Digest 66: Dapagliflozin and Liver Disease – The Newest MASH-up?

June 27, 2025 | By Nora Taranto

Welcome Back to The Curbsiders Digest!

In this issue, we discuss dapagliflozin and liver disease, plus a new treatment for IPF, platelet transfusion strategies, anticoagulation after hospitalization for afib, and a haiku for new interns, and more! Effortlessly absorb important medical news, with our twice monthly newsletter featuring easily digestible analysis of the latest practice-changing articles, and of course…bad puns. 

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Issue 66

06/27/2025

Appetizers (to whet your appetite) 

Palate Cleanser (aka the melon part of the meal) 

The Main Course

A Digestif or two

Appetizers

Brought to you hot off the stove, from a variety of specialties. Delivered in super tasty, bite-sized morsels. 
-Joshua Gilman MD, Laura Glick MD, and Alyssa Mancini MD

• Nerandomilast – a new medication in the pipeline for treatment of IPF. NEJM recently published the phase 3, double-blind, placebo-controlled FIBRONEER-IPF trial of patients with idiopathic pulmonary fibrosis (IPF). This study compared two doses (18 mg twice daily or 9 mg twice daily) of nerandomilast, an oral phosphodiesterase 4B inhibitor with antifibrotic and immunomodulatory effects, to placebo.  1177 patients were randomized to the three arms and stratified based on whether they were already taking antifibrotic therapy–with 77.7% taking nintedanib or pirfenidone (the available antifibrotic therapies for IPF) at enrollment. The adjusted mean changes in forced vital capacity (FVC) at week 52 were -114.7 ml in the 18-mg group, -138.6 ml in the nerandomilast 9-mg group, and -183.5 ml in the placebo group. This resulted in an adjusted difference of 68.8 ml (95% CI 30.3 to 107.4, P<0.001) between the nerandomilast 18-mg and placebo groups, and 44.9 ml between the 9-mg and placebo groups. The most frequent adverse event with nerandomilast was diarrhea (in 30-40% of individuals). (AM) 
• In support of restrictive platelet transfusion strategies. JAMA recently published the 2025 AABB/ICTMG International Clinical Practice Guidelines on platelet transfusion. GRADE methodology was used to analyze 21 randomized trials and 13 observational studies, with evidence demonstrating that restrictive platelet transfusion strategies likely did not increase mortality or bleeding relative to liberal strategies. Relevant recommendations for platelet transfusion in adults included: transfusion for platelets <10,000/uL (<10) in nonbleeding patients receiving chemotherapy or undergoing allogeneic stem cell transplant (strong recommendation with high/moderate-certainty evidence), and in those with platelets <20 in those undergoing lumbar puncture (strong recommendations with high/moderate-certainty evidence). Conditional recommendations with low/very-low certainty evidence included transfusion in patients with consumptive thrombocytopenia without major bleeding if platelets are <10,  if an individual requires central venous catheter placement and has platelets < 10, and if platelets are < 20 for low-risk interventional radiology procedures or <50 for high-risk interventional radiology procedures and major nonneuraxial surgery.  (AM) 
• Is a hospitalized afib worth anticoagulating on discharge?  A recent retrospective study out of Ann Intern Med evaluated the 1-year risk of stroke in 20,639 patients (age >66) who were diagnosed with a first-time episode of non-valvular atrial fibrillation during a hospitalization for other indications (admission diagnoses: 40% non-cardiac medical; 34% cardiac surgical; 17% non-cardiac surgical; 8% cardiac medical). The population was followed for the primary outcome of hospitalization for stroke, with stratification by CHA2DS2-VA score of 1-4 (lower risk; mean 3.19) vs 5-8 (higher risk; mean 5.67) and by whether patients were discharged with anticoagulation or not. 26.4% of the lower risk group and 35.2% of the higher risk group were prescribed anticoagulation 1 year after discharge. The 1-year incidence of stroke for those not on anticoagulation was low (0.7%) in the lower risk group, compared to 1.8% in the higher risk group–close to the 2% threshold for anticoagulation initiation recommended by the ACC/AHA. (JG) 
• An Exercise A Day Keeps the Cancer Away.  According to the randomized phase 3 Colon Health and Lifelong Exercise Change (CHALLENGE) clinical trial recently published in NEJM, a structured exercise program following surgery and adjuvant chemotherapy in patients with colon cancer improved disease-free survival (DFS) and overall survival (OS).  In this study, nearly 900 patients with high-risk stage II or stage III colon cancer (who had undergone surgery and adjuvant chemotherapy) were randomly assigned to participate in a structured exercise program and receive health education materials or to receive health education materials only over a 3-year period. At median follow-up of 7.9 years, disease-free survival was significantly longer in the structured exercise group compared to the health education group (hazard ratio for disease recurrence, new primary cancer, or death, 0.72; 95% CI, 0.55 to 0.94; P=0.02). Participants in the structured exercise program also had improved overall survival, patient-reported physical function, and some objective fitness measures (e.g. predicted VO2 max and 6 minute walk distance)–though there were no significant between-group differences in waist circumference or body weight. (LG) 
• Amiloride–a strike or a SPARE? The SPARE Trial, just published in JAMA, was an open-label, randomized control trial conducted in South Korea from 2020 to 2024 comparing amiloride to spironolactone in patients with resistant hypertension.  118 patients with home systolic blood pressures (SBP) of >130 mm Hg (despite being on triple therapy with an angiotensin receptor blocker, calcium channel blocker and thiazide) were randomized to receive amiloride 5 mg daily or spironolactone 12.5 mg daily.  If SBP remained >130 mm Hg and serum potassium <5 mmol/L after 4 weeks, doses were doubled to 10 mg and 25 mg daily, respectively. After 12 weeks, mean home SBP decreased by 13.6 mm Hg in the amiloride group and 14.7 mm Hg in the spironolactone group, demonstrating noninferiority of amiloride to spironolactone (between group difference -0.68 mm Hg 90% CI -3.5 to 2.1, meeting the non-inferiority margin of 4.4 mm Hg).  Subgroup analysis demonstrated a greater response to spironolactone in patients with aldosterone excess. Side effects were minimal in both groups. (LG)

