The Effects of Sodium-Glucose Cotransporter 2-Inhibitors on Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease or Steatohepatitis and Type 2 Diabetes: A Systematic Review of Randomized Controlled Trials

Type 2 Diabetes Mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are part of metabolic syndrome and share multiple causal associations. Both conditions have an alarmingly increasing incidence and lead to multiple complications, which have an impact on a variety of organs and systems, such as the kidneys, eyes, and nervous and cardiovascular systems, or may cause metabolic disruptions. Sodium-glucose cotransporter 2-inhibitors (SGLT2-i), as an antidiabetic class with well-established cardiovascular benefits, and its class members have also been studied for their presumed effects on steatosis and fibrosis improvement in patients with NAFLD or non-alcoholic steatohepatitis (NASH). The MEDLINE and Cochrane databases were searched for randomized controlled trials examining the efficacy of SGLT2-i on the treatment of NAFLD/NASH in patients with T2DM. Of the originally identified 179 articles, 21 articles were included for final data analysis. Dapagliflozin, empagliflozin, and canagliflozin are some of the most used and studied SGLT2-i agents which have proven efficacy in treating patients with NAFLD/NASH by addressing/targeting different pathophysiological targets/mechanisms: insulin sensitivity improvement, weight loss, especially visceral fat loss, glucotoxicity, and lipotoxicity improvement or even improvement of chronic inflammation. Despite the considerable variability in study duration, sample size, and diagnostic method, the SGLT2-i agents used resulted in improvements in non-invasive markers of steatosis or even fibrosis in patients with T2DM. This systematic review offers encouraging results that place the SGLT2-i class at the top of the therapeutic arsenal for patients diagnosed with T2DM and NAFLD/NASH.


Introduction
The global diabesity epidemic is closely associated with the increasing number of all manifestations of metabolic syndrome (MetS) [1]. Type 2 Diabetes Mellitus (T2DM) is a progressive, metabolic condition with increasing incidence and a pandemic prevalence, becoming a well-known public health problem [2]. Non-alcoholic fatty liver disease (NAFLD) effects on NAFLD/NASH that are partly mediated by hepatocyte GLP-1 receptors [28]. The mechanisms by which SGLT2 inhibitors can improve NAFLD and NASH are shown in Figure 1. insulin resistance, or inhibition of lipogenesis in liver cells [24,25]. SGLT2-i promise im provements in insulin sensitivity via improving glucose toxicity, caloric disposition, an weight loss, reducing the inflammatory response, reducing the oxidative stress, impro ing the beta cell function, and even alpha cell secretagogue effects [26]. Although extr renal expression of SGLT-2 was described in various tissues, the expression of SGLT-2 human hepatocytes still remains unclear [27], in contrast with GLP-1RA, with known be eficial effects on NAFLD/NASH that are partly mediated by hepatocyte GLP-1 recepto [28]. The mechanisms by which SGLT2 inhibitors can improve NAFLD and NASH a shown in Figure 1. tween NAFLD and diseases of the metabolic spectrum (Type 2 Diabetes Mellitus and other comp nents of metabolic syndrome) addresses many potential mechanisms by which SGLT-2 inhibito could act beyond inhibiting SGLT2-mediated renal glucose reabsorption and inducing glycosur Furthermore, NAFLD has been associated with an increased risk for chronic kidney disease a cardiovascular diseases, and SGLT-2i are known for their renoprotective and cardioprotective pro erties. Their different pathophysiological targets/mechanisms include the inhibition of de novo pogenesis, leading to hepatic steatosis and improving oxidative and inflammatory responses, whi directly and indirectly improve insulin sensitivity. Abbreviations: NAFLD: non-alcoholic fatty liv disease, NASH: non-alcoholic steatohepatitis, HCC: hepatocellular carcinoma, SGLT-2i: Sodiu glucose cotransporter-2 inhibitors.
Despite the clear shared metabolic pathways and multiple treatment possibilities, n FDA-approved specific agents are available to specifically target NAFLD/NASH in T2D patients. On the other hand, therapeutic inertia is still an important issue in treating p tients with T2DM [29]; therefore, it is of critical importance to find the best treatment o tion for this category of patients with NAFLD and T2DM, and consequently greater CV burden. Since several treatments, including nutraceuticals, have shown flaws in steatos and fibrosis in patients with NAFLD/NASH and Type 2 Diabetes, we performed a sy tematic review of randomized controlled trials with the use of SGLT-2i. Figure 1. Potential pathophysiological targets/mechanisms of SGLT2 inhibitors. The interplay between NAFLD and diseases of the metabolic spectrum (Type 2 Diabetes Mellitus and other components of metabolic syndrome) addresses many potential mechanisms by which SGLT-2 inhibitors could act beyond inhibiting SGLT2-mediated renal glucose reabsorption and inducing glycosuria. Furthermore, NAFLD has been associated with an increased risk for chronic kidney disease and cardiovascular diseases, and SGLT-2i are known for their renoprotective and cardioprotective properties. Their different pathophysiological targets/mechanisms include the inhibition of de novo lipogenesis, leading to hepatic steatosis and improving oxidative and inflammatory responses, which directly and indirectly improve insulin sensitivity. Abbreviations: NAFLD: non-alcoholic fatty liver disease, NASH: non-alcoholic steatohepatitis, HCC: hepatocellular carcinoma, SGLT-2i: Sodium glucose cotransporter-2 inhibitors.

