Safety and Efficacy of Glucagon-like Peptide 1 Receptor Agonists in Patients With Cirrhosis

Disease-modifying treatments remain an unmet need in the management of cirrhosis and are an ongoing focus of research. Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of entities, from simple steatosis to hepatocyte inflammation/ballooning (nonalcoholic steatohepatitis [NASH]) and advancing fibrosis through to cirrhosis; the latter bringing the greatest risk of liver-related and all-cause mortality.1Sanyal A.J. Past, present and future perspectives in nonalcoholic fatty liver disease.Nat Rev Gastroenterol Hepatol. 2019; 16: 377-386Crossref PubMed Scopus (201) Google Scholar Its prevalence has increased in parallel with type 2 diabetes (T2DM) and obesity, now representing one of the commonest causes of cirrhosis.1Sanyal A.J. Past, present and future perspectives in nonalcoholic fatty liver disease.Nat Rev Gastroenterol Hepatol. 2019; 16: 377-386Crossref PubMed Scopus (201) Google Scholar There are several pathophysiological mechanisms underpinning the complex interplay between NAFLD, T2DM, and obesity with deranged lipid metabolism, inflammation, lipotoxicity, and insulin resistance key drivers behind the process.1Sanyal A.J. Past, present and future perspectives in nonalcoholic fatty liver disease.Nat Rev Gastroenterol Hepatol. 2019; 16: 377-386Crossref PubMed Scopus (201) Google Scholar,2Khan R.S. Bril F. Cusi K. et al.Modulation of insulin resistance in nonalcoholic fatty liver disease.Hepatology. 2019; 70: 711-724PubMed Google Scholar As such, these pathways have been evaluated for potential disease-modifying agents.1Sanyal A.J. Past, present and future perspectives in nonalcoholic fatty liver disease.Nat Rev Gastroenterol Hepatol. 2019; 16: 377-386Crossref PubMed Scopus (201) Google Scholar Glucagon-like peptide 1 (GLP-1) is an endogenous hormone released in response to food consumption, lowering blood glucose through insulin secretion and glucagon inhibition, suppressing appetite, and delaying gastric emptying.3Armstrong M.J. Glucagon-like peptide-1 analogues in nonalcoholic steatohepatitis: from bench to bedside.Clin liver Dis. 2017; 10: 32-35Crossref Scopus (3) Google Scholar Long-acting analogues were licensed in the last 20 years for use in overweight patients with T2DM because of benefits with reducing glycated hemoglobin A1c and facilitating weight loss.4Knudsen L.B. Lau J. The discovery and development of liraglutide and semaglutide.Front Endocrinol (Lausanne). 2019; 10: 155Crossref PubMed Scopus (208) Google Scholar Given the link between insulin resistance, adipose tissue, and inflammation, GLP-1 research in liver disease has focused on NASH, and in several preclinical and clinical studies GLP-1 analogues have been shown to improve liver enzymes, oxidative stress, and hepatic steatosis.3Armstrong M.J. Glucagon-like peptide-1 analogues in nonalcoholic steatohepatitis: from bench to bedside.Clin liver Dis. 2017; 10: 32-35Crossref Scopus (3) Google Scholar These have been supported by promising results in key randomized control trials demonstrating enhanced histologic resolution of NASH with liraglutide5Armstrong M.J. Gaunt P. Aithal G.P. et al.Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.Lancet. 2016; 387: 679-690Abstract Full Text Full Text PDF PubMed Scopus (951) Google Scholar and semaglutide6Newsome P.N. Buchholtz K. Cusi K. et al.A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.N Engl J Med. 2020; 384: 1113-1124Crossref PubMed Scopus (289) Google Scholar compared with placebo, alongside significant improvements in glycemic control and weight loss.7Mantovani A. Petracca G. Beatrice G. et al.Glucagon-like peptide-1 receptor agonists for treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: an updated meta-analysis of randomized controlled trials.Metabolites. 2021; 11: 1-13Crossref Scopus (60) Google Scholar The beneficial effects of GLP-1 are multifactorial, through a combination of improved systemic, hepatic, and adipose insulin sensitivity, weight loss, and reduced hepatic de novo lipogenesis.3Armstrong M.J. Glucagon-like peptide-1 analogues in nonalcoholic steatohepatitis: from bench to bedside.Clin liver Dis. 2017; 10: 32-35Crossref Scopus (3) Google Scholar Beneficial effects of GLP-1 analogues are also observed in cardiovascular disease, which is the commonest cause of morbidity and mortality in patients with NAFLD.8Stefan N. Häring H.-U. Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies.Lancet Diabetes Endocrinol. 2019; 7: 313-324Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar A large meta-analysis of 7 randomized control trials totaling 56,004 patients with T2DM demonstrated that GLP-1 treatment reduced major adverse cardiovascular events by 12% (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.82–0.94; P < .001).9Kristensen S.L. Rørth R. Jhund P.S. et al.Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.Lancet Diabetes Endocrinol. 