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BARCELONA – The investigational oral agent cenicriviroc showed positive effects on liver fibrosis in adults with nonalcoholic steatohepatitis (NASH), many of whom had type 2 diabetes, in a phase 2b trial reported at the annual meeting of the European Association for the Study of Diabetes.
Other data released at the meeting, which showed potential positive effects of novel or existing diabetes treatments on nonalcoholic fatty liver disease (NAFLD), included post hoc analyses of a phase 2b study with tirzepatide and a phase 3 study that combined exenatide and dapagliflozin.
Currently, no medications for NAFLD or NASH have been approved in the United States.
CENTAUR with cenicriviroc
Results of the previously reported CENTAUR trial showed that the antifibrotic effects of cenicriviroc, a dual chemokine receptor antagonist, were greatest in patients with more-severe liver disease (Hepatology. 2018;67[5]:1754-67). At the meeting, Henrik Landgren, PhD, of Allergan, presented data from the 2-year trial overall, and specifically in patients with advanced, stage 3 fibrosis.
CENTAUR was a randomized, double-blind, placebo-controlled, multinational study with 289 adults who had biopsy-confirmed NASH, an NAFLD Activity Score (NAS; range, 0-8; score of 5 or more diagnostic of NASH) of 4 or more, and stages 1-3 liver fibrosis as determined by the NASH clinical research network system (Contemp Clin Trials. 2016;47:356-65). The mean age of the patients enrolled at baseline was 54 years, the mean body mass index was 33.9 kg/m2, and just more than half the patients (52%) had type 2 diabetes.
The patients were randomized to three treatment arms: cenicriviroc 150 mg for 2 years; placebo for 1 year, then cenicriviroc 150 mg for 1 year; or placebo for 2 years. The primary endpoint was histologic improvement (reduction of 2 or more points in overall NAS, with reduction of 1 or more points in more than one category of the NAS without worsening of fibrosis at the end of year 1. The key secondary endpoint was complete NASH resolution without worsening of fibrosis at year 2.
Dr. Landgren reported that, at year 1, of the total number of patients, 28.6% of those receiving cenicriviroc achieved an improvement in fibrosis of one or more stages, compared with 19.0% of those receiving placebo. Of the 97 patients who had advanced fibrosis at baseline, 38.3% of those on cenicriviroc and 28.0% of those on placebo achieved the same endpoint.
Those effects were sustained at year 2, Dr. Landgren emphasized, with twice as many cenicriviroc- than placebo-treated patients achieving one or more stage improvement in fibrosis and no worsening of NASH at year 2 (60% and 30%, respectively), with more pronounced improvements in those who had advanced fibrosis at baseline (86% and 60%).
In addition, analyses of biomarkers suggested that cenicriviroc had systematic anti-inflammatory activity, with reductions observed in high-sensitivity C-reactive protein; fibrinogen; and levels of interleukin-6, IL-8, and IL-1-beta.
Dr. Landgren and colleagues noted that cenicriviroc provided antifibrotic benefit in patients with NASH and fibrosis. Those benefits were sustained through year 2 and were more pronounced in patients who had advanced fibrosis at baseline.
The safety of cenicriviroc was “comparable with placebo,” he said, suggesting that the data supported the phase 3 AURORA study that is currently recruiting.
Tirzepatide for NASH
Another approach worth exploring for the treatment of NASH, is the use of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and the glucagonlike peptide–1 (GLP-1) receptor, according to Axel Haupt, MD, PhD, of Eli Lilly.
Tirzepatide (LY3298176) is currently under investigation for the treatment of type 2 diabetes, and Dr. Haupt reported data from a post hoc analysis of a double-blind, placebo-controlled, phase 2b study showing that “exploratory” serum markers of apoptosis and fibrosis – keratin-18 (K-18) and Pro-C3, respectively – were decreased from baseline to a greater extent in patients treated with tirzepatide than with placebo, while total adiponectin was increased. The latter is “thought to protect the liver from inflammation and fibrosis,” Dr. Haupt observed.