Palate Cleanser

The melon part. To get rid of the taste of those pesky apps.  And to fill your brain with some fun facts.

In the spirit of nearing July 1st (A Haiku) 

Badge now says “doctor”
Nodding like I understand
Google is my friend

– Jennifer DeSalvo MD

The Main Course

Jennifer DeSalvo MD

Targeting the root metabolic cause of MASH 
Metabolic liver disease is on the rise, currently affecting around one third of the US population.  There are different forms, with metabolic dysfunction-associated steatohepatitis (MASH, formerly known as non-alcoholic steatohepatitis, or NASH) characterized by hepatic steatosis, ballooning, and inflammation leading to hepatocyte damage. MASH, which is a more severe form of metabolic dysfunction-associated steatotic liver disease (MASLD), can lead to liver fibrosis and cirrhosis in up to 25% of individuals. But the treatment of metabolic liver disease has remained challenging.  There is currently only one FDA-approved drug, a thyroid hormone receptor beta-selective agonist (Resmetirom), approved for the treatment of patients with MASH and fibrosis stages F2/F3 based on higher rates of MASH resolution and fibrosis with resmetirom in the MAESTRO-NASH trial.  

And while patients with MASH often also have other metabolic comorbidities (e.g. obesity, type 2 diabetes (T2DM), hyperlipidemia, or cardiovascular disease), whether or not all the same treatments used in obesity and T2DM might help with metabolic liver disease remains unclear.  In 2024, the phase 2 randomized, placebo-controlled trial SYNERGY-NASH saw improved MASH resolution without worsening of fibrosis with one year of once weekly tirzepatide, a GLP1/GIP agonist.  And in ESSENCE, a phase 3, randomized, placebo-controlled trial, once weekly semaglutide resulted in greater resolution of steatohepatitis without worsening of fibrosis, and a greater reduction in fibrosis, compared to placebo.  So what about SGLT2 inhibitors? Prior studies have suggested that SGLT2 inhibitors–which are used to treat T2DM, heart failure, and kidney disease –improve non-invasive liver parameters in patients with MASLD. Now enter the placebo-controlled DEAN Trial, which assessed biopsy-confirmed liver outcomes in patients with MASH who initiated the SGLT2 inhibitor dapaglifozin.  

Breaking It Down:
DEAN, a multicenter, double-blind, randomized, placebo-controlled trial just published in BMJ, randomized 154 adults in China with biopsy-confirmed MASH, with or without T2DM, to receive either 10 mg of oral dapagliflozin or placebo once daily for 48 weeks, followed by repeat biopsy.  Biopsies were graded according to non-alcoholic fatty liver disease activity score (NAS) defined by the presence of steatosis (scale 0-3 points), hepatocellular ballooning (scale 0-2), and lobular inflammation (scale 0-3). Fibrosis was evaluated based on the following scale: F1 indicates mild fibrosis, F2 significant fibrosis, F3 advanced fibrosis, and F4 cirrhosis.  85% of participants were male, with a mean age of 35, and a mean BMI of 29.  45% had stage F2 and 19% had stage F3 liver fibrosis, and 85% also had co-morbid dyslipidemia, with T2DM in 45%.  The primary endpoint, MASH improvement without worsening of liver fibrosis at 48 weeks, occurred in 53% of dapagliflozin arm patients and 30% in the placebo group (risk ratio 1.73, 95% CI 1.16-2.58, P=0.006), with a mean adjusted NAS difference of -1.39 between the treatment and placebo groups.  MASH resolution without worsening of fibrosis occurred in 23% of participants in the dapagliflozin group and 8% with placebo, and fibrosis improvement also occurred more frequently with dapagliflozin than placebo (45% vs 20%)–in particular in those with T2DM.  Other metabolic signs also improved with dapagliflozin compared to placebo (body weight, waist circumference, abdominal fat, Hemoglobin A1c), and adverse events occurred less with dapagliflozin. 

What does this mean?
Given definitions of MASH rooted in biopsy-proven liver histology, trial endpoints have historically focused on these histologic endpoints such as fibrosis improvement and MASH improvement or resolution without worsening fibrosis. