Subscribe
  • Original Article
  • OPEN ACCESS

Pharmacological Therapeutics: Current Trends for Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)

  • Thaninee Prasoppokakorn1 ,
  • Panyavee Pitisuttithum2  and
  • Sombat Treeprasertsuk1,* 
 Author information
Journal of Clinical and Translational Hepatology 2021;9(6):939-946

DOI: 10.14218/JCTH.2021.00189

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new term from nonalcoholic fatty liver disease (NAFLD) and is a positive diagnosis based on histopathology, imaging, or blood biomarkers. MAFLD is one of the common causes of liver dysfunction worldwide, likely due to the increase in metabolic syndrome as well as the high burden of disease and its relationship to other extrahepatic conditions. However, effective pharmacological therapeutic agents are still lacking; current management largely focuses on weight reduction and lifestyle modification. The purpose of this review was to summarize the updated evidence of novel therapies targeting different pathogenetic pathways in MAFLD.

Keywords

Metabolic dysfunction-associated fatty liver disease, Nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis, Pharmacological treatment

Introduction

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new term from nonalcoholic fatty liver disease (NAFLD), which is the positive-criteria diagnosis focusing on metabolic factors and independent of alcohol use.1 The terminology of MAFLD was defined by evidence of hepatic steatosis based on histopathological examination, imaging, or blood biomarkers in association with one of three criteria, including obesity or overweight status, type 2 diabetes mellitus (T2DM) and evidence of metabolic dysregulation, with at least two metabolic risk factors, including high waist circumference, hypertension, hypertriglyceridemia, low high-density lipoprotein-cholesterolemia, prediabetes, insulin resistance, and high-sensitivity C-reactive protein level. In addition, heterogeneous factors have been found to be associated with MAFLD, including race, sex, diet, genetic predisposition, age, and gut microbiota.1,2

To date, MAFLD has become a global health issue, accounting for 25% in Western countries3 and 25–30% in the Asia Pacific region.4 MAFLD can progress to cirrhosis and develop complications, such as decompensation and hepatocellular carcinoma, and increases the risk of liver-related mortality. Moreover, the risk of cardiovascular mortality is higher among MAFLD patients.5 Previous studies have shown higher liver-related mortality among nonalcoholic steatohepatitis (NASH) patients than among those without NASH. As a result, NASH resolution has become one of the main outcomes of clinical studies of MAFLD, apart from liver fibrosis regression.6

The most effective therapy for MAFLD is weight reduction; a 10% reduction can lead to resolution of steatohepatitis and improvement of fibrosis by at least one stage. In addition, it will decrease cardiovascular and diabetes risks.7 Pharmacological interventions are reserved for some MAFLD patients who are not responding to conventional treatment. Through this article, we aimed to review the currently available medications for MAFLD treatment based on the pathophysiology of MAFLD.

Pharmacological therapeutics for MAFLD

To date, the currently available drugs for MAFLD treatment have been studied in many clinical trials. By replacing NAFLD with MAFLD, several aspects of this disease were changed, including terminology, details of the definition, pathogenesis, associated disease, and, crucially, the aspects of research and drug development demonstrated in Table 1.1,8–11 The major challenges in the research and drug development for “NASH” mainly focus on two outcomes. The first is a resolution of NASH or steatohepatitis, and the second is an improvement of fibrosis stage. Thus, changing the name from NAFLD to MAFLD as well as abandoning the term “NASH” might perturb the results of many study trials due to the limitation of MAFLD concerning steatohepatitis and hepatic fibrosis. Nonetheless, pharmacological therapeutic development for MAFLD based on the mechanisms of action, adverse events, and efficacy is reviewed and recommended in clinical practice guidelines (CPGs) issued by the liver international society in the Americas (AASLD),6 Europe (EASL),12 and Asia (APASL).13 Classification of the drugs is based on the benefits of clinical studies (Table 2). Drugs with potential benefits include thiazolidinediones (pioglitazone)14–16 and vitamin E16–18 (Table 2), supported by both randomized controlled trials (RCTs) and meta-analyses.19,20 From the current recommendation, pioglitazone has been established in both diabetic and nondiabetic MAFLD patients with significant fibrosis (≥F2), whereas vitamin E is recommended in nondiabetic MAFLD patients with ≥F2 non-cirrhosis.21

