- Email: [email protected]
Trials of obeticholic acid for non-alcoholic steatohepatitis
Correspondence
All authors acknowledge support from the National Institute for Health Research’s Health Technology Assessment Programme (NIHR HTA; Grant Reference Number HTA—07/37/69). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.
*Gavin D Perkins, Tom Quinn, Charles D Deakin, Ranjit Lall, Simon Gates [email protected] Warwick Clinical Trials Unit, University of Warwick, Coventry, UK, CV4 7AL (GDP, RL, SG); Heart of England NHS Foundation Trust, Birmingham, UK (GDP); Surrey Peri-operative Anaesthesia Critical care collaborative Research Group, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK (TQ); South Central Ambulance Service NHS Foundation Trust, Otterbourne, UK (CDD); and University Hospital Southampton, Southampton, UK (CDD)
www.thelancet.com Vol 386 July 4, 2015
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Perkins GD, Lall R, Quinn T, et al. Mechanical versus manual chest compression for out-of-hospital cardiac arrest (PARAMEDIC): a pragmatic, cluster randomised controlled trial. Lancet 2015; 385: 947–55. Perkins GD, Woollard M, Cooke MW, et al. Prehospital randomised assessment of a mechanical compression device in cardiac arrest (PARAMEDIC) trial protocol. Scand J Trauma Resusc Emerg Med 2010; 18: 58. Wik L, Olsen JA, Persse D, et al. Manual vs integrated automatic load-distributing band CPR with equal survival after out of hospital cardiac arrest. The randomized CIRC trial. Resuscitation 2014; 85: 741–48. Steinberg MT, Olsen J-A, Brunborg C, et al. Abstract 85: defibrillation during mechanical chest compressions should be avoided during the downstroke phase of the chest compression cycle. Circulation 2014; 130 (suppl 2): A85.
Trials of obeticholic acid for non-alcoholic steatohepatitis We read with interest the results of the FLINT trial (March 14, p 956)1 that investigate the effect of obeticholic acid on liver histology in non-alcoholic steatohepatitis . A remarkable yet overlooked result in the appendix of this trial was the difference in histological response between participants with diabetes and those without: for participants with diabetes, liver histology improved in 53% of patients who received obeticholic acid versus 19% for placebo (odds ratio [OR] for improvement with obeticholic acid 4·6, 95% CI 2·0–10·6, p=0·0003), while for patients without diabetes, liver histology improved in 37% patients with obeticholic acid versus 23% with placebo (OR 2·0, 95% CI 0·8–4·7, p=0·12). The effect of glucose intolerance on histological response to obeticholic acid was also shown across the progressive stages of pancreatic β cell dysfunction, as estimated by HOMA β cell index.1 Other than the FLINT trial, only one randomised trial, which enrolled participants with diabetes, has assessed obeticholic acid for nonalcoholic fatty liver disease.2 Therefore evidence for the effectiveness of
farnesoid X receptor agonists is absent for individuals without diabetes, who represent a substantial proportion of the population with non-alcoholic steatohepatitis. Additionally, consistent with other randomised trials of non-alcoholic steatohepatitis, the percentage of responders was less than 50% in the FLINT trial, leaving a substantial proportion of patients without an effective treatment.3 Non-alcoholic steatohepatitis is a heterogeneous disorder and diverse mechanisms of liver injury that promote disease progression might exist in different patient populations. Altered bile acid metabolism—the rationale for use of semisynthetic bile acids—has been more convincingly shown in individuals with diabetes than in those without,4 which might explain the absence of response to obeticholic acid in individuals without diabetes in the FLINT trial. Consequently, further assessment of farnesoid X receptor agonists for nondiabetic non-alcoholic steatohepatitis is essential, and an approach tailored to individual metabolic profiles might be needed to tackle the non-alcoholic steatohepatitis epidemic.
Sciepro/Science Photo Library
compressions, whereas compressions were paused briefly to allow defibrillation attempts in the manual group. Our predefined subgroup analysis showed that 30 day survival was lower in the group assigned to mechanical CPR (69 [18%] of 376 patients) compared with manual CPR (148 [24%] of 615 patients). Shocks were not synchronised with the LUCAS-2 device so the shock was likely to be equally distributed throughout the compression cycle. Carron and colleagues cite evidence from porcine studies which suggests a high shock success rate if shocks are delivered during the upstroke of mechanical CPR. We are unaware of any randomised human studies in which this hypothesis has been tested. In the CIRC trial3 (which assessed the AutoPulse device—a different method of chest compression), the chance that ventricular fibrillation was terminated 5 s after a shock was 5% lower when shocks were delivered during the downstroke of mechanical chest compressions. At 60 s after shock delivery, the rate of return of organised rhythm was similar irrespective of the timing of shock delivery in relation to the compression phase.4 We deem the synchronisation of shock with compression cycle in our study would have been unlikely to have led to better outcomes in the mechanical CPR group.
We declare no competing interests.
*Giovanni Musso, Maurizio Cassader, Roberto Gambino [email protected] Gradenigo Hospital, Torino 10132, Italy (GM); and Department of Medical Sciences, University of Turin, Italy (MC, RG) 1
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3
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Neuschwander-Tetri BA, Sanyal AJ, Lavine JE, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385: 956–65. Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013; 145: 574–82. Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 2012; 55: 885–904. Ma H, Patti ME. Bile acids, obesity, and the metabolic syndrome. Best Pract Res Clin Gastroenterol 2014; 28: 573–83.
