Non-alcoholic fatty liver disease and
cardiovascular diseases: associations and treatment
considerations
Stergios A. Polyzos1 | Stergios Kechagias2 | Emmanuel A. Tsochatzis3
The Handling Editor for this article was Dr Rohit Loomba, and this uncommissioned
review was accepted for publication after full peer-review.
First Laboratory of Pharmacology, School
of Medicine, Aristotle University of
Thessaloniki, Thessaloniki, Greece
Department of Health, Medicine, and
Caring Sciences, Linköping University,
Linköping, Sweden
UCL Institute for Liver and Digestive
Health, Royal Free Hospital and UCL,
London, UK
Correspondence
Stergios A. Polyzos, First Laboratory of
Pharmacology, School of Medicine, Campus
of Aristotle University of Thessaloniki,
54124 Thessaloniki, Greece.
Email: [email protected]
Funding information
There was no grant or financial support for
this study.
Summary
Background: There are increasing data on the association between non-alcoholic
fatty liver disease (NAFLD) and cardiovascular diseases (CVD).
Aim: To summarise evidence on the association between NAFLD and CVD in the
clinical setting and provide potential therapeutic implications.
Methods: We searched PubMed. Evidence was primarily derived from meta-analyses.
and then, if data were insufficient, from clinical trials, and then from observational
studies.
Results: NAFLD has been linked to arterial hypertension, arterial stiffness, ather￾osclerosis, coronary artery disease, atrial fibrillation and aortic valvular sclerosis.
Advanced liver fibrosis is a crucial prognostic factor for end-stage liver disease and
for cardiovascular and overall mortality. Weight loss through lifestyle modifications
(diet and exercise) remains the cornerstone of the management of both NAFLD
and CVD, but is difficult to achieve and possibly more difficult to sustain long term.
Therefore, pharmacological management of NAFLD seems to be important, although
no licenced medication currently exists. Pioglitazone, proposed for non-alcoholic ste￾atohepatitis (NASH) by most guidelines, increases weight and should be avoided in
congestive heart failure. Statins should not be avoided in NAFLD patients at risk for
CVD. Glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter-2
inhibitors, two classes of anti-diabetic drugs, have shown promising results in NAFLD
and CVD, but more studies with hard end points are needed. Obeticholic acid, a
promising medication for NASH under investigation, should be carefully considered,
owing to its adverse effect on lipid profile.
Conclusions: NAFLD is associated with CVD, which may have certain clinical and
therapeutic implications.
2  |    POLYZOS et al.
1 | INTRODUCTION
Non-alcoholic fatty liver disease (NAFLD) is closely associated with
the epidemics of obesity and type 2 diabetes mellitus (T2DM).1
NAFLD entails a spectrum of histopathological features that range
from simple steatosis via the establishment of inflammation and he￾patocellular injury, ie non-alcoholic steatohepatitis (NASH), with or
without fibrosis to cirrhosis with risk of developing end-stage liver
disease or hepatocellular carcinoma (HCC).2
NAFLD shares common
pathogenetic factors not only with obesity and T2DM but also with
other components of insulin resistance (IR) syndrome or metabolic
syndrome (MetS), including dyslipidemia and arterial hyperten￾sion.1,2 NAFLD seems to interplay with the components of MetS in a
dynamic way, ie it affects them and it is affected by them, and by this
way, NAFLD may add to the cardiovascular (CV) risk of affected indi￾viduals.3
In this regards, when obesity, T2DM and/or other compo￾nents of MetS coexist with NAFLD, there is a higher risk of advanced
liver disease and CV diseases.3
Although most NAFLD patients have
a BMI of >25 kg/m2
, a subset of individuals has a BMI of <25 kg/
, which is usually denoted as lean NAFLD. Most patients with
lean NAFLD have excess visceral adiposity and IR, despite normal
BMI, thus being on high CV risk.4
Based on these considerations,
the recent recommendation to change the nomenclature of NAFLD
to metabolic (dysfunction)-associated fatty liver disease (MAFLD)
seems to be rational.5,6 This recommendation does not only refer
to a simple change in the name of the disease but also to a novel
definition. Thus, although it has provoked a large-scale discussion,7
simultaneously brings to the surface the close relationship of NAFLD
with CV diseases (CVD), being the key endpoint of MetS. This is im￾mediately evident if considering that CVD is the first cause of mor￾tality in NAFLD patients.8
The aim of this review is to summarise evidence on the associ￾ation between NAFLD and CVD in the clinical setting and provide
potential therapeutic implications. Data were primarily derived from
meta-analyses; however, when meta-analyses were not available,
data from randomised controlled trials (RCTs), cohort, case–control,
and cross-sectional studies were hierarchically selected, based on
the principles of evidence-based medicine.
2 | LITERATURE SEARCH
We performed a computerised literature search using the PubMed
electronic database, not limited by publication time. The Medical
Subject Heading (MeSH) database of the US National Center for
Biotechnology Information (NCBI) was used as a terminological search
filter. Subsequently, a query was created by combining MeSH terms:
(“Non-alcoholic Fatty Liver Disease”[Mesh]) AND (“Cardiovascular
Diseases”[Mesh] OR “Heart Failure”[Mesh] OR “Myocardial
Infarction”[Mesh] OR “Stroke”[Mesh] OR “Hypertension”[Mesh]
OR “Atherosclerosis”[Mesh] OR “Coronary Artery Disease”[Mesh]
OR “Atrial Fibrillation”[Mesh] OR “Heart Valve Diseases”[Mesh] OR
“Percutaneous Coronary Intervention”[Mesh] OR “Coronary Artery
Bypass”[Mesh]). This query totally provided 1345 results (last up￾date: 21 May 2021). By applying the filters of “systematic review”
and “meta-analysis,” 34 articles were retrieved, which were studied
in full text. When a topic was not sufficiently covered by these sys￾tematic reviews and meta-analyses, specific search was performed
in PubMed, eg (“Non-alcoholic Fatty Liver Disease”[Mesh]) AND
(“Stroke”[Mesh]), by applying the filter, first of “clinical trial” and,
next, if available evidence was not satisfactory, the filter of “obser￾vational study” was used. Since this was a narrative review, some
more articles were added at the discretion of the authors, when this
was considered necessary for the flow of this review.
3 | EPIDEMIOLOGIC AL E VIDENCE ON THE
ASSOCIATION BETWEEN NAFLD AND CVD
The global prevalence of NAFLD is approximately 25% in the gen￾eral population.9
The highest prevalence has been observed in the
Middle East (32%) and South America (30%) and the lowest in Africa
(13%).9
The prevalence of NASH in the general population has been
estimated to be 3%-5%.10 Patients with NAFLD have high rates of
MetS (43%) and its components, including hyperlipidemia (69%),
obesity (51%), arterial hypertension (39%) and T2DM (23%),9
which
all contribute to CV risk.
Vice versa, the prevalence of NAFLD in obesity and T2DM is
higher than that observed in the general population. The prevalence
of obesity amongst patients with NAFLD (including simple steatosis
and NASH) has been reported to be 51% and specifically in NASH
81%.9
In studies with morbidly obese populations, the prevalence of
NAFLD has been reported to be even higher (over 90% in some stud￾ies).11 Likewise, the global prevalence of NAFLD amongst patients
with T2DM is 55%, with the highest rates being observed in Europe
(68%).12 The global prevalence of NASH and advanced fibrosis (F3-
F4) amongst patients with T2DM is 37% and 17%, respectively,12
much higher than those observed in the general population.10 This is
highly alarming, reflecting the high rates of advanced liver disease in
patients with T2DM.
The prevalence of CVD is higher in patients with than without
NAFLD (odds ratio [OR] 1.8; 95% confidence interval [CI] 1.2-2.7).13
In another meta-analysis, the OR of CV events (overall fatal and non￾fatal) was 1.6 (95% CI 1.3-2.1) in NAFLD compared with non-NAFLD
patients, being higher in patients with more severe disease (OR 2.6;
95% CI 1.8-3.8).14 Data indicate a higher prevalence of CVD in the
regions of high NAFLD prevalence.15 This is expected to a degree,
since obesity, T2DM, dyslipidemia, and arterial hypertension, which
are all observed in high rates amongst NAFLD patients,9
are mutual
risk factors of CVD, as mentioned above. For example, obese patients
with NAFLD have a higher incidence of new-onset CVD (33.3 per
1000 person-years; 95% CI 22.7-46.0)16; importantly, non-obese or
lean patients with NAFLD have also high, although lower, incidence
of new-onset CVD (18.7 per 1000 person-years; 95% CI 9.2-31.2).16
It should also be highlighted that patients with T2DM and NAFLD
have approximately double the risk of CVD (OR 2.2; 95% CI 1.7-2.9),
   | POLYZOS et al.  3
compared with those with T2DM without NAFLD,17 thus implying
an additive effect of T2DM and NAFLD to CV risk. The association
between NAFLD and CVD may be possibly modified by race and
ethnicity. For example, the Multi-Ethnic Study of Atherosclerosis
showed that African Americans with NAFLD had a higher prevalence
of abdominal aortic calcification compared with White Americans
with NAFLD.18 Interaction by race/ethnicity was also reported when
comparing Chinese and African to White Americans, regarding the
association between NAFLD and the prevalence of abdominal aortic
calcification.18 However, more longitudinal data and for other CVD
are needed to reach secure conclusions for race/ethnicity as a mod￾ifier of the association between NAFLD and CVD.
The association between NAFLD and CVD becomes more ap￾parent when considering causes of mortality in NAFLD patients.
Importantly, CVDs represent the first cause of death amongst NAFLD
patients. In a prospective long-term follow-up study (22 ± 6 years),
including biopsy-proven NAFLD patients, 43% of patients died from
CVD, followed by non-gastrointestinal malignancies (19%).8
HCC,
other gastrointestinal malignancies, and liver cirrhosis accounted
for 13% of overall mortality (5%, 4% and 4%, respectively). Thus
liver-related mortality was the third most common cause of death.8
The hazard ratio (HR) of death from CVD was 1.6 (95% CI 1.1-2.2) in
this study, being much higher for patients with advanced fibrosis/
cirrhosis (fibrosis stages F3-F4): 4.4 (95% CI 2.3-8.3).8
These results
were validated in another cohort study with biopsy-proven NAFLD
patients, followed-up for 5.2 years, showing that advanced fibrosis/
cirrhosis (fibrosis stages F3-F4) were also independently associated
with incident CVD (HR 2.9; 95% CI 1.4-6.0).19 In a multinational co￾hort with a mean follow-up of 5.5 years, it was also reported that
the incidence of CV events was higher in patients with F3 fibrosis
stage than F4 (7% vs 2%, respectively), whereas, as expected, the
incidence of hepatic decompensation (6% vs 44%, respectively) and
HCC (2% vs 17%, respectively) were lower in F3 than F4 stage.20 It
should also be highlighted that overall mortality is higher specifically
in NASH patients (26 per 1000 person-years) than in patients with
NAFLD (sum of patients with simple steatosis and NASH: 15 per
1000 person-years)9
and that overall mortality increases gradually
with increasing stage of hepatic fibrosis.21 Furthermore, mortality is
higher in hospitalised patients with CVD with than without NAFLD
(HR 2.1; 95% CI 1.6-2.6).22
Summarising, NAFLD is a highly prevalent disease, closely as￾sociated with MetS and its components, such as T2DM, obesity,
hyperlipidemia and arterial hypertension, probably adding to the
MetS-associated CV risk. Importantly, CV mortality represents the
primary component of overall mortality in NAFLD patients and is
closely associated with the stage of hepatic fibrosis.