Table 1

Comparison of NAFLD and MAFLD in each domain

Definition and diagnosisNAFLDMAFLD
Fatty liver diseaseNAFLD: encompasses the entire spectrum of FLD in individuals without significant alcohol consumption. NAFL: presence of ≥5% HS without evidence of hepatocellular injury or fibrosisMAFLD: histopathology, imaging, or blood biomarker evidence of steatosis involving >5% of hepatocytes, accompanied by obesity or overweight status (BMI >25 kg/m2 in Whites and >23 kg/m2 in Asians), T2DM, or evidence of metabolic dysregulation*
Fatty liver with hepatitisNASH: presence of ≥5% HS with inflammation and hepatocyte injury with or without fibrosis (the traditional dichotomous classification into NASH vs. non-NASH)MAFLD: single overarching term that replaces the current dichotomous stratification into steatohepatitis and nonsteatohepatitis. Moreover, MAFLD encompasses the full spectrum from simple steatosis without inflammation and fibrosis to stage 4 fibrosis.**
Fatty liver with fibrosis/cirrhosisNASH cirrhosis: presence of cirrhosis with current or previous histological evidence of steatohepatitisMAFLD-related cirrhosis: presence of cirrhosis in the absence of typical histology and meets at least one of following criteria: documentation of MAFLD on previous liver biopsy; historical documentation of steatosis by imaging. This term is expected to replace the old term ‘cryptogenic cirrhosis’ in the majority of patients
Details of definitionDefinitive diagnosis requires histology from liver biopsyDiagnosis based on histology from liver biopsy, imaging, or blood biomarker evidence of fat accumulation (hepatic steatosis)
Diagnosis by “exclusion” of other causes, especially alcoholic steatohepatitis (overemphasizes the absence of alcohol use while underemphasizing the importance of the metabolic risk factors)Positive diagnosis, rather than a “none” disease rubric
PathogenesisComplex and multifactorial, involving genetic, epigenetic and environmental factors. The term “non” limits consideration of the clinical and pathological attributes of this complex disease and does not highlight the primary role of metabolic dysfunction in its pathogenesis10Defines by the term of metabolic dysfunction as well as reflects the relevant risk factors for liver disease but no established or explained novel pathogenesis
Other common associated liver diseases“Concurrent disease”: Alcoholic FLD; - Drug-induced FLD; HCV-associated FLD; Other†: Hemochromatosis; Autoimmune hepatitis; Celiac disease; Wilson’s disease; A-/hypo-, betalipoproteinaemia lipoatrophy; Hypopituitarism, hypothyroidism; Starvation, parenteral nutrition; Inborn errors of metabolism“Concomitant disease” (dual etiology of FLD): Alcohol-use disorder; Viral infection (HIV, HBV, and HCV); Autoimmune hepatitis; Inherited liver disorders’ Drug-induced liver injury; Other known liver diseases
Research and drug developmentCurrent endpoints for NASH drug development are fibrosis improvement and resolution of steatohepatitisThe terminology MAFLD, which eliminates the term “steatohepatitis” as a distinguishing subtype and instead based on grade and stage may interfere with the process of the study in phase 2b and 3 trials in novel drug development because these trials have been designed by using the old term NASH, especially outcomes for NASH resolution and regression of fibrosis8

*At least two metabolic risk factors should be present for the definition of metabolic dysregulation: waist circumference ≥102/88 cm in white men and women or ≥90/80 cm in Asian men and women; blood pressure ≥130/85 or specific drug treatment; plasma triglycerides ≥150 mg/dL or specific drug treatment; plasma HDL cholesterol <40 mg/dL (<1.0 mmol/L) for men and <50 mg/dL (<1.3 mmol/L) for women or specific drug treatment; prediabetes (i.e. fasting glucose levels 100–125 mg/dL or 2-h postload glucose levels 140–199 mg/dL or HbA1c 5.7–6.4%; homeostasis model assessment (HOMA) of insulin resistance score ≥2.5; and plasma high-sensitivity C-reactive protein level >2 mg/L.1 ** From a pathological domain, Brunt et al.11 raised concerns regarding the accuracy of this nomenclature and suggested the term “metabolic syndrome steatohepatitis” (MESH) in 2009. MAFLD, Metabolic dysfunction-associated fatty liver disease; NAFLD, nonalcoholic fatty liver disease; NAFL, nonalcoholic fatty liver; NASH, nonalcoholic steatohepatitis; HS, hepatic steatosis; T2DM, type 2 diabetes mellitus; BMI, body mass index; HCV, hepatitis C virus; HBV, hepatitis B virus; HIV, human immunodeficiency virus.

Table 2

Summary of drug agents and benefit in MAFLD

MedicationEASL 2016AASLD 2018APASL 2020
Potential benefitVitamin ENon-DM, ≥F2 non-cirrhosis (liver biopsy-proven cases)Non-DM, non-cirrhosis (liver biopsy-proven cases)Non-DM, non-cirrhosis (liver biopsy-proven cases)
PioglitazoneWith and without DM, ≥F2 (liver biopsy-proven cases)With and without DM, ≥F2 (liver biopsy-proven cases)With and without DM, ≥F2 (liver biopsy-proven cases)
No clear benefitStatinCVD indicationCVD indicationCVD indication
MetforminNoneNoneNone
n-3 polyunsaturated fatty acidsNoneNoneNone
Ursodeoxycholic acidNoneNoneNone
PentoxifyllineNoneNoneNone
Unclear benefitLiraglutide (GLP1 agonist)NonePremature to considerSuggested in T2DM
OCANoneShould not be usedWait for study

DM, diabetes mellitus; F, fibrosis; CVD, cardiovascular disease; GLP, glucagon-like peptide-1; OCA, obeticholic acid.

