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Review
Therapeutic Potentials of Reducing Liver Fat in Non-Alcoholic
Fatty Liver Disease: Close Association with Type 2 Diabetes
Georgios Tsamos 1 , Dimitra Vasdeki 2 , Theocharis Koufakis 2, * , Vassiliki Michou 3 , Kali Makedou 4
and Georgios Tzimagiorgis 4

1 Division of Gastroenterology, Norfolk and Norwich University Hospital, Norwich NR4 7UY, UK
2 Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine,
Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece
3 Sports Medicine Laboratory, School of Physical Education & Sport Science, Aristotle University of Thessaloniki,
57001 Thessaloniki, Greece
4 Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, AHEPA University
Hospital, 54636 Thessaloniki, Greece
* Correspondence: thkoyfak@hotmail.com; Tel.: +30-693-7092331

Abstract: Nonalcoholic fatty liver disease (NAFLD), the most widespread chronic liver disease world-
wide, confers a significant burden on health systems and leads to increased mortality and morbidity
through several extrahepatic complications. NAFLD comprises a broad spectrum of liver-related
disorders, including steatosis, cirrhosis, and hepatocellular carcinoma. It affects almost 30% of adults
in the general population and up to 70% of people with type 2 diabetes (T2DM), sharing common
pathogenetic pathways with the latter. In addition, NAFLD is closely related to obesity, which acts in
synergy with other predisposing conditions, including alcohol consumption, provoking progressive
and insidious liver damage. Among the most potent risk factors for accelerating the progression of
NAFLD to fibrosis or cirrhosis, diabetes stands out. Despite the rapid rise in NAFLD rates, identifying
the optimal treatment remains a challenge. Interestingly, NAFLD amelioration or remission appears
to be associated with a lower risk of T2DM, indicating that liver-centric therapies could reduce the risk
of developing T2DM and vice versa. Consequently, assessing NAFLD requires a multidisciplinary
Citation: Tsamos, G.; Vasdeki, D.;
approach to identify and manage this multisystemic clinical entity early. With the continuously
Koufakis, T.; Michou, V.; Makedou,
emerging new evidence, innovative therapeutic strategies are being developed for the treatment of
K.; Tzimagiorgis, G. Therapeutic
NAFLD, prioritizing a combination of lifestyle changes and glucose-lowering medications. Based
Potentials of Reducing Liver Fat in
Non-Alcoholic Fatty Liver Disease: on recent evidence, this review scrutinizes all practical and sustainable interventions to achieve a
Close Association with Type 2 resolution of NAFLD through a multimodal approach.
Diabetes. Metabolites 2023, 13, 517.
https://doi.org/10.3390/ Keywords: fatty liver disease; fibrosis; resolution of NAFLD; diabetes mellitus; lifestyle approaches;
metabo13040517 glucose-lowering drugs

Academic Editor: Jan W. Eriksson

Received: 4 March 2023

Revised: 21 March 2023 1. Putting into Context the Silent Epidemic: The Rise of NAFLD
Accepted: 29 March 2023
Before the middle of the last decade, the worldwide prevalence of non-alcohol fatty
Published: 4 April 2023
liver disease (NAFLD) was approximately 25% in adult individuals. NAFLD is currently
defined as an ectopic accumulation of lipids in the liver in the absence of secondary
causes or other etiologies of liver disease [1,2]. It is histologically classified into two
Copyright: © 2023 by the authors.
types: nonalcoholic fatty liver, defined as 5% liver steatosis with no evidence of injury
Licensee MDPI, Basel, Switzerland. to hepatocytes and no evidence of fibrosis; and nonalcoholic steatohepatitis (NASH),
This article is an open access article characterized as 5% liver steatosis, including inflammation and injury to hepatocytes with
distributed under the terms and or without fibrosis [3]. NASH is estimated to be present in up to 60% of patients with
conditions of the Creative Commons NAFLD confirmed by biopsy [1]. Interestingly, while NAFLD was formally described more
Attribution (CC BY) license (https:// than 40 years ago, it has only been recognized in recent years as an important risk factor
creativecommons.org/licenses/by/ for metabolic disorders, related to the increasing burden of non-communicable diseases
4.0/). (NCDs), such as type 2 diabetes mellitus (T2DM), obesity, cardiovascular disease, and

Metabolites 2023, 13, 517. https://doi.org/10.3390/metabo13040517 https://www.mdpi.com/journal/metabolites

Metabolites 2023, 13, 517 2 of 20

malignancy [4,5]. All of the above independent risk factors for mortality and morbidity are
associated with a high economic cost to health care systems.
In the 21st century, among other metabolic diseases, diabetes mellitus has become the
main concern for societies and health care systems. In particular, T2DM is mentioned to
affect 1 in 11 adults and up to 463 million people worldwide [6]. According to the most
recent data from the International Diabetes Federation (IDF), 700 million people between
the ages of 20 and 79 will live with T2DM in 2045, around the world [7]. This type of
diabetes, previously known as adult-onset diabetes, is defined by the following criteria:
random blood sugar test ≥ 200 mg/dL (or ≥11.1 mmol/L) in symptomatic individuals,
fasting blood sugar test ≥ 126 mg/dL (or ≥7 mmol/L) in two separate tests, oral glucose
tolerance test (OGTT) ≥ 200 mg/dL (or ≥11.1 mmol/L) after two hours, and glycated
hemoglobin (HbA1c) ≥ 6.5% in two separate assessments [8]. Growing evidence suggests
that there is a strong positive association between NAFLD and diabetes mellitus, and,
more specifically, individuals with diagnosed NAFLD have a twofold increased risk of
T2DM [9]. This can be explained by the fact that the risk factors for diabetes overlap with
the factors that affect the accumulation of liver fat. Thus, robust evidence from several
epidemiological studies has reported that the detection of NAFLD in its early stages could
predict the subsequent development of incident diabetes mellitus [10,11].

