Review Article

Diabetes and NAFLD: A Synergistic Threat to Metabolic Health

Introduction

Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of liver conditions in which excessive fat accumulates in the liver (steatosis) of individuals who consume little or no alcohol. This spectrum includes nonalcoholic steatohepatitis (NASH), marked by inflammation and liver cell damage, and simple fatty liver (NAFL), which shows minimal or no inflammation or damage. NASH increases the risk of liver failure, cirrhosis, and fibrosis.^1,2 The disease can progress from steatosis to cirrhosis, often with periods of stability or regression.

Clinicians diagnose NAFLD by detecting steatosis in more than 5% of hepatocytes on histology or by measuring liver fat content above 5.6% using proton magnetic resonance spectroscopy (¹H-MRS).³ NAFLD has become a leading cause of hepatocellular carcinoma (HCC) and now ranks among the primary indications for liver transplantation in Western countries.^4,5 Rising obesity rates, particularly in rural areas, along with sedentary lifestyles and poor diets linked to urbanization, have driven this trend.^6,7 The prevalence of NAFLD also increases with age, especially among postmenopausal women.⁸

Treatment primarily aims to reduce cardiovascular (CV) and liver-related mortality. Clinicians monitor intermediate outcomes, such as hepatic fibrosis and steatosis, to track disease progression. Although many individuals with hepatic steatosis remain complication-free, some progress to NASH, which can advance to cirrhosis and HCC.⁹ Early diagnosis and management of diabetes-associated NAFLD play a crucial role in preventing progression and related complications.¹⁰ In 2023, experts revised the NAFLD nomenclature to “metabolic dysfunction-associated steatotic liver disease (MASLD)” to improve awareness and reduce stigma associated with terms like “fatty liver” and “nonalcoholic.”¹¹ However, this review uses term NAFLD, as the American Diabetes Association (ADA) has not yet formally adopted MASLD.

NAFLD often coexists with type 2 diabetes mellitus (T2DM), metabolic syndrome (MetS), obesity, and dyslipidemia.¹ Among patients with MetS, cardiovascular disease remains the leading cause of death in those with NAFLD.¹ Coexisting T2DM and NAFLD significantly raise cardiovascular risk, largely due to atherogenic dyslipidemia marked by high triglycerides, low HDL cholesterol, and small, dense LDL particles.¹² NAFLD severity—including advanced fibrosis, cirrhosis, and HCC—strongly correlates with diabetes, even when liver enzymes remain normal.^13,14

T2DM and NAFLD share a bidirectional, mutually reinforcing relationship: individuals with T2DM have a higher risk of NAFLD, and vice versa. Globally, the incidence of T2DM in individuals with NAFLD reaches 24 cases per 1,000 person-years.¹⁵ Overweight and obese individuals face nearly triple the risk of NAFLD compared to those with normal weight.¹⁶ Common pathophysiological mechanisms, such as obesity, dyslipidemia, and insulin resistance (IR), link these conditions.¹²

Given this close association, clinicians must adopt integrated treatment strategies to manage T2DM and NAFLD together. This review explores the complex interplay between these two metabolic disorders and proposes strategies for their joint prevention and management.

Global prevalence and incidence

According to the National Diabetes Statistics Report released by the Centers for Disease Control and Prevention in 2021, approximately 11.6% of Americans have T2DM, while 38% are affected by prediabetes. The burden of both conditions increases substantially with age: among individuals aged 65 and older, the prevalence of diabetes and prediabetes is reported at 29.2% and 48.8%, respectively. Stratified by ethnicity, the highest prevalence of diagnosed diabetes was observed in American Indian and Alaska Native adults (13.6%), followed by non-Hispanic Black (12.1%), Hispanic (11.7%), non-Hispanic Asian (9.1%), and non-Hispanic White adults (6.9%) (CDC, 2021).¹⁷

Globally, the prevalence of NAFLD continues to rise, particularly among individuals who are overweight or obese. Current estimates indicate that NAFLD affects nearly 38% of the world’s population. A recent meta-analysis reported a global pooled prevalence of 30.05%, with East Asia exhibiting the highest regional prevalence at 32.31%. Notably, NAFLD prevalence has increased by more than 50%, rising from 25.26% during 1990–2006 to 38.20% between 2016–2019. The more advanced and progressive form of the disease, NASH, has a global prevalence ranging from 5% to 7%. However, this figure increases substantially in individuals with T2DM, in whom the prevalence of NASH is estimated at 37%, with approximately 17% affected by advanced liver fibrosis. Additionally, the pooled incidence of NAFLD is estimated at 48.89 cases per 1,000 persons per year, reflecting a 58% increase compared to earlier estimates from 1994–2006. Males tend to exhibit a higher median prevalence of NAFLD than females (40% vs. 26%; P < 0.0001).¹⁸

Association between NAFLD and T2Dm

Cardiovascular risks

Individuals with T2DM who also have NAFLD are at significantly elevated risk for CV complications. Studies indicate that the presence of NAFLD increases the risk of developing CV disease by approximately twofold in individuals with T2DM compared to those without NAFLD.¹⁹ This increased risk is supported by evidence of greater carotid intima-media thickness in patients with NAFLD and T2DM, a surrogate marker of atherosclerosis and predictor of CV events.²⁰ Moreover, these individuals often exhibit elevated coronary artery calcium (CAC) scores, which are indicative of subclinical coronary artery disease and correlate with higher risk of adverse cardiac outcomes.²¹ Additionally, patients often present with early left ventricular diastolic dysfunction, reduced myocardial perfusion, and impaired oxygen delivery to cardiac tissue, all of which contribute to ischemic heart disease.²² These patients also show diminished myocardial high-energy phosphate metabolism, compromising cardiac contractility and overall function.²³

Microvascular complications

Beyond macrovascular disease, NAFLD exacerbates diabetic microvascular complications, such as diabetic retinopathy and chronic kidney disease.²⁴ These pathological changes are driven by a constellation of harmful mediators—pro-inflammatory, procoagulant, and prooxidant molecules—which contribute to systemic IR, atherogenic dyslipidemia, and hepatic secretion of key proteins including retinol-binding protein-4 (RBP-4), fibroblast growth factor-21 (FGF-21), and fetuin-A.²⁵ Notably, fetuin-A impairs insulin signaling by inhibiting insulin receptor tyrosine kinase activity in the liver and skeletal muscle, thereby worsening IR. This contributes to the accelerated onset of microvascular complications in diabetic patients.²⁵

Shared mechanism

Advanced stages of NAFLD—including NASH, liver fibrosis, cirrhosis, and HCC—occur more frequently in T2DM populations.²⁶ Disease progression from simple steatosis to these advanced forms is driven by worsening metabolic dysfunction.²⁷ A predictive model by Bazick et al for diagnosing NASH and advanced fibrosis in NAFLD patients with T2DM achieved 90% specificity and 56.8% sensitivity by integrating BMI, waist circumference, HbA1c, insulin resistance, ferritin, albumin, ALT, and AST.²⁸ Elevated inflammatory markers and hyperinsulinemia further link T2DM to increased HCC risk.²⁹ These associations highlight the importance of reciprocal screening for NAFLD and T2DM. Non-invasive tools like elastography are increasingly valuable for detecting hepatic fibrosis in these patients.³⁰ Although strong associations exist between NAFLD and CV disease, chronic kidney disease, and liver outcomes in T2DM, further research is essential to confirm causality and refine integrated screening and management strategies.

Pathogenesis

NAFLD develops through multiple interacting mechanisms. Excess hepatic lipid accumulates when fatty acid influx from diet, adipose lipolysis, and de novo lipogenesis surpasses disposal via VLDL export and β-oxidation.³¹ Although these pathways initially upregulate to compensate, they eventually fail, leading to hepatocyte lipid retention. Hepatic IR, partly driven by diacylglycerol (DAG)-mediated activation of PKCε, disrupts insulin signaling and aggravates systemic IR in skeletal muscle and adipose tissue.³² Inefficient mitochondrial fat oxidation and toxic lipid intermediates further induce hepatocyte injury, oxidative stress, and cytokine-driven necroinflammation—creating a “lipotoxic” environment that drives progression from simple steatosis to NASH and fibrosis.³³ Figure 1 describes the key risk factors for NAFLD development and progression.

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Figure 1.

Key risk factors for NAFLD development and progression. This figure highlights the primary risk factors linked to the onset and advancement of NAFLD. Abbreviations: NAFLD, Non-alcoholic fatty liver disease; NASH, Non-alcoholic steatohepatitis; ALT, alanine aminotransferase; AST, aspartate aminotransferase; MRI, Magnetic resonance imaging; CT, Computed Tomography

Figure 1.

