The Lancet sub-journal depth: there is no targeted treatment for fatty liver, and these three types of drugs are expected to become important choices

▎ WuXi AppTec content team editor

With the prevalence of obesity and type 2 diabetes, the incidence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly worldwide. Currently, more than 25% of adults and 3%-10% of children worldwide have NAFLD.

The natural development of NAFLD is reversible. Stages that include progression from NAFLD to non-alcoholic steatohepatitis (NASH) and liver fibrosis are influenced by disease-related genetic and environmental factors and change over time.

Current management of NAFLD is primarily lifestyle interventions (including low-calorie diet, exercise, and weight loss), as well as early treatment of patients' cardiometabolic risk factors, there are no approved pharmacotherapy specifically for NAFLD or NASH, but drugs with a variety of different mechanisms are under clinical development. Among them, because type 2 diabetes is closely related to NAFLD, more and more studies are beginning to focus on the effects of new hypoglycemic drugs on NAFLD or NASH (whether or not they also have type 2 diabetes).

Screenshot source: The Lancet Gastroenterology & Hepatology

A recent review, The Lancet Gastroenterology & Hepatology, detailed the efficacy and safety of three classes of hypoglycemic drugs that showed promise for NAFLD treatment, including PPAR (peroxisome proliferation activator activator) agonists, GLP-1R (glucagon-like peptide-1 receptor) agonists, and SGLT2 (glucose synergistic transporter 2) inhibitors.

Overall, the analysis shows:

PPAR agonists (especially pioglitazone) and some GLP-1R agonists (especially liraglutide and semegglutide) help improve nash histological features, including steatosis, balloon-like changes, and lobular inflammation; and help achieve NASH remission without progression of fibrosis.

Pioglitazone and lanifibranor in PPAR agonists also appear to have had a beneficial effect on the stage of liver fibrosis, but longer randomized controlled trials are needed to confirm this finding.

GLP-1R agonists (especially liraglutide, exenatide, and dulaglucide) and SGLT2 inhibitors (especially empagliflozin and dapagliflozin) also help reduce liver fat levels.

Image credit: 123RF

The study was a systematic review of randomized controlled trials of the above three classes of drugs specifically for the treatment of adults with NAFLD. A total of 25 trials (active or placebo in the control group) were included, covering 2597 people.

Of all participants, 53 percent were male, with an average age of 52 years and an average body mass index (BMI) of 32 kg/m2; 62 percent had type 2 diabetes at the same time. Most trial participants had high levels of serum aminotransferases. Participants in all drug trials had similar average BMI and sex ratios; participants in the SGLT2 inhibitor trial were relatively older.

Other overall features of the included trials:

Five, eight and seven trials were conducted in the United States, Asia and Europe, respectively, and the other five trials were cross-country studies.

Nine trials included biopsy-confirmed patients with NASH and 16 trials included patients with imaging-defined NAFLD.

Most trials were small (fewer than 50 people per treatment group) and had short follow-up (median duration of 24 weeks), while only 6 trials had follow-up times ≥ 52 weeks.

The study endpoints of the nine trials were the hepatic histological endpoints of biopsy.

PPAR agonists

A total of eight trials of Phase 2 randomized controlled trials evaluated the effects of the PPARγ agonist pioglitazone (5 trials), the PPARα/δ dual agonist elafibranor (1 trial), the PPAR-α/γ dual agonist saroglitazar (1 trial), or the pan-PPAR agonist lanifibranor (1 trial) in the treatment of NAFLD or NASH.

Pioglitazone: five trials showed that pioglitazone therapy (30 mg/day or 45 mg/day) was significantly associated with several improvements, including improvement in liver histology (steatosis, balloon-like changes, lobular inflammation), or a 2-point improvement in NAFLD activity score, or NASH remission without progression of fibrosis. In most cases, pioglitazone can also improve serum aminotransferase levels, insulin resistance, and lipid levels.

In terms of improved fibrosis, pioglitazone is also supported by evidence. Only one placebo-controlled randomized trial suggested that pioglitazone (45 mg/day for 72 weeks) treatment was associated with mild improvement in liver fibrosis in patients with NASH with prediabetes or type 2 diabetes. A small meta-analysis of phase 2 randomized trials reported that in biopsy-confirmed NASH patients, pioglitazone therapy (lasting 6-24 months) was associated with improved fibrosis.

Pioglitazone therapy had similar adverse event characteristics to placebo or control drugs, except for moderate weight gain (approximately 2.5 kg, 45 mg/day for 72 weeks).

Saroglitazar: This is a PPARα/γ dual agonist (only approved in India as of publication). Trials have shown that obese patients with NAFLD/NASH receiving high-dose (4 mg) saroglitazar for 16 weeks significantly reduced liver fat, insulin resistance, serum triglycerides, and aminotransferase levels. Saroglitaza was well tolerated, with patients gaining an average weight of 1.5 kg compared to 0.3 kg in the placebo group.