The main results of the trial were published last year (Lancet. 2018;392:2180-93) and showed that, after 26 weeks, there was a dose-dependent decrease in both glycated hemoglobin (HbA1c) and body weight with tirzepatide 10 mg and 15 mg, compared with placebo and an active comparator, dulaglutide 1.5 mg.
The study population was typical of type 2 diabetes: baseline HbA1c was 8.1%; the average body mass index was 32 kg/m2, with a diabetes duration of 5 years; and the main treatment (90%) had been metformin.
The rationale for the NASH-related biomarker analysis was that type 2 diabetes and NAFLD were known to be overlapping conditions, and weight loss had been shown to be an effective means of resolving NASH, Dr. Haupt said. In addition, a small “proof-of-concept” study with the GLP-1 receptor agonist liraglutide had suggested that these drugs may be effective in NASH.
Tirzepatide, at doses of 5, 10, and 15 mg, was associated with significant decreases in K-18 from baseline to week 26 and compared with placebo and the 1-mg tirzepatide dose. Mean baseline concentrations of K-18 were 394.4 U/L in the placebo group and reduced by 22.6 U/L by week 26. Corresponding baseline values for tirzepatide 5 mg were 375.8 U/L (change, –87.6 U/L); for 10 mg, 409.9 U/L (–157.8 U/L); and for 15 mg, 376.2 U/L (–110.6 U/L).
Dr. Haupt noted that a K-18 value of 250 U/L was considered a cutoff for a diagnosis of NASH. “So we really think that we have some NASH patients in this population,” he observed.
At week 26, Pro-C3 levels significantly decreased by 1.2 ng/mL from a baseline of 8.6 ng/mL with tirzepatide 15 mg, compared with an increase of 0.9 ng/mL from a baseline of 9.3 ng/mL for placebo (P less than .05). However, values of between 15-20 ng/mL would be expected for advanced fibrosis, Dr. Haupt said, “so we think we [don’t] have a lot of patients with advanced fibrosis, we have a lower grade of fibrosis or no fibrosis in our patient population.”
By week 26, adiponectin levels significantly increased by 0.9 mg/L from baseline, both with tirzepatide 10 mg (P less than .05) and 15 mg (P less than .05), compared with placebo (–0.1 mg/L; both P less than .05).
“This study was really designed as a type 2 diabetes efficacy study, so the NASH biomarker work is exploratory and only hypothesis generating,” Dr. Haupt noted. “We think there is overlap in type 2 diabetes and NASH, but it is not an ideal population to look into those biomarkers.” There are also other limitations, such as the baseline values across treatment groups not being matched, so there is likely to be some inconsistency in these data, he added.
That said, Dr. Haupt concluded that, “along with the weight-loss findings,” these exploratory biomarker findings supported the further evaluation of tirzepatide in patients with NASH.”
DURATION-8: Exenatide plus dapagliflozin
In another hypothesis-generating post hoc analysis, this time of the phase 3 DURATION-8 clinical trial, a combination of exenatide and dapagliflozin was found to have a beneficial effect on markers of hepatic steatosis and fibrosis in patients with type 2 diabetes.
“We have some good evidence that both GLP-1 receptor agonists and SGLT2 [sodium-glucose cotransporter 2] inhibitors may have benefits in reducing steatosis and even steatohepatitis in [patients with] type 2 diabetes. So the association of two diabetes drugs might provide an advantage. However, this had not previously been tested in a randomized, controlled trial,” observed Cristian Guja, MD, PhD, of Carol Davila University of Medicine and Pharmacy in Bucharest, Romania.
The main aims of the DURATION-8 clinical trial, which ran for 104 weeks, was to compare the efficacy and safety of combining exenatide (2 mg, once a week) and dapagliflozin (10 mg, daily) with either exenatide 2 mg with placebo or dapagliflozin 10 mg with placebo. Results showed greater improved glycemic control and reductions in body weight and systolic BP with the exenatide-dapagliflozin combination.