1.1. Pathophysiology of NAFLD/NASH

The development of NAFLD is an intricate process and is not completely understood.
The liver, as is widely known, promotes many functions through the mobilization, regula-
tion, and storage of nutrients. Hepatocytes play an essential role as regulators of amino
acid, triglyceride and lipoprotein metabolism, gluconeogenesis, and ketogenesis [12]. In-
terestingly, although the liver is not the primary organ for lipid storage, there can be a
few conditions that can cause ectopic lipid accumulation in it. The main causes include
excessive intake of dietary fat, de novo lipogenesis, and hepatic uptake of non-esterified
fatty acids from serum [12,13]. Insulin resistance causes lipolysis of adipose tissue, leading
to a higher concentration of non-esterified fatty acids in the circulation, which are taken
up by the liver in a concentration-dependent manner [14]. In addition, other metabolic
disturbances, such as hyperinsulinemia and hyperglycemia, promote increased liver con-
version of carbohydrates into fatty acids through de novo lipogenesis [15]. It is worth
noting that the expression and action of various enzymes involved in lipogenesis and
fatty acid storage in triglycerides are increased in individuals with NAFLD [16]. These
enzymes, including diacylglycerol acyltransferase, stearoyl-CoA desaturase, fatty acid
synthase, ketohexokinase, and acetyl-CoA carboxylase, have been explored as potential
therapeutic weapons against NAFLD.
In a small percentage of patients, NAFLD is associated with infectious pathologies
that can lead to the appearance of liver steatosis, such as hepatitis C and the human immun-
odeficiency virus (HIV). In some cases, it is related to medications (e.g., glucocorticoids,
tamoxifen, tetracycline, total parenteral nutrition, amiodarone, methotrexate, valproic acid,
and vinyl chloride) and specific toxins or acquired/inherited metabolic diseases such as
cachexia, lipodystrophy, or even gastrointestinal surgery [17,18].
The development of NASH has been reported to be divided into two phases. The
first is fatty deposition in the liver combined with an increase in insulin resistance. The
second phase is related to cellular and molecular changes, including primarily oxidative
stress and oxidation of fatty acids through lipid peroxidation, hyperinsulinemia, energy
homeostasis, variation in the extracellular matrix, and changes in immune system func-
tion [19,20]. Consequently, the development of insulin resistance is even more complex
than it appears. Although increased fat mass and adipocyte differentiation play a key
role in the development of insulin resistance, the relationship between glycemia and the
resolution of existing NAFLD/NASH (defined by the absence of ultrasound criteria for
NAFLD/NASH on repeated imaging) is still a knowledge gap.
Metabolites 2023, 13, 517 3 of 20

1.2. Unravelling the Connection: Pathophysiological Links between NAFLD and Diabetes Mellitus
Robust evidence suggests that there is a strong and bidirectional relationship between
the progression of NAFLD and T2DM. High levels of diacylglycerol or ceramides can affect
liver–insulin signaling, leading to an abnormal increase in liver insulin resistance [21].
Furthermore, elevated concentrations of circulating transaminases are strongly associated
with a future higher risk of T2DM [22]. Except for the above, patients with NAFLD and
T2DM are at an increased risk of developing macrovascular and microvascular diseases
such as cardiovascular and chronic kidney disease, which are the main causes of mortality in
these individuals [23]. Due to the intricate inter-relationship and the high global prevalence
of NAFLD and T2DM, targeting insulin sensitivity and hyperglycemia combined with
weight loss and adopting a holistic approach to the treatment of metabolic disease in
patients with NAFLD could prove advantageous. Therefore, it has been suggested that
alleviating NAFLD and NASH should be considered as part of the therapeutic strategy in
patients with T2DM [24].
It should be noted that several studies have shown that improvements in insulin sen-
sitivity have been positively associated with histological improvements in NAFLD/NASH
and regression of fibrosis [25]. In 2013, Sung et al. reported that the risk of T2DM decreased
in patients with resolved NAFLD status, as NAFLD is a reversible condition in its early
stages [26]. A meta-analysis, published in 2018, found that the severity of NAFLD is
directly related to dysglycemia, having a significant impact on the future risk of developing
T2DM [23]. However, more studies are needed to prove the causal relationship between the
two conditions and to reveal the extent of the risk of T2DM caused by the variable stages
of NAFLD.
The purpose of this narrative review is to summarize the current literature on modern
therapeutic approaches to NAFLD in patients with and without diabetes, focusing on
the targeting of metabolic disturbances. Another purpose is to discuss future potential
treatments and knowledge gaps in the therapy of NAFLD.

2. Pathways to Healing: Navigating the Therapeutic Approach

The therapeutic quiver of NAFLD consists of several levels, of which lifestyle, pharma-
ceutical, and surgical approaches are the main treatments. A multimodal intervention with
multiple aspects, such as lifestyle modification, weight loss, specific diets, and medication,
is the most appropriate and holistic approach for most people with NAFLD.

2.1. Less Is More: Unlocking the Power of Conservative Treatment

2.1.1. The Power of Lifestyle Modification in NAFLD
Robust evidence supports the crucial role of lifestyle changes as primary options
for the treatment of NAFLD. These approaches, which include diet, exercise, or physical
activity, mainly aim to control metabolic status [27]. Looking back in 2004, the World
Health Organization (WHO) established that moderate intensity exercise improves not
only physical and mental health, but also metabolic syndrome, T2DM, and cardiovascular
disease, conditions that are inseparably related to NAFLD [28]. In the 21st century, physical
activity is considered a pillar determinant of metabolic control and is recommended for
NAFLD. Different types of exercise, such as high-intensity intermittent exercise, aerobic
exercise, or resistance exercise, seem to have beneficial effects on fatty liver disease [29,30].
In 2017, Oh et al. found that high-intensity interval aerobic exercise, moderate-intensity
continuous aerobic exercise, and resistance exercise were equally effective in decreasing
liver fat content. However, only high-intensity interval aerobic exercise had a beneficial
effect on restoring Kupffer cell function [31]. A randomized control trial by Zhang et al.
indicated that after a 12-month active intervention, the two exercise groups (strong and
moderate training) showed a significant reduction in intrahepatic triglyceride content
(measured by proton magnetic resonance spectroscopy) compared to the control group [32].
Furthermore, several studies reported that resistance training leads to a reduction in liver fat
of 4–47% independently of weight loss [33]. The mechanisms underpinning the reduction
Metabolites 2023, 13, 517 4 of 20

of hepatic fat deposition due to exercise reflect changes in insulin sensitivity and circulatory
lipids. Exercise not only improves glycemic control but suppresses de novo lipogenesis
and improves blood pressure levels in people with NAFLD [34–36]. Table 1 summarizes
key studies on the effect of different exercises in patients with NAFLD.

Table 1. Effects of exercise in patients with NAFLD.