To date, many novel therapies have been studied in clinical trials for MAFLD patients (20). Due to the controversial pathogenesis of MAFLD, eight classes of new drugs act against different targets (Fig. 1). A summary of the clinical trials of these new drugs is shown in Table 3.

Pharmacological targets of NASH therapy.
Fig. 1  Pharmacological targets of NASH therapy.

FXR, Farnesoid X receptor; PPAR, Peroxisome proliferator-activated receptor; CCR, C-C chemokine receptor; GLP-1, Glucagon-like peptide-1; TSH, Thyroid hormone receptor.

Table 3

Summary of clinical trials of many novel therapies for NASH resolution

MedicationMechanism of actionTrialPhaseTrial IDNASH resolutionDecreased fibrosis
OCAFXR agonist 1st generationFLINT studyIIbNCT01265498NoYes
REGENERATE study (NASH with significant fibrosis)IIINCT02548351NoYes
REVERSE study (NASH with cirrhosis)IIINCT03439254––
CilofexorFXR agonist 2nd generationCilofexor, in patients with noncirrhotic NASHIINCT02854605NoNo
TropifexorFXR agonist 2nd generationFLIGHT-FXR studyIINCT02855164Yes–
TANDEM studyIIbNCT03517540––
ElafibranorPPAR α/δ agonistGOLDEN-505 studyIIbNCT01694849YesNo
RESOLVE-IT studyIIINCT02704403NoNo
LanifibranorPan-PPAR agonistNATIVE studyIIbNCT03008070Yes–
SaroglitazarDual PPAR-α/γ agonistEVIDENCE IV studyIINCT03061721YesNo
LiraglutideGLP-1 receptor agonistLEAN studyIINCT01237119YesYes
SemaglutideGLP-1 receptor agonistSubcutaneous semaglutide in NASHIINCT02970942YesNo
TirzapatideGIP and GLP-1 agonistSYNERGY- NASH studyIIbNCT04166773
CotadutideGlucagon and GLP-1 agonistMEDI0382 in overweight and obese individuals with T2DMIINCT02548585––
ResmetiromTSH β agonistMGL-3196 for NASHIINCT02912260Yes–
MAESTRO-NASH studyIIINCT03900429––
CenicrivirocCCR2/CCR5 antagonistCENTAUR studyIIbNCT02217475NoYes
AURORA studyIIINCT03028740–No
SelonsertibAntifibrotic drugsSTELLAR-3,4 studyIIINCT03053050, NCT03053063NoNo
SimtuzumabAntifibrotic drugsGS-6624 for NASHIIbNCT01672866, NCT01672879NoNo
EmricasanPancaspase inhibitorENCORE-NF studyIINCT02686762NoNo

FXR, Farnesoid X receptor; PPAR, Peroxisome proliferator-activated receptor; GLP-1, Glucagon-like peptide-1; GIP, Glucose-dependent insulinotropic polypeptide; TSH, Thyroid hormone receptor; CCR, C-C chemokine receptor.

Farnesoid X receptor (FXR) agonist

There are two generations of FXR agonists, First-generation is obeticholic acid (OCA) (INT-747) and Second-generation is cilofexor (GS-9674) and tropifexor.

FXR, a key nuclear receptor of lipoprotein metabolism in the liver, is activated by bile acids, which are metabolic signaling molecules assisting lipid absorption, facilitating digestion, and regulating lipid metabolism and inflammation.22 Bile acids activate the FXR receptor, which then inhibits lipogenesis, gluconeogenesis, and the regulation of insulin sensitivity.23,24

A phase IIb RCT including 283 noncirrhotic NASH patients compared OCA and placebo groups for 72 weeks and showed that more patients in the OCA group had improvement in scored liver histology without progression of fibrosis from baseline.25 The frequent adverse event in the OCA group was pruritus (33 patients, 23%), and only one patient had treatment discontinuation. Another concern was significantly increased cholesterol levels within 12 weeks after OCA treatment, which required concomitant statin therapy and returned to baseline after stopping medication. However, the long-term consequences of CVD outcomes regarding OCA need to be explored. In the interim analysis of a phase III study (REGENERATE trial) at 18 months, 931 NASH patients with stage 2–3 fibrosis were randomly assigned to placebo and showed significant fibrosis improvement without NASH deterioration. However, this study failed to show a benefit of OCA in NASH resolution without fibrosis progression. Pruritus of mild to moderate severity was reported as the most common side effect causing the discontinuation of OCA. Early increases in low-density lipoprotein (LDL)-cholesterol were reported with OCA treatment in the first month; however, levels declined close to baseline by month 18.26 Statins were initiated in 380 patients in that study and 159 patients in the 25 mg OCA group, but cardiovascular outcomes were not different between the groups.