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All authors acknowledge support from the National Institute for Health Research’s Health Technology Assessment Programme (NIHR HTA; Grant Reference Number HTA—07/37/69). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.
*Gavin D Perkins, Tom Quinn, Charles D Deakin, Ranjit Lall, Simon Gates [email protected] Warwick Clinical Trials Unit, University of Warwick, Coventry, UK, CV4 7AL (GDP, RL, SG); Heart of England NHS Foundation Trust, Birmingham, UK (GDP); Surrey Peri-operative Anaesthesia Critical care collaborative Research Group, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK (TQ); South Central Ambulance Service NHS Foundation Trust, Otterbourne, UK (CDD); and University Hospital Southampton, Southampton, UK (CDD)
www.thelancet.com Vol 386 July 4, 2015
1
2
3
4
Perkins GD, Lall R, Quinn T, et al. Mechanical versus manual chest compression for out-of-hospital cardiac arrest (PARAMEDIC): a pragmatic, cluster randomised controlled trial. Lancet 2015; 385: 947–55. Perkins GD, Woollard M, Cooke MW, et al. Prehospital randomised assessment of a mechanical compression device in cardiac arrest (PARAMEDIC) trial protocol. Scand J Trauma Resusc Emerg Med 2010; 18: 58. Wik L, Olsen JA, Persse D, et al. Manual vs integrated automatic load-distributing band CPR with equal survival after out of hospital cardiac arrest. The randomized CIRC trial. Resuscitation 2014; 85: 741–48. Steinberg MT, Olsen J-A, Brunborg C, et al. Abstract 85: defibrillation during mechanical chest compressions should be avoided during the downstroke phase of the chest compression cycle. Circulation 2014; 130 (suppl 2): A85.
Trials of obeticholic acid for non-alcoholic steatohepatitis We read with interest the results of the FLINT trial (March 14, p 956)1 that investigate the effect of obeticholic acid on liver histology in non-alcoholic steatohepatitis . A remarkable yet overlooked result in the appendix of this trial was the difference in histological response between participants with diabetes and those without: for participants with diabetes, liver histology improved in 53% of patients who received obeticholic acid versus 19% for placebo (odds ratio [OR] for improvement with obeticholic acid 4·6, 95% CI 2·0–10·6, p=0·0003), while for patients without diabetes, liver histology improved in 37% patients with obeticholic acid versus 23% with placebo (OR 2·0, 95% CI 0·8–4·7, p=0·12). The effect of glucose intolerance on histological response to obeticholic acid was also shown across the progressive stages of pancreatic β cell dysfunction, as estimated by HOMA β cell index.1 Other than the FLINT trial, only one randomised trial, which enrolled participants with diabetes, has assessed obeticholic acid for nonalcoholic fatty liver disease.2 Therefore evidence for the effectiveness of
farnesoid X receptor agonists is absent for individuals without diabetes, who represent a substantial proportion of the population with non-alcoholic steatohepatitis. Additionally, consistent with other randomised trials of non-alcoholic steatohepatitis, the percentage of responders was less than 50% in the FLINT trial, leaving a substantial proportion of patients without an effective treatment.3 Non-alcoholic steatohepatitis is a heterogeneous disorder and diverse mechanisms of liver injury that promote disease progression might exist in different patient populations. Altered bile acid metabolism—the rationale for use of semisynthetic bile acids—has been more convincingly shown in individuals with diabetes than in those without,4 which might explain the absence of response to obeticholic acid in individuals without diabetes in the FLINT trial. Consequently, further assessment of farnesoid X receptor agonists for nondiabetic non-alcoholic steatohepatitis is essential, and an approach tailored to individual metabolic profiles might be needed to tackle the non-alcoholic steatohepatitis epidemic.
Sciepro/Science Photo Library
compressions, whereas compressions were paused briefly to allow defibrillation attempts in the manual group. Our predefined subgroup analysis showed that 30 day survival was lower in the group assigned to mechanical CPR (69 [18%] of 376 patients) compared with manual CPR (148 [24%] of 615 patients). Shocks were not synchronised with the LUCAS-2 device so the shock was likely to be equally distributed throughout the compression cycle. Carron and colleagues cite evidence from porcine studies which suggests a high shock success rate if shocks are delivered during the upstroke of mechanical CPR. We are unaware of any randomised human studies in which this hypothesis has been tested. In the CIRC trial3 (which assessed the AutoPulse device—a different method of chest compression), the chance that ventricular fibrillation was terminated 5 s after a shock was 5% lower when shocks were delivered during the downstroke of mechanical chest compressions. At 60 s after shock delivery, the rate of return of organised rhythm was similar irrespective of the timing of shock delivery in relation to the compression phase.4 We deem the synchronisation of shock with compression cycle in our study would have been unlikely to have led to better outcomes in the mechanical CPR group.
We declare no competing interests.
*Giovanni Musso, Maurizio Cassader, Roberto Gambino [email protected] Gradenigo Hospital, Torino 10132, Italy (GM); and Department of Medical Sciences, University of Turin, Italy (MC, RG) 1
2
3
4
Neuschwander-Tetri BA, Sanyal AJ, Lavine JE, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385: 956–65. Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013; 145: 574–82. Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 2012; 55: 885–904. Ma H, Patti ME. Bile acids, obesity, and the metabolic syndrome. Best Pract Res Clin Gastroenterol 2014; 28: 573–83.
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