A total of 685 patients were included in the post hoc analysis, of whom 228 had been treated with the combination, 228 with exenatide plus placebo, and 230 with dapagliflozin plus placebo. At baseline, levels of the markers of NAFLD and fibrosis that were assessed were similar between the groups. Between 81% and 93% of study participants had fatty liver or steatosis as defined by a Fatty Liver Index (FLI) of 60 or more or an overall NAFLD Liver Fat Score (NLFS) of –0.64 or higher. Between 9% and 13% of patients had liver fibrosis, as defined as an NAFLD Fibrosis Score (NFS) above 0.676, a Fibrosis-4 score (FIB-4) of 1.46 or more, or both.
At 28 weeks, the proportion of patients with biomarker scores suggestive of fatty liver disease or steatosis was significantly reduced from baseline with the exenatide-dapagliflozin combination (–10.5% for FLI of 60 or more; –6.5% for NLFS of –0.640 or more), Dr. Guja said, and biomarker scores suggestive of advanced fibrosis (NFS greater than 0.676; FIB-4 of 1.46 or more) were reduced by 4.1% and 3.6%, respectively.
At 28 and 52 weeks, the combination therapy showed stronger effects than exenatide and dapagliflozin alone in improving markers of hepatic steatosis (FLI: 28 weeks, –6.81, –3.90, –4.04; and 52 weeks, –6.23, –3.00, –4.58). The combination therapy also showed improvement for advanced fibrosis biomarkers at both time points (FIB-4: 28 weeks, –0.06, –0.03, –0.04; and 52 weeks, –0.05, –0.02, –0,04).
Dr. Guja noted that, although the study was not powered to assess the effect of on fatty liver, making all these data exploratory, this was the first analysis to describe improvements in biomarkers of fatty liver or steatosis and fibrosis from a large trial. “Some specific, dedicated, prospective trials are needed in the future to validate these findings.”
The CENTAUR study was funded by Allergan, of which Dr. Landgren is an employee. The phase 2b study with tirzepatide was supported by Eli Lilly. Dr. Haupt disclosed being an employee and also holding stocks in the company. The DURATION-8 study was sponsored by AstraZeneca. Dr. Guja disclosed that he had participated in scientific advisory boards and received consulting fees from AstraZeneca and other companies.
SOURCES: Landgren H et al. EASD 2019, Oral Presentation 179; Haupt A et al. EASD 2019, Oral Presentation 177; Guja C et al. EASD 2019, Oral Presentation 178.
BARCELONA – The investigational oral agent cenicriviroc showed positive effects on liver fibrosis in adults with nonalcoholic steatohepatitis (NASH), many of whom had type 2 diabetes, in a phase 2b trial reported at the annual meeting of the European Association for the Study of Diabetes.
Other data released at the meeting, which showed potential positive effects of novel or existing diabetes treatments on nonalcoholic fatty liver disease (NAFLD), included post hoc analyses of a phase 2b study with tirzepatide and a phase 3 study that combined exenatide and dapagliflozin.
Currently, no medications for NAFLD or NASH have been approved in the United States.
CENTAUR with cenicriviroc
Results of the previously reported CENTAUR trial showed that the antifibrotic effects of cenicriviroc, a dual chemokine receptor antagonist, were greatest in patients with more-severe liver disease (Hepatology. 2018;67[5]:1754-67). At the meeting, Henrik Landgren, PhD, of Allergan, presented data from the 2-year trial overall, and specifically in patients with advanced, stage 3 fibrosis.
CENTAUR was a randomized, double-blind, placebo-controlled, multinational study with 289 adults who had biopsy-confirmed NASH, an NAFLD Activity Score (NAS; range, 0-8; score of 5 or more diagnostic of NASH) of 4 or more, and stages 1-3 liver fibrosis as determined by the NASH clinical research network system (Contemp Clin Trials. 2016;47:356-65). The mean age of the patients enrolled at baseline was 54 years, the mean body mass index was 33.9 kg/m2, and just more than half the patients (52%) had type 2 diabetes.