A recent phase II study using OCA plus atorvastatin therapy initiated at 4 weeks to ameliorate the elevation of LDL cholesterol from OCA (CONTROL) in 84 biopsies confirmed that NASH patients showed no significant elevation in LDL cholesterol at 8 weeks (27). Currently, OCA is not approved by the USA’s Food and Drug Administration (FDA) and is not recommended to treat MAFLD patients from CPGs of AASLD, EASL, and APASL.

Second-generation: cilofexor (GS-9674), tropifexor (LJN452)

Cilofexor is a potent, selective, nonsteroidal agonist of FXR that predominantly activates intestinal FXR without involvement of the enterohepatic circulation.27 A recent phase II study of cilofexor given at doses of 30/day and 100 mg/day compared with placebo in 140 noncirrhotic NASH patients for 24 weeks showed a significant reduction in hepatic steatosis measured by magnetic resonance imaging-proton density fat fraction and a reduction in serum gamma-glutamyltransferase; however, no significant difference in liver stiffness was reported. The common adverse events were moderate and severe pruritus without significant changes in the lipid profile.28

Another second-generation FXR agonist is tropifexor, a nonsteroidal FXR agonist. An interim analysis of a phase II study (FLIGHT-FXR) in biopsy-proven NASH patients with significant fibrosis (defined as stage 2–3 fibrosis) exhibited significant efficacy of tropifexor in hepatic steatosis reduction at 12 weeks after treatment. However, pruritus and increased blood LDL-cholesterol were still the most common adverse events causing discontinuation.29

Another double-blinded phase IIb RCT (TANDEM) of the combination therapy of tropifexor and cenicriviroc, an antiretroviral agent inhibiting CCR2 and CCR5 receptors, of 200 biopsy-proven NASH patients evaluated the safety and tolerability accompanied by liver fibrosis improvement over a 48-week period.30 The results of the study are expected to be announced soon.

Peroxisome proliferator-activated receptor (PPAR) agonists

PPARs agonists are classified into three groups: 1) PPAR α/δ is elafibranor (GFT505), 2) Pan-PPAR agonist (PPAR-α, PPAR-β/δ, and PPAR-γ) is lanifibranor (IVA337), and 3) Dual agonist of PPAR-α/γ is saroglitazar.

PPARs are ligand-activated transcription factors regulating energy homeostasis, especially lipid and glucose metabolisms.31 The family of PPARs encompasses three subtypes: PPAR-α, PPAR-β/δ, and PPAR-γ. The activation of PPAR-α reduces plasma triglyceride levels. The activation of PPAR-γ promotes insulin sensitization and has a role in lipid storage, whereas the activation of PPAR-β/δ enhances fatty acid metabolism and reveals anti-inflammatory effects by inhibiting inflammatory macrophage phenotypes.32

Elafibranor (GFT505) is the first member of the PPAR-α/PPAR-δ agonist family. A recent multicenter international phase II RCT (GOLDEN-505) in noncirrhotic biopsy-proven NASH patients showed an insignificant difference in NASH resolution without fibrosis progression between the elafibranor and placebo groups at 52 weeks of treatment. However, a post hoc analysis of 234 patients with an NAFLD activity score (NAS) of more than 4 at baseline showed the significant resolution of NASH using a modified definition of response (19% in 120 mg elafibranor group and 9% in placebo, p=0.013).33 An international phase III RCT (RESOLVE-IT, NCT02704403) comparing elafibranor with placebo in NASH patients was terminated early due to insignificant efficacy but without significant adverse events at 72 weeks of treatment.34

Lanifibranor (IVA337) is a pan-PPAR agonist of PPAR-α, PPAR-β/δ, and PPAR-γ. Several preclinical studies have shown that lanifibranor has both antifibrotic and positive metabolic effects.35 A phase IIb study (NATIVE) comparing lanifibranor with placebo in biopsy-proven NASH patients at 24 weeks of treatment demonstrated the efficacy in NASH resolution.36 Lanifibranor achieved the primary endpoint with a statistically significant reduction in steatohepatitis evaluated by the steatosis activity fibrosis histological score without worsening fibrosis. Lanifibranor is the first drug candidate to achieve statistically significant results on the USA FDA and European Medicine Agency (EMA) primary endpoints.37 Thus, outcomes relevant for seeking accelerated approval during future phase III RCTs with a longer duration of follow-up are ongoing.

