Surfing the MASH Tsunami

Send us Fan Mail

In this closing conversation, updated MASLD CPG co-authors Frank Tacke and Elisabetta Bugianesi and podcast co-hosts Louise Campbell and Roger Green consider what the guidelines might foretell in changes in provider education, structure of patient visits and treatment in less affluent or medically advanced countries.

The last set of questions begins with Roger asking what kinds of changes the authors would like to see in the healthcare system.  Frank likes Louise's idea of cardiometabolic pathological nursing and, more broadly, motivating physicians and nurses to view MASLD holistically. Elisabetta envisions a world where not only are there multidisciplinary teams, but each physician asks what they can do for the "liver/kidney/metabolic alliance." Frank describes this as "like a dream" and would like a world where the patient comes to the hepatologist for a cardiac workout, endocrine workout, nutritional counseling and other holistic support. It would also help get the correct patients triaged in primary care or referred to specialists.
 
 Roger asks whether Tumor Boards in oncology serve as a model for integrated metabolic disease treatment. Frank says in his institution, boards exist for cirrhosis patients but will never be realistic for the number of patients needing treatment.
 
As the episode winds down, several issues emerge. Louise wonders how these guidelines might be used in less affluent countries or those with less advanced/resourced healthcare systems. Elisabetta stresses the importance of generating awareness. Roger asks how the guidelines will incorporate updates for future drugs and bariatric surgery data; Frank feels this will not be a particular challenge and cites the upcoming data on obesity drugs and the SPECIAL study as information that might drive updates. Frank also suggests that all listeners should download the guidelines (the link is listed on the Surfing the MASH Tsunami web page.) And with one final set of congratulations to the authors, the episode ends.
 
 

Send us Fan Mail

For most of this conversation, updated MASLD CPG co-authors Frank Tacke and Elisabetta Bugianesi discuss key issues related to pharmacology and prescribing choices. At the end, the focus shifts to the guidelines' overall benefits and some new kinds of education they call for. 

The conversation starts with co-host Roger Green asking about key issues from the pharmacology section. Frank states that one benefit of the CPG is the clarity around the point that optimal treatment for a co-morbidity must involve thinking holistically about the liver in the overall metabolic context.

Elisabetta notes that while no drugs are efficacious for cirrhosis, the document does report that some drugs are safe for these patients, although sometimes with adjusted doses.

Frank concurs that the document provides guidance on managing patients with end-stage liver disease and also discusses how to manage cirrhosis and its various complications. Elisabetta notes that these can be the most difficult patients to screen for HCC because "the fat liver is sort of foggy."

This leads co-host Louise Campbell to discuss a point that arises frequently on this podcast: the positive value of simply stabilizing disease through medication and lifestyle.

Roger adds that many primary care physicians in the US find managing metabolic multi-comorbid patients confusing and frustrating. These guidelines, with an integrated vision of metabolic diseases and the idea that stabilization might be a sound strategy, simplified the perceived task.

Louise suggests that these guidelines "pinpoint...a role of the potential future" for nurses who can support the entire cardiometabolic syndrome. As she points out, even hepatology nurses are "not good at fatty liver disease." This document might drive a curriculum for such a specialization.

Send us Fan Mail

In this conversation, updated MASLD CPG co-authors Frank Tacke and Elisabetta Bugianesi discuss some of the guidelines' key goals and issues surrounding the screening, diagnosis and management of MASLD patients. 

As the conversation starts, co-host Roger Green says that he, too, was impressed that all these adjustments were made within a month at the end of the process. Frank praises the "very engaged Delphi panel" that reacted and voted quickly, and fairly consistently.  He proceeds to discuss how the Delphi panel was formed.
 
From here, the discussion shifts into its key focus: patients. Roger asks for high points in the discussion of screening, diagnosing and managing patients. Elisabetta starts by stating that the resmetirom approval is creating a great push for screening because physicians feel that there is something they can do to help their patients. She describes an approach that begins with FIB-4, proceeds to VCTE and offers two paths for patient management. This should help the system identify patients before cirrhosis or HCC in pre-cirrhotic patients.
 