The patients were randomized to three treatment arms: cenicriviroc 150 mg for 2 years; placebo for 1 year, then cenicriviroc 150 mg for 1 year; or placebo for 2 years. The primary endpoint was histologic improvement (reduction of 2 or more points in overall NAS, with reduction of 1 or more points in more than one category of the NAS without worsening of fibrosis at the end of year 1. The key secondary endpoint was complete NASH resolution without worsening of fibrosis at year 2.
Dr. Landgren reported that, at year 1, of the total number of patients, 28.6% of those receiving cenicriviroc achieved an improvement in fibrosis of one or more stages, compared with 19.0% of those receiving placebo. Of the 97 patients who had advanced fibrosis at baseline, 38.3% of those on cenicriviroc and 28.0% of those on placebo achieved the same endpoint.
Those effects were sustained at year 2, Dr. Landgren emphasized, with twice as many cenicriviroc- than placebo-treated patients achieving one or more stage improvement in fibrosis and no worsening of NASH at year 2 (60% and 30%, respectively), with more pronounced improvements in those who had advanced fibrosis at baseline (86% and 60%).
In addition, analyses of biomarkers suggested that cenicriviroc had systematic anti-inflammatory activity, with reductions observed in high-sensitivity C-reactive protein; fibrinogen; and levels of interleukin-6, IL-8, and IL-1-beta.
Dr. Landgren and colleagues noted that cenicriviroc provided antifibrotic benefit in patients with NASH and fibrosis. Those benefits were sustained through year 2 and were more pronounced in patients who had advanced fibrosis at baseline.
The safety of cenicriviroc was “comparable with placebo,” he said, suggesting that the data supported the phase 3 AURORA study that is currently recruiting.
Tirzepatide for NASH
Another approach worth exploring for the treatment of NASH, is the use of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and the glucagonlike peptide–1 (GLP-1) receptor, according to Axel Haupt, MD, PhD, of Eli Lilly.
Tirzepatide (LY3298176) is currently under investigation for the treatment of type 2 diabetes, and Dr. Haupt reported data from a post hoc analysis of a double-blind, placebo-controlled, phase 2b study showing that “exploratory” serum markers of apoptosis and fibrosis – keratin-18 (K-18) and Pro-C3, respectively – were decreased from baseline to a greater extent in patients treated with tirzepatide than with placebo, while total adiponectin was increased. The latter is “thought to protect the liver from inflammation and fibrosis,” Dr. Haupt observed.
The main results of the trial were published last year (Lancet. 2018;392:2180-93) and showed that, after 26 weeks, there was a dose-dependent decrease in both glycated hemoglobin (HbA1c) and body weight with tirzepatide 10 mg and 15 mg, compared with placebo and an active comparator, dulaglutide 1.5 mg.
The study population was typical of type 2 diabetes: baseline HbA1c was 8.1%; the average body mass index was 32 kg/m2, with a diabetes duration of 5 years; and the main treatment (90%) had been metformin.
The rationale for the NASH-related biomarker analysis was that type 2 diabetes and NAFLD were known to be overlapping conditions, and weight loss had been shown to be an effective means of resolving NASH, Dr. Haupt said. In addition, a small “proof-of-concept” study with the GLP-1 receptor agonist liraglutide had suggested that these drugs may be effective in NASH.
Tirzepatide, at doses of 5, 10, and 15 mg, was associated with significant decreases in K-18 from baseline to week 26 and compared with placebo and the 1-mg tirzepatide dose. Mean baseline concentrations of K-18 were 394.4 U/L in the placebo group and reduced by 22.6 U/L by week 26. Corresponding baseline values for tirzepatide 5 mg were 375.8 U/L (change, –87.6 U/L); for 10 mg, 409.9 U/L (–157.8 U/L); and for 15 mg, 376.2 U/L (–110.6 U/L).