4 | CLINIC AL E VIDENCE ON THE
ASSOCIATION BETWEEN NAFLD AND CVD
Based on evidence from meta-analyses, NAFLD has been linked to
arterial hypertension,13 arterial stiffness,23 atherosclerosis,13,24-26
coronary artery disease,13,25,27 atrial fibrillation,28,29 aortic valvular
sclerosis30 and stroke.31 The main results of these meta-analyses
are summarised in Table 1. Specifically for atrial fibrillation, the
meta-analysis of cross-sectional studies or the combination of
cross-sectional and cohort studies provided statistically significant
results (two meta-analyses; OR 2.1)28,29; however, the synthesis
of only cohort studies provided non-significant association. This
seeming paradox is not rare in meta-analyses in which the synthe￾sis of cross-sectional or case–control studies tends to overestimate
the association, whereas the synthesis of cohort studies usually
provides a more conservative association. Regarding stroke, the
above-mentioned meta-analysis was referred to the association be￾tween γ-glutamyltransferase with stroke31; however, another meta￾analysis on the same topic, but with better characterised NAFLD
populations, is ongoing.32 Regarding aortic valvular stenosis, meta￾regression analysis in one of the above-mentioned meta-analyses,30
showed that obesity, T2DM, arterial hypertension and dyslipidemia
partly accounted for the difference in the rates of aortic valvular
stenosis between patients with and without NAFLD, thus implying
an indirect association between NAFLD and aortic valvular stenosis.
There are also meta-analyses of observational studies show￾ing the association of NAFLD with altered cardiac function and
structure. Two meta-analyses have shown that NAFLD is associ￾ated with diastolic cardiac dysfunction.33,34 A similar association
with systolic cardiac dysfunction was not shown in one of them.34
Importantly, significant associations were also shown between
NAFLD and structural parameters, including greater left ventricu￾lar mass, left ventricle end-diastolic diameter, left atrial diameter,
posterior wall thickness and septum thickness.34 Based on these
findings, we could hypothesise that functional and structural
changes may initially occur in NAFLD patients, which may remain
to a degree silent and underdiagnosed. If NAFLD and associated
metabolic conditions are not effectively managed, the aggrava￾tion of the above functional and structural changes may progress
to clinically significant diseases. However, this hypothesis on the
natural course of the association between NAFLD and CVD re￾mains to be elucidated.
Although the above-mentioned meta-analyses on the associa￾tion between NAFLD and structural or functional parameters may
imply a higher probability of cardiomyopathy and heart failure in
NAFLD patients,33,34 these are referred mainly to subclinical al￾terations. Limited data from observational studies suggest an as￾sociation between NAFLD and clinically overt heart failure. More
specifically, higher fatty liver index (FLI), a non-invasive index of
hepatic steatosis, was associated with new-onset heart failure in
a large cohort of apparently healthy individuals at baseline, fol￾lowed-up for a median of 5.4 years.35 Higher rehospitalisation rate
was also observed in NAFLD compared with non-NAFLD patients
with heart failure, after a 1-year follow-up.36 Likewise, higher mor￾tality was observed in NAFLD than non-NAFLD patients admitted
for acute heart failure after a mean follow-up of approximately
2 years.37 Higher NAFLD fibrosis score (NFS), a non-invasive index
of hepatic fibrosis, was independently associated with overall
4  |    POLYZOS et al.
mortality in a cohort study of hospitalised patients with heart fail￾ure with preserved ejection fraction at baseline, followed-up for a
median of 3 years.38 Thus, although no meta-analysis to date exists
on the association between NAFLD and clinically overt heart fail￾ure, existing data support this association.
An interesting meta-analysis of observational studies has shown
that the epicardial adipose tissue (EAT) was thicker in NAFLD pa￾tients than controls; an association between the thickness of EAT
and severity of hepatic steatosis and fibrosis was also evident.39
Notably, the rates of arterial hypertension and atherosclerotic CVD
OR 3.31 (2.21-4.95) 38%
Fraser 200731 Stroke 6 Cross-sectional HR 1.54 (1.19-1.99) 82%
Abbreviations: CI, confidence interval; CIMT, carotid intimal medial thickness; CVD, cardiovascular disease; HR, hazard ratio; LVEF, left ventricle
ejection fraction; MD, mean difference; NAFLD, nonalcoholic fatty liver disease; OR, odds ratio; PWV, pulse wave velocity; RR, risk ratio; SMD,
standardised mean difference.
Data are sorted alphabetically according to the CVD (or condition).
Paediatric population.
   | POLYZOS et al.  5
were higher in NAFLD patients with greater EAT.39 Although a caus￾ative effect cannot be shown by this meta-analysis, we could specu￾late that thicker EAT may be associated with unfavourable adipokine
and cytokine profile,40 thus with a locally produced source of factors
associated with both hepatic and cardiac inflammation and fibrosis.
However, any causative interplay amongst EAT, NAFLD and CVD re￾mains to be established by future studies.