Number of Duration of
Study Type of Exercise Outcomes
Patients Intervention
Goodpaster et al. ↓ hepatic lipid content in 12 months,
n = 130 Aerobic Exercise with diet 6 months vs. 12 months
(2010) [37] equal ↓ of insulin resistant
Finucane et al.
n = 100 Aerobic Exercise vs. control 12 weeks ↓ hepatic lipid content
(2010) [38]
Aerobic Exercise vs. Resistance Groups including aerobic exercise:
Slentz et al.
n = 196 Exercise vs. Aerobic 8 months higher ↓ hepatic fat content, ↓ ALT,
(2011) [39]
+ Resistance Exercise and ↓ insulin resistance
Jakovljevic et al. ↓ hepatic fat contents in resistance
n = 17 Resistance training vs. Control 8 weeks
(2013) [33] training group
Wong et al.
n = 154 Aerobic Exercise vs. Control 12 months ↓ hepatic fat content
(2013) [40]
Zelber-Sagi et al.
n = 82 Resistance Exercise vs. Control 12 weeks Improving of steatosis and inflammation
(2014) [41]
Balducci et al. Aerobic Exercise + Resistance Exercise
n = 606 12 months ↓ fatty liver index
(2015) [42] vs. Control
Cuthbertson et al. ↓ hepatic lipid content, ↑peripheral
n = 69 Aerobic Exercise vs. Control 16 weeks
(2016) [43] insulin sensitivity
Zhang et al.
n = 220 Aerobic Exercise vs. control 12 months ↓ hepatic fat content
(2016) [32]
Skrypnik et al. Aerobic Exercise vs. Aerobic +
n = 44 3 months Greater reduction in ALT and AST
(2016) [44] Resistance Exercise
Oh et al. (2017)
n = 61 Aerobic + Resistance training 12 weeks ↓ ALT, ↓ AST and ↓ TG
[31]
Farzanegi et al. ↓ hepatic cell apoptosis, ↓ ALT, ↓ AST
n = 49 (rats) Aerobic training 4 weeks
(2018) [45] and ↓ ALP
AST: aspartate aminotransferase, ALT: alanine aminotransferase, TG: triglycerides, ALP: alkaline phosphatase,
↓: decrease.

2.1.2. Shedding Pounds: The Science of Weight Loss and Calorie Restriction
Weight loss is a gold standard therapy for most patients with NAFLD and can regress
liver disease, along with the reduction of cardiovascular disease and the risk of T2DM [46].
Some researchers support that a weight reduction of 10% is capable of inducing the res-
olution of NASH and improving fibrosis by at least one stage [47]. According to the
guidelines of the American Association for the Study of Liver Diseases (AASLD), a weight
loss of 5–10% in overweight or obese individuals and 3–10% in non-obese individuals with
NAFLD is the primary objective of lifestyle interventions. In accordance with the above,
there are also the National Institute of Health and Care Excellence (NICE) guidelines [48,49].
In addition, obesity, as a result of excess caloric consumption, is one of the leading factors
for NAFLD. Caloric restriction acts on metabolic reprogramming and on the utilization of
body energy, reducing oxidative damage to cells [50]. Because carbohydrates (which are
the main energy source of the human body) are linked to NAFLD, their restriction in the
diet can lead to lower glycemic load, increased insulin sensitivity, and pancreatic β-cell
insulin secretion of pancreatic cells [51].
A clinical trial by Holmer et al., which recruited 74 patients with NAFLD, indicated
that intermittent calorie restriction and a low carbohydrate high fat diet (LCHF) are more
effective in reducing liver steatosis and body weight compared to general lifestyle mod-
ification. Participants were randomized into 3 groups: intermittent calorie restriction,
including 500 kcal/day for women and 600 kcal/day for men; LCHF, with an average daily
Metabolites 2023, 13, 517 5 of 20

calorie intake of 1600 kcal/day for women and 1900 kcal/day for men; and general lifestyle
advice [52]. Furthermore, in a prospective study by Vilar et al., a combination of exercise
and a hypocaloric diet revealed a dose–response relationship between weight reduction
and general histological parameters, with the greatest improvement detected in those with
the greatest weight loss [53]. However, the beneficial effects of a low-carbohydrate diet are
only in the short term. In the long term, a reduced carbohydrate and a reduced fat diet has
results similar to those who achieved a 7% weight loss [54]. Table 2 presents the effect of
dietary intervention on NAFLD.
In addition to the above, it should be noted that some studies reported the beneficial
effect of diabetes remission on NAFLD and pancreatic morphology. In 2020, a post hoc
analysis of the DiRECT trial showed changes in the gross morphology of the pancreas
2 years post T2DM remission. The size of the pancreas had increased in patients who
achieved remission and weight loss, compared to those who did not respond to the weight
loss intervention. Intrahepatic fat and levels of FGF-21 and FGF-19 also decreased. However,
it is notable that there is no significant increase in pancreas volume after 6 months of reversal
of type 2 diabetes [55]. Additional trials might be of interest from a scientific point of view
to investigate further data on the progression of NAFLD and changes in pancreatic tissue
after remission of diabetes.

2.1.3. Breaking the Link between Fatty Liver and Type 2 Diabetes: The Power of
Nutritional Interventions
Numerous studies have corroborated the pivotal role of certain macronutrients in the
initiation and progression of NAFLD, regardless of caloric intake. In particular, macronu-
trients such as saturated fatty acids (SFA), trans fats, simple sugars such as sucrose and
fructose, and animal proteins are known to inflict damage on the liver through the accumu-
lation of triglycerides and impaired antioxidant activity, compromising insulin sensitivity
and postprandial triglyceride metabolism [56]. In contrast, the consumption of monounsat-
urated fatty acids (MUFA), ω3 polyunsaturated fatty acids (PUFA), plant-based proteins,
and dietary fibers such as whole grain cereals, fruits and vegetables, fatty fish (which
are primarily rich in ω3), and extra virgin olive oil have been found to confer beneficial
effects [57,58]. Gupta et al. suggest that oily fish (2–4 g/d), coffee (≥3 cups/day), and
nuts (100 g/d) are recommended as suitable additions to physical activity and caloric
restriction for patients with fatty liver disease, based on strong evidence from human
trials. Although tea, red wine, avocado and olive oil can be consumed moderately without
harm, more research is needed to investigate their therapeutic benefits for patients with
NAFLD/NASH [59].
Furthermore, Halima et al. conducted a study investigating the impact of apple
cider vinegar on rats with diabetes and demonstrated that in addition to its potent anti-
hyperglycemic properties, it also exhibited a crucial hepatoprotective effect. In particular,
indicators of liver toxicity, namely ALT, AST, total and direct bilirubin, as well as lev-
els of TC, TG, and LDL-c, demonstrated a significant reduction, which was particularly
prominent after four weeks of treatment, together with an elevation in HDL-c [60]. These
findings are consistent with several other studies [61–63]. The above elucidated results
unequivocally demonstrate that daily ingestion of vinegar can mitigate the increase in
blood glucose levels and lipid profile, which is typically induced by a hypercaloric diet in
rats, as posited by Ousaaid et al. [64]. Therefore, the use of apple cider vinegar could confer
considerable advantages in avoiding metabolic irregularities commonly associated with a
high-calorie diet.
Metabolites 2023, 13, 517 6 of 20

Table 2. Dietary interventions and outcomes in NAFLD patients.