Dr. Haupt noted that a K-18 value of 250 U/L was considered a cutoff for a diagnosis of NASH. “So we really think that we have some NASH patients in this population,” he observed.
At week 26, Pro-C3 levels significantly decreased by 1.2 ng/mL from a baseline of 8.6 ng/mL with tirzepatide 15 mg, compared with an increase of 0.9 ng/mL from a baseline of 9.3 ng/mL for placebo (P less than .05). However, values of between 15-20 ng/mL would be expected for advanced fibrosis, Dr. Haupt said, “so we think we [don’t] have a lot of patients with advanced fibrosis, we have a lower grade of fibrosis or no fibrosis in our patient population.”
By week 26, adiponectin levels significantly increased by 0.9 mg/L from baseline, both with tirzepatide 10 mg (P less than .05) and 15 mg (P less than .05), compared with placebo (–0.1 mg/L; both P less than .05).
“This study was really designed as a type 2 diabetes efficacy study, so the NASH biomarker work is exploratory and only hypothesis generating,” Dr. Haupt noted. “We think there is overlap in type 2 diabetes and NASH, but it is not an ideal population to look into those biomarkers.” There are also other limitations, such as the baseline values across treatment groups not being matched, so there is likely to be some inconsistency in these data, he added.
That said, Dr. Haupt concluded that, “along with the weight-loss findings,” these exploratory biomarker findings supported the further evaluation of tirzepatide in patients with NASH.”
DURATION-8: Exenatide plus dapagliflozin
In another hypothesis-generating post hoc analysis, this time of the phase 3 DURATION-8 clinical trial, a combination of exenatide and dapagliflozin was found to have a beneficial effect on markers of hepatic steatosis and fibrosis in patients with type 2 diabetes.
“We have some good evidence that both GLP-1 receptor agonists and SGLT2 [sodium-glucose cotransporter 2] inhibitors may have benefits in reducing steatosis and even steatohepatitis in [patients with] type 2 diabetes. So the association of two diabetes drugs might provide an advantage. However, this had not previously been tested in a randomized, controlled trial,” observed Cristian Guja, MD, PhD, of Carol Davila University of Medicine and Pharmacy in Bucharest, Romania.
The main aims of the DURATION-8 clinical trial, which ran for 104 weeks, was to compare the efficacy and safety of combining exenatide (2 mg, once a week) and dapagliflozin (10 mg, daily) with either exenatide 2 mg with placebo or dapagliflozin 10 mg with placebo. Results showed greater improved glycemic control and reductions in body weight and systolic BP with the exenatide-dapagliflozin combination.
A total of 685 patients were included in the post hoc analysis, of whom 228 had been treated with the combination, 228 with exenatide plus placebo, and 230 with dapagliflozin plus placebo. At baseline, levels of the markers of NAFLD and fibrosis that were assessed were similar between the groups. Between 81% and 93% of study participants had fatty liver or steatosis as defined by a Fatty Liver Index (FLI) of 60 or more or an overall NAFLD Liver Fat Score (NLFS) of –0.64 or higher. Between 9% and 13% of patients had liver fibrosis, as defined as an NAFLD Fibrosis Score (NFS) above 0.676, a Fibrosis-4 score (FIB-4) of 1.46 or more, or both.
At 28 weeks, the proportion of patients with biomarker scores suggestive of fatty liver disease or steatosis was significantly reduced from baseline with the exenatide-dapagliflozin combination (–10.5% for FLI of 60 or more; –6.5% for NLFS of –0.640 or more), Dr. Guja said, and biomarker scores suggestive of advanced fibrosis (NFS greater than 0.676; FIB-4 of 1.46 or more) were reduced by 4.1% and 3.6%, respectively.