Regarding lean or “non-obese” NAFLD, a recent population￾based study showed that patients with lean NAFLD had similar rates
of CVD and malignancy compared with obese NAFLD patients and,
interestingly, higher overall mortality than obese NAFLD patients.41
It was also shown that lean and obese NAFLD share common met￾abolic and CV risk factors, including IR, dyslipidemia, hypertension
and high waist circumference, implying high visceral adiposity.42
Not all data support a positive association between NAFLD and
CVD. For example, a meta-analysis of 10 observational studies pro￾vided opposite results on the association between the transmem￾brane 6 superfamily 2 (TM6SF2) gene variant E167K (rs58542926
C/T) and circulating lipid profile or NAFLD.43 More specifically, the
carriers of the minor T allele (EK/KK) were shown to have a higher
probability of NAFLD (OR 2.1; 95% CI 1.4-3.3) and higher hepatic
fat content compared with the homozygous for the C allele (EE). On
the contrary, the former had lower circulating triglyceride, total cho￾lesterol and low-density lipoprotein-cholesterol (LDL-C) concentra￾tions compared to the latter.43 Although this meta-analysis cannot
show causality, the authors hypothesised that the T allele variant
may offer protection against CVD at the expense of an increased
risk of NAFLD.43 In any case, regardless if this hypothesis proves to
be true or not, the traits of this variant do not imply this variant as a
link between NAFLD and CVD. Likewise, a large cohort study per￾formed together with a meta-analysis of two studies showed that
the variant I148M (rs738409) of the patatin-like phospholipase do￾main containing 3 protein (PNPLA3) gene, which is strongly associated
with NAFLD and advanced liver disease,44 was not associated with
coronary artery disease.45 This lack of genetic association may imply
that NAFLD and CVD may share only some common pathogenetic
mechanisms or both may be affected by confounding factors (eg
obesity, T2DM, dyslipidemia).
5 | SCREENING FOR C V RISK FAC TORS IN
PATIENTS WITH NAFLD
Based on the potential association between NAFLD and CVD, it
seems rational that most expert committees have recommended
regular screening for CVD in patients with NAFLD. The European
Association for the Study of Diabetes (EASD)/European Association
for the Study of the Liver (EASL)/European Association for the
Study of Obesity (EASO) combined guidelines strongly recommend
the screening for CVD in all NAFLD patients, at least by a detailed
assessment of CV risk factors.46 The American Gastroenterological
Association (AGA) suggests that all patients with NAFLD and co￾existing metabolic conditions, such as obesity, T2DM, dyslipidemia
and arterial hypertension, should be stratified for CV risk47 as pro￾posed per American College of Cardiology (ACC)/American Heart
Association (AHA) guidelines.48 The Latin American Association for
the study of the liver (ALEH) also suggests that CV risk should be
performed in every follow-up visit of NAFLD patients; ALEH pro￾pose the use of the Framingham score as an efficient, simple and
cost-effective tool that may result in early referral to a cardiologist
of patients with high CV risk.49 However, it should be noted that the
Framingham score as well as other CV risk calculators have not yet
been validated specifically for NAFLD populations. The Asia–Pacific
Working Party (APWP) on NAFLD recommends that patients with
NAFLD should be assessed for other components of MetS, includ￾ing T2DM, dyslipidemia and arterial hypertension, but they also
underline that data to support screening for CVD are considered
insufficient.50
Although screening for CV risk factors in NAFLD is recom￾mended by most guidelines, given that CVD is the leading cause of
mortality,8
the recommendations mentioned above lie to the most
at the level of expert opinion, since there are scarce well-designed
studies evaluating the usefulness and the cost-effectiveness of the
recommended screening in the long-term. Until more specific data
emerge, we of course would agree with a regular assessment for CV
risk factors (eg lifestyle, including eating and exercise habits, smok￾ing and alcohol consumption), and measurement of at least blood
pressure, weight, height, central adiposity (eg waist circumference),
serum glucose and lipid profile in all NAFLD patients, as other au￾thors have also previously supported (Figure 1).51
6 | MANAGEMENT CONSIDERATIONS
Since patients with NAFLD are at high risk for CV morbidity and
mortality, most guidelines recommend management of CV risk fac￾tors,46,47,49,52 targeting to reduce CV morbidity and mortality.
6.1 | Diet and physical activity
All guidelines recommend weight loss through lifestyle modifica￾tion (diet and physical activity), as an effective measure against both
NAFLD46,47,49,52 and CVD.48 It has been proposed that weight loss of
≥3% is required to improve hepatic steatosis, ≥5% to improve hepatic
inflammation and ≥10% to improve hepatic fibrosis.3
Structured pro￾grammes combining a healthy diet and regular physical activity, tar￾geting a gradual weight loss, are recommended.46,47,49,52
Hypocaloric diets with daily deficit of 500-1000 kcal from base￾line or with a daily consumption of 1200-1800 kcal should be ad￾vised.46,47,49,52 Regarding the diet type, the APWP guidelines do not
recommend any specific diet type for NAFLD50; this is supported
by two meta-analyses that did not show superiority of low fat or
low carbohydrate diet on liver function tests and hepatic fat con￾tent.53,54 Although it seems that the calorie restriction rather than
the macronutrient composition mainly drives the beneficial effect of
6  |    POLYZOS et al.
dietary intervention in NAFLD,3
another meta-analysis showed that
the Mediterranean diet simultaneously improves NAFLD-related CV
risk factors (IR, triglycerides, total cholesterol),55 thus possibly offer￾ing additional benefits to NAFLD patients, with regards to CVD. This
additional CV benefit is the reason why the Mediterranean diet is
recommended for NAFLD by some guidelines.46,47,49
Physical activity is recommended by all guidelines for
NAFLD46,47,49,52; similarly, its beneficial role in CVD is established.48
Regarding the type of exercise, two meta-analyses did not show
that aerobic training was more effective than resistance training
in reducing hepatic steatosis.56,57 Another meta-analysis showed
that aerobic training improves more CV risk factors (circulating
triglycerides, total cholesterol, LDL-C, high-density lipoprotein￾cholesterol [HDL-C], body mass index [BMI]) than resistance training
(triglycerides) in patients with NAFLD.58 On the other hand, the ef￾fort and energy consumption needed to achieve a comparable result
was lower for resistance than for aerobic training,57 thus possibly
rendering the former more suitable for NAFLD patients with poor
cardiorespiratory fitness or those being unwilling to participate in
aerobic programmes. Therefore, most guidelines suggest a combi￾nation of aerobic and resistance exercise,46,47,49,52 albeit with minor
variations. EASL/EASD/EASO and ALEH propose 150-200 min/
wk of moderate intensity in three to five sessions,46,49 tailored ac￾cording to individual preferences, so as to increase the possibility of
long-term maintenance46; APWP and AGA propose 150-300 min/
wk of moderate-intensity or 75-150 min/wk of vigorous-intensity
aerobic exercise.47,50 Of note, AGA suggests resistance training as
complementary to aerobic but not as its substitution.47 An exercise
“prescription” consisting of the recommended type, frequency, in￾tensity and duration is also recommended by ACC/AHA,48 which
may improve the compliance and adherence of patients to exercise
programmes.