2019; 7: 776-785Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar There are several mechanisms contributing to the observed effect including weight loss, blood pressure, and glycemic control in addition to improved endothelial function, reduced vascular inflammation, and lipid accumulation.10Sharma A. Verma S. Mechanisms by which glucagon-like-peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors reduce cardiovascular risk in adults with type 2 diabetes mellitus.Can J Diabetes. 2020; 44: 93-102Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Many of the trials evaluating the efficacy of GLP-1 agonists in patients with T2DM excluded those with significantly deranged liver enzymes and/or known cirrhosis. In a systematic review and meta-analysis of 11 trials (N = 936) in NAFLD and NASH, GLP-1 analogues were safe and well tolerated albeit with an increased rate of gastrointestinal disturbances (nausea, abdominal discomfort) compared with placebo.7Mantovani A. Petracca G. Beatrice G. et al.Glucagon-like peptide-1 receptor agonists for treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: an updated meta-analysis of randomized controlled trials.Metabolites. 2021; 11: 1-13Crossref Scopus (60) Google Scholar The gastrointestinal side effects tended to be mild and transient, only lasting 1–2 weeks. It should be noted, however, that patients included mostly had varying degrees of steatosis and fibrosis without established cirrhosis. In this issue of Clinical Gastroenterology and Hepatology, Simon et al11Simon T.G. Patorno E. Schneeweiss S. Glucose-like peptide-1 receptor agonists and hepatic decompensation events in patients with cirrhosis and diabetes.Clin Gastroenterol Hepatol. 2022; 20: 1382-1393Abstract Full Text Full Text PDF Scopus (5) Google Scholar present a retrospective population-based cohort study comparing the effectiveness of GLP-1 receptor agonists (GLP-1RA) with other second-line antidiabetic agents (dipeptidyl peptidase-4 inhibitor [DPP4i], sulfonylureas, and sodium-glucose cotransporter-2 [SGLT2] inhibitors) at reducing risk of hepatic decompensation events in patients with cirrhosis and T2DM. A large nationwide US commercial claims dataset (IBM MarketScan) was used, and patients aged 18 and older were included with a diagnosis of T2DM and cirrhosis based on International Classification of Diseases coding. One-to-one propensity score–matched cohorts were identified based on >90 baseline characteristics and subjects with a diagnosis of type 1 diabetes, gestational diabetes, end-stage renal failure, or HIV infection were excluded. Incidence of hepatic decompensation was designated as the primary outcome, defined as hospitalization for ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, bleeding esophageal varices, or hepatic encephalopathy. Secondary outcomes included individual decompensation events. Patient follow-up started from date of drug initiation until study outcome reached, discontinuation or switch to a comparator, end of continuous health enrolment, end of study period or death. A limitation of the study was the length of follow-up (median, 132 days; interquartile range, 73–290 days), hence exclusion of hepatocellular cancer development as an endpoint. In cohorts receiving GLP-1RAs significantly fewer hepatic decompensation events were observed compared with DDP4i (1431 matched pairs; HR, 0.68; 95% CI, 0.53–0.88) and sulfonylureas (1246 matched pairs; HR, 0.64; 95% CI, 0.48–0.84), a finding also observed for individual decompensation events. These findings were also observed in multiple sensitivity analyses. Matched cohorts receiving GLP-1RAs or SGLT2 inhibitors experienced similar rates of decompensation events (845 matched pairs; HR, 0.89; 95% CI, 0.62–1.28); this was maintained in secondary outcome analysis of individual events. In the cohorts, unsurprisingly, >60% of patients had a diagnosis of NAFLD and findings persisted in subgroup analysis. Interestingly, these findings also persisted for viral hepatitis, but not alcohol-related liver disease. Subgroup analysis was not undertaken for SGLT2 inhibitors because of insufficient sample sizes. Importantly, in separate matched cohorts, the positive effect of GLP-1RA was observed in decompensated in addition to compensated cirrhosis and an independent study population (Optum). There are several strengths to this study deserving mention. This is a large study evaluating the association between GLP-1RA and hepatic decompensation events for the first time in patients with cirrhosis and T2DM. The authors undertook numerous sensitivity and subgroup analyses accounting for known triggers of decompensation and as far as is possible in a retrospective study have accounted for potential confounding factors. Moreover, reduction in hepatic decompensation persisted in an independent population with differing demographics and insurance scheme. The authors were rightly cautious to avoid drawing conclusions regarding a beneficial role exhibited by SGLT2 inhibitors because of a smaller sample size and as the newest drug class, although feasible physiological mechanisms have been proposed.8Stefan N. Häring H.-U. Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies.Lancet Diabetes Endocrinol. 