Saroglitazar is a dual agonist of PPAR-α/γ. From real-world clinical studies in India, saroglitazar had a benefit in reducing transaminase levels and improving liver steatosis determined by noninvasive methods in NASH patients as well as improving lipid and glycemic profiles in patients with diabetes and dyslipidemia.38 A multicenter phase II study (EVIDENCE IV) comparing saroglitazar magnesium with placebo in NASH patients achieved the primary endpoint: improvement of hepatitis from baseline at 16 weeks and improvement of liver fat content measured by magnetic resonance imaging-proton density fat fraction. However, no significant difference in liver stiffness measurement was reported.39,40

Glucagon-like peptide-1 (GLP-1) agonists

GLP-1 agonist has three subclasses; 1) GLP-1 receptor agonist: liraglutide, semaglutide, 2) Dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist: tirzapatide (LY3298176), and 3) Dual glucagon and GLP-1 receptor agonist: cotadutide (MEDI0382).

GLP-1 is a hormone with an incretin effect that stimulates insulin secretion secreted by intestinal cells after a meal, in addition to glucagon suppression. GLP-1 exerts an effect on weight reduction by activating hypothalamic GLP-1 receptors, enhancing satiety and delaying gastric emptying time.41

A multicenter phase II study (LEAN) demonstrated the efficacy of liraglutide (a GLP-1 agonist) in NASH resolution based on the disappearance of hepatocyte ballooning without fibrosis worsening among NASH patients after 48 weeks of treatment. However, this study failed to demonstrate the efficacy of liraglutide in improving lobular inflammation and NAS.42 The hypothesis of liver histologic improvement from liraglutide is probably based upon the synergistic and multifactorial effects from both directing effects on liver histology and indirect effects on weight reduction.

There were additional nonhepatic benefits of liraglutide in the significant reduction of major cardiovascular events, comprising cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, found in a recent RCT involving diabetic patients.43

Semaglutide, another next-generation GLP-1 agonist, has a longer half-life, conferring the advantage of weekly subcutaneous injection. A recent multicenter phase II study in biopsy-proven NASH patients demonstrated that semaglutide had significantly higher efficacy for NASH resolution than placebo. However, there was no significant improvement in fibrosis stage evaluated by liver biopsy at week 72.44 Phase III RCTs to confirm the benefit of semaglutide in NASH resolution without worsening fibrosis are underway.

Tirzapatide (LY3298176) is a dual GIP and GLP-1 agonist. A phase II RCT showed superior glycemic control and weight reduction in tirzepatide compared with dulaglutide (another GLP-1 agonist) or placebo, with good tolerability and acceptable safety profiles.45 A combination of GIP and GLP-1 agonists might offer a new therapeutic option in the treatment of T2DM. A phase IIb study of the efficacy and safety of tirzepatide in NASH patients is ongoing (SYNERGY-NASH, NCT04166773).

Cotadutide is a dual glucagon and GLP-1 agonist. A phase IIb RCT in overweight patients with T2DM showed the efficacy of cotadutide in reducing weight and serum transaminases in comparison with placebo (NCT03235050).46

Thyroid hormone receptor β agonist: resmetirom (MGL-3196)

Thyroid hormone receptor β agonist, highly expressed in hepatocytes, regulates many metabolic pathways, including the reduction of triglyceride and cholesterol levels, improvement of insulin sensitivity, promotion of liver regeneration, and reduction of cell apoptosis. Resmetirom (MGL-3196) is a liver-directed, orally active agonist of the thyroid hormone receptor. A multicenter phase IIb RCT in NASH with fibrosis stages 1-3 demonstrated the efficacy of resmetirom in reducing hepatic steatosis at 12 and 36 weeks compared with placebo.47 The efficacy and safety of resmetirom are currently being studied in a phase III RCT (MAESTRO-NASH) in stage 2–3 fibrosis NASH patients (NCT03900429).

C-C chemokine receptor type 2 (CCR2) and type 5 (CCR5) antagonist: cenicriviroc

CCR2 plays a central role in monocyte and macrophage recruitment and activation at the hepatic injury site. CCR5 promotes the proliferation of collagen-producing activated hepatic stellate cells/myofibroblasts and is associated with fibrosis progression. Cenicriviroc is a dual CCR2/CCR5 antagonist. A recent phase IIb RCT (CENTAUR) showed that cenicriviroc had no efficacy on NASH resolution but improved at least one fibrosis stage at 1 year of treatment but not after 2 years.48 A recent phase III RCT of cenicriviroc in NASH patients (AURORA) was terminated early, due to a lack of benefit based on the part 1 results.49 Currently, there are no approved treatments with agents of this class in NASH patients.