Materials and Methods
Despite the clear shared metabolic pathways and multiple treatment possibilities, no FDA-approved specific agents are available to specifically target NAFLD/NASH in T2DM patients. On the other hand, therapeutic inertia is still an important issue in treating patients with T2DM [29]; therefore, it is of critical importance to find the best treatment option for this category of patients with NAFLD and T2DM, and consequently greater CVD burden. Since several treatments, including nutraceuticals, have shown flaws in steatosis and fibrosis in patients with NAFLD/NASH and Type 2 Diabetes, we performed a systematic review of randomized controlled trials with the use of SGLT-2i.

Materials and Methods
We developed a reproducible protocol for our study following the recommendations of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for the systematic review protocol checklist [30]. Furthermore, we used the Population, Intervention, Comparison, Outcome and Study Design (PICOS) strategy to guide our study rationale and to carry out a clear, helpful, and systematic literature search. A systematic review of the literature was performed in February 2023 under the CRD42023397432 PROSPERO registration number. We searched the MEDLINE and Cochrane databases for randomized controlled trials that reported the effect of SGLT2 inhibitors on NAFLD/NASH, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement for the conduction of meta-analyses of the observational studies [30].
We included in our systematic review only studies published in English, conducted on humans, with latest access on 25 February 2023. The search terms included: (fatty liver OR NASH OR non-alcoholic steatohepatitis OR NAFLD OR non-alcoholic fatty liver disease OR non-alcoholic) AND (SGLT2-i OR sodium-glucose cotransporter-2 inhibitors OR empagliflozin OR dapagliflozin OR canagliflozin OR ipragliflozin OR luseogliflozin OR tofogliflozin OR licogliflozin AND (randomized controlled-trial OR RCT) AND (type 2 diabetes mellitus OR type 2 DM OR T2DM). Two readers (ICB, TS) reviewed the title and abstract of the selected articles for the determination of inclusion as well as the full text of the selected studies. The included studies were RCTs conducted on non-pregnant adults aged 18 or above and published in peer-reviewed journals published before 25 February 2023. Other included studies were randomized, double-blind, placebo-controlled studies, or active-controlled, parallel-group studies.
Full-text articles were eligible for inclusion if they utilized a SGLT2-inhibitor agent, included NAFLD patients, included recognized NAFLD/NASH tools for diagnosing (imaging, biopsy, and established hepatic steatosis and fibrosis scores), and provided details regarding clinical outcomes (change in hepatic steatosis and lobular inflammation, ballooning, and fibrosis) related to NAFLD. Studies evaluating other causes of liver diseases were excluded. Letters, editorials, conference abstracts, reviews, and commentaries were not included. Only the article with the most comprehensive data was included for multiple publications of the same RCT. The exclusion criteria referred to studies published in other languages than English, and which had no data on alcohol consumption or other liver diseases, such as viral hepatitis B or C.
This systematic review included 21 randomized controlled trials. We used the Newcastle-Ottawa Quality Assessment Scale to evaluate the quality of the trials and we included only studies that scored intermediate (4-6 points) or high (7-9 points) on this scale. Additionally, we used the Cochrane risk-of-bias tool (RoB2 version) to assess the quality of RCTs, and we only included low-risk bias studies.