Type of Number of Patients with

Study Type of Diet Duration Insulin Resistance Outcomes
Study Patients NAFLD
Haufe et al. Hypocaloric LCD Overweight/ ↓ to a
RCT 52 vs. 50 6 months 42% vs. 47% ↓ in IHLC
(2011) [65] vs. LFD obese similar extent
Browning et al. VLCD vs. Without
Non-RCT 9 vs. 9 2 weeks Not evaluated 55% vs. 28% ↓ in IHLC
(2011) [66] Hypocaloric diet cirrhosis
Ryan et al., Med. vs. LFD ↓ with the
RCT 6 vs. 6 Biopsy-proven 6 weeks 39% vs. 7% ↓ of IHLC
(2013) [67] or HCD Med. diet
Associations between
Vilar-Gomez et al. Hypocaloric LFD Histological
Single-arm 261 52 weeks ↓ weight loss and
(2015) [53] + PA NASH
histological improvement
Misciagna et al. Moderate- Significant improvement
RCT 44 vs. 46 Med. vs. CD 6 months Improvement
(2017) [68] severe (US) of NAFLD score
Med. ± Antioxidant
↓ of insulin
Abenavoli et al. 20 vs. 20 supplementation ↓ of FLI and LSM in
RCT Overweight 6 months resistance and
(2017) [69] vs. 10 (1400–1600 kcal/d) both diets
fasting glucose
vs. CD
Isocaloric ↓ of insulin
Markova et al.
RCT 18 vs. 19 animal-protein T2DM 6 weeks resistance and 48% vs. 35.7% ↓ in IHLC
(2017) [70]
vs. plant-protein diet fasting glucose
↓ of LSM in both diets,
Hypocaloric Med. vs.
Katsagoni et al. 21 vs. 21 Overweight/ improvement in ALT only
RCT Med. + lifestyle 6 months Not evaluated
(2018) [71] vs. 21 obese in Med. + lifestyle
intervention vs. CD
intervention-group
Significant
Marin-Alejandre Hypocaloric diet Overweight/ ↓ in IHLC + FLI following
RCT 37 vs. 39 6 months reduction in
et al. (2019) [72] vs. CD obese both diets
glucose and insulin
7.3% (Med./LCD) vs. 5.8
76 vs. 63 vs. LFD vs. LFD with PA Significant (LFD) ↓ in IHLC after
Gepner et al. Abdominal
RCT 73 vs. Med./LCD vs. 18 months reduction in 6 months,
(2019) [73] obesity
vs. 66 Med./LCD with PA glucose and insulin 4.2% vs. 3.8% after
18 months
Hypocaloric Med.
Yaskolka Meir 89 vs. 84 (1500–1800 kcal/d ♂, Abdominal
RCT 18 months Not evaluated ↓ IHLC following all diets
et al. (2020) [74] vs. 91 1200–1400 kcal/d ♀vs. obesity
healthy diet
Hypocaloric LPD
Xu et al. 10 vs. 9 vs. HPD 36.7% vs. 42.6% ↓ in IHLC
RCT Obese 3 weeks Not evaluated
(2020) [75] vs. 10 vs. reference-protein vs. no changes in IHLC
diet
Goss et al. ↓ of insulin No significant
RCT 14 vs. 11 LCD vs. LFD Obese 8 weeks
(2020) [76] resistance difference
53.1% vs. 50.9% vs.
16.8% ↓ in
IHLC, 61.9% vs. 63.8% vs.
20.2% ↓ in CAP, change in
↓ of insulin IHLC 3.9%
Holmer et al. 20 vs. 24 LCD vs. 5:2 diet
RCT NAFLD 12 weeks resistance and greater in LCD compared
(2021) [52] vs. 20 vs. CD
HbA1c to CD and 2.6% in 5:2 diet
compared to CD, ↓ in LSM
in 5:2 diet and CD
compared to
LCD
CAP: controlled attenuation parameter, CD: control diet, NAFLD: non-alcoholic fatty liver disease, NASH: non-
alcoholic steatohepatitis, LCD: low-carbohydrate diet, LFD: low-fat diet, PA: physical activity, HPD: high-protein
diet, LPD: low-protein diet, LSM: liver stiffness measurement, IHLC: intrahepatic lipid content, LFD: low-fat diet,
Med.: Mediterranean diet, FLI: fatty liver index, ↓: decrease, ♂: male, ♀: female

2.2. Cutting-Edge Solutions: Exploring Surgical Therapies for NAFLD

The potential effects of bariatric surgery on liver fat disease may extend beyond
weight loss. In fact, serum concentrations of glucagon-like peptide-1 (GLP-1) increase after
metabolic surgery, leading to decreased appetite, slower gastric emptying, and improved
insulin sensitivity [77]. Furthermore, the main role of GLP-1 is to modulate bile acid
signaling through the farnesoid X receptor (FXR), which can modify the gut microbiome
and promote NAFLD [78]. Therefore, current guidelines recommend that metabolic surgery
can be a potential approach in patients with T2DM or overweight/obese individuals
(i.e., BMI > 35 kg/m2 ) [48,79]. Although bariatric surgery has a beneficial effect, various
Metabolites 2023, 13, 517 7 of 20

limitations such as patient acceptability of complications, availability of services, and high

cost make its use difficult and highlight the need to carefully select eligible candidates [80].
The most common bariatric surgery procedures include adjustable gastric band (AGB),
biliopancreatic diversion (BPD), vertical sleeve gastrectomy (SG) and Roux-en-Y gastric
bypass (RYGB). Consequently, different methods might induce variable biological effects
depending on the surgical procedure. The most common metabolic operations are SG
and RYGB. In the first, about 80% of the stomach portion is removed along the gastric
greater curvature and the small dimensions of the stomach, along with the changes in
the hormonal environment, reduce hunger and delay gastric emptiness. In the second
procedure, the stomach is separated into a smaller pouch in the smaller curvature (through
stapling) and anastomosed with the jejunum [81,82]. In fact, by restricting food intake
and by promoting malabsorption of nutrients, these techniques can cause weight loss.
Both the reduction in body weight and decrease in waist circumstance through bariatric
surgery led to improvement in insulin resistance, T2DM, obesity, fatty liver disease, and
dyslipidemia [80]. Interestingly, one of the most important outcomes of bariatric surgery is
that it can markedly improve all histological characteristics of NAFLD, including fibrosis.
According to Lee et al., a resolution of steatosis was observed in 66% of patients, a resolution
of inflammation in 50% of patients, and a resolution of fibrosis in 40% of patients after
bariatric surgery [83]. Another recent study published in 2018, showed a resolution of
NAFLD of 78% after RYGB [84]. Furthermore, Weiner reported that patients after AGB,
RYGB and BPD achieved complete regression of NAFLD in up to 82.8% of the cases [85].
Table 3 presents studies that have investigated the effectiveness of bariatric surgery
management in alleviating NAFLD.