Key risk factors for NAFLD development and progression. This figure highlights the primary risk factors linked to the onset and advancement of NAFLD. Abbreviations: NAFLD, Non-alcoholic fatty liver disease; NASH, Non-alcoholic steatohepatitis; ALT, alanine aminotransferase; AST, aspartate aminotransferase; MRI, Magnetic resonance imaging; CT, Computed Tomography

Recent findings expand this mechanistic view to include broader metabolic and cardiometabolic implications. For example, a paediatric meta-analysis reported that structured lifestyle interventions and targeted supplementation reduce ALT, AST, BMI, and insulin resistance in children with NAFLD. However, the review also revealed major evidence gaps and heterogeneity in trial design, highlighting the need for more robust studies.³⁴

Clinical presentation and diagnostic approaches

Most patients with NAFLD remain asymptomatic in early stages and report no liver-related symptoms. Hepatomegaly is the most common clinical finding, detected by abdominal palpation. As the disease progresses to NASH or cirrhosis, complications such as portal hypertension become more evident.³⁴ Clinicians should suspect NAFLD in patients with MetS components—obesity, hypertension, hyperglycemia, or dyslipidemia—and hepatic steatosis on imaging. Diagnosis relies on exclusion of other causes like alcohol use or hepatotoxic drugs.^28,34

After identifying NAFLD, clinicians must determine progression to NASH or fibrosis because these increase complication risk and worsen outcomes. Liver biopsy remains the gold standard for differentiating NAFL from NASH, staging fibrosis, and excluding other chronic liver diseases.³⁵ However, its invasiveness, cost, and associated risks—pain, bleeding, and rare complications—limit its routine use.

Non-invasive tools, such as elastography for liver stiffness assessment, now play a key role in fibrosis evaluation.^36,37 Clinicians also use scoring systems like NAFLD Fibrosis Score, FIB-4, and APRI, based on clinical and biochemical data.³⁸ Table 1 summarizes these serum-based markers.

Despite progress, these methods lack the accuracy of biopsy in some cases.³⁹ Current guidelines recommend biopsy for patients with high suspicion of NASH or advanced fibrosis, while non-invasive tests guide evaluation and monitoring in low-risk cases.^40-42 Research is advancing novel tools—biomarkers, metabolomics, and genetic testing—to improve diagnostic precision and enable early risk stratification.⁴³

Current guidance on screening for NAFLD in High-risk patients

There is increasing recognition of the need for early identification of NAFLD, particularly within primary care settings, given its high prevalence and severity in individuals with MetS and T2DM.⁴⁵ Due to the often-silent nature of the disease, a significant proportion of individuals with undiagnosed NAFLD and advanced fibrosis remain in the community. Detecting these cases early is critical, as no pharmacological treatments are currently approved for NAFLD or NASH.⁴⁶ While routine population-based screening remains controversial—primarily due to concerns about cost-effectiveness, test reliability, biopsy-related risks, and the absence of disease-specific therapies—there is growing consensus that targeted screening of high-risk groups (such as individuals over 50 years of age, and those with T2DM or MetS) is important for prognostic assessment, particularly when advanced fibrosis is suspected.^47,48

However, existing clinical guidelines offer divergent recommendations regarding NAFLD screening. The American Association for the Study of Liver Diseases (AASLD) currently discourages routine screening in the general population, irrespective of body mass index (BMI), though it emphasizes the importance of increased awareness among individuals with T2DM.⁴⁸ Similarly, the National Institute for Health and Care Excellence (NICE) in the United Kingdom has not recommended routine screening in its clinical guidelines.³⁴ In contrast, the European Association for the Study of the Liver (EASL), along with the European Association for the Study of Diabetes (EASD) and the European Association for the Study of Obesity (EASO), advocates for targeted screening in individuals with MetS or obesity, particularly those meeting specific risk criteria.⁴⁹ Likewise, regional organizations such as the Asian Pacific Association for the Study of the Liver (APASL) and the Korean Association for the Study of the Liver (KASL) also support risk-based screening strategies.^50,51 Furthermore, screening recommendations vary across professional societies, including those specializing in diabetes, paediatrics, and endocrinology, reflecting ongoing debate and evolving evidence in these subpopulations.^52-54 Figure 2 outlines a proposed protocol for screening and managing NAFLD, incorporating current international recommendations and risk stratification strategies.

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Figure 2.

Proposed protocol for NAFLD screening and management. A stepwise approach for the screening and management of non-alcoholic fatty liver disease (NAFLD) is illustrated. The protocol incorporates initial risk stratification followed by non-invasive assessment using either the Enhanced Liver Fibrosis (ELF) test or vibration-controlled transient elastography (VC-TE). Patients are guided through diagnostic and management pathways based on fibrosis risk, aiming for early identification of advanced liver disease and timely intervention

Figure 2.

Proposed protocol for NAFLD screening and management. A stepwise approach for the screening and management of non-alcoholic fatty liver disease (NAFLD) is illustrated. The protocol incorporates initial risk stratification followed by non-invasive assessment using either the Enhanced Liver Fibrosis (ELF) test or vibration-controlled transient elastography (VC-TE). Patients are guided through diagnostic and management pathways based on fibrosis risk, aiming for early identification of advanced liver disease and timely intervention

Lifestyle and pharmacological approaches in NAFLD management

No anti-diabetic drug currently holds approval for NAFLD treatment. Weight loss and physical activity remain the only consistently effective interventions for improving biochemical markers and histological features—steatosis, inflammation, and fibrosis. Evidence shows physical activity benefits liver health even without significant weight loss,^55,56 but sustained weight reduction offers the greatest improvements.^57,58

RCTs and observational studies confirm that weight loss correlates with better liver biomarkers in NAFLD and NASH.⁵⁹ A ≥ 5% weight loss improves steatosis, while 7–9% reduces inflammation and ballooning. Meaningful fibrosis regression usually requires > 10% reduction.^2,60 Despite proven benefits, maintaining such weight loss remains challenging, especially in obese and insulin-resistant patients.

Because NAFLD and T2DM share epidemiological and metabolic pathways, researchers have explored antidiabetic agents—such as insulin sensitizers, GLP-1 receptor agonists, and SGLT2 inhibitors—for NAFLD treatment. Many show promise in reducing steatosis and inflammation, but large-scale, long-term trials are needed before recommending them clinically.^61-63

Metformin

Metformin, a widely prescribed biguanide for T2DM, reduces hepatic glucose production and improves insulin sensitivity, thereby lowering blood sugar levels without causing weight gain.^64,65 It primarily activates AMP-activated protein kinase (AMPK) in hepatocytes, which suppresses gluconeogenesis and decreases hepatic lipid accumulation.⁶⁶ Additionally, metformin inhibits de novo lipogenesis and promotes fatty acid oxidation, reducing liver fat content.⁶⁷ These actions make metformin effective for glycemic control in T2DM and for addressing metabolic dysfunctions linked to NAFLD and MetS.^68,69

Metformin also modulates gut microbiota by promoting beneficial bacteria and reducing harmful microbes, potentially enhancing gut barrier function and preventing harmful substances from entering the bloodstream—key factors in NAFLD pathogenesis.^68,69 Studies, including those by Mazza et al, indicate that metformin may benefit NAFLD management even in non-diabetic patients, especially when combined with a hypocaloric diet and weight control.⁷⁰

Thiazolidinediones (TZDs)

TZDs primarily manage T2DM by activating peroxisome proliferator-activated receptor-gamma (PPAR-γ) receptors. These nuclear receptors, present in adipose tissue, liver, skeletal muscle, and the gastrointestinal tract, regulate energy balance, lipid storage, and glucose metabolism. By activating PPAR-γ, TZDs promote adipogenesis to lower free fatty acids, improve insulin sensitivity in the liver, adipose tissue, and muscles, enhance glucose uptake in peripheral and splanchnic regions, and reduce hepatic glucose production.^71,72

Troglitazone, the first TZD, improved liver histology in NASH patients but was later withdrawn due to liver toxicity.⁷³ Newer TZDs—pioglitazone and rosiglitazone—remain approved and have not shown a similar risk of hepatotoxicity, even with extensive clinical and post-marketing exposure.⁷⁴ Both agents improve histological and biochemical features of NASH, reinforcing the role of insulin resistance in its pathogenesis.⁷⁵

Pioglitazone

Clinicians recommend pioglitazone, a TZD derivative and PPAR-γ agonist, for T2DM.⁷⁶ At low doses, it reduces inflammation and fibrosis in NAFLD, increases adiponectin, and enhances insulin sensitivity. Pioglitazone improves glucose and lipid metabolism, lowers triglycerides and small, dense LDL, raises HDL, and normalizes free fatty acids, reversing atherogenic dyslipidemia.⁷⁴ Studies show pioglitazone improves liver histology and biochemical markers, while discontinuation worsens NASH.⁷⁷ Mahady et al reported improvements in steatosis, inflammation, ballooning, and fibrosis.⁷⁸

Pioglitazone promotes adipogenesis and can cause weight gain, especially with long-term use.⁷⁹ Meta-analyses confirm higher weight and BMI in non-diabetic patients vs. placebo, consistent with earlier studies.^78-80 Weight gain in diabetic NAFLD patients was not statistically significant and may result from increased fat and fluid retention.⁸¹

Pioglitazone slows progression from prediabetes to T2DM^82,83 and reduces CVD risk in both diabetic and non-diabetic individuals.^83,84 It also slows atherosclerosis, improves diastolic function, and reduces epicardial fat.^85,86 In Sanyal’s trial of 247 non-diabetic NASH patients, vitamin E—but not pioglitazone—showed significant NASH improvement, although both improved LFTs.⁸⁷ Cusi et al observed NASH resolution in 51% of pioglitazone-treated patients vs. 19% placebo (P < 0.001).⁸⁸

Use of pioglitazone in non-diabetic patients is debated. Tang and Ferwana linked long-term use to bladder cancer,^89,90 though Korhonen disputed this claim.⁹¹ Meta-analyses indicate risks of heart failure⁹² and fractures,⁹³ while edema is more common when combined with insulin.

