Semaglutide 2.4 mg once weekly improved liver and metabolic parameters, and was well tolerated, in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial

Loomba, Rohit; Abdelmalek, Manal F.; Armstrong, Matthew J.; Jara, Maximilian; Kjær, Mette; Krarup, Niels; Lawitz, Eric; Ratziu, Vlad; Sanyal, Arun J.; Schattenberg, Jörn M.; Newsome, Philip

doi:10.1016/s0168-8278(22)00440-8

Cited by 42 publications

(53 citation statements)

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“…Exenatide (3 RCTs), liraglutide (6 RCTs), dulaglutide (1 RCT) and semaglutide (4 RCT) have been tested in patients with NAFLD to assess their efficacy 56–60 . All these drugs improve the clinical features of NAFLD, and all reduce plasma levels of aminotransferases.…”

Section: Glucagon‐like Peptide‐1 Receptor Agonistsmentioning

confidence: 99%

“…All these drugs improve the clinical features of NAFLD, and all reduce plasma levels of aminotransferases. Exenatide, liraglutide and dulaglutide reduce hepatic fat content assessed by magnetic resonance; liraglutide and semaglutide reduce the histological features of NASH, thus preventing the worsening of inflammation but have no effect on liver fibrosis stages or in NASH‐related cirrhosis 58,61–65 . A trial has been designed to evaluate oral semaglutide in hepatic steatosis (NCT03884075) and a pilot study has shown that this new drug formulation improves indexes of hepatic steatosis and fibrosis in T2D subjects 66 …”

Section: Glucagon‐like Peptide‐1 Receptor Agonistsmentioning

confidence: 99%

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Why do some glucose‐lowering agents improve non‐alcoholic fatty liver disease whereas others do not? A narrative review in search of a unifying hypothesis

Ciccarelli

Giuseppe

Cinti

et al. 2023

Diabetes Metabolism Res

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Non‐alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are metabolic disorders connected by common pathophysiological mechanisms. Since insulin resistance (IR) and metabolic alterations are common to both conditions, almost all glucose‐lowering agents which improve IR have also been studied in patients with NAFLD. Some have shown great efficacy, others none. Thus, the mechanisms behind the efficacy of these drugs in improving hepatic steatosis, steatohepatitis, and eventually fibrosis remain controversial. Glycaemic control improves T2D, but probably has limited effects on NAFLD, as all glucose‐lowering agents ameliorate glucose control but only a few improve NAFLD features. In contrast, drugs that either improve adipose tissue function, reduce lipid ingestion, or increase lipid oxidation are particularly effective in NAFLD. We therefore hypothesise that improved free fatty acid metabolism may be the unifying mechanism behind the efficacy of some glucose‐lowering agents on NAFLD and may represent the key to NAFLD treatment.

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Section: Glucagon‐like Peptide‐1 Receptor Agonistsmentioning

confidence: 99%

Section: Glucagon‐like Peptide‐1 Receptor Agonistsmentioning

confidence: 99%

Why do some glucose‐lowering agents improve non‐alcoholic fatty liver disease whereas others do not? A narrative review in search of a unifying hypothesis

Ciccarelli

Giuseppe

Cinti

et al. 2023

Diabetes Metabolism Res

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“…While weight loss of 5%–10% in compensated cirrhosis has been shown to reduce liver disease progression and improve portal pressures,132 there have been residual concerns about the potential to precipitate sarcopenia and decompensation. Reassuringly, no decompensating events were reported in a randomised trial of semaglutide in compensated NASH cirrhosis despite 9% wt loss 133. Trials of IF in both elderly populations and in high-performance athletes have also not demonstrated any associations with reduced muscle mass or function 134 135.…”

Section: Introductionmentioning

confidence: 99%

Timing of energy intake and the therapeutic potential of intermittent fasting and time-restricted eating in NAFLD

Marjot

Tomlinson

Hodson

et al. 2023

Gut

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Non-alcoholic fatty liver disease (NAFLD) represents a major public health concern and is associated with a substantial global burden of liver-related and cardiovascular-related morbidity and mortality. High total energy intake coupled with unhealthy consumption of ultra-processed foods and saturated fats have long been regarded as major dietary drivers of NAFLD. However, there is an accumulating body of evidence demonstrating that the timing of energy intake across a the day is also an important determinant of individual risk for NAFLD and associated metabolic conditions. This review summarises the available observational and epidemiological data describing associations between eating patterns and metabolic disease, including the negative effects of irregular meal patterns, skipping breakfast and night-time eating on liver health. We suggest that that these harmful behaviours deserve greater consideration in the risk stratification and management of patients with NAFLD particularly in a 24-hour society with continuous availability of food and with up to 20% of the population now engaged in shiftwork with mistimed eating patterns. We also draw on studies reporting the liver-specific impact of Ramadan, which represents a unique real-world opportunity to explore the physiological impact of fasting. By highlighting data from preclinical and pilot human studies, we present a further biological rationale for manipulating timing of energy intake to improve metabolic health and discuss how this may be mediated through restoration of natural circadian rhythms. Lastly, we comprehensively review the landscape of human trials of intermittent fasting and time-restricted eating in metabolic disease and offer a look to the future about how these dietary strategies may benefit patients with NAFLD and non-alcoholic steatohepatitis.