6.2 | Pharmacological management
Although lifestyle modifications targeting weight loss are effec￾tive as preventive and therapeutic measures against NAFLD, they
are difficult to achieve and possibly more difficult to sustain in the
long term.59 This renders the pharmacological treatment of NAFLD
highly important, but currently, there is no licenced medication for
NAFLD.60 Current guidelines suggest the off-label use of pioglita￾zone (30-45 mg/d) or vitamin E (800 IU/d) in selected non-cirrhotic
patients with NASH.46,49,52,61 It seems rational that pioglitazone
may be preferred in NASH patients with T2DM, whereas vitamin
E in NASH patients without T2DM62; however, pioglitazone has
been also successfully used in NASH patients without T2DM.63
Pioglitazone seems to act, at least partly, via upregulation of adi￾ponectin,64 which is closely related with both NAFLD and its se￾verity.65 Contrary to rosiglitazone, which also belongs to the same
drug class (thiazolidinediones), shown to have an adverse effect
on serum lipid profile and being associated with an increased risk
FIGURE 1 Proposed assessment of parameters related to CV risk at diagnosis and during follow-up of NAFLD patients. Lifestyle should
be assessed at diagnosis and during follow-up, including diet and exercise habits, smoking and alcohol consumption; the evaluation of
lifestyle modifications during follow-up is considered important. Simple clinical and biochemical tests are also recommended, including
the measurement of systolic and diastolic blood pressure, weight, height, waist circumference, lipid profile and glucose levels to evaluate
arterial hypertension, obesity, dyslipidemia and T2DM. In cases of intermediate results, eg impaired fasting glucose for the assessment of
T2DM, other tests may be also considered, ie HbA1c and OGTT. Abbreviations: BMI, body mass index; CV, cardiovascular; HbA1c, glycated
haemoglobin; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; NAFLD, non-alcoholic fatty liver
disease; OGTT, oral glucose tolerance test; T2DM, type 2 diabetes mellitus
of myocardial infarction,66 pioglitazone has a rather neutral effect
on serum lipid profile.64 However, pioglitazone should be avoided
in patients with congestive heart failure, mainly due to an increase
in body weight (2.0-3.5 kg on average) and fluid retention.64,67
Furthermore, it seems somehow oxymoron to recommend a weight￾increasing medication in a patient that is counselled to lose weight.
There may also be a possible small increase in the risk of bladder
cancer with long-term pioglitazone treatment, needing further in￾vestigation, but the benefit in terms of NASH improvement seems
to be much greater.68 Of course, pioglitazone should be avoided in
patients with bladder cancer.60 The way of action of vitamin E on
NASH has not been fully elucidated, but it may be partly achieved
via its anti-oxidative effect.60 Nonetheless, vitamin E in high dose
(≥400 IU/day) for long-term, as required for NASH treatment, has
been associated with a dose-dependent higher overall mortality.69
Furthermore, there is a possible increased risk of prostate cancer,
therefore, vitamin E should be avoided in male patients with a per￾sonal or family history of prostate cancer.70 Thus, it seems to be
prudent that vitamin E is not administered for longer than the dura￾tion of the PIVENS study (2 years),63 a key study for the treatment
of NASH with vitamin E and pioglitazone.
Another relevant topic is the use of statins in patients with
NAFLD. Dyslipidemia is very common in NAFLD, with an estimated
prevalence of 69%.9
The use of statins is recommended for the man￾agement of dyslipidemia in NAFLD patients, thus reducing the in￾creased CV risk observed in NAFLD patients.71 Despite the notion of
their detrimental effect in patients with elevated liver function tests
in the past (many NAFLD patients have elevated liver function tests),
statins were shown to decrease liver function tests and decrease
CV mortality more in patients with mild-to-moderately abnormal
liver function tests than in those with normal liver function tests.72
Moreover, a meta-analysis of studies with histological end points
reported a reduction of hepatic steatosis, but no significant effect
on hepatic fibrosis.73 Accordingly, the use of statins should not be
avoided in NAFLD patients, at least for the prevention of CVD, al￾though their definite effect on hepatic histology remains to be fully
clarified by larger and mainly longer clinical trials.
Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and
sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are two classes
of anti-diabetic drugs that have shown promising results in NAFLD
and CVD, which are both commonly encountered in patients with
T2DM.74 Despite their different mode of action, they both result in
weight loss, so their beneficial effect on NAFLD and CVD may be me￾diated, at least partly, through weight loss.60 To date, GLP-1RAs have
more evidence based on RCTs with repeat liver biopsies compared
with SGLT-2i. In a meta-analysis, GLP-1RAs were shown to reduce
hepatic steatosis and hepatocellular ballooning, the latter being the
hallmark of hepatocellular injury; however, they showed no effect
on hepatic fibrosis.75 More specifically, liraglutide (1.8 mg/d), admin￾istered in NASH patients for 48 months, improved hepatic steatosis
at higher rates than placebo (83% vs 45%, respectively) and resulted
in NASH resolution in higher rates (39% vs 9%, respectively).76
Although the worsening of hepatic fibrosis was less frequent in
patients on liraglutide than on placebo (9% vs 36%, respectively),
liraglutide did not result in improvement of fibrosis at higher rates
than placebo.76 More recently, administration of semaglutide for
72 weeks in a phase IIb trial for patients with NASH, resulted in
NASH resolution with no worsening of fibrosis in higher rates than
placebo (40% in the 0.1 mg group, 36% in the 0.2 mg group, 59%
in the 0.4 mg group and 17% in the placebo group).77 Nonetheless,
semaglutide did not improve hepatic fibrosis in higher rates than
placebo.77 Likewise, two meta-analyses on SGLT-2i in NAFLD re￾ported a decrease in liver function tests and hepatic fat78,79; how￾ever, studies with SGLT-2i and histological end points are scarce.
Importantly, a large network meta-analysis of RCTs in patients with
T2DM showed that both GLP-1RA and SGLT-2i decrease overall
mortality, CV mortality, non-fatal myocardial infarction and kidney
failure,80 thus adding CV and renal benefits. It should be highlighted
that NAFLD is associated with chronic kidney disease, with the risk
being higher in those with NASH and/or hepatic fibrosis.81 It is note￾worthy that SGLT-2i decreased mortality and admission to hospital
for heart failure more than GLP-1RA, whereas GLP-1RA decreased
non-fatal stroke more than SGLT-2 inhibitors, with the latter having
no effect on this endpoint.80 The main adverse events of GLP-1RA
are nausea, vomiting, reduced appetite, abdominal pain and diar￾rhoea, which, however, tend to be resolved within a few weeks of
treatment.75 The main adverse events of SGLT-2i are genito-urinary
tract infections, hypotension, dehydration and increased appetite,
as shown in a meta-analysis of studies with T2DM patients82; no dif￾ference was found in serious adverse events between SGLT-2i and
placebo.82 Rare cases of ketoacidosis and leg or toe amputation have
been reported in T2DM patients and should be considered in the
follow-up of patients. However, it should be underlined that both
GLP-1RA and SGLT-2i are licenced for T2DM, therefore, their use in
NASH patients without T2DM remains off label. It is important to
note that GLP-1RA, and more specifically liraglutide, may be consid￾ered for the management of obesity; liraglutide has been approved
for obesity in a higher dose than that suggested for T2DM (3.0 mg vs
1.8 mg [maximum], respectively) and has also provided some favour￾able results in hepatic histology in NASH patients76 as mentioned
above.
Obeticholic acid (OCA) is a farnesoid X receptor (FXR) agonist,
approved for the treatment of primary biliary cholangitis.83 OCA
has provided some of the most encouraging results in clinical trials
with NASH and fibrosis.83 A 72-week treatment, with OCA (25 mg)
improved hepatic steatosis, inflammation and, most importantly, fi￾brosis at higher rates than placebo (phase IIb RCT).84 An 18-month
interim analysis of phase III, ongoing RCT in NASH patients without
cirrhosis, OCA (25 or 10 mg) improved fibrosis with no worsening
of NASH in higher rates than placebo (23% vs 18% vs 12%, respec￾tively).85 In a network meta-analysis of emerging medications under
evaluation for NAFLD, only OCA was shown to substantially im￾prove hepatic histology.86 Nonetheless, OCA increased LDL-C and
decreased HDL-C, resulting in treatment discontinuation in some
patients.84 To address this issue of a presumably increased CV risk
in a population with already high CV risk, atorvastatin (10 mg with
8  |    POLYZOS et al.
subsequent titration as needed) initiated 4 weeks after OCA (5, 10
or 25 mg) was shown to reduce the adverse effect of OCA on LDL-C,
but not on HDL-C.87 OCA represents an example of a medication
whose beneficial effect on NASH and fibrosis may be limited by its
adverse effect on lipid profile, at least in terms of CVD. Future stud￾ies are expected to show whether OCA will be co-administered with
statins or will be replaced by another FXR agonist without adverse
effect on lipid profile. Beyond the CV adverse effect, OCA results in
high rates of pruritus (23%-50%) that may also lead to its discontinu￾ation in some patients.84,85
Regarding the management of arterial hypertension in patients
with NAFLD, the above-mentioned guidelines recognise it as an im￾portant risk factor that should be managed accordingly, but they do
not suggest specific drug classes.46,47,49,52 Although head-to-head
comparative studies for the management of arterial hypertension
specifically in NAFLD are scarce, angiotensin II type 1 receptor
blockers (ARB) may be considered as first-line options in NAFLD
patients: some ARB provided favourable histological results in clini￾cal trials88,89 and they also constitute the first-line option in T2DM.
However, more data are needed to reach more secure conclusions
for the management of arterial hypertension specifically in NAFLD
patients. All the above considering, we propose an algorithm for the
management of NAFLD and related co-morbidities in patients with
co-existent CVD (Figure 2).