European guidelines (EASL, EASD, EASO) recommend pioglitazone for treating NAFLD in patients with T2DM and occasionally off-label for non-diabetics. In contrast, American (AASLD) and UK (NICE) guidelines restrict its use to diabetic patients with NAFLD.⁹⁴ Recently, the ADA included pioglitazone in its recommendations for drug classes that improve NASH in diabetic patients.⁹⁵

Rosiglitazone

The FDA approved rosiglitazone for T2DM, but Europe withdrew it in 2010 and the U.S. restricted its use in 2011 due to CV safety concerns, despite favourable NAFLD outcomes.⁹⁶ In a single-arm study of 30 NASH patients with impaired glucose tolerance or T2DM, 8 mg/day for 48 weeks resolved NASH in 45% and significantly reduced ALT.⁹⁷ A larger trial of 68 patients showed improved glycemic control and liver enzymes after 24 weeks, with a mean weight gain of 2.6 ± 2.4 kg.⁹⁸

The FLIRT trial reported that rosiglitazone improved steatosis in 47% vs. 16% with placebo and normalized transaminases, but prolonged use did not improve fibrosis and caused weight gain.^99,100 A subsequent study of 135 NASH patients found no significant histological benefit from adding metformin or losartan; metformin slightly reduced weight gain, but not significantly.¹⁰¹ Further FLIRT analysis showed increased hepatic PPARγ and pro-inflammatory gene expression, raising safety concerns.¹⁰² These findings, combined with CV risk and weight gain, limit rosiglitazone’s role in NAFLD management.

Lobeglitazone

Lobeglitazone, a newer TZD and dual PPARγ/partial PPARα agonist, is marketed in Korea as Duvie® for diabetes.¹⁰³ In a mouse model of diet-induced NAFLD, 4 weeks of lobeglitazone improved glucose regulation, steatosis, and lipid levels by upregulating fatty acid β-oxidation genes and downregulating lipogenesis and gluconeogenesis genes.¹⁰⁴ Human data are limited. In a single-arm trial of 50 T2DM patients with NAFLD (CAP > 250 dB/m), 0.5 mg lobeglitazone for 24 weeks modestly but significantly reduced steatosis, improved glycemic control, and decreased atherogenic dyslipidemia.¹⁰⁵

Sodium–glucose linked transporter-2 (SGLT2) inhibitors

SGLT2 inhibitors improve NAFLD via multiple mechanisms: better glycemic control, reduced visceral fat, increased adiponectin, lower uric acid, reduced oxidative stress and inflammation, and weight loss. They also provide cardiorenal protection.¹⁰⁶ These agents block renal glucose reabsorption, causing glycosuria, and are effective in heart failure and CKD, even without diabetes.¹⁰⁷ They improve mitochondrial function and increase β-hydroxybutyrate levels but carry risks of genitourinary infections and rare ketoacidosis.¹⁰⁶ Studies show SGLT2 inhibitors lower AST more effectively than pioglitazone, though their advantage over GLP-1 RAs is not significant.¹⁰⁸ GLP-1 RAs remain effective but limited by GI side effects and injection requirements.

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

GLP-1 RAs reduce major adverse cardiovascular events (MACEs) and slow kidney disease progression in T2DM.¹⁰⁹ These agents improve insulin sensitivity, suppress hepatic glucose production, and reduce hepatic fat via decreased lipogenesis and increased fatty acid oxidation.^110,111 They also promote weight loss and are approved for obesity treatment.¹¹² FDA-approved agents include exenatide, lixisenatide, liraglutide, semaglutide, dulaglutide, and albiglutide, administered daily or weekly.¹¹³ Long-term use lowers HbA1c by 0.8–1.9%, with long-acting forms offering superior glycemic control.^114,115

Liraglutide is the most studied GLP-1 RA for NAFLD. It improves insulin sensitivity, reduces liver fat, and lowers fibrosis risk (3.1% vs. 6.1%) in T2DM patients.¹¹⁶ A Phase II trial showed daily 1.8 mg liraglutide for 48 weeks improved histology and resolved NASH in 39% vs. 9% with placebo (P= 0.019).¹¹⁷

Semaglutide demonstrated safety and improved glycemic control in compensated NASH cirrhosis but did not significantly improve fibrosis after 48 weeks. Non-invasive measures and MRI-PDFF showed fat reduction.¹¹⁸

Tirzepatide, a dual GIP/GLP-1 agonist, reduced liver fat in the SURPASS-3 substudy across all doses.¹¹⁹

α-Glucosidase inhibitors

Agents like acarbose, miglitol, and voglibose slow carbohydrate digestion and modestly lower glucose but have limited NAFLD data.¹²⁰ A 24-week mouse study combining ezetimibe and acarbose improved histology.¹²¹ In a human trial of 17 T2DM patients with NASH, miglitol (150 mg/day, 12 months) reduced BMI, ALT, and improved steatosis and inflammation, but not fibrosis or ballooning.¹²² Acarbose appears safe in cirrhosis^123,124 and reduces CV events and hypertension in prediabetes,¹²⁵ though it can mildly raise ALT and, rarely, cause hepatotoxicity.¹²⁶

Recent evidences and pipeline studies

Recent evidence strengthens the role of IR and metabolic dysfunction in NAFLD and highlights its bidirectional relationship with T2DM. Oh et al reported that NAFLD independently increases the risk of heart failure and CV mortality in T2DM patients.¹²⁷ Zhang et al identified triglyceride-glucose (TyG) indices—especially TyG-WWI—as strong predictors of all-cause and CV mortality in MASLD with diabetes or prediabetes.¹²⁸ Novel biomarkers, including the TG/APOA1 ratio¹²⁹ and TyG-BMI index,¹³⁰ show superior diagnostic value for detecting NAFLD in T2DM patients. Nontraditional lipid markers, such as the atherogenic index of plasma (AIP) and residual cholesterol (RC), outperform traditional lipid panels in predicting abnormal glucose metabolism.¹³¹ Wu et al also linked elevated thyroid autoantibodies to a higher risk of NAFLD in T2DM.¹³² In paediatric NAFLD, lifestyle changes and nutritional supplements significantly improved liver enzymes and insulin resistance, emphasizing early intervention benefits.¹³³ Collectively, these findings underscore the metabolic and cardiovascular impact of NAFLD and the need for early detection and integrated care.

In March 2024, the US FDA approved resmetirom as the first drug specifically for NAFLD treatment.¹³⁴ Previously, no FDA-approved therapy existed for NAFLD, including antidiabetic agents. Although clinicians frequently used drugs like metformin, thiazolidinediones, SGLT2 inhibitors, and GLP-1 RAs off-label to manage metabolic dysfunction in NAFLD, none held official approval for this indication. Numerous studies remain ongoing, and over 10 active trials are investigating antidiabetic drugs for NAFLD treatment (Supplementary file 1, Table S1).¹³⁵

Several clinical trials aim to identify effective treatments for NAFLD and NASH. A trial measuring hepatic mitochondrial fluxes will compare pioglitazone to placebo, with results expected by March 2027.¹³⁶ AIM 2 is testing low-dose pioglitazone in NASH, with completion anticipated in August 2027.¹³⁷ Another study is evaluating efinopegdutide versus Semaglutide and placebo in precirrhotic NASH, with results expected in February 2026.¹³⁸ The WAYFIND trial is assessing semaglutide combined with cilofexor and firsocostat in cirrhotic NASH patients, reporting in December 2024.¹³⁹ Additional trials with dapagliflozin, bempedoic acid, and henagliflozin are underway, with completion dates between December 2024 and November 2026.^140-142 Upcoming trials will also compare empagliflozin with pioglitazone in non-diabetic NASH and examine SGLT2 inhibitors in MASLD, both launching later in 2024.¹⁴³ These studies reflect a comprehensive effort to develop targeted therapies for NAFLD and NASH across different disease stages.