Literature Search and the Characteristics of the Included Studies
SGLT2 inhibitors have been studied in several randomized controlled clinical trials for their promising effects on improving NAFLD/NASH in patients with T2DM. The literature search resulted in the identification of 179 articles. A total of 40 articles were appropriate for a full review. After excluding studies without a definitive diagnosis of NAFLD with only surrogate liver outcomes, ongoing studies, and studies without relevance to the aim of this article, a total of 21 articles were included for data analysis (Figure 2). Hepatic injury was diagnosed through different methods, from Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) to Fibro-Scan, computed tomography (CT), Positron Emission Tomography-Computed Tomography (PET-CT), bioelectrical impedance, liver proton-magnetic resonance spectroscopy ( 1 H-MRS), different hepatic steatosis or fibrosis scores (FLI, NAFLD score, FIB4, NAFLD fibrosis score), or even liver biopsy.
Most studies included well-controlled T2DM patients, but two studies included p tients with NAFLD, without DM, to explore the impact of this drug class on steatosis a fibrosis, independent from the benefits of improved glucose control [37,38].
The overlap in inclusion criteria of the included studies was substantial, name T2DM, non-pregnant adults, alcohol consumption of less than 10 g/day in women and g/day in men, and DM (except "Effect of Empagliflozin on Liver Steatosis and Fibrosis Patients With Non-Alcoholic Fatty Liver Disease Without Diabetes: A Randomized, Do ble-Blind, Placebo-Controlled Trial" and "Comparison between dapagliflozin and te Most studies included well-controlled T2DM patients, but two studies included patients with NAFLD, without DM, to explore the impact of this drug class on steatosis and fibrosis, independent from the benefits of improved glucose control [37,38]. The overlap in inclusion criteria of the included studies was substantial, namely: T2DM, non-pregnant adults, alcohol consumption of less than 10 g/day in women and 20 g/day in men, and DM (except "Effect of Empagliflozin on Liver Steatosis and Fibrosis in Patients With Non-Alcoholic Fatty Liver Disease Without Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial" and "Comparison between dapagliflozin and teneligliptin in non-alcoholic fatty liver disease patients without type 2 diabetes mellitus: a prospective randomized study"). The exclusion criteria included: liver disease of other etiology, including hepatitis B, hepatitis C, autoimmune hepatitis, drug-induced liver disease, alcohol consumption >20 g per day in women or >30 g in men, advanced renal insufficiency, heart failure class II-IV New York Heart Association (NYHA), and pregnancy.
The significant variability in study duration, population, and/or diagnostic tools is illustrative of the massive scientific interest and the constant need for further research on how the SGLT2-I antidiabetic class can improve hepatic steatosis and even fibrosis in this vulnerable subset of patients.

