Pharmacological Approaches to Nonalcoholic Fatty Liver Disease: Current and Future Therapies

Abstract

Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), can promote the development of cirrhosis, hepatocellular carcinoma, cardiovascular disease, and type 2 diabetes. Similarly, type 2 diabetes confers the greatest risk for the development of NASH, especially when associated with obesity. Although lifestyle changes are critical to success, early implementation of pharmacological treatments for obesity and type 2 diabetes are essential to treat NASH and avoid disease progression. This article reviews current guidance regarding the use of pharmacological agents such as pioglitazone, glucagon-like peptide 1 receptor agonists, and sodium–glucose cotransporter 2 inhibitors in the setting of NAFLD and NASH. It also reviews the latest information on new drugs currently being investigated for the treatment of NASH.

A healthy lifestyle is the cornerstone of management for nonalcoholic fatty liver disease (NAFLD), as reviewed elsewhere in this article collection (1) and in recent guidelines on optimal lifestyle strategies for people with NAFLD (2–5). However, lifestyle changes frequently are insufficient to reach the weight loss threshold needed to significantly reverse nonalcoholic steatohepatitis (NASH) and avoid cirrhosis. Weight regain is also fairly common (6). Given that obesity and type 2 diabetes are so often associated with NASH and both worsen disease progression and outcomes (7,8), treatments for NASH must include careful management of obesity and type 2 diabetes.

The prevalence of NAFLD is rapidly increasing, with the highest prevalence in people who have both type 2 diabetes and obesity (7,9). Type 2 diabetes is associated with NAFLD and poses the highest risk for its progression to NASH with advanced hepatic fibrosis. The severity of fibrosis is the most significant predictor of adverse liver outcomes (10). In the United States, the prevalence in people with type 2 diabetes of clinically significant fibrosis (defined on liver histology as having moderate or more severe fibrosis [stage ≥F2]), is estimated to be ∼15–25% (11–14). This estimate is consistent with prevalence rates reported in European (15–17) and worldwide (9). Furthermore, patients with NAFLD have a two- to threefold increased risk of progression from prediabetes to type 2 diabetes (18,19).

For these reasons, it is important that clinicians following patients at high risk for NAFLD become aware of the problem and implement early screening and management strategies (20). Early diagnosis and treatment can prevent or delay liver disease progression, optimize management of early cirrhosis when present, and reduce the risk of developing diabetes or cardiovascular disease (CVD).

Obesity, NAFLD, and type 2 diabetes share underlying altered pathophysiological mechanisms, including insulin resistance (8), so it is not unexpected that some treatments for type 2 diabetes (e.g., pioglitazone and glucagon-like peptide 1 [GLP-1] receptor agonists) have demonstrated benefits in NASH (21). Treatment should follow a dual goal of treating hyperglycemia and obesity, as well as targeting liver disease in individuals with NASH, as recommended in current guidelines (2–5). Treatments that offer cardiovascular protection also should be considered, given that CVD is the leading cause of mortality of patients with NAFLD (22).

To summarize, the reasons to recommend pharmacological treatment for NASH in patients with type 2 diabetes include the following:

• Patients with type 2 diabetes, in particular when obesity is present, have a high prevalence of significant liver fibrosis and thus a higher risk of developing cirrhosis and even hepatocellular carcinoma (HCC).

• Type 2 diabetes is likely to accelerate steatohepatitis progression to cirrhosis.

• Some treatments for type 2 diabetes (e.g., pioglitazone and GLP-1 receptor agonists) are effective to treat NASH and may reduce cardiovascular risk.

• Early intervention and treatment may prevent cirrhosis (23).

Increased awareness about these risks should encourage physicians and all caregivers to educate patients about healthy lifestyle modifications and to prescribe pharmacological treatment with established benefits for NASH as needed.

This article reviews pharmacological approaches to type 2 diabetes and obesity for people who have NAFLD or NASH and provides a brief description of agents currently in phase 3 development for the treatment of NASH itself.