Table S2 summarizes key studies on pioglitazone in NAFLD.

Challenges and future directions

Managing NAFLD and T2DM remains challenging despite increasing recognition of their interconnection. Clinicians often miss NAFLD in T2DM patients because it typically remains asymptomatic until advanced stages. The lack of standardized screening protocols further complicates detection and management. Current pharmacological options—metformin, thiazolidinediones, SGLT2 inhibitors, and GLP-1 RAs—show promise but do not fully address NAFLD pathogenesis and exhibit inconsistent efficacy. Researchers must also clarify the long-term safety and potential adverse effects of these drugs across diverse populations.

This review has limitations. Included studies vary widely in design, sample size, and diagnostic criteria, limiting comparability and generalizability. Long-term outcomes, such as fibrosis regression and cardiovascular risk reduction, remain underexplored due to short follow-up durations. Most pharmacological evidence relies on off-label use and preliminary findings rather than robust, large-scale randomized controlled trials. Additionally, publication bias and the exclusion of unpublished or ongoing trial data may have influenced the completeness of this review.

Future research should focus on developing precise diagnostic tools and early-stage biomarkers, especially for T2DM patients. Personalized medicine approaches using genetic, epigenetic, and metabolic profiling could enable tailored therapies. Large-scale, long-term clinical trials are essential to confirm the safety and efficacy of both existing and emerging treatments. Integrating lifestyle interventions such as dietary modifications and physical activity with pharmacotherapy offers additional benefits. Progress will require close collaboration among endocrinologists, hepatologists, and primary care providers. Ultimately, a multidisciplinary approach and sustained research are critical to reducing the global burden of NAFLD and T2DM.

Conclusion

NAFLD and T2DM are closely linked metabolic disorders that demand a unified, comprehensive management approach. There is an urgent need to raise awareness, promote early detection, and implement evidence-based strategies to alleviate the burden of these comorbidities. A holistic approach that considers the complex relationship between NAFLD and T2DM can help healthcare providers improve patient outcomes and reduce the societal impact of these growing public health challenges. Due to its asymptomatic nature, NAFLD often remains undiagnosed. Early screening and risk stratification are essential to prevent progression to advanced liver disease.

Competing Interests

The authors declare that they have no competing interests.

Ethical Approval

Not applicable.