Antifibrotic drugs

Selonsertib (GS-4997) is a selective inhibitor of apoptosis signal-regulating kinase 1 (ASK1). Two phase III studies have investigated the efficacy of selonsertib in NASH patients with bridging fibrosis (STELLAR-3) and compensated cirrhosis (STELLAR-4) over a period of 48 weeks. However, both of them failed to show the efficacy of selonsertib in fibrosis reduction.50

Simtuzumab (GS-6624) is a humanized monoclonal antibody directed against lysyl oxidase-like molecule 2 (LOXL2). LOXL2 is an enzyme that catalyzes the cross-linkage of extracellular matrix components, such as collagen and elastin. Thus, inhibition of LOXL2 by an anti-LOXL2 monoclonal antibody may lead to a reduction in fibrosis. Phase IIb RCTs failed to show the efficacy of simtuzumab in fibrosis reduction in NASH patients with bridging fibrosis or compensated cirrhosis.51

Pancaspase inhibitor: emricasan

Caspases are intracellular proteases regulating apoptotic cell death. Emricasan is an oral irreversible pancaspase inhibitor.52 A phase II RCT failed to show the efficacy of emricasan in fibrosis reduction in NASH patients with fibrosis stages 1–3.53

Natural plant drugs: curcumin

Herbal medicine, formerly whole medicinal plants and unpurified plant extracts, affects several pathogenetic pathways for MAFLD that interfere with hepatic lipogenesis, improving lipid overload, reducing hepatic inflammatory cytokines, and diminishing steatohepatitis. However, some herbal medicines can cause the demotion of hepatocellular endoplasmic reticulum stress as well as enhancement of the insulin signaling pathway.54 Cucurmin, a potential natural plant drug that shows lipid-modifying, antioxidant, and anti-inflammatory effects, has demonstrated potential benefits for MAFLD. The results of a meta-analysis of RCTs showed that curcumin provided favorable lipid profiles, and a relative advantage in liver pathologic improvement but did not reach statistical significance.55

Moreover, many novel monotherapies target different mechanistic approaches, so “combination therapy” is an attractive approach that is currently under investigation. The comprising core drug or ultimate combination will need further studies and outcomes. Because FXR agonists are the most favorable agents, they may be fundamental drugs for combination. Nonetheless, combined possibilities will need additional clinical data composing benefits in NASH as well as safety profiles.

Conclusions

Pharmacological treatment for MAFLD, especially NASH, by definition in clinical trials focuses on NASH resolution and fibrosis improvement. The mainstay treatment for MAFLD remains weight loss through dietary and lifestyle modifications. Regarding current liver-directed pharmacotherapy, CPGs recommend using pioglitazone and vitamin E in select patient groups with significant fibrosis (≥F2 fibrosis) by biopsy-proven cases with or without T2DM. To date, many novel therapies targeting different pathogenetic pathways as well as the combination of different types of targeted pharmacotherapies are currently under investigation. These results provide the hope of effective targeted pharmacology for these patients.

Abbreviations

AASLD: 

American Association for the Study of Liver Diseases

APASL: 

Asian Pacific Association for the Study of the Liver

BMI: 

body mass index

CCR: 

C-C chemokine receptor

CPGs: 

clinical practice guidelines

CVD: 

cardiovascular disease

EASL: 

European Association for the Study of Diabetes

F: 

fibrosis

FXR: 

Farnesoid X receptor

GIP: 

glucose-dependent insulinotropic polypeptide

GLP: 

glucagon-like peptide-1

HBV: 

hepatitis B virus

HCV: 

hepatitis C virus

HIV: 

human immunodeficiency virus

HS: 

hepatic steatosis

LOXL2: 

lysyl oxidase-like molecule 2

MAFLD: 

Metabolic dysfunction-associated fatty liver disease

NAFLD: 

nonalcoholic fatty liver disease

NASH: 

nonalcoholic steatohepatitis

OCA: 

obeticholic acid

PPAR: 

Peroxisome proliferator-activated receptors

RCT: 

randomized controlled trial

T2DM: 

type 2 diabetes mellitus

TSH: 

Thyroid hormone receptor

Declarations

Acknowledgement

This manuscript was supported in English editing from the research team of the Department of Medicine, Faculty of Medicine, Chulalongkorn University.

Funding

Fatty Liver Unit, Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand (grant number 001/2565).

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Conceptualization and study design (TP, PP, ST), data acquisition (TP, ST), initial drafting of the manuscript (TP, ST), critical assessment of the manuscript and provision of intellectual input (TP, PP, ST). All authors approved the final draft.