2019; 7: 313-324Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar Although it is promising to observe possible benefit after a short treatment duration, in keeping with other trials,5Armstrong M.J. Gaunt P. Aithal G.P. et al.Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.Lancet. 2016; 387: 679-690Abstract Full Text Full Text PDF PubMed Scopus (951) Google Scholar median follow-up was <6 months. Indeed, modelling based on the Hagstrom dataset in 201812Hagström H. Nasr P. Ekstedt M. et al.Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD.J Hepatol. 2017; 67: 1265-1273Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar estimates the cumulative risk of hepatic decompensation to be 18% in patients with NASH cirrhosis over a period of 10 years, as compared with <5% over 1 year. Therefore, long-term follow-up in larger study populations is important to understand the true impact of GLP-1RA in patients with cirrhosis. The study population was formed from a US-based commercial claims dataset incorporating individuals commercially insured or with primary traditional Medicare insurance. Although differences were observed in a further database (Optum), it is important to evaluate uninsured patients and those outside of the United States, where demographics are likely to differ and where GLP-1 usage may be started at a later stage. Finally, the datasets lacked specific information regarding relative timing of diagnoses; indices of cirrhosis severity (ie, baseline portal hypertension); and relevant markers of GLP-1 efficacy, such as hemoglobin A1c or weight loss. It is important to identify whether timing of diagnoses impacts on rate of decompensation and useful to evaluate whether observed differences are related to change in hemoglobin A1c or weight. One of the concerns about GLP-1 usage in patients with cirrhosis relates to the potential impact on lean body mass (in particular skeletal muscle) and associated physical/muscle function. This is critical because patients with cirrhosis are already at significant risk of muscle wasting (sarcopenia), because of a multitude of reasons including marked protein catabolism, physical inactivity, and malabsorption. Although this may be offset by reductions in visceral fat, it is important to study this prospectively because it may require careful titration of GLP-1RA dosage3Armstrong M.J. Glucagon-like peptide-1 analogues in nonalcoholic steatohepatitis: from bench to bedside.Clin liver Dis. 2017; 10: 32-35Crossref Scopus (3) Google Scholar and close monitoring of muscle mass (imaging) and function (ie, hand grip strength, chair stands).13El-Sherif O. Dhaliwal A. Newsome P.N. et al.Sarcopenia in nonalcoholic fatty liver disease: new challenges for clinical practice.Expert Rev Gastroenterol Hepatol. 2020; 14: 197-205Crossref PubMed Scopus (17) Google Scholar In summary the retrospective study by Simon et al11Simon T.G. Patorno E. Schneeweiss S. Glucose-like peptide-1 receptor agonists and hepatic decompensation events in patients with cirrhosis and diabetes.Clin Gastroenterol Hepatol. 2022; 20: 1382-1393Abstract Full Text Full Text PDF Scopus (5) Google Scholar is an important contribution to GLP-1 research in cirrhosis, being the first to evaluate the role of GLP-1RA in reducing hepatic decompensation. Even though the observed treatment duration was short (<6 months) and the severity of cirrhosis (ie, presence of portal hypertension) was not available, the study highlights a similar safety and tolerability profile in cirrhosis to those previously reported in patients without cirrhosis.5Armstrong M.J. Gaunt P. Aithal G.P. et al.Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.Lancet. 2016; 387: 679-690Abstract Full Text Full Text PDF PubMed Scopus (951) Google Scholar,6Newsome P.N. Buchholtz K. Cusi K. et al.A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.N Engl J Med. 2020; 384: 1113-1124Crossref PubMed Scopus (289) Google Scholar Given the impact of elevated body mass index in preventing regression of cirrhosis in patients with hepatitis B receiving tenofovir,14Marcellin P. Gane E. Buti M. et al.Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.Lancet. 2013; 381: 468-475Abstract Full Text Full Text PDF PubMed Scopus (1168) Google Scholar it also raises the possibility of the value of GLP-1 in patients with non-NAFLD etiologies. This study should now be followed by longer-term, including mechanistic analyses, studies of the efficacy and safety of GLP-1RA in varying stages of cirrhosis. This paper presents independent research supported by the Birmingham NIHR Biomedical Research Centre based at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham . The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Glucagon-Like Peptide-1 Receptor Agonists and Hepatic Decompensation Events in Patients With Cirrhosis and DiabetesClinical Gastroenterology and HepatologyVol. 20Issue 6PreviewThe study sought to compare the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, or sodium-glucose cotransporter-2 (SGLT-2) inhibitors in reducing decompensation events, among patients with cirrhosis and type 2 diabetes. Full-Text PDF