 Frank points out that this set of guidelines does not rely on biopsy for risk assessment, which he terms "a major breakthrough."
 
 Co-host Louise Campbell lauds the document's approach to diet advice, specifically the broad range of diets that will make it valuable worldwide and for primary care physicians to work from.
 
 Frank adds that the guidelines have adjusted thresholds and other "adaptations to the ethnic background of the individual." This included considering the socioeconomic factors of a target country.
 
 

Send us Fan Mail

In this conversation, updated MASLD CPG co-authors Frank Tacke and Elisabetta Bugianesi explain how the guidelines process benefitted from the close collaboration between EASL, EASD, and EASO.  

The conversation starts with Elisabetta conveying the "big advantage" that came from this collaboration. The presence of the three organizations conveyed the need to create a common way to manage patients with MASLD, many of whom live with diabetes and obesity. The guideline also used the new nomenclature, which highlighted the metabolic root of the disease.

Frank notes that the three societies have their own approval processes, which led to increased rigor from having to meet three standards. He concurs that the collaboration and approach strengthened the guidelines by putting the liver in the broader context on the disease.

After co-host Roger Green notes how much more complete this is than the previously released clinical care pathway documents, co-host Louise Campbell asks whether the guidelines will increase the profile of liver disease in other specialties. Elisabetta refers to Ken Cusi's view that "it takes time," but points out two reasons for this integration to be smoother: (i) "you can't hide cirrhosis" and (ii) diabetes and other components of the general metabolic syndrome are pivotal risk factors not only for cirrhosis, but also HCC.

Frank had been concerned at first that the name change would "lose the other societies," but the reverse was true: putting "metabolic dysfunction into the center of disease definition" links overall cardiometabolic risk to liver disease. Further, the guideline has a chapter on prevention and case-finding strategies that are relevant to primary care and diabbetology or endocrinology practices.

Earlier in the episode, Louise commended the guideline for including resmetirom even before its approval in Europe. Frank thanks her, and notes that the decision to add resmetirom came after US approval and was included within the month before the guidelines were released, similar to discussion of how some glucose-lowering drugs could help treat cardiometabolic comorbidities.

Send us Fan Mail

Two of the co-authors of the upgraded MASLD Clinical Practice Guidelines,  Elisabetta Bugianesi and Frank Tacke join Louise Campbell and Roger Green to discuss the guidelines. 

The theme for the conversation is "introductions". First, the audience is introduced to co-authors Elisabetta Bugianesi and Frank Tacke, neither of whom has Surfed the Tsunami before. Both Elisabetta and Frank have unusual answers to the "one thing our audience would not expect about you if you didn't tell them" question, although in very different ways. 

After this, the Surfers and guests begin the process of introducing us to the updating process. Frank Tacke describes when the idea to upgrade arose, where it came from, and the two mechanisms, co-authors and Delphi panels, that became the foundation for the upgrade. 

Send us Fan Mail

00:00:00 - Surf's Up: Season 5 Episode 21 
One important session at the EASL Congress 2024 involved the presentation of the new MASLD Clinical Practice Guidelines. CPG co-authors Elisabetta Bugianesi and Frank Tacke join Louise Campbell and Roger Green to share their perspectives on the guidelines' development some key recommendations.  

00:09:36 - Revising the guidelines 
Roger asks the co-authors to describe the process that led to the 2021 decision to revise the guidelines. EASL was the initial driver; EASD and EASO joined the process. They formed a committee of 15 leaders and assembled a Delphi panel of 46 individuals from different stakeholder communities.  

Elisabetta describes the "big advantage" of this collaboration: it conveyed the need for a common way to manage co-morbid patients with MASLD. To Frank, this approach strengthened the guidelines by putting the liver in the center of metabolic disease. 

Louise asks whether the guidelines will increase the profile of liver disease in other specialties. Elisabetta says "it takes time" but says that the nature of cirrhosis and HCC might make this easier.

00:19:07 - Adding resmetirom before approval
Earlier, Louise praised the inclusion of resmetirom in the guidelines, Frank notes that this section was added to the guidelines within a month before their release and praises the "very engaged Delphi panel" that reacted and voted quickly.  He proceeds to discuss how the Delphi panel was formed.

00:23:24 - Major issues in screening, diagnosing and case-managing patients
Elisabetta starts by saying that resmetirom's approval created momentum for screening. She says the approach identifies patients before cirrhosis or HCC in pre-cirrhotic patients. Frank points out "a major breakthrough": these guidelines do not rely on biopsy.  

00:28:04 - Non-medical factors 
Louise lauds the document's the broad range of diets that will make the document valuable around the world . Frank adds that the guidelines have adjusted thresholds  adapted to the ethnic and socioeconomic background of the individual. 

00:30:52 - Pharmacological issues in the new CPG 
Frank starts the pharmacological discussion noting that the CPG drives holistic thinking about the liver in a metabolic context. Elisabetta notes that while no drugs are efficacious for cirrhosis, the document does report that some drugs are safe for these patients, although sometimes with adjusted doses. 

00:33:39 - Screening for cirrhosis
Frank concurs that the document provides guidance on managing patients with end-stage liver disease and also discusses how to manage cirrhosis and its various complications. Elisabetta says that HCC can be hard to find in a fatty liver. 

00:36:36 - Cardiometabolic nursing as a future training and specialty
Louise suggests that these guidelines "pinpoint...a role of the potential future" for nurses who can support the entire cardiometabolic syndrome. This document might drive a curriculum for such a specialization.

00:38:48 - What adjustments would you like to see in the healthcare system?
The last set of questions begins with Roger asking what kinds of changes the authors would like to see in the healthcare system.  The discussion revolves around a "cardiometabolic" perspective but in terms of nurse training and the care provided in a hepatologist's office. 

00:43:18 - Winding down
As the conversation winds down, each panelist offers a final comment or question.

00:47:59 - Question of the Week
Roger asks how readily listeners believe the guidelines will be implemented, and which sections will be easiest and hardest to implement. 

00:48:32 - Business Report
The next EASL Congress review episodes, starting office hours, and a vault discussion from 2023's clinical care pathway document. 

Send us Fan Mail

In this conversation from July 2023, Stephen Harrison, Jörn Schattenberg and Roger Green discuss the implications of presentations on the FGF-21 agent efruxifermin and the dual GLP/glucagon agonists pemvidutide and efinopegdutide. 

Here is the description Roger wrote for the original conversation:

In this session, conversation shifts from resmetirom to Mazen Noureddin's "NASH Monopoly" game and focuses on the value of FGF-21s and glucagon agents. Stephen posits two comments about GLP-1s. First, there is now adequate data suggesting that GLP-1s will not melt away all liver fat and as a result lead to dramatic fibrosis regression. Second, we know from a small sub-cohort of patients in Akero's SYMMETRY trial that patients already on fairly low doses of GLP-1s saw what Stephen describes as an 'incredible' and incremental benefit for the FGF-21 agent, efruxifermin. The group notes that while glucagon dual and treble agents are likely to produce dramatically more robust results in weight loss and liver defatting than GLP-1s alone, they still seem unlikely to 'usurp the need for other types of agents.' From here discussion considers the FGF-21 class. Stephen notes that two drugs, efruxifermin and pegozafermin, have demonstrated significant efficacy against fibrosis. As the conversation concludes, the panelists agree that earlier, more aggressive screening to arrest cirrhosis will become pivotal and will not occur until the right drug becomes available. 