Pharmacological Treatments for Type 2 Diabetes With Benefits in NAFLD

Among the many pharmacological treatments for type 2 diabetes, agents from two drug classes have been demonstrated to improve NASH: the thiazolidinedione (TZD) pioglitazone and the GLP-1 receptor agonists (Table 1). Metformin has not been shown to improve steatohepatitis in controlled, paired biopsy studies (8,21). Other drug classes such as sodium–glucose cotransporter 2 (SGLT2) inhibitors and insulin may improve hepatic steatosis, but at present lack evidence of promoting histological improvement of steatohepatitis or fibrosis. The sections below summarize the most recent evidence on the safety and efficacy of available glucose-lowering drugs for the treatment of NAFLD. The effects of these drugs in NAFLD are shown in Figure 1.

Table 1.

Summary: Effects in RCTs of Pharmacological Treatments for Type 2 Diabetes in Patients With NAFLD

Drug/Drug Class	Steatosis	Steatohepatitis	Fibrosis	Cardiovascular Risk
Pioglitazone	Improves	Improves	Reduces progression	Benefit
GLP-1 receptor agonists	Improves	Improves	Reduces progression	Benefit
SGLT2 inhibitors	Improves	Unknown	Unknown	Benefit

Figure 1.

Hepatic and metabolic effects of pioglitazone, GLP-1 receptor agonist, and SGLT2 inhibitor therapy in NAFLD. People with type 2 diabetes and NAFLD share common pathophysiological mechanisms, among which insulin resistance plays a central role. Excess energy intake and sedentarism promote weight gain that exacerbates potential genetic traits for insulin resistance. Dysfunctional, insulin-resistant adipose tissue promotes excess lipolysis and flow of FFA flux to the liver, increasing de novo lipogenesis (DNL) and intrahepatic triglyceride accumulation (simple steatosis), which, by a number of mechanisms, may progress over time to NASH, fibrosis, and eventually cirrhosis. Hepatic insulin resistance leads to excess hepatic glucose production (HGP), which, with dysfunctional pancreatic β-cell function, will lead to hyperlgycemia. Pioglitazone (PIO), GLP-1 receptor agonists (GLP-1RAs) and SGLT2 inhibitors (SGLT2i) are effective in treating hyperglycemia, reducing cardiovascular risk, and conferring multiple hepatic benefits in NAFLD. Pioglitazone is also a potent insulin sensitizer that restores the normal biology of adipose tissue and its response to insulin, which translates into increases in plasma adiponectin and reduction in FFA flux to the liver. GLP-1 receptor agonists reduce appetite, promote glucose-dependent insulin secretion, restore normal glucagon secretion, and have many pleiotropic metabolic and vascular effects. Both pioglitazone and GLP-1 receptor agonists decrease hepatic glucose production and improve plasma lipid metabolism. SGLT2 inhibitors promote glycosuria and a state of ketosis that induces moderate weight loss with metabolic improvement and cardiorenal protection. CKD, chronic kidney disease; TG, triglycerides; VLDL, very-low-density lipoprotein cholesterol. This figure includes pictures from Servier Medical Art used under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0).

Pioglitazone

Mechanism of action and systemic effects

Pioglitazone, a TZD derivative, is a peroxisome proliferator–activated receptor (PPAR) γ agonist used for the treatment of type 2 diabetes (24). It improves insulin sensitivity and glucose and lipid metabolism, restoring plasma free fatty acid levels (21,25) and reversing atherogenic dyslipidemia by lowering plasma triglycerides and small, dense LDL cholesterol and increasing HDL cholesterol (26). Pioglitazone increases plasma adiponectin, which, together with a reduction in visceral fat and improvement in insulin sensitivity, contributes to reversing steatohepatitis (27).

Pioglitazone may cause a dose-dependent weight gain (1–2% with 15 mg/day and 3–5% with 45 mg/day) (28); therefore, nutritional counseling is of particular importance (8). Complete medical histories and physical exams are needed in individuals taking TZDs because some patients may experience weight gain from fluid retention, which will be evident as lower-extremity edema. Of note, the improvement in steatohepatitis with pioglitazone has been reported with doses of 30–45 mg/day (29–34). Because lower pioglitazone doses (15 mg/day) can improve glucose and lipid metabolism with minimal weight gain (8,9), it is currently also being investigated for the treatment of NASH (ClinicalTrials.gov identifier NCT04501406).