Supplementary Files

References

1. Marchesini G, Day CP, Dufour JF, Canbay A, Nobili V, Ratziu V. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016; 64(6):1388-402. doi: 10.1016/j.jhep.2015.11.004 [Crossref] [ Google Scholar]
2. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M. 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):328-57. doi: 10.1002/hep.29367 [Crossref] [ Google Scholar]
3. Bugianesi E. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease: disease mongering or call to action?. Diabetologia 2016; 59(6):1145-7. doi: 10.1007/s00125-016-3930-7 [Crossref] [ Google Scholar]
4. Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol 2015; 62(1 Suppl):S47-64. doi: 10.1016/j.jhep.2014.12.012 [Crossref] [ Google Scholar]
5. Younossi Z, Stepanova M, Ong JP, Jacobson IM, Bugianesi E, Duseja A, et al. Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates. Clin Gastroenterol Hepatol 2019;17(4):748-55.e3. doi: 10.1016/j.cgh.2018.05.057.
6. Zhang X, Goh GB, Chan WK, Wong GL, Fan JG, Seto WK. Unhealthy lifestyle habits and physical inactivity among Asian patients with non-alcoholic fatty liver disease. Liver Int 2020; 40(11):2719-31. doi: 10.1111/liv.14638 [Crossref] [ Google Scholar]
7. Wong VW, Ekstedt M, Wong GL, Hagström H. Changing epidemiology, global trends and implications for outcomes of NAFLD. J Hepatol 2023; 79(3):842-52. doi: 10.1016/j.jhep.2023.04.036 [Crossref] [ Google Scholar]
8. Wang W, Chen J, Wang Z, Chen J, Cheng W, Zhou Z. An estimation model of urban land accessibility. Int J Environ Res Public Health 2021; 18(3):1258. doi: 10.3390/ijerph18031258 [Crossref] [ Google Scholar]
9. Mehta SR. Advances in the treatment of nonalcoholic fatty liver disease. Ther Adv Endocrinol Metab 2010; 1(3):101-15. doi: 10.1177/2042018810379587 [Crossref] [ Google Scholar]
10. Khandelwal R, Dassanayake AS, Conjeevaram HS, Singh SP. Non-alcoholic fatty liver disease in diabetes: when to refer to the hepatologist?. World J Diabetes 2021; 12(9):1479-93. doi: 10.4239/wjd.v12.i9.1479 [Crossref] [ Google Scholar]
11. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Hepatology 2023; 78(6):1966-86. doi: 10.1097/hep.0000000000000520 [Crossref] [ Google Scholar]
12. Bril F, Cusi K. Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: a call to action. Diabetes Care 2017; 40(3):419-30. doi: 10.2337/dc16-1787 [Crossref] [ Google Scholar]
13. Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013; 10(6):330-44. doi: 10.1038/nrgastro.2013.41 [Crossref] [ Google Scholar]
14. Golabi P, Otgonsuren M, de Avila L, Sayiner M, Rafiq N, Younossi ZM. Components of metabolic syndrome increase the risk of mortality in nonalcoholic fatty liver disease (NAFLD). Medicine (Baltimore) 2018; 97(13):e0214. doi: 10.1097/md.0000000000010214 [Crossref] [ Google Scholar]
15. Cao L, An Y, Liu H, Jiang J, Liu W, Zhou Y. Global epidemiology of type 2 diabetes in patients with NAFLD or MAFLD: a systematic review and meta-analysis. BMC Med 2024; 22(1):101. doi: 10.1186/s12916-024-03315-0 [Crossref] [ Google Scholar]
16. Younossi ZM, Henry L. Understanding the burden of nonalcoholic fatty liver disease: time for action. Diabetes Spectr 2024; 37(1):9-19. doi: 10.2337/dsi23-0010 [Crossref] [ Google Scholar]
17. Centers for Disease Control and Prevention (CDC). National Diabetes Statistics Report. CDC; 2023. Available from: https://www.cdc.gov/diabetes/data/statistics-report/index.html.
18. Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology 2023; 77(4):1335-47. doi: 10.1097/hep.0000000000000004 [Crossref] [ Google Scholar]
19. Ruan S, Yuan X, Liu J, Zhang Q, Ye X. Predictors of high cardiovascular risk among nonobese patients with type 2 diabetes and non-alcoholic fatty liver disease in a Chinese population. Diabetes MetabSyndrObes 2024; 17:493-506. doi: 10.2147/dmso.S441641 [Crossref] [ Google Scholar]
20. Shabbirhussain BV, Singh S, Dixit VK, Verma A, Singh SK. Carotid intima media as predictor of liver fibrosis in type 2 diabetes mellitus with NAFLD. Diabetes MetabSyndr 2022; 16(7):102560. doi: 10.1016/j.dsx.2022.102560 [Crossref] [ Google Scholar]
21. Kwak MS, Yim JY, Kim D, Park MJ, Lim SH, Yang JI. Nonalcoholic fatty liver disease is associated with coronary artery calcium score in diabetes patients with higher HbA1c. DiabetolMetabSyndr 2015; 7:28. doi: 10.1186/s13098-015-0025-4 [Crossref] [ Google Scholar]
22. Wang S, Zhang X, Zhang Q, Zhang B, Zhao L. Is non-alcoholic fatty liver disease a sign of left ventricular diastolic dysfunction in patients with type 2 diabetes mellitus? A systematic review and meta-analysis. BMJ Open Diabetes Res Care 2023; 11(1):e003198. doi: 10.1136/bmjdrc-2022-003198 [Crossref] [ Google Scholar]
23. Rijzewijk LJ, Jonker JT, van der Meer RW, Lubberink M, de Jong HW, Romijn JA. Effects of hepatic triglyceride content on myocardial metabolism in type 2 diabetes. J Am Coll Cardiol 2010; 56(3):225-33. doi: 10.1016/j.jacc.2010.02.049 [Crossref] [ Google Scholar]
24. Targher G, Lonardo A, Byrne CD. Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus. Nat Rev Endocrinol 2018; 14(2):99-114. doi: 10.1038/nrendo.2017.173 [Crossref] [ Google Scholar]
25. Ix JH, Sharma K. Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK. J Am Soc Nephrol 2010; 21(3):406-12. doi: 10.1681/asn.2009080820 [Crossref] [ Google Scholar]
26. Anstee QM, McPherson S, Day CP. How big a problem is non-alcoholic fatty liver disease?. BMJ 2011; 343:d3897. doi: 10.1136/bmj.d3897 [Crossref] [ Google Scholar]
27. Pais R, Charlotte F, Fedchuk L, Bedossa P, Lebray P, Poynard T. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol 2013; 59(3):550-6. doi: 10.1016/j.jhep.2013.04.027 [Crossref] [ Google Scholar]
28. Bazick J, Donithan M, Neuschwander-Tetri BA, Kleiner D, Brunt EM, Wilson L. Clinical model for NASH and advanced fibrosis in adult patients with diabetes and NAFLD: guidelines for referral in NAFLD. Diabetes Care 2015; 38(7):1347-55. doi: 10.2337/dc14-1239 [Crossref] [ Google Scholar]
29. Aleksandrova K, Boeing H, Nöthlings U, Jenab M, Fedirko V, Kaaks R. Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer. Hepatology 2014; 60(3):858-71. doi: 10.1002/hep.27016 [Crossref] [ Google Scholar]
30. Constantinescu C, Săndulescu L, Săftoiu A. The role of elastography in non-alcoholic fatty liver disease. Curr Health Sci J 2020; 46(3):255-69. doi: 10.12865/chsj.46.03.07 [Crossref] [ Google Scholar]
31. Petersen MC, Shulman GI. Roles of diacylglycerols and ceramides in hepatic insulin resistance. Trends Pharmacol Sci 2017; 38(7):649-65. doi: 10.1016/j.tips.2017.04.004 [Crossref] [ Google Scholar]
32. Zhang CH, Zhou BG, Sheng JQ, Chen Y, Cao YQ, Chen C. Molecular mechanisms of hepatic insulin resistance in nonalcoholic fatty liver disease and potential treatment strategies. Pharmacol Res 2020; 159:104984. doi: 10.1016/j.phrs.2020.104984 [Crossref] [ Google Scholar]
33. du Plessis J, van Pelt J, Korf H, Mathieu C, van der Schueren B, Lannoo M, et al. Association of adipose tissue inflammation with histologic severity of nonalcoholic fatty liver disease. Gastroenterology 2015;149(3):635-48.e14. doi: 10.1053/j.gastro.2015.05.044.
34. Glen J, Floros L, Day C, Pryke R. Non-alcoholic fatty liver disease (NAFLD): summary of NICE guidance. BMJ 2016; 354:i4428. doi: 10.1136/bmj.i4428 [Crossref] [ Google Scholar]
35. Forlano R, Sigon G, Mullish BH, Yee M, Manousou P. Screening for NAFLD-current knowledge and challenges. Metabolites 2023; 13(4):536. doi: 10.3390/metabo13040536 [Crossref] [ Google Scholar]
36. Neuberger J, Patel J, Caldwell H, Davies S, Hebditch V, Hollywood C. Guidelines on the use of liver biopsy in clinical practice from the British Society of Gastroenterology, the Royal College of Radiologists and the Royal College of Pathology. Gut 2020; 69(8):1382-403. doi: 10.1136/gutjnl-2020-321299 [Crossref] [ Google Scholar]
37. Rinaldi L, Giorgione C, Mormone A, Esposito F, Rinaldi M, Berretta M, et al. Non-invasive measurement of hepatic fibrosis by transient elastography: a narrative review. Viruses 2023;15(8). doi: 10.3390/v15081730.
38. Zain SM, Tan HL, Mohamed Z, Chan WK, Mahadeva S, Basu RC. Use of simple scoring systems for a public health approach in the management of non-alcoholic fatty liver disease patients. JGH Open 2020; 4(6):1155-61. doi: 10.1002/jgh3.12414 [Crossref] [ Google Scholar]
39. Sumida Y, Nakajima A, Itoh Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol 2014; 20(2):475-85. doi: 10.3748/wjg.v20.i2.475 [Crossref] [ Google Scholar]
40. Spengler EK, Loomba R. Recommendations for diagnosis, referral for liver biopsy, and treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mayo Clin Proc 2015; 90(9):1233-46. doi: 10.1016/j.mayocp.2015.06.013 [Crossref] [ Google Scholar]