At 28 and 52 weeks, the combination therapy showed stronger effects than exenatide and dapagliflozin alone in improving markers of hepatic steatosis (FLI: 28 weeks, –6.81, –3.90, –4.04; and 52 weeks, –6.23, –3.00, –4.58). The combination therapy also showed improvement for advanced fibrosis biomarkers at both time points (FIB-4: 28 weeks, –0.06, –0.03, –0.04; and 52 weeks, –0.05, –0.02, –0,04).
Dr. Guja noted that, although the study was not powered to assess the effect of on fatty liver, making all these data exploratory, this was the first analysis to describe improvements in biomarkers of fatty liver or steatosis and fibrosis from a large trial. “Some specific, dedicated, prospective trials are needed in the future to validate these findings.”
The CENTAUR study was funded by Allergan, of which Dr. Landgren is an employee. The phase 2b study with tirzepatide was supported by Eli Lilly. Dr. Haupt disclosed being an employee and also holding stocks in the company. The DURATION-8 study was sponsored by AstraZeneca. Dr. Guja disclosed that he had participated in scientific advisory boards and received consulting fees from AstraZeneca and other companies.
SOURCES: Landgren H et al. EASD 2019, Oral Presentation 179; Haupt A et al. EASD 2019, Oral Presentation 177; Guja C et al. EASD 2019, Oral Presentation 178.
BARCELONA – The investigational oral agent cenicriviroc showed positive effects on liver fibrosis in adults with nonalcoholic steatohepatitis (NASH), many of whom had type 2 diabetes, in a phase 2b trial reported at the annual meeting of the European Association for the Study of Diabetes.
Other data released at the meeting, which showed potential positive effects of novel or existing diabetes treatments on nonalcoholic fatty liver disease (NAFLD), included post hoc analyses of a phase 2b study with tirzepatide and a phase 3 study that combined exenatide and dapagliflozin.
Currently, no medications for NAFLD or NASH have been approved in the United States.
CENTAUR with cenicriviroc
Results of the previously reported CENTAUR trial showed that the antifibrotic effects of cenicriviroc, a dual chemokine receptor antagonist, were greatest in patients with more-severe liver disease (Hepatology. 2018;67[5]:1754-67). At the meeting, Henrik Landgren, PhD, of Allergan, presented data from the 2-year trial overall, and specifically in patients with advanced, stage 3 fibrosis.
CENTAUR was a randomized, double-blind, placebo-controlled, multinational study with 289 adults who had biopsy-confirmed NASH, an NAFLD Activity Score (NAS; range, 0-8; score of 5 or more diagnostic of NASH) of 4 or more, and stages 1-3 liver fibrosis as determined by the NASH clinical research network system (Contemp Clin Trials. 2016;47:356-65). The mean age of the patients enrolled at baseline was 54 years, the mean body mass index was 33.9 kg/m2, and just more than half the patients (52%) had type 2 diabetes.
The patients were randomized to three treatment arms: cenicriviroc 150 mg for 2 years; placebo for 1 year, then cenicriviroc 150 mg for 1 year; or placebo for 2 years. The primary endpoint was histologic improvement (reduction of 2 or more points in overall NAS, with reduction of 1 or more points in more than one category of the NAS without worsening of fibrosis at the end of year 1. The key secondary endpoint was complete NASH resolution without worsening of fibrosis at year 2.
Dr. Landgren reported that, at year 1, of the total number of patients, 28.6% of those receiving cenicriviroc achieved an improvement in fibrosis of one or more stages, compared with 19.0% of those receiving placebo. Of the 97 patients who had advanced fibrosis at baseline, 38.3% of those on cenicriviroc and 28.0% of those on placebo achieved the same endpoint.
Those effects were sustained at year 2, Dr. Landgren emphasized, with twice as many cenicriviroc- than placebo-treated patients achieving one or more stage improvement in fibrosis and no worsening of NASH at year 2 (60% and 30%, respectively), with more pronounced improvements in those who had advanced fibrosis at baseline (86% and 60%).