Pioglitazone decreases the progression from prediabetes to type 2 diabetes (35,36) and reduces CVD in people with (37,38) or without (36) type 2 diabetes. The general perception about this TZD is also changing (8,25,26,39) because it can slow the progression of atherosclerosis (40), improve left ventricular diastolic function, and reduce epicardial adipose tissue (41). The American Diabetes Association’s Standards of Care in Diabetes—2023 suggest its use to lower the risk of cerebrovascular events and myocardial infarction in patients with a history of stroke who also have prediabetes and insulin resistance (42). However, pioglitazone should be avoided in patients with symptomatic heart failure (HF) and is contraindicated if New York Heart Association class III and IV HF is present because, if treatment causes fluid retention, especially when combined with high-dose insulin therapy (28,43–45), it may exacerbate preexisting HF and lead to clinical decompensation. However, no increase in HF was reported in recent large randomized controlled trials (RCTs) of pioglitazone when patients with HF were excluded (8,39). Should HF be suspected, proper work-up is warranted.

Whether pioglitazone increases the risk of bone fractures is controversial. Some studies have reported no increased risk (46), but others found increased risk with long-term use (47). This outcome may be time- and dose-dependent and more significant in higher-risk groups. In a relatively small 3-year prospective study in individuals with type 2 diabetes and NASH (48), a lower bone density at the level of the spine (but no increase in fractures) was found in patients taking pioglitazone compared with those in the placebo group. It appears that calcium and vitamin D supplementation may prevent bone loss and fractures, although this strategy requires further testing. A baseline level of bone mineral density may be recommended in people with a higher risk of fracture.

There also has been controversy regarding bladder cancer with pioglitazone. Current evidence does not support this relationship (36,49,50); however, because of discrepancies in the literature, guidelines recommend against its use in patients with active bladder cancer (51).

Pioglitazone treatment in patients with NASH

Pioglitazone was the first glucose-lowering agent shown in an RCT to reverse NASH. There have been six RCTs with liver histology as the primary outcome that compared the effect of pioglitazone versus placebo for the treatment of NASH (Table 2). Doses of pioglitazone varied from 30 to 45 mg/day. Improvement in steatohepatitis was first reported in a 6-month proof-of-concept study in people with impaired glucose tolerance or type 2 diabetes (29). This report was followed by additional studies ranging from 6 to 36 months in this population (31,33,34). In the trial of longest duration, Cusi et al. (31) treated 101 patients with prediabetes or type 2 diabetes with pioglitazone or placebo for 18 months. Fifty-one percent of those in the pioglitazone group had resolution of NASH versus 19% in placebo (P <0.001). Pioglitazone treatment led to a reduction in mean fibrosis score, but the proportion of patients with fibrosis improvement fell short of statistical significance (39 vs. 25%, P = 0.130), although fewer individuals exhibited fibrosis progression compared with placebo (12 vs. 28%, P = 0.039).

Table 2.

RCTs Reporting Histological Outcomes in People With NASH Treated With Pioglitazone

Study	n	Pioglitazone Dose, mg/day	Patients With Type 2 Diabetes, %	Duration, weeks	Patients With NASH Resolution, %*	People With Fibrosis Improvement, %*
Belfort et al. (29)	55	45	42	24	Not reported†	13
Aithal et al. (30)	74	30	0	50	Not reported†	9
Sanyal et al. (32)	247	30	0	96	26‡	13
Cusi et al. (31)	101	45	51	72	32‡	14
Bril et al. (34)	105	45 + vitamin E	100	72	31‡	22
Huang et al. (33)	90	30	23	24	16	1

^*Resolution of NASH and fibrosis improvement are rounded, placebo-subtracted data.

^†Histological data are not reported as NASH resolution; improved necroinflammation (Belfort et al. [29]): 47%; improved hepatocellular injury (Aithal et al. [30]): 22%.

^‡Significant vs. placebo.

As summarized in Table 2, pioglitazone has also been proven safe and effective to ameliorate steatohepatitis in people without type 2 diabetes (30,32). Benefit has also been reported in an Asian population study (33). In 90 patients with biopsy-proven NASH (only 23% of whom had type 2 diabetes), pioglitazone treatment for 24 weeks improved steatohepatitis (46.7 vs. 11.1% with placebo, P = 0.002), although it fell short of the end point of NASH resolution (26.7 vs. 11.1%, P = 0.1). There was less progression of fibrosis in the pioglitazone group (6.7 vs. 33.3% with placebo, P = 0.02) (33).