41. Neuberger J, Cain O. The need for alternatives to liver biopsies: non-invasive analytics and diagnostics. Hepat Med 2021; 13:59-69. doi: 10.2147/hmer.S278076 [Crossref] [ Google Scholar]
42. Lai JC, Liang LY, Wong GL. Noninvasive tests for liver fibrosis in 2024: are there different scales for different diseases?. Gastroenterol Rep (Oxf) 2024; 12:goae024. doi: 10.1093/gastro/goae024 [Crossref] [ Google Scholar]
43. Piazzolla VA, Mangia A. Noninvasive diagnosis of NAFLD and NASH. Cells 2020; 9(4):1005. doi: 10.3390/cells9041005 [Crossref] [ Google Scholar]
44. Ahn SB. Noninvasive serum biomarkers for liver steatosis in nonalcoholic fatty liver disease: current and future developments. Clin Mol Hepatol 2023; 29(Suppl):S150-6. doi: 10.3350/cmh.2022.0362 [Crossref] [ Google Scholar]
45. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update. J Hepatol 2021;75(3):659-89. doi: 10.1016/j.jhep.2021.05.025
46. Vieira Barbosa J, Lai M. Nonalcoholic fatty liver disease screening in type 2 diabetes mellitus patients in the primary care setting. Hepatol Commun 2021; 5(2):158-67. doi: 10.1002/hep4.1618 [Crossref] [ Google Scholar]
47. Byrne CD, Targher G. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease: is universal screening appropriate?. Diabetologia 2016; 59(6):1141-4. doi: 10.1007/s00125-016-3910-y [Crossref] [ Google Scholar]
48. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012; 142(7):1592-609. doi: 10.1053/j.gastro.2012.04.001 [Crossref] [ Google Scholar]
49. Neuschwander-Tetri BA. Pharmacologic management of nonalcoholic steatohepatitis. Gastroenterol Hepatol (N Y) 2018; 14(10):582-9. [ Google Scholar]
50. Eslam M, Sarin SK, Wong VW, Fan JG, Kawaguchi T, Ahn SH. 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. doi: 10.1007/s12072-020-10094-2 [Crossref] [ Google Scholar]
51. Kang SH, Lee HW, Yoo JJ, Cho Y, Kim SU, Lee TH. KASL Clinical Practice Guidelines: management of nonalcoholic fatty liver disease. Clin Mol Hepatol 2021; 27(3):363-401. doi: 10.3350/cmh.2021.0178 [Crossref] [ Google Scholar]
52. Estrada E, Eneli I, Hampl S, Mietus-Snyder M, Mirza N, Rhodes E. Children’s Hospital Association consensus statements for comorbidities of childhood obesity. Child Obes 2014; 10(4):304-17. doi: 10.1089/chi.2013.0120 [Crossref] [ Google Scholar]
53. McPherson S, Armstrong MJ, Cobbold JF, Corless L, Anstee QM, Aspinall RJ. Quality standards for the management of non-alcoholic fatty liver disease (NAFLD): consensus recommendations from the British Association for the Study of the Liver and British Society of Gastroenterology NAFLD Special Interest Group. Lancet Gastroenterol Hepatol 2022; 7(8):755-69. doi: 10.1016/s2468-1253(22)00061-9 [Crossref] [ Google Scholar]
54. Vos MB, Abrams SH, Barlow SE, Caprio S, Daniels SR, Kohli R. NASPGHAN clinical practice guideline for the diagnosis and treatment of nonalcoholic fatty liver disease in children: recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr 2017; 64(2):319-34. doi: 10.1097/mpg.0000000000001482 [Crossref] [ Google Scholar]
55. Houghton D, Thoma C, Hallsworth K, Cassidy S, Hardy T, Burt AD, et al. Exercise reduces liver lipids and visceral adiposity in patients with nonalcoholic steatohepatitis in a randomized controlled trial. Clin Gastroenterol Hepatol 2017;15(1):96-102.e3. doi: 10.1016/j.cgh.2016.07.031.
56. Ratziu V. Non-pharmacological interventions in non-alcoholic fatty liver disease patients. Liver Int 2017; 37 Suppl 1:90-6. doi: 10.1111/liv.13311 [Crossref] [ Google Scholar]
57. Glass LM, Dickson RC, Anderson JC, Suriawinata AA, Putra J, Berk BS. Total body weight loss of ≥ 10 % is associated with improved hepatic fibrosis in patients with nonalcoholic steatohepatitis. Dig Dis Sci 2015; 60(4):1024-30. doi: 10.1007/s10620-014-3380-3 [Crossref] [ Google Scholar]
58. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015;149(2):367-78.e5. doi: 10.1053/j.gastro.2015.04.005.
59. Koutoukidis DA, Astbury NM, Tudor KE, Morris E, Henry JA, Noreik M. Association of weight loss interventions with changes in biomarkers of nonalcoholic fatty liver disease: a systematic review and meta-analysis. JAMA Intern Med 2019; 179(9):1262-71. doi: 10.1001/jamainternmed.2019.2248 [Crossref] [ Google Scholar]
60. Bischoff SC, Bernal W, Dasarathy S, Merli M, Plank LD, Schütz T. ESPEN practical guideline: clinical nutrition in liver disease. Clin Nutr 2020; 39(12):3533-62. doi: 10.1016/j.clnu.2020.09.001 [Crossref] [ Google Scholar]
61. Budd J, Cusi K. Role of agents for the treatment of diabetes in the management of nonalcoholic fatty liver disease. Curr Diab Rep 2020; 20(11):59. doi: 10.1007/s11892-020-01349-1 [Crossref] [ Google Scholar]
62. Gastaldelli A, Cusi K. From NASH to diabetes and from diabetes to NASH: mechanisms and treatment options. JHEP Rep 2019; 1(4):312-28. doi: 10.1016/j.jhepr.2019.07.002 [Crossref] [ Google Scholar]
63. Ong Lopez AM, Pajimna JA. Efficacy of sodium glucose cotransporter 2 inhibitors on hepatic fibrosis and steatosis in non-alcoholic fatty liver disease: an updated systematic review and meta-analysis. Sci Rep 2024; 14(1):2122. doi: 10.1038/s41598-024-52603-5 [Crossref] [ Google Scholar]
64. Flory J, Lipska K. Metformin in 2019. JAMA 2019; 321(19):1926-7. doi: 10.1001/jama.2019.3805 [Crossref] [ Google Scholar]
65. American Diabetes Association. 9 Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2021. Diabetes Care 2021; 44(Suppl 1):S111-24. doi: 10.2337/dc21-S009 [Crossref] [ Google Scholar]
66. Pinyopornpanish K, Leerapun A, Pinyopornpanish K, Chattipakorn N. Effects of metformin on hepatic steatosis in adults with nonalcoholic fatty liver disease and diabetes: insights from the cellular to patient levels. Gut Liver 2021; 15(6):827-40. doi: 10.5009/gnl20367 [Crossref] [ Google Scholar]
67. Lin HV, Accili D. Hormonal regulation of hepatic glucose production in health and disease. Cell Metab 2011; 14(1):9-19. doi: 10.1016/j.cmet.2011.06.003 [Crossref] [ Google Scholar]
68. Brandt A, Hernández-Arriaga A, Kehm R, Sánchez V, Jin CJ, Nier A. Metformin attenuates the onset of non-alcoholic fatty liver disease and affects intestinal microbiota and barrier in small intestine. Sci Rep 2019; 9(1):6668. doi: 10.1038/s41598-019-43228-0 [Crossref] [ Google Scholar]
69. Matafome P, Louro T, Rodrigues L, Crisóstomo J, Nunes E, Amaral C. Metformin and atorvastatin combination further protect the liver in type 2 diabetes with hyperlipidaemia. Diabetes Metab Res Rev 2011; 27(1):54-62. doi: 10.1002/dmrr.1157 [Crossref] [ Google Scholar]
70. Mazza A, Fruci B, Garinis GA, Giuliano S, Malaguarnera R, Belfiore A. The role of metformin in the management of NAFLD. Exp Diabetes Res 2012; 2012:716404. doi: 10.1155/2012/716404 [Crossref] [ Google Scholar]
71. Francque S, Szabo G, Abdelmalek MF, Byrne CD, Cusi K, Dufour JF. Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors. Nat Rev Gastroenterol Hepatol 2021; 18(1):24-39. doi: 10.1038/s41575-020-00366-5 [Crossref] [ Google Scholar]
72. Raschi E, Mazzotti A, Poluzzi E, De Ponti F, Marchesini G. Pharmacotherapy of type 2 diabetes in patients with chronic liver disease: focus on nonalcoholic fatty liver disease. Expert OpinPharmacother 2018; 19(17):1903-14. doi: 10.1080/14656566.2018.1531126 [Crossref] [ Google Scholar]
73. Caldwell SH, Hespenheide EE, Redick JA, Iezzoni JC, Battle EH, Sheppard BL. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol 2001; 96(2):519-25. doi: 10.1111/j.1572-0241.2001.03553.x [Crossref] [ Google Scholar]
74. Lebovitz HE. Thiazolidinediones: the forgotten diabetes medications. Curr Diab Rep 2019; 19(12):151. doi: 10.1007/s11892-019-1270-y [Crossref] [ Google Scholar]
75. 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 PharmacolTher 2012; 35(1):66-75. doi: 10.1111/j.1365-2036.2011.04912.x [Crossref] [ Google Scholar]
76. Davies MJ, Aroda VR, Collins BS, Gabbay RA, Green J, Maruthur NM. Management of hyperglycemia in type 2 diabetes, 2022 A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2022; 45(11):2753-86. doi: 10.2337/dci22-0034 [Crossref] [ Google Scholar]
77. Lutchman G, Modi A, Kleiner DE, Promrat K, Heller T, Ghany M. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology 2007; 46(2):424-9. doi: 10.1002/hep.21661 [Crossref] [ Google Scholar]
78. Mahady SE, Webster AC, Walker S, Sanyal A, George J. The role of thiazolidinediones in non-alcoholic steatohepatitis - a systematic review and meta-analysis. J Hepatol 2011; 55(6):1383-90. doi: 10.1016/j.jhep.2011.03.016 [Crossref] [ Google Scholar]
79. Boeckmans J, Natale A, Rombaut M, Buyl K, Rogiers V, De Kock J. Anti-NASH drug development hitches a lift on PPAR agonism. Cells 2019; 9(1):37. doi: 10.3390/cells9010037 [Crossref] [ Google Scholar]
80. Wang Z, Du H, Zhao Y, Ren Y, Ma C, Chen H. Response to pioglitazone in non-alcoholic fatty liver disease patients with vs without type 2 diabetes: a meta-analysis of randomized controlled trials. Front Endocrinol (Lausanne) 2023; 14:1111430. doi: 10.3389/fendo.2023.1111430 [Crossref] [ Google Scholar]