In addition, analyses of biomarkers suggested that cenicriviroc had systematic anti-inflammatory activity, with reductions observed in high-sensitivity C-reactive protein; fibrinogen; and levels of interleukin-6, IL-8, and IL-1-beta.
Dr. Landgren and colleagues noted that cenicriviroc provided antifibrotic benefit in patients with NASH and fibrosis. Those benefits were sustained through year 2 and were more pronounced in patients who had advanced fibrosis at baseline.
The safety of cenicriviroc was “comparable with placebo,” he said, suggesting that the data supported the phase 3 AURORA study that is currently recruiting.
Tirzepatide for NASH
Another approach worth exploring for the treatment of NASH, is the use of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and the glucagonlike peptide–1 (GLP-1) receptor, according to Axel Haupt, MD, PhD, of Eli Lilly.
Tirzepatide (LY3298176) is currently under investigation for the treatment of type 2 diabetes, and Dr. Haupt reported data from a post hoc analysis of a double-blind, placebo-controlled, phase 2b study showing that “exploratory” serum markers of apoptosis and fibrosis – keratin-18 (K-18) and Pro-C3, respectively – were decreased from baseline to a greater extent in patients treated with tirzepatide than with placebo, while total adiponectin was increased. The latter is “thought to protect the liver from inflammation and fibrosis,” Dr. Haupt observed.
The main results of the trial were published last year (Lancet. 2018;392:2180-93) and showed that, after 26 weeks, there was a dose-dependent decrease in both glycated hemoglobin (HbA1c) and body weight with tirzepatide 10 mg and 15 mg, compared with placebo and an active comparator, dulaglutide 1.5 mg.
The study population was typical of type 2 diabetes: baseline HbA1c was 8.1%; the average body mass index was 32 kg/m2, with a diabetes duration of 5 years; and the main treatment (90%) had been metformin.
The rationale for the NASH-related biomarker analysis was that type 2 diabetes and NAFLD were known to be overlapping conditions, and weight loss had been shown to be an effective means of resolving NASH, Dr. Haupt said. In addition, a small “proof-of-concept” study with the GLP-1 receptor agonist liraglutide had suggested that these drugs may be effective in NASH.
Tirzepatide, at doses of 5, 10, and 15 mg, was associated with significant decreases in K-18 from baseline to week 26 and compared with placebo and the 1-mg tirzepatide dose. Mean baseline concentrations of K-18 were 394.4 U/L in the placebo group and reduced by 22.6 U/L by week 26. Corresponding baseline values for tirzepatide 5 mg were 375.8 U/L (change, –87.6 U/L); for 10 mg, 409.9 U/L (–157.8 U/L); and for 15 mg, 376.2 U/L (–110.6 U/L).
Dr. Haupt noted that a K-18 value of 250 U/L was considered a cutoff for a diagnosis of NASH. “So we really think that we have some NASH patients in this population,” he observed.
At week 26, Pro-C3 levels significantly decreased by 1.2 ng/mL from a baseline of 8.6 ng/mL with tirzepatide 15 mg, compared with an increase of 0.9 ng/mL from a baseline of 9.3 ng/mL for placebo (P less than .05). However, values of between 15-20 ng/mL would be expected for advanced fibrosis, Dr. Haupt said, “so we think we [don’t] have a lot of patients with advanced fibrosis, we have a lower grade of fibrosis or no fibrosis in our patient population.”
By week 26, adiponectin levels significantly increased by 0.9 mg/L from baseline, both with tirzepatide 10 mg (P less than .05) and 15 mg (P less than .05), compared with placebo (–0.1 mg/L; both P less than .05).
“This study was really designed as a type 2 diabetes efficacy study, so the NASH biomarker work is exploratory and only hypothesis generating,” Dr. Haupt noted. “We think there is overlap in type 2 diabetes and NASH, but it is not an ideal population to look into those biomarkers.” There are also other limitations, such as the baseline values across treatment groups not being matched, so there is likely to be some inconsistency in these data, he added.