6.3 | Bariatric surgery
Bariatric surgery may be considered in selected morbidly obese
NAFLD patients, when lifestyle modifications and pharmacotherapy
fail, as proposed by most guidelines.3
A network meta-analysis sup￾ported that all bariatric interventions lead to more effective weight
loss compared with standard care.90 The most frequently performed
techniques are currently adjustable gastric banding (AGB) and the
Roux en-Y gastric bypass (RYGB).90 RYGB has higher weight loss
efficacy than AGB, but also leads to more serious adverse effects
since it is more amputation.90 A meta-analysis of cohort studies with
morbidly obese NAFLD patients reported that bariatric surgery re￾sulted in resolution of hepatic steatosis, ballooning and fibrosis in
66%, 50% and 40% of patients, respectively,91 possibly rendering
bariatric surgery the most effective to date management of NAFLD,
but also the most riskiest regarding its complications.3
Other meta￾analyses showed that bariatric surgery reduces CV risk factors, in￾cluding T2DM, hypertension and dyslipidemia,92 as well as major CV
events.93 The above considering, bariatric surgery may be alterna￾tive management of both NAFLD and CVD in carefully selected mor￾bidly obese individuals. However, studies that have evaluated the
effect of weight loss on both NAFLD and CVD are scarce. In a study
from the US Nationwide Inpatient Sample database with a large sam￾ple (over 45 ,000 patients with NAFLD and morbid obesity), prior
FIGURE 2 Proposed management of patients with NAFLD and CVD. Diet and exercise are regarded as the standard care for all patients.
Vitamin E or pioglitazone should be considered in carefully selected patients with NASH and fibrosis stage ≥2. Metabolic co-morbidities
should also be managed appropriately. GLP-1RA may be considered in obese patients who fail to lose weight via lifestyle modifications;
currently, liraglutide is the only GLP-1RA that is licenced for the management of obesity. In patients with co-existing T2DM, pioglitazone
should be considered as a first-line choice in the absence of congestive heart failure; GLP-1RA and SGLPT-2i should also be considered for
co-treatment or alternative treatment; to date, GLP-1RAs have evidence of higher quality than SGLT-2i, so the use of GLP-1RAs may be
preferred in patients with T2DM and NASH. Statins should be administered for dyslipidemia. ARB may be considered as a first-line choice
for patients with arterial hypertension. Abbreviations: ARB, angiotensin II type 1 receptor blockers; CVD, cardiovascular disease; F, fibrosis
stage; GLP-1RA, glucagon-like peptide-1 receptor agonists; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis;
SGLT-2i, sodium-glucose cotransporter-2 inhibitors; T2DM, type 2 diabetes mellitus
bariatric surgery was independently associated with a lower risk of
myocardial infarction and stroke, compared with no bariatric sur￾gery.94 However, more and specifically designed prospective stud￾ies are required to evaluate the effect of different bariatric surgery
techniques on NAFLD and CVD in the long term.
7 | CLOSING REMARKS
NAFLD is closely associated with the epidemics of obesity and
T2DM as well as other components of the MetS.9
It is of utmost im￾portance that CVD represents the first cause of mortality in NAFLD
patients.8
However, the existing meta-analyses on this association
are based on observational studies (cross-sectional and/or cohort
studies) (Table 1). It should also be underlined that there are scarce
meta-analyses of exclusively prospective cohort studies (eg Fraser
et al31), which usually provide higher quality evidence on the asso￾ciation between NAFLD and specific CVD; existing meta-analyses
of cohort studies included a small number of both prospective and
retrospective cohorts, the latter considered to be more prone to
bias (eg record or recall) and to be of lower quality. Other important
issues, when translating the results of existing meta-analyses, are
the high heterogeneity of most of them and the small number of
included studies in some of them (Table 1). Therefore, considering
these two characteristics, the results of most meta-analyses should
be cautiously interpreted. Furthermore, since these meta-analyses
consist of observational studies, a cause–effect association could
not be established, which would require meta-analyses of studies
of different design. Therefore, their data cannot show either cau￾sality or the direction of the association, ie whether NAFLD pre￾disposes to CVD, or CVD predisposes to NAFLD (reverse causality)
or both (bi-directional causality). Apart from limited data showing
that obesity, T2DM, hypertension and dyslipidemia may mediate
the association between NAFLD and aortic valvular stenosis,30 as
mentioned above, current evidence does not generally allow secure
conclusions on whether NAFLD may directly affect CVD or whether
co-morbidities closely related to NAFLD, eg hypertension, obesity,
T2DM and dyslipidemia, may indirectly affect CVD, and to what
extent each co-morbidity contributes to CVD. Moreover, based on
existing data, the presence of common denominators (confounding
factors) predisposing to both NAFLD and CVD, without a direct as￾sociation between NAFLD and CVD, cannot be excluded. For exam￾ple, obesity, T2DM or dyslipidemia may result in both NAFLD and
CVD; so NAFLD and CVD may seem to be associated but without
a direct link between them. In other words, it should be elucidated
whether the presence of NAFLD is an independent risk factor for
CVD or an epiphenomenon, ie this seeming risk is just the sum of
risks of common denominators (ie obesity, T2DM, dyslipidemia, ar￾terial hypertension). In this regard, we need large well-designed co￾hort studies with NAFLD patients without CVD at baseline that will
undergo extensive follow-up; hard CV end points should be set, ie
major CV events (myocardial infarction, stroke, hospitalisation due
to CVD, percutaneous coronary intervention, coronary artery by￾pass graft, death from CVD).