References

  1. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol 2020;73(1):202-209 View Article PubMed/NCBI
  2. Parthasarathy G, Revelo X, Malhi H. Pathogenesis of nonalcoholic steatohepatitis: an overview. Hepatol Commun 2020;4(4):478-492 View Article PubMed/NCBI
  3. Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol 2019;71(4):793-801 View Article PubMed/NCBI
  4. Chan WK, Treeprasertsuk S, Imajo K, Nakajima A, Seki Y, Kasama K, et al. Clinical features and treatment of nonalcoholic fatty liver disease across the Asia Pacific region-the GO ASIA initiative. Aliment Pharmacol Ther 2018;47(6):816-825 View Article PubMed/NCBI
  5. Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis. J Hepatol 2016;65(3):589-600 View Article PubMed/NCBI
  6. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018;67(1):328-357 View Article PubMed/NCBI
  7. Romero-Gomez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol 2017;67(4):829-846 View Article PubMed/NCBI
  8. Younossi ZM, Rinella ME, Sanyal AJ, Harrison SA, Brunt EM, Goodman Z, et al. From NAFLD to MAFLD: implications of a premature change in terminology. Hepatology 2021;73(3):1194-1198 View Article PubMed/NCBI
  9. Yilmaz Y, Byrne CD, Musso G. A single-letter change in an acronym: signals, reasons, promises, challenges, and steps ahead for moving from NAFLD to MAFLD. Expert Rev Gastroenterol Hepatol 2021;15(4):345-352 View Article PubMed/NCBI
  10. Fouad Y, Waked I, Bollipo S, Gomaa A, Ajlouni Y, Attia D. What’s in a name? renaming ‘NAFLD’ to ‘MAFLD’. Liver Int 2020;40(6):1254-1261 View Article PubMed/NCBI
  11. Brunt EM. What’s in a NAme?. Hepatology 2009;50(3):663-667 View Article PubMed/NCBI
  12. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64(6):1388-1402 View Article PubMed/NCBI
  13. Eslam M, Sarin SK, Wong VW, Fan JG, Kawaguchi T, Ahn SH, et al. The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol Int 2020;14(6):889-919 View Article PubMed/NCBI
  14. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006;355(22):2297-2307 View Article PubMed/NCBI
  15. Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008;135(4):1176-1184 View Article PubMed/NCBI
  16. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362(18):1675-1685 View Article PubMed/NCBI
  17. Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2003;98(11):2485-2490 View Article PubMed/NCBI
  18. Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, et al. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2006;4(12):1537-1543 View Article PubMed/NCBI
  19. Boettcher E, Csako G, Pucino F, Wesley R, Loomba R. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2012;35(1):66-75 View Article PubMed/NCBI
  20. Said A, Akhter A. Meta-analysis of randomized controlled trials of pharmacologic agents in non-alcoholic steatohepatitis. Ann Hepatol 2017;16(4):538-547 View Article PubMed/NCBI
  21. Ando Y, Jou JH. Nonalcoholic fatty liver disease and recent guideline updates. Clin Liver Dis (Hoboken) 2021;17(1):23-28 View Article PubMed/NCBI
  22. van de Wiel SMW, Bijsmans I, van Mil SWC, van de Graaf SFJ. Identification of FDA-approved drugs targeting the Farnesoid X Receptor. Sci Rep 2019;9(1):2193 View Article PubMed/NCBI
  23. Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 2008;48(5):1632-1643 View Article PubMed/NCBI
  24. Wagner M, Zollner G, Trauner M. Nuclear bile acid receptor farnesoid X receptor meets nuclear factor-kappaB: new insights into hepatic inflammation. Hepatology 2008;48(5):1383-1386 View Article PubMed/NCBI
  25. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015;385(9972):956-965 View Article PubMed/NCBI
  26. Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2019;394(10215):2184-2196 View Article PubMed/NCBI
  27. Schwabl P, Hambruch E, Budas GR, Supper P, Burnet M, Liles JT, et al. The non-steroidal FXR agonist cilofexor improves portal hypertension and reduces hepatic fibrosis in a rat NASH model. Biomedicines 2021;9(1):60 View Article PubMed/NCBI
  28. Patel K, Harrison SA, Elkhashab M, Trotter JF, Herring R, Rojter SE, et al. Cilofexor, a nonsteroidal FXR agonist, in patients with noncirrhotic NASH: a phase 2 randomized controlled trial. Hepatology 2020;72(1):58-71 View Article PubMed/NCBI
  29. Lucas KJ, Lopez P, Lawitz E, Sheikh A, Aizenberg D, Hsia S, et al. Tropifexor, a highly potent FXR agonist, produces robust and dose-dependent reductions in hepatic fat and serum alanine aminotransferase in patients with fibrotic NASH after 12 weeks of therapy: FLIGHT-FXR Part C interim results. Dig Liver Dis 2020;52(Suppl 1):E38 View Article PubMed/NCBI
  30. Pedrosa M, Seyedkazemi S, Francque S, Sanyal A, Rinella M, Charlton M, et al. A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: study design of the TANDEM trial. Contemp Clin Trials 2020;88:105889 View Article PubMed/NCBI
  31. Grygiel-Górniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications—a review. Nutr J 2014;13:17 View Article PubMed/NCBI