Dapagliflozin and NAFLD/NASH
Dapagliflozin was studied in several clinical trials and it demonstrated benefits in terms of improving NAFLD (non-alcoholic fatty liver disease) and even NASH, as presented in Table 1.  The trial showed that the administration of dapagliflozin 5 mg/day for 24 weeks led to the improvement of liver steatosis through significant improvement in CAP in the study group, compared to the active-controlled group. Moreover, they discovered that dapagliflozin could prevent the progression of liver fibrosis in patients with T2DM and NAFLD, with baseline fibrosis (LS > 8 kPa). Furthermore, liver stiffness measurement (LSM) showed a strong positive correlation with validated liver fibrosis indexes, such as the FIB-4 index and the NAFLD fibrosis score [20].
Another team of researchers from Japan used computed tomography to assess the comparative effect of dapagliflozin (5 mg/day), glimepiride (0.5-1 mg/day), and pioglitazone (7.5-15 mg/day) on visceral fat loss and liver-to-spleen ratio after 28 weeks. The SGLT2-i agent and the thiazolidinedione had comparable effects on increasing liver-to-spleen ratio, but patients receiving dapagliflozin experienced significant weight loss and visceral fat loss compared to the ones in the glimepiride or pioglitazone groups, respectively [35].
Furthermore, Johansson et al. conducted a 52-week randomized trial in which they compared the effects of dapagliflozin (10 mg/day) plus saxagliptin (5 mg/day) as an add-on to metformin with glimepiride (1, 2, 3, 4 or 6 mg) as an add-on to metformin. Not at all surprisingly, the patients in the first group benefited from a significant reduction in liver fat (PDFF-IRM), visceral fat, and subcutaneous adipose tissue, all measured through MRI [36].
The EFFECT-II (effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in individuals with type 2 diabetes) trial was a randomized placebo-controlled trial that also used MRI-PDFF to assess the liver fat content in patients with NAFLD and T2 diabetes mellitus. The effects of dapagliflozin (10 mg daily) and omega 3 carboxylic acids were investigated on liver fat content, either together or separately. After 12 weeks of treatment, the patients receiving omega 3 (4 g daily) plus dapagliflozin (10 g daily) had the best reduction in liver volume and liver fat content measured by means of PDFF-MRI. Furthermore, dapagliflozin improved fasting and 2 h plasma glucose levels, fasting insulin concentrations, and insulin sensitivity as measured by homeostasis-model-assessmentestimated insulin resistance (HOMA-IR), none of these effects being observed in the omega 3 or placebo groups [39].
Another RCT, with a duration of 8 weeks, demonstrated that dapagliflozin 10 mg/day decreased visceral fat tissue, liver volume, and liver fat content, all measured by means of MRI, and also interleukin-6 and N-terminal prohormone of brain natriuretic peptide levels. However, the study did not find any effect on tissue insulin sensitivity, measured by means of [ 18 F]-fluorodeoxyglucose and positron emission tomography (PET-CT) during a hyper insulin-euglycemic clamp [31].
Other researchers used validated scores and indices based on metabolic and hepatic parameters to diagnose and evaluate the outcome, such as fatty liver index (FLI), the Fibrosis-4 (FIB-4) index, non-alcoholic fatty liver disease (NAFLD) score, or non-alcoholic fatty liver disease fibrosis score (NFS) [33,34]. Gastaldelli et al. demonstrated that the combination of dapagliflozin 10 mg on a daily basis and exenatide 2 mg once a week was more efficient at reducing non-alcoholic steatosis and fibrosis measured by FLI, FIB-4, NAFLD score, and NFS in patients with T2DM than dapagliflozin plus placebo or exenatide plus placebo [33].
On the other hand, EXENDA (The Effects of Combined Dapagliflozin and Exenatide Versus Dapagliflozin and Placebo on Ectopic Lipids in Patients with Uncontrolled Type 2 Diabetes Mellitus) was a randomized controlled trial that demonstrated no additional effects on the reduction of hepatocellular lipids despite better glycemic control in patients with T2DM and NAFLD treated with a combination of dapagliflozin 10 mg on a daily basis and exenatide 2 mg once a week. Unlike the previously mentioned study, this trial was a single-center study with a small population size. MRS was used for diagnosis and follow-up, in addition to validated scores such as FLI, FIB-4, or NFS [40].
A team of researchers from Thailand studied the effect of dapagliflozin 10 mg on a daily basis compared to placebo in reducing intrahepatic lipid content in patients with T2DM. Using computed tomography (CT), they found that patients in the active group had significant reductions in body weight, body fat, and visceral fat/subcutaneous fat ratio, as well in hemoglobin A1c (HbA1c) and alanine aminotransferase (ALT), with no difference in adiponectin, leptin, and tumor necrosis factor (TNF-alfa) levels after 12 weeks of treatment [41].
A phase 3 liver fat MRI understudy of dapagliflozin and saxagliptin (10/5 mg) versus glimepiride (1-6 mg) demonstrated favorable effects on liver fat in addition to improved glucose control and metabolic variables [32].

