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MASLD and MASH Therapeutics

CE / CME

Advances in MASLD/MASH Therapeutics and Updates to the Development Pipeline

Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit

Nurses: 0.50 Nursing contact hour

Physicians: maximum of 0.50 AMA PRA Category 1 Credit™

Released: March 13, 2024

Expiration: March 12, 2025

Mazen Noureddin
Mazen Noureddin, MD, MHSc
CME/CE Information

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Weight Loss Works—But It Can Be Difficult

There are numerous emerging therapeutic approaches for MASLD. It is widely known that the most crucial part of managing MASLD/MASH is losing weight through diet and exercise.3 Regardless of the stage of the disease, presence of MASH, or possibility of fibrosis, all patients have to engage in lifestyle management. Patients need to reach specific weight-loss goals to simultaneously resolve complications of MASLD/MASH. It is also important to note that although patients need to resolve fibrosis, most do not lose 10% of their weight. In fact, according to this study, fewer than 10% of patients lost 10% of their weight on this trial.4

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Diet: To Do

It is widely known that fibrosis improvement is important in the management of MASH, as it correlates with morbidity and mortality. Therefore, diet is very important. The Mediterranean diet has been associated with beneficial effects in MASH management. Some data demonstrate that intermittent fasting and low-carb diets are helpful, but more data are needed on these. In addition, the type of food consumed is very important. For instance, it has been shown that coffee has helped with MASLD/MASH, including MASH with fibrosis. By contrast, other diets and types of foods are not helpful, such as red meat/processed red meat, and can contribute to worsening of MASLD/MASH. Data published by our group also demonstrated that a high-cholesterol diet is harmful, whereas a high-fiber diet is beneficial.5

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FDA-Approved Drugs, Endoscopic and Surgical Bariatric Procedures

Many weight loss options are available in the United States, including FDA-approved drugs and other approaches. GLP-1 RAs have been in popular demand because of positive effects on body weight, as well as positive cardiovascular effects. Nevertheless, trials for MASH are ongoing. On the left are various types of drugs that have been used for weight loss, including the GLP-1 RAs semaglutide and tirzepatide.

Regarding endoscopic approaches, although the gastric balloon gained some popularity and showed some data in patients with MASH, lack of insurance coverage and weight rebound have led to less use of this method with patients with obesity and MASLD. The OverStitch system, or sleeve gastroplasty, is very popular in the United States, but more data are needed for efficacy in MASH. Gastric bypass and sleeve gastroplasty remain effective ways to lose weight; both approaches have been used in patients with obesity and have shown improvement in MASH and fibrosis. Let’s look at some of these data.6,7

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Is MASH Reversible With Bariatric Surgery?

These data are from a well-known French cohort. The trial was single center, but patients had an initial baseline biopsy with a follow-up of up to 5 years. Not all patients had liver biopsies done at the 5-year mark, but of those who did, 84% had MASH resolution.8 This is very encouraging, and it demonstrates the huge effect of bariatric surgery on these patients. It is not recommended by the guidelines yet for MASH, as more studies are needed—especially randomized, controlled trials in multicenter studies—yet the benefit is significant.

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SPLENDOR: Cumulative Incidence Estimates for Major Adverse Liver Outcomes and
Major Adverse Cardiovascular Events

In the SPLENDOR study, a cohort of patients with biopsy-proven MASH underwent bariatric surgery. What is important here is that patients who underwent bariatric surgery had favorable outcomes in terms of major adverse cardiac events. Of interest, patients who underwent bariatric surgery also had improvement in major adverse liver outcomes such as ascites, hepatic encephalopathy, and vascular bleeding.9 This again emphasizes the effect of bariatric surgery on liver outcomes.

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PIVENS: 96-Week Results of Pioglitazone and Vitamin E in Patients With MASH

Moving onto medications, today we still have guidelines about vitamin E and pioglitazone. In this study, Sanyal and colleagues10 demonstrated that vitamin E in particular was helpful for MASH resolution in patients who did not have diabetes or cirrhosis.

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Pioglitazone in MASH and Prediabetes or T2D: 18-Month Outcomes

Subsequent studies of pioglitazone in patients with T2D have shown improvement regarding ≥2-point reduction in the MASH score, as well as MASH resolution. However, it did not appear to improve fibrosis. The current guidelines recommend vitamin E for patients with MASH without cirrhosis or T2D. On the other hand, pioglitazone is recommended for patients with MASH with T2D without cirrhosis.11 These guidelines will change quickly in the next few months or years with the expected FDA approval of multiple medications for MASH.

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Safety and Tolerability of Recommended Therapies (Off Label)

Vitamin E and pioglitazone are associated with numerous adverse events; prostate cancer and cardiovascular events with vitamin E are a concern. Effects on the heart, bladder, and bone have been reported with pioglitazone.12

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Clinical Care Pathway for Risk Stratification and Management of Patients With MASLD

More recently, the AGA implemented a clinical care pathway. This pathway implements risk stratification using fibrosis stage through noninvasive testing such as FIB-4 and transient elastography. The recommended approaches, such as weight loss and exercise, are listed. Using medications such as vitamin E and pioglitazone—and hopefully medications that are approved in the future—patients can manage their diabetes, reduce their weight, and in turn help alleviate their MASH. Of note, these are medications such as GLP-1 RAs.1

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Management

Currently, there are no FDA-approved drugs for the treatment of MASH and to prevent patients from progression, but patients with MASH and fibrosis stage F2 or F3 without T2D are candidates for liver-directed pharmacotherapy with vitamin E. In patients with MASH and T2D, treatment with pioglitazone or a GLP-1 RA is suggested along with lifestyle interventions.13

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STEP1: Effects of Once-Weekly Semaglutide (2.4 mg)

At Week 68, more patients receiving semaglutide 2.4 mg vs placebo achieved weight reductions of 5% or more (1047 [86.4%] vs 182 [31.5%]), 10% or more (838 [69.1%] vs 69 [12.0%]), and 15% or more (612 [50.5%] vs 28 [4.9%]). One thing to emphasize about GLP-1 RAs—specifically semaglutide—is that patients can lose up to 18% of their body weight depending on agent and dose, which has been demonstrated in weight loss programs where they combine medication with exercise.14 Of note, patients receiving the T2D dose of semaglutide 2.0 mg might not have the same weight loss effect described above.

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STEP1 Weight Regain and Cardiometabolic Effects at Week 120

It has been reported that if the drug is discontinued, patients may gain some weight back, and their A1C may increase after improvement. In fact, blood pressure also might increase. Therefore, it is important to continue lifestyle interventions when these medications are stopped.14

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