Nonalcoholic fatty liver disease (NAFLD) is a broad term that includes nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), and cirrhosis.² Nonalcoholic fatty liver is characterized by macrovesicular hepatic steatosis that may be accompanied by mild inflammation; NASH is characterized by inflammation and cellular injury with or without the presence of fibrosis; and cirrhosis is characterized by the formation of cirrhotic nodules.^2,3 Prevalence of NAFLD and NASH is estimated to be 25%–30% in the general population and is increasing worldwide with the increase in metabolic comorbidities such as type 2 diabetes (T2D), dyslipidemia, central obesity, and hypertension.³ The pathogenesis of NASH includes adipose tissue dysfunction and an imbalance between nutrient delivery, use, and disposal to the liver.⁴ Treatment consists of lifestyle modifications, but medications including vitamin E, thiazolidinediones, some glucagon-like-peptide-1 receptor agonists (GLP-1 RAs), tirzepatide, and sodium-glucose cotransporter-2 inhibitors have data that suggest their benefit for NAFLD. Although benefits have been shown as secondary or confounding outcomes, there are currently no FDA-approved medications for NAFLD or NASH.^2,3 The GLP-1 RA medications play a role in liver disease by normalizing plasma aminotransferase concentrations and reducing liver fat content (LFC) on imaging in individuals.^3,6 Although GLP-1 RA medications are not currently approved for NAFLD or NASH, semaglutide was studied in a phase II trial of adult patients with NASH and shown to be superior in the resolution of NASH after 72 weeks of treatment compared with placebo (59% vs. 17%, respectively).⁶ This was a phase IIa study to evaluate the efficacy and safety of efinopegdutide, a GLP-1 RA and glucagon receptor co-agonist, compared with semaglutide in patients with NAFLD.¹

The study was a phase IIa, 32-week, active-comparator-controlled, randomized, multisite, parallel-group trial. Inclusion consisted of men and women 18–70 years of age with NAFLD on the basis of an LFC of 10% or greater as assessed by MRI-estimated proton density fat fraction (MRI-PDFF).

Participants were required to have a BMI of 25 kg/m² or greater and 50 kg/m² or less with a stable body weight, no history of T2D, or T2D with an A1C of 8.5% or less controlled by diet or a stable dose of metformin for at least 3 months. Patients were excluded if they had a history of chronic liver disease other than NAFLD or NASH, history of cirrhosis, decompensated liver disease, treatment with any GLP-1 RA or the investigational drug, treatment with thiazolidinediones within 6 months, prescription weight-management medications in the past 3 months, a hyperlipidemic therapy not at a stable dose for at least 1 month, or treatment with vitamin E not at a stable dose for at least 3 months. Participants were randomized in a 1:1 ratio and stratified according to T2D diagnosis to efinopegdutide 10 mg subcutaneously once weekly or semaglutide 1 mg subcutaneously once weekly. Both groups had a three-step dose escalation over the course of 8 weeks, and participants’ regimens could be titrated one step depending on tolerability. Participants received dietary and activity counseling at the randomization visit, and at additional visits, the staff reviewed the diet and activity guidance sheets with the participants. The primary efficacy end point was a relative reduction from baseline in LFC as measured by MRI-PDFF after 24 weeks. Secondary efficacy end points included percent change from baseline in body weight and fasting lipid concentrations (LDL, HDL, TG) after 24 weeks, and safety was assessed by monitoring adverse drug reactions (ADRs), vital signs, and laboratory safety tests. There were 145 patients randomized, and 6.9% dropped out before the primary analysis. Baseline characteristics included a mean age of 49.5 years, 55.2% female, 35.15% Hispanic ethnicity, and 9.65% Asian race, and a mean BMI was 34.35 kg/m². At baseline, 33.1% had T2D, and the LFC percent at baseline was 21.1 (±8.1) in the efinopegdutide group and 19.4 (±8.1) in the semaglutide group.

Efinopegdutide showed a significant decrease in LFC percent at 24 weeks compared with semaglutide with a p value less than 0.001 (-30.4% with a 90% CI of -38.7% to -22.1%). The least-squares (LS) mean relative reduction from baseline in LFC was -72.7% in the efinopegdutide group and -42.3% in the semaglutide group. The LS mean percent reduction from baseline in body weight at week 24 was not statistically significant with a p value of 0.085 (-8.5% in the efinopegdutide group vs. -7.1% in the semaglutide group). Both groups experienced a percent reduction in TC (-15.2% in efinopegdutide; -8.0% in semaglutide), LDL (-13.0% in efinopegdutide; -6.9% in semaglutide), and TG (-30.9% in efinopegdutide; -23.3% in semaglutide), but the efinopegdutide group had a decrease in HDL (-8.1%), whereas the semaglutide group had an increase in HDL (3.6%). A safety analysis included all participants receiving at least one dose of the assigned intervention dose or active comparator. Of the participants in each group, 88.9% in the efinopegdutide group and 72.6% in the semaglutide group experienced an ADR. A higher incidence of constipation (16.7% vs. 5.5%) and abdominal pain (12.5% vs. 2.7%) was observed in the efinopegdutide group than in the semaglutide group.

More participants achieved a normal LFC concentration at week 24 with efinopegdutide compared with semaglutide (66.7% vs. 17.8%). A major critique of this study was that the phase II study of semaglutide in NASH used a total weekly dosage of 2.8 mg, whereas this study compared semaglutide at a 1-mg-weekly dosage. If investigators used the maximum weekly dosage for patients in the active-comparator group, it may change the data and show an increased reduction in LFC percentage in the active-comparator group. Using the current maximum semaglutide weekly dose can also identify how efinopegdutide compares with what is currently available. Although efinopegdutide was superior to semaglutide in the primary outcome, this medication did show a decrease in HDL by -8.1%, which is not a favorable outcome. A statistical analysis or postmarketing analysis on HDL concentrations may be appropriate in this study because HDL is shown to be cardioprotective, and lower concentrations can increase the risk of heart disease, stroke, and other cardiovascular disease.

In the efinopegdutide group, seven participants did not tolerate the target dose of 10 mg once weekly, which led to six participants tapering and completing the study on a dose of 5 mg once weekly and one tapering to 5 mg once weekly but discontinuing the study medication. In phase I trials, investigators looked at 5 mg, 7.4 mg, and 10 mg of efinopegdutide with no dose escalation, which led to increased GI issues and a dose escalation protocol for phase II trials.⁷ Although this trial did outline dose escalations, the trial may decrease ADRs by using 7.4 mg of efinopegdutide once a week for 4 weeks before the 10-mg maintenance. Investigators should also stratify their trial to see how the tolerability and effectiveness of 7.4 mg compares with 10 mg to determine whether 7.4 mg would be an effective dose in LFC decrease while being a safer maximum dose than 10 mg. Overall, efinopegdutide from this trial showed superiority over semaglutide in LFC reduction within NAFLD, but future trials evaluating the maximum weekly dose available of semaglutide compared with efinopegdutide and a slower dose escalation including 4 weeks of efinopegdutide at 7.4 mg once a week would be appropriate. Efinopegdutide has the potential to change NAFLD management in both nondiabetic adult patients who are overweight and adult patients with T2D who are overweight.