More recently, to assess the additive effect of vitamin E plus pioglitazone, Bril et al. (34) compared vitamin E and vitamin E plus pioglitazone versus placebo in 105 patients with type 2 diabetes and NASH. Pioglitazone added to vitamin E (but not vitamin E alone) reached the primary end point of a reduction of ≥2 points in the NAFLD activity score (from two different liver histological parameters) without worsening fibrosis and achieved resolution of NASH in 43% of patients (vs. 12% with placebo) (P <0.001 for both).

A meta-analysis (52) of eight RCTs with TZD treatment in patients with NASH, including five studies with pioglitazone, confirmed that pioglitazone (but not rosiglitazone) induces NASH resolution (odds ratio [OR] 3.65, 95% CI 2.32–5.74, P <0.001) compared with placebo and improves liver fibrosis at any stage (OR 1.77, 95% CI 1.15–2.72, P = 0.009). More recently, a meta-analysis focusing on the effect of pioglitazone in individuals with prediabetes or type 2 diabetes and NAFLD (53) reported improvement in steatosis and in resolution of steatohepatitis (OR 1.78, 95% CI 1.05–3.04, P = 0.03) but not of fibrosis. In contrast to pioglitazone, rosiglitazone does not improve steatohepatititis (54).

GLP-1 Receptor Agonists and Dual Agonists

Mechanism of action and systemic effects

In recent years, GLP-1 receptor agonists have become a powerful tool for the treatment of type 2 diabetes and obesity, improving glycemic control, inducing weight loss, and reducing CVD (55,56). They induce glucose-dependent insulin secretion, improve dysregulated glucagon secretion, and increase satiety. GLP-1 receptor agonists also reduce hepatic de novo lipogenesis, hepatic glucose production, and very-low-density lipoprotein and triglyceride secretion (57). They have an excellent safety profile; gastrointestinal side effects are the most common barrier to long-term adoption but are usually dose-dependent and transitory (58).

In addition, many dual agonists are being developed. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonist, has been approved for the treatment of type 2 diabetes and of obesity, providing significant benefits in terms of glycemic and weight control (59).

GLP-1 receptor agonist treatment in patients with NASH

The beneficial effect of GLP-1 receptor agonists on the liver are mediated by multiple pathways, but apparently not by direct effects on hepatocytes, which lack GLP-1 receptors (60). As summarized in Table 3, several RCTs have reported that GLP-1 receptor agonist treatment yielded reductions in hepatic triglycerides on imaging (61–65). However, few RCTs have included paired liver biopsy histological outcomes. In an early RCT pilot study (66), liraglutide treatment for 48 weeks yielded histological improvement in people with or without type 2 diabetes (39% resolution of NASH vs. 9% in the placebo group, P = 0.019). In a landmark study by Newsome et al. (67), treatment for 72 weeks with semaglutide yielded more patients with NASH resolution compared with placebo (59% at the higher semaglutide dose vs. 17% with placebo, P <0.001). Although neither study demonstrated an improvement in liver fibrosis, fewer patients had a worsening of fibrosis compared with placebo.

Table 3.

RCTs With GLP-1 Receptor Agonists in People With NAFLD

Studies Showing Relative Reduction in Liver Fat on Imaging (MRI-Based Methods Only)
Study	Agent	n	Duration, weeks	Patient With Type 2 Diabetes, %	Weight Loss, %	Reduction of Steatosis, %
Vanderheiden et al. (61)	Liraglutide	71	24	100	2	−30*
Frøssing et al. (62)	Liraglutide	72	26	0	6	−32*
Guo et al. (63)†	Liraglutide	96	26	100	5	−24*
Bizino et al. (65)	Liraglutide	49	26	100	5	−12
Flint et al. (64)	Semaglutide	67	72	73	10	−41*
Harreiter et al. (99)‡	Exenatide	30	24	100	2	−4

Studies Showing NASH Resolution in Histology
Study	Agent	n	Duration, weeks	Patient With Type 2 Diabetes, %	Weight Loss, %	People With NASH Resolution, %
Armstrong et al. (66)	Liraglutide	52	48	33	5	30*
Newsome et al. (67)	Semaglutide	320	72	62	4–12	19–42*
Loomba et al. (69)§	Semaglutide	71	48	75	9	13

Weight loss, reduction on steatosis, and NASH resolution are rounded, placebo-substracted data.

^*Significant treatment difference versus placebo.

^†Compared liraglutide versus placebo; unblinded study.