Table 3. The effectiveness of bariatric surgery management in alleviating NAFLD.

Study Number of Patients Type of Surgery Outcomes

Weiner et al. (2010) [85] n = 116 RYGB, AGB, BPD Complete regression of NAFLD in 82.8%
Moretto et al. (2012) [86] n = 78 RYGB Improvement of fibrosis from 44.8% to 30.8%
Tai et al. (2012) [87] n = 21 RYGB ↓ of steatosis, NASH, and fibrosis
Vargas et al. (2012) [88] n = 26 RYGB ↓ of steatosis, NASH, and fibrosis
75% resolution of steatosis, 90% resolution of
Taitano et al. (2014) [89] n = 160 RYGB, AGB
NASH, 50% resolution of fibrosis
Resolution of NASH in 85% of patients
Lassailly et al. (2015) [90] n = 109 RYGB, AGB, BIB
Reduction of fibrosis in 34% of patients
Aldoheyan et al. (2017) [91] n = 27 RYGB, BPD Improvement of steatosis and fibrosis
Parker et al. (2017) [92] n = 37 RYGB RYGB reverses NASH and fibrosis
Esquivel et al. (2018) [93] n = 43 SG 100% improvement of NAFLD
78% resolution of NAFLD
Schwenger et al. (2018) [84] n = 42 RYGB
9.5% worsening of fibrosis
Pooler et al. (2019) [94] n = 50 RYGB Improvement of steatosis
NAFLD: non-alcoholic fatty liver disease, NASH: non-alcoholic steatohepatitis, RYGB: Roux-en-Y gastric bypass,
SG: sleeve gastrectomy, AGB: adjustable gastric banding, BIB: biliointestinal bypass, BPD: biliary-pancreatic
diversion, ↓: decrease.

2.3. Exploring the Innovative World of Pharmaceutical Solutions

2.3.1. Effects of Anti-Diabetic Agents on NAFLD
It is well established that fatty liver and T2DM are the two sides of the same coin,
sharing common pathogenic pathways and factors such as insulin resistance. Although
the coexistence of fatty liver and T2DM is increasing, the treatment is not adequate. Due
to this close link between T2DM and NAFLD, various glucose-lowering drugs have been
used as NAFLD therapeutics. Numerous clinical trials have shown the beneficial effects
of GLP-1 receptor agonists, insulin-sensitizing thiazolidinediones, and sodium-glucose
Metabolites 2023, 13, 517 8 of 20

cotransporter 2 (SGLT2) inhibitors on liver fat content. GLP-1 binds to a specific GLP-1
receptor, whose activation can promote the reduction of liver steatosis by improving insulin
signaling pathways, hepatocyte lipotoxicity, and mitochondrial function [95,96]. On the
contrary, SGLT2 inhibition promotes negative energy balance through increased glycosuria
and a change of the substrate to lipids as an energy source, which inhibit liver steatosis,
inflammation, and fibrosis [97]. In 2021, a meta-analysis by Mantovani et al. showed that
treatment with GLP-1 receptor agonists or SGLT2 inhibitors compared to placebo decreased
the absolute percentage of liver fat content and serum levels of ALT [98]. These findings
have been replicated by several other studies [99].
It is significant to mention that a multitude of studies have recently elucidated the
efficacy of SGLT2 inhibitors in alleviating liver steatosis. Of particular interest, in 2018,
Shibuya et al. revealed, for the first time, the statistically significant and advantageous
impact of luseogliflozin, compared to metformin, on NAFLD and weight loss [100]. The
results manifested a superior effect of the former, particularly on body mass index (BMI),
after a six-month period. Luseogliflozin facilitates the mitigation of visceral adiposity by
excreting energy through urine glucose excretion [100]. Additionally, in the same year, a
double-blind randomized controlled study revealed that dapagliflozin monotherapy can
reduce the levels of hepatocyte injury biomarkers, such as ALT, AST, γ-glutamyl transferase
(γ-GT), cytokeratin 18-M30, cytokeratin 18-M65, and plasma fibroblast growth factor 21
(FGF21). With the combination of omega-3 carboxylic acids, not only can glucose control
be improved, but body weight and abdominal fat volumes can also be reduced [101].
Analogous results were observed in a study by Sattar et al. using empagliflozin, in which
the decline in ALT was consistently more notable than that of AST. The reductions were
most prominent in participants with the highest baseline ALT levels and were primarily
unaffected by changes in HbA1c and body weight [102]. However, the exact mechanisms
through which empagliflozin mitigates aminotransferases or liver fat remain ambiguous;
therefore, more research is needed.
Thiazolidinediones increase peripheral insulin sensitivity by stimulating adipokines,
promoting triglyceride storage in adipose tissue, and improving the suppressive action
of insulin on lipolysis [103]. In this way, thiazolidinediones lead to lower serum levels of
free fatty acids and reduced hepatic lipid accretion [103]. The most common and approved
are pioglitazone and rosiglitazone, which are powerful activators of the nuclear receptor
PPARγ and are expressed mainly in adipose tissue [104]. Numerous studies have shown
that pioglitazone has a beneficial effect on insulin sensitivity, inflammation, and hepatocyte
degeneration, but there was no difference in the resolution of fibrosis [105]. A recent meta-
analysis of randomized controlled trials using pioglitazone or rosiglitazone revealed that
both drugs led to enhanced liver histology, including decreased steatosis, inflammation,
and hepatocyte degeneration [106].
Recently, semaglutide and tirzepatide have been added to the therapeutic quiver
against T2DM and obesity. Semaglutide is a GLP-1 analogue, and tirzepatide is a dual
analogue of GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) [107]. Both
delivered impressive results in the phase 3 trials and can be considered future game
changers in the realm of T2DM remission. Due to their importance in NASH therapy, these
agents will be discussed in detail at a later part of the review. Table 4 summarizes the
clinical trials that have examined the effects of antidiabetic drugs on NAFLD.
Metabolites 2023, 13, 517 9 of 20

Table 4. Beneficial effects of anti-diabetic drugs on NAFLD.