81. Derosa G. Efficacy and tolerability of pioglitazone in patients with type 2 diabetes mellitus: comparison with other oral antihyperglycaemic agents. Drugs 2010; 70(15):1945-61. doi: 10.2165/11538100-000000000-00000 [Crossref] [ Google Scholar]
82. DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med 2011; 364(12):1104-15. doi: 10.1056/NEJMoa1010949 [Crossref] [ Google Scholar]
83. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016; 374(14):1321-31. doi: 10.1056/NEJMoa1506930 [Crossref] [ Google Scholar]
84. Zhou Y, Huang Y, Ji X, Wang X, Shen L, Wang Y. Pioglitazone for the primary and secondary prevention of cardiovascular and renal outcomes in patients with or at high risk of type 2 diabetes mellitus: a meta-analysis. J Clin Endocrinol Metab 2020; 105(5):dgz252. doi: 10.1210/clinem/dgz252 [Crossref] [ Google Scholar]
85. Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 2008; 299(13):1561-73. doi: 10.1001/jama.299.13.1561 [Crossref] [ Google Scholar]
86. Moody AJ, Molina-Wilkins M, Clarke GD, Merovci A, Solis-Herrera C, Cersosimo E. Pioglitazone reduces epicardial fat and improves diastolic function in patients with type 2 diabetes. Diabetes ObesMetab 2023; 25(2):426-34. doi: 10.1111/dom.14885 [Crossref] [ Google Scholar]
87. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362(18):1675-85. doi: 10.1056/NEJMoa0907929 [Crossref] [ Google Scholar]
88. Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med 2016; 165(5):305-15. doi: 10.7326/m15-1774 [Crossref] [ Google Scholar]
89. Tang H, Shi W, Fu S, Wang T, Zhai S, Song Y. Pioglitazone and bladder cancer risk: a systematic review and meta-analysis. Cancer Med 2018; 7(4):1070-80. doi: 10.1002/cam4.1354 [Crossref] [ Google Scholar]
90. Ferwana M, Firwana B, Hasan R, Al-Mallah MH, Kim S, Montori VM. Pioglitazone and risk of bladder cancer: a meta-analysis of controlled studies. Diabet Med 2013; 30(9):1026-32. doi: 10.1111/dme.12144 [Crossref] [ Google Scholar]
91. Korhonen P, Heintjes EM, Williams R, Hoti F, Christopher S, Majak M. Pioglitazone use and risk of bladder cancer in patients with type 2 diabetes: retrospective cohort study using datasets from four European countries. BMJ 2016; 354:i3903. doi: 10.1136/bmj.i3903 [Crossref] [ Google Scholar]
92. Varas-Lorenzo C, Margulis AV, Pladevall M, Riera-Guardia N, Calingaert B, Hazell L. The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: systematic review and meta-analysis of published observational studies. BMC Cardiovasc Disord 2014; 14:129. doi: 10.1186/1471-2261-14-129 [Crossref] [ Google Scholar]
93. Zhang YS, Zheng YD, Yuan Y, Chen SC, Xie BC. Effects of anti-diabetic drugs on fracture risk: a systematic review and network meta-analysis. Front Endocrinol (Lausanne) 2021; 12:735824. doi: 10.3389/fendo.2021.735824 [Crossref] [ Google Scholar]
94. Ciardullo S, Vergani M, Perseghin G. Nonalcoholic fatty liver disease in patients with type 2 diabetes: screening, diagnosis, and treatment. J Clin Med 2023; 12(17):5597. doi: 10.3390/jcm12175597 [Crossref] [ Google Scholar]
95. ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D. 4 Comprehensive medical evaluation and assessment of comorbidities: standards of care in diabetes-2023. Diabetes Care 2023; 46(Suppl 1):S49-67. doi: 10.2337/dc23-S004 [Crossref] [ Google Scholar]
96. Lu Y, Ma D, Xu W, Shao S, Yu X. Effect and cardiovascular safety of adding rosiglitazone to insulin therapy in type 2 diabetes: a meta-analysis. J Diabetes Investig 2015; 6(1):78-86. doi: 10.1111/jdi.12246 [Crossref] [ Google Scholar]
97. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 2003; 38(4):1008-17. doi: 10.1053/jhep.2003.50420 [Crossref] [ Google Scholar]
98. Wang CH, Leung CH, Liu SC, Chung CH. Safety and effectiveness of rosiglitazone in type 2 diabetes patients with nonalcoholic fatty liver disease. J Formos Med Assoc 2006; 105(9):743-52. doi: 10.1016/s0929-6646(09)60202-3 [Crossref] [ Google Scholar]
99. Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A, Serfaty L. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 2008; 135(1):100-10. doi: 10.1053/j.gastro.2008.03.078 [Crossref] [ Google Scholar]
100. Ratziu V, Charlotte F, Bernhardt C, Giral P, Halbron M, Lenaour G. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 2010; 51(2):445-53. doi: 10.1002/hep.23270 [Crossref] [ Google Scholar]
101. Torres DM, Jones FJ, Shaw JC, Williams CD, Ward JA, Harrison SA. Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12-month randomized, prospective, open- label trial. Hepatology 2011; 54(5):1631-9. doi: 10.1002/hep.24558 [Crossref] [ Google Scholar]
102. Lange NF, Graf V, Caussy C, Dufour JF. PPAR-targeted therapies in the treatment of non-alcoholic fatty liver disease in diabetic patients. Int J Mol Sci 2022; 23(8):4305. doi: 10.3390/ijms23084305 [Crossref] [ Google Scholar]
103. Han L, Shen WJ, Bittner S, Kraemer FB, Azhar S. PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease Part I: PPAR-α. Future Cardiol 2017; 13(3):259-78. doi: 10.2217/fca-2016-0059 [Crossref] [ Google Scholar]
104. Choung S, Joung KH, You BR, Park SK, Kim HJ, Ku BJ. Treatment with lobeglitazone attenuates hepatic steatosis in diet-induced obese mice. PPAR Res 2018; 2018:4292509. doi: 10.1155/2018/4292509 [Crossref] [ Google Scholar]
105. Lee YH, Kim JH, Kim SR, Jin HY, Rhee EJ, Cho YM. Lobeglitazone, a novel thiazolidinedione, improves non-alcoholic fatty liver disease in type 2 diabetes: its efficacy and predictive factors related to responsiveness. J Korean Med Sci 2017; 32(1):60-9. doi: 10.3346/jkms.2017.32.1.60 [Crossref] [ Google Scholar]
106. Xu B, Li S, Kang B, Zhou J. The current role of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus management. Cardiovasc Diabetol 2022; 21(1):83. doi: 10.1186/s12933-022-01512-w [Crossref] [ Google Scholar]
107. Veelen A, Andriessen C, Op den Kamp Y, Erazo-Tapia E, de Ligt M, Mevenkamp J. Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on substrate metabolism in prediabetic insulin resistant individuals: a randomized, double-blind crossover trial. Metabolism 2023; 140:155396. doi: 10.1016/j.metabol.2022.155396 [Crossref] [ Google Scholar]
108. Wei Q, Xu X, Guo L, Li J, Li L. Effect of SGLT2 inhibitors on type 2 diabetes mellitus with non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Front Endocrinol (Lausanne) 2021; 12:635556. doi: 10.3389/fendo.2021.635556 [Crossref] [ Google Scholar]
109. Zhang Y, Jiang L, Wang J, Wang T, Chien C, Huang W. Network meta-analysis on the effects of finerenone versus SGLT2 inhibitors and GLP-1 receptor agonists on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus and chronic kidney disease. Cardiovasc Diabetol 2022; 21(1):232. doi: 10.1186/s12933-022-01676-5 [Crossref] [ Google Scholar]
110. Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab 2018; 27(4):740-56. doi: 10.1016/j.cmet.2018.03.001 [Crossref] [ Google Scholar]
111. Nevola R, Epifani R, Imbriani S, Tortorella G, Aprea C, Galiero R. GLP-1 receptor agonists in non-alcoholic fatty liver disease: current evidence and future perspectives. Int J Mol Sci 2023; 24(2):1703. doi: 10.3390/ijms24021703 [Crossref] [ Google Scholar]
112. Updike WH, Pane O, Franks R, Saber F, Abdeen F, Balazy DD. Is it time to expand glucagon-like peptide-1 receptor agonist use for weight loss in patients without diabetes?. Drugs 2021; 81(8):881-93. doi: 10.1007/s40265-021-01525-x [Crossref] [ Google Scholar]
113. Kalra S, Bhattacharya S, Kapoor N. Contemporary classification of glucagon-like peptide 1 receptor agonists (GLP1RAs). Diabetes Ther 2021; 12(8):2133-47. doi: 10.1007/s13300-021-01113-y [Crossref] [ Google Scholar]
114. Trujillo JM, Nuffer W, Smith BA. GLP-1 receptor agonists: an updated review of head-to-head clinical studies. Ther Adv Endocrinol Metab 2021; 12:2042018821997320. doi: 10.1177/2042018821997320 [Crossref] [ Google Scholar]
115. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab 2021; 46:101102. doi: 10.1016/j.molmet.2020.101102 [Crossref] [ Google Scholar]
116. Tan Y, Zhen Q, Ding X, Shen T, Liu F, Wang Y. Association between use of liraglutide and liver fibrosis in patients with type 2 diabetes. Front Endocrinol (Lausanne) 2022; 13:935180. doi: 10.3389/fendo.2022.935180 [Crossref] [ Google Scholar]
117. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R. 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):679-90. doi: 10.1016/s0140-6736(15)00803-x [Crossref] [ Google Scholar]
118. Loomba R, Abdelmalek MF, Armstrong MJ, Jara M, Kjær MS, Krarup N. Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol Hepatol 2023; 8(6):511-22. doi: 10.1016/s2468-1253(23)00068-7 [Crossref] [ Google Scholar]