That said, Dr. Haupt concluded that, “along with the weight-loss findings,” these exploratory biomarker findings supported the further evaluation of tirzepatide in patients with NASH.”
DURATION-8: Exenatide plus dapagliflozin
In another hypothesis-generating post hoc analysis, this time of the phase 3 DURATION-8 clinical trial, a combination of exenatide and dapagliflozin was found to have a beneficial effect on markers of hepatic steatosis and fibrosis in patients with type 2 diabetes.
“We have some good evidence that both GLP-1 receptor agonists and SGLT2 [sodium-glucose cotransporter 2] inhibitors may have benefits in reducing steatosis and even steatohepatitis in [patients with] type 2 diabetes. So the association of two diabetes drugs might provide an advantage. However, this had not previously been tested in a randomized, controlled trial,” observed Cristian Guja, MD, PhD, of Carol Davila University of Medicine and Pharmacy in Bucharest, Romania.
The main aims of the DURATION-8 clinical trial, which ran for 104 weeks, was to compare the efficacy and safety of combining exenatide (2 mg, once a week) and dapagliflozin (10 mg, daily) with either exenatide 2 mg with placebo or dapagliflozin 10 mg with placebo. Results showed greater improved glycemic control and reductions in body weight and systolic BP with the exenatide-dapagliflozin combination.
A total of 685 patients were included in the post hoc analysis, of whom 228 had been treated with the combination, 228 with exenatide plus placebo, and 230 with dapagliflozin plus placebo. At baseline, levels of the markers of NAFLD and fibrosis that were assessed were similar between the groups. Between 81% and 93% of study participants had fatty liver or steatosis as defined by a Fatty Liver Index (FLI) of 60 or more or an overall NAFLD Liver Fat Score (NLFS) of –0.64 or higher. Between 9% and 13% of patients had liver fibrosis, as defined as an NAFLD Fibrosis Score (NFS) above 0.676, a Fibrosis-4 score (FIB-4) of 1.46 or more, or both.
At 28 weeks, the proportion of patients with biomarker scores suggestive of fatty liver disease or steatosis was significantly reduced from baseline with the exenatide-dapagliflozin combination (–10.5% for FLI of 60 or more; –6.5% for NLFS of –0.640 or more), Dr. Guja said, and biomarker scores suggestive of advanced fibrosis (NFS greater than 0.676; FIB-4 of 1.46 or more) were reduced by 4.1% and 3.6%, respectively.
At 28 and 52 weeks, the combination therapy showed stronger effects than exenatide and dapagliflozin alone in improving markers of hepatic steatosis (FLI: 28 weeks, –6.81, –3.90, –4.04; and 52 weeks, –6.23, –3.00, –4.58). The combination therapy also showed improvement for advanced fibrosis biomarkers at both time points (FIB-4: 28 weeks, –0.06, –0.03, –0.04; and 52 weeks, –0.05, –0.02, –0,04).
Dr. Guja noted that, although the study was not powered to assess the effect of on fatty liver, making all these data exploratory, this was the first analysis to describe improvements in biomarkers of fatty liver or steatosis and fibrosis from a large trial. “Some specific, dedicated, prospective trials are needed in the future to validate these findings.”
The CENTAUR study was funded by Allergan, of which Dr. Landgren is an employee. The phase 2b study with tirzepatide was supported by Eli Lilly. Dr. Haupt disclosed being an employee and also holding stocks in the company. The DURATION-8 study was sponsored by AstraZeneca. Dr. Guja disclosed that he had participated in scientific advisory boards and received consulting fees from AstraZeneca and other companies.
SOURCES: Landgren H et al. EASD 2019, Oral Presentation 179; Haupt A et al. EASD 2019, Oral Presentation 177; Guja C et al. EASD 2019, Oral Presentation 178.
REPORTING FROM EASD 2019