Number of
Study Duration Study Population Drug Name Dose Liver Outcomes Diabetes Outcomes
Patients
5 µg twice daily
Dutour A et al. Obesity, T2DM, ↓ Hepatic
n = 44 26 weeks Exenatide 4 weeks and ↓ Weight
(2016) [108] NAFLD triglyceride
after 10 µg/day
Armstrong MJ Meta-
n = 4442 Obesity, T2DM Liraglutide 1.8 mg/day ↓ ALT Not mentioned
et al. (2013) [109] analysis
↓Weight and adipose mass, ↓
Armstrong MJ HbA1c and serum levels of
n=7 12 weeks Obesity, NASH Liraglutide 1.8 mg/day ↓ ALT, AST, DNL
et al. (2016) [110] glucose, ↓ LDL cholesterol, ↑
insulin sensitivity
↓ Weight, ↓ HbA1c and
Armstrong MJ
n = 26 48 weeks Obesity, NASH Liraglutide 1.8 mg/day ↑ NASH resolution serum levels of glucose, ↑
et al. (2016) [111]
HDL cholesterol
Escalation from
Newsome P et al. Meta- Obesity, with or
n = 957 Semaglutide 0.05 to ↓ ALT Not mentioned
(2019) [112] analysis without T2DM
0.4 mg/day
Newsome P et al. Obesity, NASH 0.1, 0.2, or ↑ NASH resolution,
n = 320 72 weeks Semaglutide ↓ Weight, ↓ HbA1c
(2021) [113] (F1–F3 fibrosis) 0.4 mg/day ↓ ALT, AST
Obesity,
Cui J et al.
n = 25 24 weeks pre-diabetes, Sitagliptin 100 mg/day No changes No changes
(2016) [114]
early T2DM
Joy TR et al. Obesity, T2DM,
n = 12 24 weeks Sitagliptin 100 mg/day No changes No changes
(2017) [115] NASH
Neuschwander- ↓ ALT and AST, ↓
↓ HbA1c and fasting insulin,
Tetri BA et al. n = 30 48 weeks Obesity, NASH Rosiglitazone 4 mg twice daily steatosis and
↑ glucose tolerance, ↑ weight
(2003) [116] inflammatory
4 mg/day
Ratziu V et al. ↓ Fasting glucose and
n = 63 52 weeks Obesity, NASH Rosiglitazone 1 month and ↓ ALT, ↓ steatosis
(2008) [117] insulin, ↑ weight
after 8 mg/day
↓ ALT and AST, ↓ ↓ Fasting glucose and
Belfort R et al. Obesity, T2DM,
n = 55 24 weeks Pioglitazone 45 mg daily steatosis and insulin, ↑ insulin sensitivity,
(2006) [104] NASH
inflammatory ↑ HDL cholesterol, ↑ weight
Cusi K et al. and ↓ Fasting glucose, insulin
↓ ALT and AST, ↓
Sanyal AJ et al. n = 101, 45 mg/day, and triglyceride, ↑ insulin
96 weeks Obesity, NASH Pioglitazone NAS, ↑ NASH
(2016 + 2010) n = 247 30 mg/day sensitivity, ↑ HDL
resolution
[118,119] cholesterol, ↑ weight
↓ Weight, ↓ HbA1c, fasting
Cusi K et al.
n = 56 24 weeks Obesity, T2DM Canagliflozin 300 mg/day No changes glucose and insulin, ↑
(2019) [120]
hepatic insulin sensitivity
Latva-Rasku A ↓ Liver lipids, ↓ ↓ Weight, ↓ HbA1c,
n = 32 8 weeks Obesity, T2DM Dapagliflozin 10 mg/day
et al. (2019) [121] liver stiffness fasting glucose
Shimizu M et al.
n = 57 24 weeks T2DM, NAFLD Dapagliflozin 5 mg/day ↓ ALT ↓ Weight
(2019) [122]
Kahl S et al.
n = 42 24 weeks Obesity, T2DM Empagliflozin 25 mg/day ↓ Liver lipids ↓ Weight, ↓ glucose
(2020) [123]
Kuchay MS et al.
n = 25 20 weeks T2DM, NAFLD Empagliflozin 10 mg/day ↓ ALT, ↓ liver lipids No changes
(2018) [124]
T2DM: type 2 diabetes mellitus, HbA1c: glycated hemoglobin, NAFLD: non-alcoholic fatty liver disease, NASH:
non-alcoholic steatohepatitis, NAS: NAFLD Activity Score, AST: aspartate aminotransferase, ALT: alanine amino-
transferase, HDL: high-density lipoproteins, LDL: low-density lipoproteins, ↓: decrease, ↑: increase.

2.3.2. Effects of Statins and Other Lipid-Lowering Drugs

Realizing that NALFD is strongly related to metabolic syndrome, there is a need for an
integrated approach for individuals with a high liver fat content. The definition of metabolic
syndrome includes the following criteria: abdominal obesity, with waist circumference of
≥90 cm in men or ≥85 cm in women; low high-density lipoprotein (HDL) cholesterol with
HDL-cholesterol of <40 mg/dL in men and <50 mg/dL in women; hypertriglyceridemia
with triglyceride (TG) of ≥150 mg/dL; high systolic blood pressure (BP), with systolic
BP of ≥130 mmHg and/or diastolic BP of ≥85 mmHg; or hyperglycemia, with fasting
plasma glucose (FPG) of >100 mg/dL [125,126]. Consequently, abnormal blood cholesterol
levels play a key role in the progression of NAFLD and can be controlled with statins [127].
Except for this action, statins exhibit pleiotropic properties, such as antioxidant and anti-
inflammatory effects, neoangiogenesis, and improvement of endothelial functions [127].
Metabolites 2023, 13, 517 10 of 20

Interestingly, a large amount of data recommended that a statin remedy is correlated with
a significant improvement in liver steatosis, inflammation, and even fibrosis [128,129]. For
example, an observational study by Lee et al. found a lower risk of NAFLD in patients
who received statin therapy [129]. According to a meta-analysis of six studies, ezetimibe,
which is a lipid lowering agent acting by reducing cholesterol absorption in the intestines,
significantly reduced plasma liver enzyme levels, as well as improved liver steatosis [130].
On the contrary, fenofibrate, a PPAR-a agonist, does not have a significant effect on liver fat
content [131].
Furthermore, the category of omega-3 polyunsaturated fatty acids (n-3 PUFAs), such
as a-linolenic acid (a-ALA), stearidonic acid (SDA), eicosapentaenoic acid (EPA), docos-
apentaenoic acid (DPA) and docosahexaenoic acid (DHA), has a beneficial effect on pe-
ripheral insulin sensitivity and on triglycerides levels, leading to a lower deposition of
liver fat [132]. A randomized control trial published in 2020 reported lower liver fat in
patients who received n-3 PUFA supplementation compared to those who received the
placebo [132]. Similar outcomes were observed in another meta-analysis [133]. However,
more well-designed randomized clinical trials are necessary to suggest omega-3 PUFA
supplementation for the treatment of NAFLD in patients with and without T2DM.
Although statins have long been used as a widely accepted method for reducing
cholesterol and minimizing the risk and mortality associated with cardiovascular disease,
recent years have seen increasing scrutiny of their potential side effects. It should be
noted, in particular, the increasing evidence linking prolonged statin use with diabetes
progression and ectopic fat deposition, particularly in the kidneys of patients with diabetic
nephropathy [134]. Recently, a study by Huang et al. revealed that statin administration
for a period of more than 10 years was found to increase insulin resistance, alter lipid
metabolism, provoke inflammation and fibrosis, and ultimately exacerbate the progression
of diabetic nephropathy in diabetic mice. It is worth noting that the duration of the study
spanned 50 weeks, which is equivalent to at least 35 years in the human life cycle [134].
Similar results were reported in the retrospective cohort study by Mansi et al., which
followed patients with diabetes for a 12-year period and highlighted the need to carefully
consider the metabolic effects of statin use when evaluating its risk–benefit ratio for diabetic
individuals [135]. However, these findings are in stark contrast to the beneficial effects
of statins in the treatment of NAFLD. Future research efforts are expected to provide
more information on whether prolonged statin use may yield more detrimental than
advantageous outcomes.