119. Gastaldelli A, Cusi K, Fernández Landó L, Bray R, Brouwers B, Rodríguez Á. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol 2022; 10(6):393-406. doi: 10.1016/s2213-8587(22)00070-5 [Crossref] [ Google Scholar]
120. American Diabetes Association. 8 Pharmacologic approaches to glycemic treatment. Diabetes Care 2017; 40(Suppl 1):S64-74. doi: 10.2337/dc17-S011 [Crossref] [ Google Scholar]
121. Nozaki Y, Fujita K, Yoneda M, Wada K, Shinohara Y, Takahashi H. Long-term combination therapy of ezetimibe and acarbose for non-alcoholic fatty liver disease. J Hepatol 2009; 51(3):548-56. doi: 10.1016/j.jhep.2009.05.017 [Crossref] [ Google Scholar]
122. Komatsu M, Tanaka N, Kimura T, Fujimori N, Sano K, Horiuchi A. Miglitol attenuates non-alcoholic steatohepatitis in diabetic patients. Hepatol Res 2018; 48(13):1092-8. doi: 10.1111/hepr.13223 [Crossref] [ Google Scholar]
123. Yamagishi S, Nakamura K, Inoue H. Acarbose is a promising therapeutic strategy for the treatment of patients with nonalcoholic steatohepatitis (NASH). Med Hypotheses 2005; 65(2):377-9. doi: 10.1016/j.mehy.2005.01.032 [Crossref] [ Google Scholar]
124. Gentile S, Turco S, Guarino G, Oliviero B, Rustici A, Torella R. [Non-insulin-dependent diabetes mellitus associated with nonalcoholic liver cirrhosis: an evaluation of treatment with the intestinal alpha-glucosidase inhibitor acarbose]. Ann Ital Med Int 1999; 14(1):7-14. [ Google Scholar]
125. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA 2003; 290(4):486-94. doi: 10.1001/jama.290.4.486 [Crossref] [ Google Scholar]
126. Carrascosa M, Pascual F, Aresti S. Acarbose-induced acute severe hepatotoxicity. Lancet 1997; 349(9053):698-9. doi: 10.1016/s0140-6736(05)60134-1 [Crossref] [ Google Scholar]
127. Oh R, Kim G, Lee KN, Cho SH, Kim JY, Kim S. Metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes: risk of heart failure. Cardiovasc Diabetol 2024; 23(1):391. doi: 10.1186/s12933-024-02489-4 [Crossref] [ Google Scholar]
128. Zhang Y, Wu J, Li T, Qu Y, Wang Y. Association of triglyceride-glucose related indices with mortality among individuals with MASLD combined with prediabetes or diabetes. Cardiovasc Diabetol 2025; 24(1):52. doi: 10.1186/s12933-025-02616-9 [Crossref] [ Google Scholar]
129. Wang W, Chen Y, Tu M, Chen HJ. Triglycerides to apolipoprotein A1 ratio: an effective insulin resistance-associated index in identifying metabolic dysfunction-associated fatty liver disease in type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2024; 15:1384059. doi: 10.3389/fendo.2024.1384059 [Crossref] [ Google Scholar]
130. Qian X, Wu W, Chen B, Zhang S, Xiao C, Chen L. Value of triglyceride glucose-body mass index in predicting nonalcoholic fatty liver disease in individuals with type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2024; 15:1425024. doi: 10.3389/fendo.2024.1425024 [Crossref] [ Google Scholar]
131. Liu J, Fu Q, Su R, Liu R, Wu S, Li K. Association between nontraditional lipid parameters and the risk of type 2 diabetes and prediabetes in patients with nonalcoholic fatty liver disease: from the national health and nutrition examination survey 2017-2020. Front Endocrinol (Lausanne) 2024; 15:1460280. doi: 10.3389/fendo.2024.1460280 [Crossref] [ Google Scholar]
132. Wu W, Yang Z, Li O, Gan L, Gao Y, Xiang C. Elevated thyroid autoantibodies as risk factors for metabolic dysfunction-associated fatty liver disease in type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2024; 15:1478818. doi: 10.3389/fendo.2024.1478818 [Crossref] [ Google Scholar]
133. Omaña-Guzmán I, Rosas-Diaz M, Martínez-López YE, Perez-Navarro LM, Diaz-Badillo A, Alanis A. Strategic interventions in clinical randomized trials for metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity in the pediatric population: a systematic review with meta-analysis and bibliometric analysis. BMC Med 2024; 22(1):548. doi: 10.1186/s12916-024-03744-x [Crossref] [ Google Scholar]
134. Joszt L. FDA Approves Resmetirom, First Treatment for NASH with Liver Fibrosis. The American Journal of Managed Care (AJMC); 2024. Available from: https://www.ajmc.com/view/fda-approves-resmetirom-first-treatment-for-nash-with-liver-fibrosis. Accessed August 21, 2024.
135. Clinical Trial. ClinicalTrials.gov. Available from: https://clinicaltrials.gov/search?cond=NAFLD%20-%20Nonalcoholic%20Fatty%20Liver%20Disease&term=NASH%20-%20Nonalcoholic%20Steatohepatitis&intr=Anti-Diabetics&aggFilters=status:act%20not. Published 2024. Accessed August 21, 2024.
136. The University of Texas Health Science Center at San Antonio. Quantifying Hepatic Mitochondrial Fluxes in Humans. ClinicalTrials.gov. Available from: https://clinicaltrials.gov/study/NCT05305287?cond=NAFLD%20-%20Nonalcoholic%20Fatty%20Liver%20Disease&term=NASH%20-%20Nonalcoholic%20Steatohepatitis&intr=Anti-Diabetics&aggFilters=status:rec%20act&rank=1. Published 2024. Accessed August 22, 2024.
137. University of Florida. Low-Dose Pioglitazone in Patients with NASH (AIM 2). ClinicalTrials.gov. Available from: https://clinicaltrials.gov/study/NCT04501406?cond=NAFLD%20-%20Nonalcoholic%20Fatty%20Liver%20Disease&term=NASH%20-%20Nonalcoholic%20Steatohepatitis&intr=Anti-Diabetics&aggFilters=status:not%20rec%20act&rank=2. Published 2024. Accessed August 22, 2024.
138. Merck Sharp & Dohme LLC. A Clinical Study of Efinopegdutide in Participants with Precirrhotic Nonalcoholic Steatohepatitis (NASH) (MK-6024-013). ClinicalTrials.gov. Available from: https://clinicaltrials.gov/study/NCT05877547?cond=NAFLD%20-%20Nonalcoholic%20Fatty%20Liver%20Disease&term=NASH%20-%20Nonalcoholic%20Steatohepatitis&intr=Anti-Diabetics&aggFilters=status:not%20rec%20act&rank=3. Published 2024. Accessed August 22, 2024.
139. Gilead Sciences. Study of Semaglutide, and Cilofexor/Firsocostat, Alone and in Combination, in Adults with Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH) (WAYFIND). ClinicalTrials.gov. Available from: https://clinicaltrials.gov/study/NCT04971785?cond=NAFLD%20-%20Nonalcoholic%20Fatty%20Liver%20Disease&term=NASH%20-%20Nonalcoholic%20Steatohepatitis&intr=Anti-Diabetics&aggFilters=status:not%20rec%20act&rank=4. Published 2024. Accessed August 22, 2024.
140. Medanta. Effect of Bempedoic Acid on Liver Fat in Individuals with Nonalcoholic Fatty Liver Disease and Type 2 Diabetes (B-LIFT). ClinicalTrials.gov. Available from: https://clinicaltrials.gov/study/NCT06035874?cond=NAFLD%20-%20Nonalcoholic%20Fatty%20Liver%20Disease&term=NASH%20-%20Nonalcoholic%20Steatohepatitis&intr=Anti-Diabetics&aggFilters=status:not%20rec%20act&rank=7. Published 2024. Accessed August 22, 2024.
141. Werida R. Dapagliflozin in Type 2 Diabetes Mellitus Patients (T2DM) with Nonalcoholic Fatty Liver Disease (NAFLD). ClinicalTrials.gov. Available from: https://clinicaltrials.gov/study/NCT05459701?cond=NAFLD%20-%20Nonalcoholic%20Fatty%20Liver%20Disease&term=NASH%20-%20Nonalcoholic%20Steatohepatitis&intr=Anti-Diabetics&aggFilters=status:not%20rec%20act&rank=6. Published 2024. Accessed August 22, 2024.
142. Zhujiang Hospital. Effect of Henagliflozein on Hepatic Fat Content in Patients with T2DM and NAFLD (HHTN). ClinicalTrials.gov. Available from: https://clinicaltrials.gov/study/NCT06449833?cond=NAFLD%20-%20Nonalcoholic%20Fatty%20Liver%20Disease&term=NASH%20-%20Nonalcoholic%20Steatohepatitis&intr=Anti-Diabetics&aggFilters=status:not%20rec%20act&rank=8. Published 2024. Accessed August 22, 2024.
143. Tanta University. Comparative Clinical Study Between Empagliflozin Versus Pioglitazone in Non-Diabetic Patients with Non-Alcoholic Steatohepatitis. ClinicalTrials.gov. Available from: https://clinicaltrials.gov/study/NCT05605158?cond=NAFLD%20-%20Nonalcoholic%20Fatty%20Liver%20Disease&term=NASH%20-%20Nonalcoholic%20Steatohepatitis&intr=Anti-Diabetics&aggFilters=status:not%20rec%20act&rank=5. Published 2024. Accessed August 22, 2024.
144. Yoneda M, Kobayashi T, Honda Y, Ogawa Y, Kessoku T, Imajo K. Combination of tofogliflozin and pioglitazone for NAFLD: extension to the ToPiND randomized controlled trial. Hepatol Commun 2022; 6(9):2273-85. doi: 10.1002/hep4.1993 [Crossref] [ Google Scholar]
145. Huang JF, Dai CY, Huang CF, Tsai PC, Yeh ML, Hsu PY. First-in-Asian double-blind randomized trial to assess the efficacy and safety of insulin sensitizer in nonalcoholic steatohepatitis patients. Hepatol Int 2021; 15(5):1136-47. doi: 10.1007/s12072-021-10242-2 [Crossref] [ Google Scholar]
146. Bril F, Biernacki DM, Kalavalapalli S, Lomonaco R, Subbarayan SK, Lai J. Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 2019; 42(8):1481-8. doi: 10.2337/dc19-0167 [Crossref] [ Google Scholar]
147. Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008; 135(4):1176-84. doi: 10.1053/j.gastro.2008.06.047 [Crossref] [ Google Scholar]
148. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355(22):2297-307. doi: 10.1056/NEJMoa060326 [Crossref] [ Google Scholar]