  32. Tyagi S, Gupta P, Saini AS, Kaushal C, Sharma S. The peroxisome proliferator-activated receptor: a family of nuclear receptors role in various diseases. J Adv Pharm Technol Res 2011;2(4):236-240 View Article PubMed/NCBI
  33. Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016;150(5):1147-1159, e1145 View Article PubMed/NCBI
  34. Phase 3 study to evaluate the efficacy and safety of elafibranor versus placebo in patients with nonalcoholic steatohepatitis (NASH) (RESOLVE-IT). 2020:NCT02704403. View Article PubMed/NCBI
  35. Lefere S, Puengel T, Hundertmark J, Penners C, Frank AK, Guillot A, et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages. J Hepatol 2020;73(4):757-770 View Article PubMed/NCBI
  36. Sven MF, Pierre B, Manal FA, Quentin MA, Elisabetta B, Vlad R, et al. A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: design of the NATIVE study. Contemp Clin Trials 2020;98:106170 View Article PubMed/NCBI
  37. Inventiva announces design of Phase III clinical trial with lanifibranor in NASH. Inventiva 2021, January Available from: https://www.globenewswire.com/news-release/2021/01/05/2153793/0/en/Inventiva-announces-design-of-Phase-III-clinical-trial-with-lanifibranor-in-NASH.html View Article PubMed/NCBI
  38. Kaul U, Parmar D, Manjunath K, Shah M, Parmar K, Patil KP, et al. New dual peroxisome proliferator activated receptor agonist-Saroglitazar in diabetic dyslipidemia and non-alcoholic fatty liver disease: integrated analysis of the real world evidence. Cardiovasc Diabetol 2019;18(1):80 View Article PubMed/NCBI
  39. Siddiqui MS, Idowu MO, Parmar D, Borg BB, Denham D, Loo NM, et al. A phase 2 double blinded, randomized controlled trial of saroglitazar in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2020:S1542-3565(20)31509-3 View Article PubMed/NCBI
  40. Gawrieh S, Noureddin M, Loo N, Mohseni R, Awasty V, Cusi K, et al. Saroglitazar, a PPAR-alpha/gamma agonist, for treatment of nonalcoholic fatty liver disease: a randomized controlled double-blind phase 2 trial. Hepatology 2021 View Article PubMed/NCBI
  41. Aroda VR. A review of GLP-1 receptor agonists: evolution and advancement, through the lens of randomised controlled trials. Diabetes Obes Metab 2018;20(Suppl 1):22-33 View Article PubMed/NCBI
  42. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016;387(10019):679-690 View Article PubMed/NCBI
  43. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375(4):311-322 View Article PubMed/NCBI
  44. Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med 2021;384(12):1113-1124 View Article PubMed/NCBI
  45. Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 2018;392(10160):2180-2193 View Article PubMed/NCBI
  46. Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, Plum-Moerschel L, et al. MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet 2018;391(10140):2607-2618 View Article PubMed/NCBI
  47. Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet 2019;394(10213):2012-2024 View Article PubMed/NCBI
  48. Ratziu V, Sanyal A, Harrison SA, Wong VW, Francque S, Goodman Z, et al. Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study. Hepatology 2020;72(3):892-905 View Article PubMed/NCBI
  49. Anstee QM, Neuschwander-Tetri BA, Wong VW, Abdelmalek MF, Younossi ZM, Yuan J, et al. Cenicriviroc for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis: AURORA phase 3 study design. Contemp Clin Trials 2020;89:105922 View Article PubMed/NCBI
  50. Harrison SA, Wong VW, Okanoue T, Bzowej N, Vuppalanchi R, Younes Z, et al. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials. J Hepatol 2020;73(1):26-39 View Article PubMed/NCBI
  51. Harrison SA, Abdelmalek MF, Caldwell S, Shiffman ML, Diehl AM, Ghalib R, et al. Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis. Gastroenterology 2018;155(4):1140-1153 View Article PubMed/NCBI
  52. Barreyro FJ, Holod S, Finocchietto PV, Camino AM, Aquino JB, Avagnina A, et al. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int 2015;35(3):953-966 View Article PubMed/NCBI
  53. Harrison SA, Goodman Z, Jabbar A, Vemulapalli R, Younes ZH, Freilich B, et al. A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. J Hepatol 2020;72(5):816-827 View Article PubMed/NCBI
  54. Xu Y, Guo W, Zhang C, Chen F, Tan HY, Li S, et al. Herbal medicine in the treatment of non-alcoholic fatty liver diseases-efficacy, action mechanism, and clinical application. Front Pharmacol 2020;11:601 View Article PubMed/NCBI
  55. Zhou J, Chen Y, Yu J, Li T, Lu Z, Chen Y, et al. The efficacy of novel metabolic targeted agents and natural plant drugs for nonalcoholic fatty liver disease treatment: a PRISMA-compliant network meta-analysis of randomized controlled trials. Medicine (Baltimore) 2021;100(12):e24884 View Article PubMed/NCBI

Copyright © 2022 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

Download PDF

Metrics

Article accesses:
10749

Citation

Order Reprints
  • Copyright © 2022 JCTH. All Rights Reserved.
  • Published by Xia & He Publishing Inc.
  • Address: 14090 Southwest Freeway, Suite 300, Sugar Land, Texas 77478, USA
  • Email: service@xiahepublishing.com