2.3.3. From Lab to Liver: The Promising Future of Developing New Drugs for NAFLD
More recently, new potential drugs for NAFLD have been studied. The most common
treatment targets are the farnesoid X receptor (FXR), a nuclear receptor, and obeticholic
acid (OCA), which is a synthetically modified analogue of chenodeoxycholic acid [136].
These agents improve insulin resistance, regulate glucose and lipid metabolism, and have
anti-inflammatory and anti-fibrotic effects in NAFLD [137]. Yonoussi et al. observed that
308 patients who received OCA 25 mg daily had an improvement in fibrosis, compared
to the control group [138]. Interestingly, the multicenter, randomized, placebo-controlled
FLINT trial documented that those who responded to OCA, defined as patients with a
≥30% reduction in liver lipid content, had an improvement in the histological features
of NASH, including fibrosis and steatosis as well as reduced cell death [139]. However,
one of the limitations of OCA use is that it can increase serum LDL levels. Therefore, the
safety of the combination of OCA with statin in patients with NASH is being tested in
ongoing studies. Non bile acid farnesoid X-activated receptor (FXR) agonists, including
tropifexor, cilofexor, EDP-305, and nidufexo, have also been tested for NAFLD [140]. The
main difference between OCA and cilofexor is that the latter caused a reduction in liver
lipid content in patients with NASH without altering blood levels of lipids or indicators of
insulin resistance [141]. An anti-inflammatory drug, the stearoyl-CoA desaturase (SCD)
1 inhibitor, plays a key role in liver lipogenesis. The main action is to catalyze the con-
Metabolites 2023, 13, 517 11 of 20

version of saturated fatty acids to MUFA, protecting against hepatic steatosis [142,143].
Two animal studies showed that SCD1 activity was elevated in proportion to liver lipid
content in models of NAFLD and genetic knockout of hepatic SCD1 expression effectively
reduced fatty liver and insulin resistance in animals fed a high-fat diet [144,145]. Recently,
a clinical trial revealed a reduction in liver fat content, resolution of NASH, and improve-
ment of liver fibrosis in individuals with NAFLD and prediabetes or T2DM after the use
of aramchol [146]. Given that to date there is no FDA-approved therapy for the treat-
ment of NAFLD, evaluating the efficacy and safety profile of new agents is of paramount
importance. However, the fact that liver biochemistry does not always reflect hepatic
histology makes the conduction of biopsy studies important, which on the other hand,
present significant technical challenges for obvious reasons.
Table 5 presents ongoing trials investigating the safety and efficacy of new medications
for the treatment of NAFLD.

Table 5. Ongoing trials of new medications for the treatment of NAFLD.

Number of T2DM Inclusion

Drug Trial Identifier Mechanism Primary Endpoint
Patients Criteria
% of patients with NASH
resolution without fibrosis
PPARα/δ dual T2DM only with
Elafibranor NCT02704403 2000 worsening at
agonist HbA1c ≤ 9%
week 72 from BL, long term
liver-related outcomes
PPAR-α/γ Change in NFS at week 8, 16,
Saroglitazar NCT04193982 250 NA
agonist and 24
% of patients with improvement
T2DM only with of liver fibrosis by ≥1 stage
Obeticholic Acid NCT03439254 919 FXR agonist
HbA1c ≤ 9.5% with no worsening of NASH
after 18 months
Improvement of liver fibrosis by
≥1stage with no worsening of
NASH OR achieving NASH
T2DM only with resolution without worsening
Obeticholic Acid NCT02548351 2480 FXR agonist
HbA1c ≤ 9.5% of liver
fibrosis at month 18 from BL,
long term
liver-related outcomes
Improvement of liver fibrosis by
CCR2/5 dual T2DM with ≥1 stage with no worsening of
Cenicriviroc NCT03028740 2000
antagonist HbA1c ≤ 10% NASH after 12 months, long
term liver-related outcomes
NASH resolution with no
worsening of fibrosis OR fibrosis
T2DM with controlled
improvement by ≥1 stage with
Aramchol NCT04104321 2000 SCD1 inhibitor glycemia or
no worsening of NASH at week
prediabetes
52 from BL, Long term
liver-related outcomes
NASH resolution in patients
T2DM with with F2-F3 fibrosis after
Resmetirom NCT03900429 2000 THR-β agonist
HbA1c < 9% 52 weeks, long term
liver-related outcomes
BL: baseline, CCR2/5: C-C chemokine receptors type 2 and type 5, FXR: farnesoid X receptor, HbA1c: glycated
hemoglobin, LXR: liver X receptor, NA: data not available, NAFLD: non-alcoholic fatty liver disease, NFS:
NAFLD fibrosis score, PPAR: peroxisome proliferator-activated receptor, NASH: non-alcoholic steatohepatitis,
SCD: stearoyl-CoA desaturase, SGLT: sodium-glucose cotransporter, THR: thyroid hormone receptor, T2DM:
type 2 diabetes.
Metabolites 2023, 13, 517 12 of 20

2.3.4. Effects of Anti-Obesity Drugs

During recent years, weight loss pharmacotherapy has been an attractive option for
patients with NAFLD, with or without T2DM and with a BMI > 30 kg/m2 or >27 kg/m2
in the presence of at least one metabolic comorbidity, because it can lead to the remission
of diabetes and improves the progression of fatty liver disease [143,146]. The US Food
and Drug Administration (FDA) has approved six medications for chronic weight man-
agement: orlistat, lorcaserin, phentermine/topiramate, bupropion/noltrexone, liraglutide
and semaglutide that are associated with a decrease in body weight of at least 5% in one
year [146]. Interestingly, a closer look at the literature reveals that, except for the long-
term effects on glycemic control, orlistat selectively reduces visceral fat and prevents the
digestion of free fatty acids that are responsible for the increase in liver and peripheral
insulin resistance [147]. In 2005, a meta-analysis of seven randomized control trials showed
that patients who received 120 mg orlistat three times received an average weight loss of
3.8 kg compared to 1.4 kg in the placebo group after 12 weeks [148]. In contrast, no data
are available on the effects of topiramate, naltrexone, bupropion, and phentermine on liver
outcomes in patients with NAFLD [149].