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“…As mentioned by Dr. Di Bisceglie, semaglutide was associated with reductions in body weight and glycated haemoglobin. In a phase 2 trial in patients with NASH and cirrhosis (F4), once‐weekly semaglutide 2.4 mg led to similar metabolic improvements, although the primary endpoint of fibrosis improvement without worsening of NASH was not met 7 . It is thus also probable that the final effect on QoL in these patients depends on three factors: semaglutide, NASH resolution, and improvement in metabolic parameters.…”

mentioning

confidence: 99%

“…In a phase 2 trial in patients with NASH and cirrhosis (F4), once-weekly semaglutide 2.4 mg led to similar metabolic improvements, although the primary endpoint of fibrosis improvement without worsening of NASH was not met. 7 It is thus also probable that the final effect on QoL in these patients depends on three factors: semaglutide, NASH resolution, and improvement in metabolic parameters. Including patient-reported outcome and HRQoL analyses in clinical trials could allow us to better understand the effect of these drugs on the overall health of people living with non-alcoholic fatty liver disease.…”

mentioning

confidence: 99%

Editorial: Feeling better about NASH—Authors' reply

Romero‐Gómez

Armstrong

Funuyet‐Salas

et al. 2023

Aliment Pharmacol Ther

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We would like to comment on the excellent editorial by Dr. Di Bisceglie discussing our study on quality of life (QoL) outcomes in patients with non-alcoholic steatohepatitis (NASH) and fibrosis stage (F) 2-3 who were treated with semaglutide or placebo in a phase 2 randomised trial. 1,2 The association between NASH and QoL has been largely addressed. Fatigue, together with pruritus, sleep disorders, abdominal pain, anxiety and somnolence, is common in patients with NASH. These patient-reported outcomes promoted an impairment in health-related QoL (HRQoL). 3 Hepatic fibrosis is a major driver of poor HRQoL, but there is also an association with inflammation and female sex.Dr. Di Bisceglie raises the question of the mechanism(s) by which improvements in QoL may have occurred with once-daily semaglutide 0.4 mg, and in patients with resolution of NASH in both arms, postulating that reduced liver inflammation may be relevant for improving QoL. This naturally leads to consideration of potential mechanistic links between the liver and brain. Could semaglutide promote changes in the liver that affect perceptions of bodily pain? And, if so, which biomarkers could help to evaluate this? Fatty liver disease is associated with brain inflammation, and monocarboxylate transporter-1 has recently been identified as a potential mechanistic link between steatosis and alterations in brain chemistry. 4 Semaglutide is currently being studied in brain disorders due to its potential ability to improve neuroinflammation. 5 Nevertheless, more research on a potential modifying effect of semaglutide on biomarkers could help to further elucidate liver-brain mechanisms in NASH.Dr. Di Bisceglie correctly notes that, as well as improving symptoms related to QoL, a therapy that mitigates liver disease itself is still needed for patients with NASH. It is therefore worth reiterating the primary outcome of this trial, namely that once-daily semaglutide 0.4 mg led to significantly greater rates of NASH resolution without worsening of fibrosis than placebo over 72 weeks. 6 As mentioned by Dr. Di Bisceglie, semaglutide was associated with reductions in body weight and glycated haemoglobin. In a phase 2 trial in patients with NASH and cirrhosis (F4), once-weekly semaglutide 2.4 mg led to similar metabolic improvements, although the primary endpoint of fibrosis improvement without worsening of NASH was not met. 7 It is thus also probable that the final effect on QoL in these patients depends on three factors: semaglutide, NASH resolution, and improvement in metabolic parameters. Including patient-reported outcome and HRQoL analyses in clinical trials could allow us to better understand the effect of these drugs on the overall health of people living with non-alcoholic fatty liver disease.

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Semaglutide 2.4 mg once weekly improved liver and metabolic parameters, and was well tolerated, in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial

Cited by 42 publications

References 0 publications

Why do some glucose‐lowering agents improve non‐alcoholic fatty liver disease whereas others do not? A narrative review in search of a unifying hypothesis

Why do some glucose‐lowering agents improve non‐alcoholic fatty liver disease whereas others do not? A narrative review in search of a unifying hypothesis

Timing of energy intake and the therapeutic potential of intermittent fasting and time-restricted eating in NAFLD

Editorial: Feeling better about NASH—Authors' reply

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