Empagliflozin and NAFLD/NASH
The E-LIFT (The effects of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Non-alcoholic Fatty Liver Disease) trial was one of the relevant RCTs that studied empagliflozin's effects on liver fat in patients with T2DM. The 50 included patients were randomly assigned to either the empagliflozin group (10 mg daily) or the control one (standard treatment, without empagliflozin) for 20 weeks. The NAFLD-related outcomes were assessed by means of MRI-PDFF. The patients in the empagliflozin group experienced significant reductions in liver fat, despite similar glycemic control [21], as seen in Table 2. A similar RCT, conducted by Kahl et al., demonstrated the effect of empagliflozin (25 mg daily) in reducing liver fat content, measured by means of MRI, promoting weight loss and increasing adiponectin levels, but without improvement in insulin sensitivity [42].
The EMPACEF (The effects of empagliflozin on ectopic fat stores and myocardial energetics in type 2 diabetes) study searched for a beneficial effect of empagliflozin 10 mg on a daily basis for 12 weeks in terms of ectopic fat in high-risk patients with T2DM. The authors discovered that the SGLT2-i agent could decrease liver fat content, but not epicardial adipose tissue (an important metabolic active fat tissue), as they used MRI to measure visceral fat [43]. This is in line with the recent findings of Chehrehgosha et al., who demonstrated in their RCT that empagliflozin 10 mg improved the CAP score and LSM compared to pioglitazone, while significant body weight and abdominal visceral fat reductions were observed only in the empagliflozin group, while both increased in the placebo and pioglitazone groups [44].
The impact of the most frequently studied SGLT-2i empagliflozin 25 mg was compared to ursodeoxycholic acid 250 mg and/or placebo in decreasing liver fat content (LFC). In this study, the use of empagliflozin was associated with improvement in hepatic steatosis as measured by MRI-PDFF [45] at 24 weeks.

Canagliflozin and NAFLD/NASH
Cusi et al. investigated the effect of canagliflozin on hepatic triglyceride content and glucose metabolism in patients with T2DM. In this randomized placebo-controlled group, patients receiving canagliflozin 300 mg daily for 24 weeks experienced an improvement in hepatic insulin sensitivity, along with a decrease in intrahepatic triglyceride content (measured by means of MRS) proportionate to the magnitude of weight loss, compared to the placebo group [46], as seen in Table 3.

Other SGLT2-i and NAFLD/NASH
Other SGLT2-i agents, such as ipragliflozin (50 mg) and luseogliflozin (2.5 mg), demonstrated significant effects in reducing liver fat deposition, measured as liver-to-spleen attenuation ratio on CT, in patients with T2DM [47][48][49]. Both agents were studied for 6 months, with pioglitazone and metformin as comparators and also exerted beneficial effects in terms of weight loss and glycemic control [48,49]. Furthermore, the additive effect of ipragliflozin 50 mg in well-controlled T2DM patients treated with metformin and pioglitazone was demonstrated as reduced hepatic fat content, measured as FLI, CAP, and NAFLD liver fat score. Ipragliflozin add-on therapy also reduced whole-body and abdominal visceral fat [50], as seen in Table 4. Takahashi et al. investigated the effect of ipragliflozin on hepatic outcomes in patients with NAFLD and T2DM. The RCT included 55 patients with NAFLD (diagnosed through liver biopsy) and T2DM. Patients received treatment with ipragliflozin 50 mg on a daily basis of the standard of care treatment (except SGLT-2i, GLP-1 RA, or pioglitazone). More patients in the ipragliflozin group obtained a reduction in ballooning and fibrosis (52.4% vs. 24%, respectively; 57.1% vs. 16%) after 72 weeks of treatment [51].
ToPiND study is an RCT that evaluated the effects of 20 mg tofogliflozin compared to pioglitazone 15-30 mg in patients with T2DM and NAFLD. After 6 months of treatment, patients in both the SGLT2-i group and the thiazolidinedione one had a significant decrease in hepatic steatosis, appreciated by means of MRI-PDFF, with no difference in the FIB-4 index and type IV collagen between baseline and post-treatment in both groups. Interestingly enough, there were no differences between the groups regarding the relative change in hepatic steatosis. Even though tofogliflozin-treated patients experienced body weight loss and the pioglitazone ones had gained weight, all of them had similar changes in terms of hepatic steatosis. Another strength of this trial is the PNLPLA3 and TM6SF2 genotyping use. The researchers did not find any significant difference in allele frequency of PNPLA3 and TM6SF2, respectively, in both groups and the efficacy of the treatment did not undergo any variations in both groups after the stratification dependent on PNLPLA3 and TM6SF2 genotype [52], as it can be observed in Table 5. In a 48-week RCT, tofogliflozin 20 mg on a daily basis led to the improvement of hepatocellular ballooning (p = 0.002), and lobular inflammation (p = 0.003) in 40 T2DM patients with NAFLD, evaluated by means of liver biopsy. Moreover, changes in energy metabolism, inflammation, and fibrosis were correlated with hepatic gene expression in the tofogliflozin group, compared to the glimepiride (0.5 mg daily) group [53].