Send us Fan Mail

Mazen Noureddin and Naim Alkhouri join Jörn Schattenberg and Roger Green to discuss some of the other major drug development stories from the EASL Congress 2024, with special focus on denifenstat, ION-224 and TAK-227, and to review the SPECIAL study on bariatric surgery and cirrhosis. 

The panelists concur that all three of these agents have potential value in therapy. Naim expresses some concern about how broad denifestat use will be based on its side effect profile. Later in this conversation, Mazen belives that denifenstat has broad potential for use, given that the most prominent side effect, hair thinning, appears transient and readily manageable. He also notes that denifenstat's impressive results were based on Intent to Treat analysis, which is more rigorous.  

Naim states his interest in the ION-224 agent based on its mode of action, which is RNA interference. He also discusses SPECIAL, a study he conducted with the bariatric surgery group at Cleveland Clinic. This study, which evaluated patients with cirrhosis at the time of surgery, demonstrated a 72% risk reduction in major adverse liver outcomes over a 10-year period and 80% risk reduction in decompensation. 

Jörn discusses a study he presented on TAK-227, a TG2 inhibitor originally developed for celiac disease. Early results here are quite promising and, as Aleksander Krag mentioned in S5 E17, demonstrates exciting potential for collaboration with drug developers for other diseases. 

As the conversation ends, Roger asks Mazen and Jörn what they consider likely to be the biggest MASLD stories at the AASLD Liver Congress in November. Mazen selects the Phase 3 ESSENCE study for semaglutide, while Jörn suggests NITs. 

Send us Fan Mail

Mazen Noureddin and Naim Alkhouri join Jörn Schattenberg and Roger Green to focus on the role FGF-21s will play in long-term advanced fibrosis treatment: induction or long-term therapy...or might we even think of the class as being able to produce a "MASH cure?" 

Responding to Naim's comment closing the previous discussion, Mazen questions why we regard FGF-21 agents as induction therapies given that it appears to be as well tolerated as the oral agents and maintains such efficacy over time. In fact, he adds, its sustained efficacy might make it possible for livers to eliminate fibrosis and return to their "normal" state, almost like a "cure." 

Jörn adds a comment about pegozafermin, another FGF-21 in development. Jörn notes that this agent is a pegylated molecule, which makes it different from efruxifermin. He notes that NITs show sustained enzyme response at 48 weeks. Mazen reiterates his optimism about the FGF-21 class and reminds us that there is a third FGF-21 in development. 

Roger raises Michael Charlton's question (Season 5 Episode 11) whether an induction therapy strategy for FGF-21s might not work if removing the drug allows the MAS activity to return. On the other hand, he notes, it might take years for fibrosis to return. Mazen agrees that many unanswered questions exist, but reiterates his belief in long-term therapeutic value. 
 

Send us Fan Mail

Naim Alkhouri and Mazen Noureddin join Jörn Schattenberg and Roger Green to discuss issues regarding incretin agonists and results from the efruxiermin late-breaker at the EASL Congress 2024.

Naim shares his general excitement about glucagon agents in general. He mentions that the efinopegdutide study included a semaglutide cell, which showed further reduction in liver fat vs. the GLP-1 agent.

Jörn comments on the high level of tolerability in the survodutide trials. Mazen shares his high hopes for GLP/glucagons and the triple agents. He goes back to review the survodutide data from the NEJM article. 

Mazen shares the late-breaker data that Vlad Ratziu presented on behalf of Stephen. This is a 96-week, triple biopsy study showing dramatic, sustained fibrosis improvement with a 30% delta for one level and a 21% delta for two levels. Jörn notes that the triple biopsies are demonstrate the durability of the agent against fibrosis. Roger notes this is particularly encouraging because of the previous pegbelfermin data showing loss of efficacy and tachyphylaxis. Naim concurs and adds that if the two-stage drop in fibrosis can be sustained, this would be a "big deal for the field" that might lead prescribers to think about FGF-21 as indication therapy with a "more tolerated" oral later on.