^‡Compared dapagliflozin + exenatide versus dapagliflozin + placebo.

^§Only participants with cirrhosis were studied.

Cirrhosis is a condition in which treatment of hyperglycemia is challenging because patients with cirrhosis are prone to hypoglycemia and pharmacological treatment options are limited (68). A recent study by Loomba et al. (69) examined the effect of 48 weeks of semaglutide treatment in 71 patients with obesity and NASH-related compensated cirrhosis. Although there was no significant improvement in liver fibrosis or in resolution of NASH, likely because of the advanced liver disease state and short treatment duration, semaglutide was well tolerated and found to be safe overall, with improved glycemic control, minimal hypoglycemia, weight loss, and other cardiometabolic benefits.

The effects of tirzepatide in NAFLD have also been assessed by MRI-Proton Density Fat Fraction (MRI-PDFF) in an imaging substudy of the SURPASS-3 trial (70), in which 296 patients with type 2 diabetes were randomized to tirzepatide 5, 10, or 15 mg or basal insulin degludec. All doses of tirzepatide significantly reduced liver fat content (relative reduction of 40–47 vs. 11% with insulin, P <0.001).

SGLT2 Inhibitors

Mechanism of action and systemic effects

SGLT2 inhibitors are another important class of agents for the treatment of type 2 diabetes. They are potent and selective inhibitors of SGLT2 glucose transporters in the proximal tubule of the kidney, which is responsible for 90% of the filtered glucose reabsorption, inducing glucose urinary excretion. These agents improve glucose control, lipid levels, and blood pressure; induce weight loss; and—of particular interest—confer cardiorenal protection (71). In fact, in addition to treating type 2 diabetes, SGLT2 inhibitors have been proven effective for the treatment of HF and chronic kidney disease in patients without type 2 diabetes. These agents also increase mitochondrial oxidative capacity and induce higher β-hydroxibutirate levels (72). Their main adverse events are genito-urinary tract infections, osmotic diuresis, and diabetic ketoacidosis (rare in patients with type 2 diabetes) (71).

SGLT2 inhibitor treatment in patients with NASH

There has been significant interest in exploring the effects of SGLT2 inhibitors for the treatment of NAFLD (73). In RCTs using as a primary outcome MRI-measured changes in liver triglyceride content (Table 4), SGLT2 inhibitors have been shown to decrease hepatic steatosis. This result occurred with either dapagliflozin (74), empagliflozin (75–77), or canagliflozin (78). This outcome has been also evaluated in an RCT in which liver steatosis was measured by computed tomography scan (79) in 38 patients with type 2 diabetes who were treated with dapagliflozin (vs. placebo) for 12 weeks and showed improvement in steatosis. A similar trend has been reported in two RCTs with empagliflozin that evaluated liver fat with transient elastography (80,81).

Table 4.

RCTs With SGLT2 Inhibitors in People With Type 2 Diabetes and NAFLD (MRI-Based Methods Only)

Study	Agent	n	Duration, weeks	Weight Loss, %	Reduction of Steatosis, %
Bolinder et al. (100)	Dapagliflozin	80	24	−2	NS
Eriksson et al. (101)	Dapagliflozin	84	12	−2	10
Cusi et al. (78)	Canagliflozin	56	24	−3	18
Latva-Rasku et al. (74)	Dapagliflozin	32	8	−3	13*
Kahl et al. (75)	Empagliflozin	84	24	−3	22*
Gaborit et al. (76)	Empagliflozin	56	12	−3	25*
Elhini et al. (77)	Empagliflozin	256	24	−7	31*

Weight loss and reduction of steatosis are rounded, placebo-substracted data.

^*Significant compared with placebo group.

We lack placebo-controlled RCTs assessing liver histology outcomes. However, two open-label trials with ipragliflozin (82) and tofogliflozin (83) evaluated histological outcomes. Takahashi et al. (82) compared ipragliflozin to lifestyle changes during 72 weeks of treatment in 55 patients with type 2 diabetes and NAFLD and found that some features of steatohepatitis improved (specifically, ballooning [52 vs. 24%, P = 0.02] and liver fibrosis [57 vs. 16%, P = 0.01]). Takeshita et al. (83) randomized 40 patients with type 2 diabetes and NAFLD to receive tofogliflozin or glimepiride for 48 weeks but reported no significant differences in histological outcomes between the groups. Larger RCTs with paired biopsies are greatly needed to clarify the effects of SGLT2 inhibitors on NASH.