The potential pathophysiological links between NAFLD and
CVD have been reported elsewhere95 and are beyond the scope
of this review. Briefly, (a) systemic and hepatic IR as well as related
aberrations (dyslipidemia, dysglycemia, arterial hypertension), (b)
vasoactive and thrombogenic factors (eg fibrinogen, transforming
growth factor-β, plasminogen activator inhibitor), (c) inflammatory
factors (eg cytokines, adipokines, hepatokines, C-reactive protein,
fetuin-A), (d) oxidative stress and the production of reactive oxygen
species, (e) mitochondrial dysfunction, (f) gut-derived factors (lipo￾polysaccharide, products from intestinal dysbiosis) may all contrib￾ute to atherosclerosis, structural changes in the cardiac muscle and
valves, but also to defects in the conduction system of the heart.95
Based on the diversity of the putative links, it seems that there are
multiple potential mechanisms that may affect to a different extent
each patient, who may also carry different genetic predispositions
or epigenetic modifications for NAFLD and CVD. Thus, similar to the
TABLE 2 Treatment targets for NAFLD-related co-morbidity empirically proposed for patients with NAFLD
Co-morbidity of NAFLD Treatment target(s)a Comments
Obesity Steatosis improvement: ≥3% weight loss
Inflammation improvement: ≥5% weight loss
Resolution of NASH: ≥7% weight loss
Fibrosis improvement: ≥10% weight loss
Even minimal weight loss may have beneficial effects and
should be encouraged.3
T2DM HbA1c <7% The target of HbA1c may be more stringent in younger
patients with long life expectancy, lack of other co￾morbidities and lack of vascular complications and in
those with low risk associated with hypoglycemias.99
Dyslipidemia LDL-C <70 mg/dL
Triglycerides <150 mg/dL
Triglycerides >500 may increase the risk of acute
pancreatitis.100
Arterial hypertension <130/80 mm Hg The target may be <140/90 for patients at lower CV risk,
ie when the 10-y risk of atherosclerotic cardiovascular
disease <15%.100
Abbreviations: CV, cardiovascular; HbA1c, glycated haemoglobin; LDL-C, low-density lipoprotein cholesterol; NASH, nonalcoholic steatohepatitis;
T2DM, type 2 diabetes mellitus.
Treatment targets are mainly adopted from those proposed for patients with T2DM.
10  |    POLYZOS et al.
pathogenesis of NAFLD, which is a typically multifactorial disease,96
the interplay of NAFLD with CVD seems to be multifactorial too.
However, these pathogenetic hypotheses cover mostly a direction
from NAFLD to CVD and do not consider the above-mentioned re￾verse of bi-directional causality.
Regarding the treatment of CVD in NAFLD patients, specific
data are scarce. Therefore, CVD should be managed similarly in pa￾tients with or without NAFLD, until definite data support specific
modifications. Summarising the above-mentioned data, pioglitazone
should be avoided in NAFLD patients with congestive heart failure
due to weight gain and fluid retention64,67 and vitamin E should
not be administered longer than the duration of the PIVENS trial
(2 years),63 due to a yet unclear increase in overall mortality. GLP-
1RA and SGLT-2i seem to offer advantages in both NAFLD and CVD,
but more studies with hepatic histological end points are required
to reach secure conclusions. Notably, OCA, one of the most prom￾ising emerging medication for NASH, adversely affect lipid profile
and should be cautiously administered in NAFLD patients with CVD,
even in the setting of clinical trials.
Regarding lean NAFLD, there are no specific guidelines for its
management. However, based on the common metabolic and CV
risk factors in lean and obese NAFLD,42 as well as the similar risk
of CVD in patients with lean and obese NAFLD,41 it seems ratio￾nal that lean NAFLD may be managed in a similar way to obese
NAFLD. This management includes lifestyle modifications that tar￾get to reduce visceral adiposity, which may be masked in lean pa￾tients with NAFLD but does not include anti-obesity medications
or bariatric surgery.
While waiting for the approval of medications for NASH, an in￾dividualised, diabetes-like approach may be possibly considered.97,98
In this regard, metabolic and non-metabolic CV risk factors (eg
T2DM, obesity, dyslipidemia, arterial hypertension, smoking, exces￾sive alcohol consumption, sedentary lifestyle) should be evaluated
and appropriately managed in NAFLD patients in a similar way that
they are managed in patients with diabetes, so as to reduce the CV
risk in the long-term in a multi-disciplinary setting. In the absence of
treatment targets of NAFLD-related co-morbidity, we may adopt the
respective targets proposed for patients with T2DM (Table 2),99,100
until novel data guide the global community to tailor these treatment
targets specifically for patients with NAFLD. This may be rational
since NAFLD and T2DM share common epidemiological trends and
pathophysiological factors.97
In summary, NAFLD is associated with CVD, the latter being the
leading cause of mortality in NAFLD patients, especially in those
with NASH and advanced fibrosis. Since there is currently no ap￾proved medication specifically for NASH, the early identification
and management of metabolic and non-metabolic risk factors of
CVD amongst NAFLD patients seem to be important to reduce the
CV risk.
ACKNOWLEDGEMENT
Declaration of personal interest: None.
Personal and funding interest: None.
AUTHORSHIP
Guarantor of article: SAP.
Author contributions: SAP: conception and design, acquisition
of data, interpretation of data; drafting the manuscript and revis￾ing it critically for important intellectual content; final approval
of the version to be published; agreed to be accountable for all
aspects of the work in ensuring that questions related to the ac￾curacy or integrity of any part of the work are appropriately in￾vestigated and resolved. SK: interpretation of data; revising the
manuscript critically for important intellectual content; final ap￾proval of the version to be published; agreed to be accountable
for all aspects of the work in ensuring that questions related to
the accuracy or integrity of any part of the work are appropriately
investigated and resolved. EAT: interpretation of data; revising
the manuscript critically for important intellectual content; final
approval of the version to be published; agreed to be accountable
for all aspects of the work in ensuring that questions related to
the accuracy or integrity of any part of the work are appropriately
investigated and resolved.
DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were gener￾ated or analysed during the current study.
ORCID
Stergios A. Polyzos https://orcid.org/0000-0001-9232-4042
Emmanuel A. Tsochatzis https://orcid.
org/0000-0001-5069-2461
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How to cite this article: Polyzos SA, Kechagias S, Tsochatzis
EA. Review article: non-alcoholic fatty liver disease and
cardiovascular diseases: associations and treatment
considerations. Aliment Pharmacol Ther. 2021;00:1–13.

https://doi.org/10.1111/apt.16575