-
leukin 10 increased with habitual coffee consump-
tion.82,83 However, a few cross-sectional studies found
411
either no correlation155 or a positive correlation be-
tween coffee consumption and inflammation.156
In a clinical study by Kempf et al.,157 the effects
of coffee consumption on subclinical inflammation
and oxidative stress were assessed in 47 habitual cof-
fee drinkers. Coffee consumption (8 cups/d for 4 wk),
compared with coffee abstinence (0 cups/d), in-
creased levels of adiponectin and decreased IL-18,
but not IL-6 or C-reactive protein, and reduced the
oxidative stress biomarker 8-isoprostane. Moreover,
in vitro experiments using human carcinoma cells
(A549 and HT29) have suggested that the coffee com-
ponents CGA and caffeine can, in a dose-dependent
manner, inhibit the activation of NF-kB,158 which
may be linked to modulatory effects on Nrf2 nuclear
translocation and antioxidant response element–
dependent gene expression.159 Additional studies are
warranted to investigate these effects in other cell
types.
Multiple studies have demonstrated that coffee
consumption is associated with higher adiponectin
and lower leptin levels in serum, as well as reduced
markers for inflammation and metabolic dysfunc-
tion.70,160–163 Experimental animal studies have con-
firmed that coffee consumption reduced the
production of proinflammatory adipocytokines in
spontaneously diabetic mice.164 Yamauchi and col-
leagues showed that 5 weeks of coffee or caffeine inges-
tion attenuated the development of hyperglycemia and
insulin resistance, which was associated with lower IL-
6, TNF-a, and monocyte chemoattractant protein-1 in
white adipose tissue or serum. The mechanism(s) re-
quire further investigations, but a report of a recent
study suggested a potential role of modulating the
adenosine A1 receptor. Yang et al showed that genetic
deletion of the A1 receptor ameliorated aging-related
metabolic abnormalities, resulting in reduced oxida-
tive stress, lower levels of proinflammatory cytokines
(IL-1b, IL-6, TNF-a, and interleukin 12), and less ac-
cumulation of CD4(þ) T cells in visceral adipose
tissue.117
Oxidative stress and progressive inflammation are
often paralleled and are considered pathological events
in the development of T2D and associated complica-
tions. Although additional studies are warranted, cur-
rent knowledge indicates that high habitual intake of
coffee prevents oxidative stress and blocks the activation
and release of several proinflammatory cytokines. At
the same time, high levels of coffee consumption may
exert protective effects in T2D through stimulation of
anti-inflammatory cytokines. The specific compo-
nent(s) in coffee mediating these favorable effects
requires further investigations.
412
Modulation of microbiome content and diversity
Studies have demonstrated that the gut microbiota may
contribute to the development of cardiovascular and
metabolic disorders, such as atherosclerosis, obesity,
and T2D.165,166 Hence, there is growing interest in the
therapeutic possibilities of modulating the gut micro-
biota in cardiometabolic disorders.165 Human
metagenome-wide association study analysis demon-
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strated correlations of specific gut microbial content,
bacterial genes, and metabolic signaling pathways in
patients with T2D.167 Interestingly, the study by Qin
and colleagues167 indicated increased bacterial gene
functions related to gut oxidative stress response.
Few studies that found this correlation between gut
microbiota and metabolic function took into account
that the antidiabetic drugs may influence microbiotic
content and diversity. A recent study demonstrated that
antidiabetic treatment altered the gut microbiota in
patients with T2D;168 however, among several different
antidiabetic medications, only treatment with metfor-
min was associated with changed composition and
function of the gut microbiota. For example,
metformin-treated T2D patients had more Escherichia
spp., which have the potential to stimulate intestinal
gluconeogenesis (via production of fatty acids like buty-
rate and propionate) and hence contribute to the blood
glucose–lowering effects of metformin.168,169 Moreover,
statins can be effective at lowering cholesterol in obese
T2D patients, but they have a perplexing tendency to
work for some people and not others. A metabolomics
study by Kaddurah-Daouk et al suggested that differen-
ces in the gut bacteria might play an important role.170
Exercise, stress levels, genetic predisposition, and
environment are factors that define an individual’s gut
microbiome, but the diet may also have a modulatory
role. Previous studies have found that polyphenol-
containing foods and beverages, such as fruit, wine, and
coffee, may alter the gut microbiota in a favorable
way.171–173 A recent study by Zhernakova and col-
leagues174 that investigated 1135 healthy people sug-
gested that regular coffee consumption helped to
improve gut microbiota diversity, whereas consumption
of large amounts of carbohydrates or foods with low-
fiber, which have been linked with obesity and diabetes,
correlated to decreased gut bacteria diversity or total
population. The specific component(s) in coffee con-
tributing to the observed effects warrants further inves-
tigation, but high content of the polyphenol CGA in
coffee has been suggested to exert prebiotic-like
actions.175 The amount of CGA in coffee is rather vari-
able, with 1 cup delivering between 15 and 325 mg.176
The amount of CGA depends largely on coffee process-
ing, with roasting the major factor that reduces the
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levels of CGA.177 Approximately one third of CGA is
absorbed in the small intestine, and hence a consider-
able proportion of ingested CGA can reach the large in-
testine without prior metabolism to exert its actions.178
An in vitro study by Mills et al.175 suggested that coffee
with the highest levels of CGA, or CGA alone (80 mg),
induced an increase in the growth of Bifidobacterium
spp. A previous study in rats with high fat diet–induced
obesity demonstrated that chronic consumption of cof-
fee (10 wk) altered the gut microbiota and had a positive
impact on the serum metabolome.179 This was associ-
ated with decreased body weight, adiposity, liver trigly-
cerides, and energy intake, as well as increased
metabolites indicative of carbohydrate and fatty acid
metabolism. Paradoxically, coffee in high fat–fed rats
was associated with impaired insulin sensitivity despite
lower levels of circulating insulin. Further mechanistic
and clinical studies are required to conclude causality
and to determine the specific component(s) in coffee
that may influence the content and function of the gut
microbiota, especially in relation to the development or
progression of T2D.