Pharmacological Treatments for Obesity With Benefit in NAFLD

Current guidelines (2–4) recommend weight loss of at least 5%, preferably ≥10%, in people with NAFLD because it can reverse NASH and even liver fibrosis (84) in addition to ameliorating obesity-related comorbidities. However, lifestyle changes do not always achieve this weight loss goal, calling for the use of adjunctive pharmacological treatment.

GLP-1 Receptor Agonists

The use of GLP-1 receptor agonists in patients with NASH was discussed above. Two of these agents also have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of obesity: liraglutide 3 mg/day and semaglutide 2.4 mg/week. The dual agonist tirzepatide at its highest dose (15 mg) reduced body weight by 20.9% (95% CI 19.9–21.8%) compared with a reduction of 3.1% (95% CI 1.9–4.3%) with placebo (P <0.001) (85) and has been recently approved for the treatment of obesity. Triple agonists are also being investigated for the treatment of obesity; one such treatment, retatrutide, has been associated with significant weight reductions (86).

Other Pharmacological Treatments for Obesity

Other FDA-approved pharmacological treatments for obesity include orlistat, naltrexone/bupropion, and phentermine/topiramate. There are scarce data about the effects of these treatments on NASH (2,87). Orlistat is a lipase inhibitor that induces weight loss by inhibiting the absorption of dietary triglycerides (87). A meta-analysis of three RCTs and four single-arm trials showed improvement in ALT and AST but with no histological effect (88). In a trial with 50 patients randomized to orlistat/diet/vitamin E or diet/vitamin E for 9 months, there was no additive effect of orlistat on hepatic histology; there was only an improvement in histology in relation to weight loss irrespective of treatment group (89). Regarding naltrexone/bupropion, in a post hoc analysis of four phase 3 RCTs with a total of 2,073 subjects, a weight loss–related improvement in ALT was observed (90).

Other Pharmacological Treatments for NASH

Vitamin E

Vitamin E has demonstrated benefit for the treatment of NASH. Sanyal et al. (32) reported on an RCT involving 247 adults without type 2 diabetes with biopsy-proven NASH. Treatment with vitamin E (800 IU/day) for 96 weeks led to resolution of steatohepatitis in 36% of the vitamin E group versus 21% of those taking placebo (P = 0.05). No improvement in fibrosis was observed. A more recent RCT (34) compared the efficacy of vitamin E 800 IU/day, vitamin E 800 UI/day plus pioglitazone 30 mg/day, or placebo for 18 months in 105 patients with type 2 diabetes and NASH. The group taking vitamin E alone did not achieve the primary outcome (reduction of ≥2 points in the NAFLD activity score without worsening of fibrosis) compared with placebo (31 vs. 19%, P = 0.26).

A meta-analysis (91) of RCTs of vitamin E (with and without histologic data) reported some liver histological benefit but did not differentiate patients with or without type 2 diabetes. Thus, there is not enough evidence for the use of vitamin E as a treatment for NASH in patients with type 2 diabetes (34) and should be considered only on a case-by-case basis.

Additional Treatments

As previously mentioned, assessment of cardiovascular risk in patients with NAFLD is mandatory, and treatment of associated risk factors should follow current established management guidelines. Lipid-lowering and antihypertensive treatments should be prescribed in people with NAFLD when needed. There is some concern among clinicians about statin therapy, but statins have been shown to be safe in patients with NAFLD (92,93); however, they should be avoided in those with decompensated cirrhosis (2–5).

Drugs in Advanced Stages of Development for the Treatment of NASH

There are many drugs in development for the treatment of NASH, with a broad spectrum of mechanisms of action and metabolic targets (94). The sections below briefly summarize those in advanced stages of development (i.e., phase 3 clinical trials).

Lanifibranor

Lanifibranor is a pan-PPAR agonist. In a phase 2b RCT (95), 247 patients with NASH (with and without type 2 diabetes) received lanifibranor 1,200 mg/day, lanifibranor 800 mg/day, or placebo for 6 months. Significantly more patients in the group taking lanifibranor 1,200 mg than in the placebo group achieved NASH resolution without worsening fibrosis (49 vs. 22%), and more had improved fibrosis without worsening NASH (48 vs. 29%; relative risk 1.68 [95% CI 1.15–2.46]). These effects are being further assessed in an ongoing phase 3 RCT (ClinicalTrials.gov identifier NCT04849728) with 2,000 participants with NASH and fibrosis (stage F2–F3) receiving either lanifibranor 800 mg/day, lanifibranor 1,200 mg/day, or placebo for 72 weeks.