Elafibranor: This is a PPARα/δ dual agonist. In the Phase 2 trial, a higher proportion of patients in the elafibranor 120 mg/day treatment group achieved NASH response (defined as steatosis only or with only mild inflammation) and no progression of fibrosis (including any changes in fibrosis stage) (19% [n=17] vs 12% [n=11]) in the phase 2 trial. However, the RESOLVE-IT Phase 3 trial did not meet the primary endpoint (NASH remission and fibrosis did not progress) and failed to improve metabolic parameters, so elafibranor discontinued development.

Lanifibranor: This is a pan-PPAR agonist that activates all 3 subtypes of PPAR α, γ, δ. In the Phase 2b NATIVE trial, lanifibranor 1200 mg/day for 24 weeks significantly reduced the SAF-A (steatosis, mobility, fibrosis activity) scores of obese patients who were biopsy-confirmed. In addition, the study also met multiple secondary endpoints, including NASH remission and no progression of fibrosis, improvement in fibrosis staging at least 1 stage and no deterioration in NASH, and NASH remission and improvement in fibrosis staging at least 1 stage.

Lanifibranor treatment also significantly improved serum aminotransferase levels, biomarkers of liver damage, inflammation, and fibrosis, glycosylated hemoglobin (HbA1c), lipid levels, and insulin levels.

The safety of Lanifibranor treatment is well tolerated. At 24 weeks, the average weight gain in the lanifibranor group was about 2.5 kg more than in the placebo group.

GLP-1R agonist

A total of 10 trials evaluated the effects of GLP-1R agonists in the treatment of NAFLD or NASH.

Only 2 of these included patients whose biopsy confirmed NASH and used a hepatic histological endpoint. Both trials showed that the proportion of patients with NASH response was significantly higher than in the placebo group after treatment with liraglutide (1.8 mg/day for 48 weeks) or semegglutide (0.1 mg/day, 0.2 mg/day, or 0.4 mg/day for 72 weeks). The proportion of patients with type 2 diabetes in the liraglutide and smeglutide trials was 33% and 62%, respectively. However, neither trial showed any significant improvement in liver fibrosis.

Most studies (8 studies in total, including 5 trials of liraglutide, 2 trials of exenatide, and 1 trial of dula glycopeptide) evaluated the efficacy of GLP-1R agonists on NAFLD by magnetic resonance techniques. In five of these trials, GLP-1R agonist therapy was associated with a significant reduction in liver fat content compared with control drugs or placebo, while in the remaining three trials (all using liraglutide) there was no advantage in the effect on liver fat content.

In all trials, GLP-1R agonists treating NAFLD or NASH were associated with significant reductions in serum aminotransferase levels, weight loss (up to approximately 5 kg), and reductions in HbA1c levels (up to approximately 1%).

GLP-1R agonists are well tolerated, except for an increased frequency of gastrointestinal events such as loss of appetite, nausea, constipation, or diarrhea. However, these digestive tract problems are usually mild, moderate and short-lived.

SGLT2 inhibitors

Seven trials evaluated SGLT2 inhibitors for NAFLD, including two empagliflozin trials, four dagliflozin trials and one cabrelliflozin trial.

SGLT2 inhibitor treatment was associated with a reduction in liver fat content compared with placebo or control drugs (statistically significant in 4 trials). The effects of empagliflozin and dapagliflozin on liver fat content appear to be greater than that of carbagliflozin, and body weight (up to about 3.5 kg) and HbA1c (up to about 0.5%) are significantly lower. SGLT2 inhibitor therapy has also been associated with a significant decrease in serum transaminases levels.

SGLT2 inhibitors have similar adverse event characteristics with placebo or control drugs, except that there is an increased risk of genitourinary infection.

Discussion and prospects

The review notes that the results of this systematic review provide new evidence to support pioglitazone as one of the best long-term drug treatments for NASH, regardless of whether patients have type 2 diabetes. However, longer randomized controlled trials are needed to confirm the improvement of pioglitazone in liver fibrosis. In addition, pioglitazone also has an improving effect on cardiovascular risk in patients with type 2 diabetes and in patients with non-type 2 diabetes. Adverse events that prevent its broader clinical use include moderate weight gain and increased risk of non-osteoporotic fractures (particularly in postmenopausal women). At present, several authorities in Europe and the United States also recommend that adult patients with BIOPS-confirmed NASH (whether diabetes mellitus or not) may consider using pioglitazone.

In addition to the termination of development by elafibranor, only one randomized trial of Lanifibranor, liraglutide and semegglutide each evaluated its specific efficacy on NASH, so the research team believes that there is still insufficient evidence to support the efficacy of these drugs on NASH, which needs to be further validated in large Phase 3 trials.

Although GLP-1R agonists and SGLT2 inhibitors have been associated with improvements in liver fat content in patients with NAFLD or NASH, most of whom have type 2 diabetes, reliable data from large trials and liver histological evaluations of the long-term efficacy of these drugs for NASH are lacking.

But overall, GLP-1R agonists (especially liraglutide and somaglutide) are potential treatment options for NAFLD or NASH, especially for those with both type 2 diabetes or obesity.

In summary, if confirmed in large Phase 3 trials with hepatic histological endpoints, PPAR agonists, GLP-1R agonists, and SGLT2 inhibitors are expected to be important treatment options for patients with NAFLD or NASH. Moreover, the mechanism of action of these three types of drugs is different, and combination therapy is also a direction worth exploring in the future.