CONCLUSION
Numerous preclinical and clinical studies have been
conducted regarding the effects of coffee consumption
(or caffeine intake) and the risk of developing T2D, and
the conclusions have been variable or inconsistent.
However, in aggregation, there is evidence from epide-
miological studies (as concluded from the current
meta-analysis) that habitual coffee consumption
reduces the risk of developing T2D by approximately
30% (pooled RR, 0.71; 95%CI, 0.67–0.76; n ¼ 1 185 210
persons), when comparing the highest vs lowest cate-
gory of coffee consumption in 30 studies conducted be-
tween 2002 and 2015. It is important to note that few
studies were adjusted for additives (ie, milk, cream, and
sugar), which may contribute to the variability among
studies.
Results obtained suggest that both caffeinated and
decaffeinated coffee have favorable metabolic effects, al-
though the risk reduction of new-onset T2D appears to
be somewhat stronger with caffeinated coffee. Due to
discrepancies among studies, further investigations are
needed to clarify the role and contribution of caffeine
in the coffee. Several studies have suggested that caf-
feine, via different mechanisms, may prevent develop-
ment of overweight and obesity, which in the chronic
setting may reduce the risk of T2D and associated renal
and cardiovascular complications.
Data on unfiltered coffee (eg, boiled coffee) and
T2D are sparse, but available data suggest that unfil-
tered coffee consumption also may reduce the risk of
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T2D. Epidemiological studies do not suggest any major
differences between men or women or between differ-
ent geographical regions on the associations between
total coffee consumption and risk of T2D. High intake
of coffee has also been associated with reduced cardio-
vascular- and T2D-associated mortality. This is of im-
portance considering the close association between the
development of T2D and adverse cardiovascular and
complications. Coffee is a complex mixture of poten-
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tially bioactive compounds, and the underlying mecha-
nism(s) contributing to its favorable effects are not yet
clear but are probably multifactorial. Recent data sug-
gest that coffee-mediated effects on metabolic functions
(eg, improved insulin signaling and glucose disposal, as
well as reduced adiposity) can be linked to reduction of
oxidative stress and modulation of immune cell func-
tion and perhaps also through modulation of the micro-
biome. Future long-term, clinical, randomized
intervention trials are needed to further investigate the
therapeutic potential of coffee in individuals with T2D
or those with an increased risk of developing the dis-
ease. Because studies have suggested an important role
of gene polymorphism in the observed effects of caf-
feine, future interventional studies with coffee should
also stratify participants (eg, by their CYP1A2 geno-
type). Studies should also adjust for additives (ie, cream,
milk, and sugar). It is possible that future identification
and characterization of the active components in coffee
may offer new therapeutic opportunities for T2D and
associated complications.
Acknowledgments
Author contributions. M.C. had a substantial role in the
development of the review question(s) and drafted the
manuscript. S.C.L. and M.C. designed and conducted
the search strategy, screened for articles, extracted and
entered data, and interpreted the analyses. S.C.L. sub-
stantially contributed to the systematic review and
meta-analysis and the writing of the manuscript.
Funding. This work was supported by grants from the
Swedish Research Council (2016–01381 and 521–2011-
2639), the Swedish Heart and Lung Foundation
(20140448 and 20170124), Karolinska Institutet
Research Funding (2–560/2015), and the Institute for
Scientific Information on Coffee (ISIC).
Declaration of interest. M.C. has received funding from
ISIC, which is a not-for-profit organization founded in
1990 and devoted to the study and disclosure of science
related to coffee and health. The author assures that
funding obtained from ISIC has not in any way affected
the production or content of the current study. Finally,
413
both authors of the current work declare that there is
no duality of interest associated with this work.
Supporting Information
The following Supporting Information is available
through the online version of this article at the publish-
er’s website:
Appendix S1 Completed MOOSE Checklist for
Meta-analyses of Observational Studies
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