Metabolic dysfunction-associated steatotic liver disease and type 2 diabetes: Pathophysiology, diagnosis, and emerging therapeutic strategies

Table 1 Pharmacologic therapies for metabolic dysfunction-associated steatotic liver disease: Liver fat, cardiometabolic, and fibrosis impact[9,92,160-162]

Drug	Class	Liver effects	CV/metabolic effects	Fibrosis impact	Ref.
Metformin	Biguanide	Unchanged	Improves insulin sensitivity	Neutral	Cusi et al[9]
Pioglitazone	PPAR-γ agonist	Decreased	Improves insulin sensitivity	Improved	Cusi et al[9]
Insulin	Hormone	Decreased	Glucose control	Unknown	Cusi et al[9]
GLP-1 RAs (semaglutide, liraglutide)	GLP-1 RA	Decreased	Weight loss, CV benefit	Improved	Cusi et al[9]; Lin et al[92]
SGLT2 inhibitors (dapagliflozin, empagliflozin, canagliflozin)	SGLT2 inhibitor	Decreased	Weight loss, glycemic control	Effect unknown	Cusi et al[9]
DPP-IV inhibitors (sitagliptin, vildagliptin)	DPP-IV inhibitor	Unchanged (in RCTs)	Modest glucose control	Effect unknown	Cusi et al[9]
Vitamin E	Antioxidant	Not specified	Neutral	Improved (non-diabetics)	Cusi et al[9]
Obeticholic acid	FXR agonist	Not specified	Raises LDL, pruritus	Improved (fibrosis)	Lin et al[92]; Marek and Malhi[161]
Elafibranor	PPAR-α/δ agonist	Not specified	Improves lipids	Improved	Lin et al[160]; Marek and Malhi[161]
Cenicriviroc	CCR2/CCR5 antagonist	Not specified	Neutral	Improved	Lin et al[160]; Marek and Malhi[161]
Aramchol	SCD1 inhibitor	Not specified	Neutral	Improved	Lin et al[160]; Marek and Malhi[161]
Selonsertib	ASK1 inhibitor	Not specified	Neutral	Improved	Marek and Malhi[161]
Resmetirom	THR-β agonist	Not specified	Neutral	Improved	Marek and Malhi[161]
Tirzepatide	GLP-1/GIP RA	Decreased	Weight loss, metabolic improvement	Improved	Handu et al[162]
Survodutide	GLP-1/glucagon RA	Not specified	Weight loss	Improved	Handu et al[162]
FGF-21 analogues	FGF-21 mimetic	Decreased	Improves lipid and glucose metabolism	Improved	Lin et al[160]; Marek and Malhi[161]
THR-β agonists	Thyroid hormone receptor-β agonist	Decreased	Neutral	Improved	Lin et al[160]; Marek and Malhi[161]
Pan-PPAR agonists	Pan-PPAR agonist	Decreased	Improves lipids, insulin sensitivity	Improved	Lin et al[160]; Marek and Malhi[161]
Curcumin	Polyphenol	Not specified	Antioxidant effects	Improved	Handu et al[162]
Silymarin	Flavonoid	Not specified	Hepatoprotective	Improved	Handu et al[162]
Resveratrol	Polyphenol	Not specified	Antioxidant/anti-inflammatory	Improved	Handu et al[162]
Coffee	Dietary	Not specified	Anti-inflammatory, antioxidant	Improved	Handu et al[162]
Green tea	Catechin-rich beverage	Not specified	Anti-inflammatory	Improved	Handu et al[162]
Berberine	Plant alkaloid	Not specified	Improves insulin resistance	Improved	Handu et al[162]

This table summarizes pharmacologic agents studied in the management of metabolic dysfunction-associated steatotic liver disease, detailing their effects on hepatic steatosis, cardiometabolic outcomes, and hepatic fibrosis. It includes both antidiabetic and emerging investigational agents. Reference numbers correspond to clinical trials and major reviews. Therapies such as glucagon-like peptide-1 receptor agonists, peroxisome proliferator-activated receptor agonists, and thyroid hormone receptor-β agonists demonstrate multifaceted benefits, while others remain investigational or population-specific. CV: Cardiovascular; GLP-1 RA: Glucagon-like peptide-1 receptor agonists; DPP: Diabetes prevention program; SGLT2: Sodium-glucose cotransporter 2; THR: Thyroid hormone receptor; FGF: Fibroblast growth factor; PPAR: Peroxisome proliferator-activated receptor; SCD1: Stearoyl-CoA desaturase 1; FXR: Farnesoid X receptor; ASK1: Apoptosis signal-regulating kinase 1; LDL: Low density lipoprotein; RCT: Randomized clinical trial.