New Perspectives
Licogliflozin, leading to the inhibition of both sodium-glucose cotransporters 1 and 2, was tested in 107 patients with phenotypic or histologic NASH. After 12 weeks of treatment with licogliflozin 150 mg, they showed a significant 32% placebo-adjusted reduction in serum ALT [54]. The occurrence of diarrhea in 77% of the patients and the fact that the lower 30 mg dose did not reach this primary endpoint make licogliflozin a candidate for combination treatment.

Discussion
Regardless of the established cardiovascular benefits that the SGLT-2i class is known for, there are some precaution measures for this antidiabetic class that clinicians must take into account.
One of the most acknowledged side effects when using SGLT-2i therapy is genitourinary infection [55]. Nevertheless, a recent Korean study demonstrated that genital and urinary tract infections appear to be two-to three-fold more frequent in females and patients over 60 years old [56], emphasizing the need for the rigorous monitoring of these categories.
Another concern for this class of therapy has been acute kidney injury (AKI) after initiation [57], but recent data prove that SGLT-2i class is safe and presents substantial renal protection in patients with T2DM [58,59]. Moreover, canagliflozin has demonstrated significant effects in reducing blood pressure, attributed to the osmotic diuresis this therapy produces [60]. However, the blood pressure reduction may represent an adverse effect in patients with already low intravascular volume, leading to hypotension, with a risk of unsafe falls [61] or representing a considerable factor in SGLT-2i-induced AKI through renal hypoperfusion [57,60].
Another possible adverse event (AE) that was discussed is the risk of ketoacidosis, but the data from a meta-analysis of RCTs prove that SGLT-2i did not increase the risk of ketoacidosis in patients treated with an SGLT-2i agent, compared to other antidiabetic classes [62].
A serious, but rare AE for this class is the risk of bone fracture in patients with T2DM treated with canagliflozin [63]. The CANVAS study revealed that patients treated with canagliflozin had a slightly greater risk of fracture (HR, 1.26; 95% CI, 1.04 to 1.52) than the placebo-treated ones [64].
Clinicians should reflect on the balance between risk and benefits, as well as strictly monitor vulnerable patients, who have been demonstrated to be at risk for these AEs.

Conclusions
The SGLT2-i class has proven benefits in reducing the risk of cardiovascular events and chronic renal impairment in patients with T2DM [65]. Knowing that NAFLD/NASH has been associated with greater risks for CV and chronic kidney disease, it seems that this drug class may address several treatment targets in individuals with T2DM and NAFLD/NASH. Furthermore, the importance of using SGLT2i for patients with NAFLD/NASH and T2DM is reinforced by mechanism research attributing the SGLT-2i class alleviation of insulin resistance, the hallmark of NAFLD [10,66,67].
Hopefully, future, more comprehensive, clinical trials will assess the efficacy, safety, and tolerability of drug candidates and lead to the approval of new pharmaceuticals for NAFLD that can be used in T2DM patients. Taking into consideration the natural evolution of NAFLD, upcoming research should clarify what stage is critical for the treatment initiation, for how long the treatment should be followed for the achievement of the best results, what the optimal dosage is for every agent, and, finally, which agent is the most appropriate for this condition. Further research is needed to clarify whether the proposed beneficial effects of SGLT-2 inhibitors are direct or mediated by body weight reduction and improved glucose control. The promise of their indirect disease-modifying action is being investigated in clinical trials including non-diabetic subjects. Overall, SGLT-2i are effective in managing glycemic control and cardio-renal risks; however, histological analyses are needed to evaluate their role in NAFLD/NASH. Furthermore, head-to-head comparison studies will be needed to consolidate individual SGLT-2i class member benefits.
For the moment, we still have lifestyle measures at our fingertips, one of the least expensive therapeutic interventions [14,68] and the cornerstone of the treatment in patients with NAFLD/NASH with or without T2DM. The present review offers insights for clinicians working with T2DM patients with NAFLD with the hope that it will provide them with the best available treatment option to mitigate their increased cardiovascular risk and possibly offer liver-related benefits.