A recent 24-week RCT examined the mechanism of action of lanifibranor in people with NAFLD and type 2 diabetes and reported a marked improvement in glucose (i.e., reductions in A1C and hepatic and muscle insulin resistance) and lipid metabolism, with an ∼50% reduction in intrahepatic triglyceride content (96).

GLP-1 Receptor Agonists and Dual Agonists

There is considerable research activity exploring the many metabolic effects of GLP-1 receptor agonists, as well as dual- and triple-peptide agonists in people with NAFLD (57). The evidence for semaglutide was discussed earlier. Of note, there is an ongoing paired-biopsy phase 3 clinical trial (ClinicalTrials.gov identifier NCT04822181) in which 1,200 participants with NASH and significant fibrosis (stages F2–F3) are to receive semaglutide 2.4 mg/week or placebo for 72 weeks. A phase 2 paired-biopsy RCT with the dual agonist tirzepatide (also discussed earlier) is also ongoing in people with NASH and fibrosis (stage F2–F3), who are randomized to receive tirzepatide 5, 10, or 15 mg or placebo to assess tirzepatide’s effect on steatohepatitis and liver fibrosis (ClinicalTrials.gov identifier NCT04166773).

Resmetirom

Resmetirom is a selective thyroid hormone receptor β agonist that has been studied for the treatment of NASH. A phase 2 clinical trial (97) evaluated resmetirom 80 mg/day in 125 patients with NASH with fibrosis stage 1–3 for 36 weeks. The researchers found a significant reduction in liver fat (measured by MRI-PDFF) in the resmetirom group compared with placebo (40 vs. 14%). Histologically, 27% of participants in the resmetirom group had resolution of NASH compared with 6% in the placebo group (P = 0.018). Fibrosis improved in 28.8% of the patients treated with resmetirom compared with 23.5% of those taking placebo (P = 0.65).

The resmetirom NASH development program involves four ongoing phase 3 clinical trials: MAESTRO-NASH, MAESTRO-NAFLD-1, MAESTRO-NAFLD-OLE, and MAESTRO-NASH-OUTCOMES. Results were recently reported from the MAESTRO-NASH (ClinicalTrials.gov identifier NCT03900429) trial in ∼1,000 participants with NASH and fibrosis who were randomized to resmetirom 80 mg/day (n = 316), resmetirom 100 mg/day (n = 321), or placebo (n = 318), with a second biopsy performed after 52 weeks of treatment. The investigators reported significant benefit in the primary outcomes of NASH resolution (without worsening of fibrosis) (26–30 vs. 10% with placebo) and improvement in fibrosis without worsening of NAFLD activity score (24–26 vs. 14% with placebo).

Other Drugs in Development

Several fibroblast growth factor 21 analogs are in development for the treatment of NASH (94). Recently, the results of a phase 2b RCT reported on pegozafermin (98). In 222 participants with biopsy-proven NASH and fibrosis (stage F2–F3), there was an improvement in liver fibrosis in 27% of patients in the pegozafermin group compared with 7% with placebo (P = 0.008). NASH resolution was also more frequent with pegozafermin (26 vs. 2% with placebo).

Conclusion

There are effective treatments—namely, pioglitazone and GLP-1 receptor agonists—to ameliorate NASH for people with type 2 diabetes, a population at the highest risk of disease progression. Physicians managing these individuals must use these drugs as recommended in recent guidelines (2–5). Early intervention could prevent the development of cirrhosis, progression from prediabetes to type 2 diabetes, and CVD, which is the main cause of death in people with NAFLD. For cardiorenal protection, SGLT2 inhibitors should also be considered, although their role for the treatment of NASH remains unclear. Novel drugs for steatohepatitis are under intense investigation and will soon become available. Screening individuals at high risk for steatohepatitis and intervening early to prevent hepatic and extrahepatic complications is the responsibility of all caregivers who wish to improve the quality of life of people with obesity, prediabetes, or type 2 diabetes.