Table 2 Risk factors for metabolic dysfunction-associated steatotic liver disease progression in patients with type 2 diabetes

Risk factor	Mechanism	Associated outcome
Insulin resistance	Promotes de novo lipogenesis and reduces fatty acid oxidation	Steatosis, progression to MASH
Visceral obesity	Pro-inflammatory adipokine secretion, lipotoxicity	Fibrosis progression, inflammation
Poor glycemic control	Increases oxidative stress, mitochondrial dysfunction	Fibrosis, hepatocellular injury
Dyslipidemia	Elevated triglycerides and LDL lead to hepatocyte stress	Lipotoxicity, NASH progression
Hypertension	Induces endothelial dysfunction and chronic inflammation	Increased risk of fibrosis
Sedentary lifestyle	Reduces insulin sensitivity and promotes weight gain	Increased steatosis and metabolic burden
Genetic variants (e.g., PNPLA3, TM6SF2)	Impaired lipid export and processing	Accelerated fibrosis progression
Gut microbiota dysbiosis	Increased endotoxin (LPS) translocation and inflammation	Worsening hepatic inflammation and fibrosis
Advanced age	Reduced hepatic regeneration capacity, cumulative metabolic injury	Greater risk of advanced fibrosis
Diet high in saturated fats/fructose	Increases hepatic fat accumulation and lipotoxic intermediates	Steatohepatitis and fibrosis
Smoking	Oxidative stress and impaired insulin sensitivity	Fibrosis and cardiovascular risk

This table outlines the key clinical, metabolic, genetic, and lifestyle-related factors that contribute to the progression of metabolic dysfunction-associated steatotic liver disease in individuals with type 2 diabetes. Insulin resistance, visceral adiposity, dyslipidemia, and poor glycemic control are core drivers that promote hepatic steatosis, inflammation, and fibrosis. Additionally, environmental and genetic influences such as sedentary behavior, dietary composition, gut microbiota alterations, and PNPLA3 variants can further accelerate disease severity. Recognizing these risk factors is essential for targeted intervention and prevention of progression to advanced liver disease. LPS: Lipopolysaccharide; LDL: Low density lipoprotein; NASH: Nonalcoholic fatty liver disease; MASH: Metabolic dysfunction-associated steatohepatitis.

Table 3 Timeline of key clinical trials in metabolic dysfunction-associated steatotic liver disease: Drug classes, endpoints, and outcomes[84,117,123,129,133,139,163-166]

Year	Trial	Drug/class	Primary endpoint	Key outcome	Ref.
2015	LEAN	Liraglutide (GLP-1 RA)	NASH resolution without fibrosis worsening	Met endpoint; improved NASH resolution	Armstrong et al[84]
2019	REGENERATE (Interim)	Obeticholic acid (FXR agonist)	Fibrosis improvement without NASH worsening	Improved fibrosis in 23% vs 12% placebo	Ratziu et al[163]
2020	REVERSE	Lanifibranor (pan-PPAR agonist)	Improvement in NAS and fibrosis	Significant histologic improvement	Francque et al[129]
2021	FLINT	Obeticholic acid	NAS improvement ≥ 2 points without fibrosis worsening	Positive results in steatosis and inflammation	Sanyal et al[164]
2022	MAESTRO-NAFLD-1	Resmetirom (THR-β agonist)	Liver fat reduction via MRI-PDFF	Significant reduction in liver fat content	Harrison et al[165]
2022	MAESTRO-NASH	Resmetirom (THR-β agonist)	NASH resolution and fibrosis improvement	Met both primary endpoints	Harrison et al[123]
2022	SYNERGY	Semaglutide + cagrilintide	Liver fat reduction	Significant additive effect on steatosis	Frias et al[166]
2023	SURMOUNT-1	Tirzepatide (GLP-1/GLP RA)	Weight reduction	Robust weight loss and decrease liver fat (MRI)	Loomba et al[117]
2023	ESSENCE	Efruxifermin (FGF-21 analogue)	Histologic NASH resolution and fibrosis improvement	Positive early-phase results	Harrison et al[133]
2023	CENTURION	Survodutide (GLP-1/glucagon RA)	Liver fat reduction	Marked liver fat loss on imaging	Sanyal et al[139]

This table presents a chronological overview of major clinical trials conducted in metabolic dysfunction-associated steatotic liver disease, highlighting the evolving therapeutic landscape. Each trial is listed with its year of publication, pharmacologic class, primary endpoints, and key outcomes. Studies such as LEAN, REGENERATE, and MAESTRO-NASH have laid the foundation for understanding drug efficacy in nonalcoholic fatty liver disease resolution and fibrosis improvement. Newer trials like SURMOUNT-1 and ESSENCE continue to explore novel agents, including dual incretin therapies and fibroblast growth factor-21 analogues, with promising metabolic and histologic effects. This timeline illustrates the progression from early histologic endpoints to robust, non-invasive imaging and metabolic markers. GLP-1 RA: Glucagon-like peptide-1 receptor agonists; FXR: Farnesoid X receptor; PPAR: Peroxisome proliferator-activated receptor; THR: Thyroid hormone receptor; FGF: Fibroblast growth factor; NASH: Nonalcoholic fatty liver disease; NAS: Nonalcoholic fatty liver disease activity score; MRI: Magnetic resonance imaging; MRI-PDFF: Magnetic resonance imaging-proton density fat fraction.