3. Tirzepatide and Semaglutide: New Weapons against NAFLD

As previously stated, two recently approved drugs, tirzepatide, a dual analogue of
GIP/GLP-1, and semaglutide, a GLP-1 analogue, were added to the therapeutic arsenal of
NAFLD [150]. A phase 3 trial reported that the liver fat content was significantly reduced
after tirzepatide therapy compared to baseline measures [151]. On the other hand, a phase
2 trial involving patients with NASH revealed that semaglutide treatment resulted in a
significantly higher percentage of patients with NASH resolution than the placebo [113].
Tirzepatide is associated with a significant reduction in liver fat content (LFC), subcuta-
neous abdominal adipose tissue (ASAT), and volume of visceral adipose tissue
(VAT) [152,153]. A multicenter phase 3 clinical trial reported a significant reduction in LFC,
ASAT, and VAT volumes compared to insulin degludec in individuals with T2DM [151].
The results were more prominent in groups receiving 10 mg and 15 mg of tirzepatide. An
MRI scan was performed in participants before randomization and the primary efficacy
endpoint was identified by MRI-proton density fat fraction (MRI-PDFF) at week 52 of drug
administration [151]. According to a meta-analysis of 11 phase 2 randomized controlled
trials, the treatment regimen with a GLP-1 receptor agonist (liraglutide or semaglutide) for
a median of 26 weeks was strongly associated with significant reductions in LFC, as well as
increased histological resolution of NASH without worsening of fibrosis, compared to the
placebo or reference therapy group [154].
In 2020, Hartman et al. determined the result of tirzepatide on the biomarkers of
NASH and fibrosis in people with diabetes. A reduction in ALT, AST, keratin-18 (K-18),
and N-terminal pro-peptide of type III collagen (Pro-C3) levels was revealed, combined
with a significant increase in adiponectin levels that was dose-dependent [155]. It is a well-
established fact that K-18 and Pro-C3 serve as biomarkers of fibrogenesis in individuals
afflicted with NAFLD. As mentioned above, to date, there has not been approved phar-
macological therapy to resolve NAFLD. However, the remarkable effects of tirzepatide on
LFC promise that it can be more effective than GLP-1 receptor agonists, but the preliminary
promising findings should be confirmed by further studies. An ongoing trial, SYNERGY-
NASH, will provide specific data on the beneficial effect of tirzepatide in participants with
biopsy-proven NASH.
Semaglutide has also been effective in improving liver biochemistry. A prospective
study by Volpe et al. showed a significant decrease in glucometabolic parameters, liver
enzymes, and laboratory indicators of liver steatosis during therapy, as well as a reduction
in fat mass and VAT. Interestingly, liver steatosis improved in 70% of participants after
52 weeks of treatment [156]. Furthermore, in 2021, a randomized control trial compared
changes in liver stiffness and liver fat in individuals with NAFLD who received semaglu-
tide and placebo therapy, respectively. The results revealed a significant reduction in liver
Metabolites 2023, 13, 517 13 of 20

steatosis with an improvement in liver enzymes and metabolic parameters in the semaglu-
tide group versus the placebo group. However, no significant differences in liver stiffness
were observed in both groups [157]. This year, Mantovani et al. published a systematic
review providing data on the beneficial effect of GLP-1 receptor antagonists on the histo-
logical features of NAFLD, including steatosis, ballooning, and lobular inflammation, as
well as on the resolution of NASH without worsening of fibrosis [158].
Recently, an open-label phase 2 trial by Alkhouri et al. reported that the combination of
semaglutide with cilofexor and firsocostat achieved greater improvements in liver steatosis
and biochemistry profile than monotherapy [159]. Based on the evidence mentioned above,
semaglutide in combination with weight loss and a specific diet should be recommended
as an optimal approach for the treatment of individuals with T2DM and fatty liver disease.
Future studies are expected to add additional evidence on the effects of new antidia-
betic agents on NAFLD progression and clarify whether the benefits are driven primarily
by weight loss or by the pleiotropic actions of the drugs.

4. Conclusions
The review of available evidence supports the notion that NAFLD is an important
risk factor for the development of T2DM, but also underlines the bidirectional relationship
between these conditions. Despite many advances in our knowledge on the epidemiology
and pathogenesis of NAFLD, the most established treatment so far is intensive weight loss.
The importance of weight reduction is highlighted in people with NASH, where weight loss
greater than 7% is associated with a clinically significant regression of disease status [45].
Exercise compared to weight loss produces significant but modest changes in liver fat.
Lifestyle modification, including specific diets and physical activity, is and should be the
first line of treatment in NAFLD and NASH because it has been shown to ameliorate the
risk of extrahepatic comorbidities and complications. On this basis, the current European
and American clinical guidelines for the treatment of NAFLD have strongly suggested the
importance of routine screening for T2DM in all patients with NAFLD [160].
Today, the question is no longer whether lifestyle modification is an effective clinical
therapy, but how we implement lifestyle as a therapy in daily clinical care. However, most
studies indicate several barriers to maintaining a healthy lifestyle in the long term and that
weight regain is very common among people with diabetes and/or obesity, making the use
of pharmacotherapy a necessity in most cases. In this context, a better understanding of the
mechanisms linking NAFLD and T2DM will help design targeted therapies that can stop
or reverse disease progression.

Author Contributions: G.T. (Georgios Tsamos), T.K. and D.V. reviewed the literature and drafted
the first version of the manuscript. V.M., K.M. and G.T. (Georgios Tzimagiorgis) reviewed the
literature and edited the manuscript. All authors have read and agreed to the published version of
the manuscript.
Funding: This review received no external funding.
Conflicts of Interest: T.K. has received honoraria for lectures from AstraZeneca, Boehringer Ingel-
heim, Pharmaserve Lilly and Novo Nordisk, for advisory boards from Novo Nordisk and Boehringer
Ingelheim, and has participated in sponsored studies by Eli-Lilly and Novo Nordisk. The other
authors report no conflict of interest.

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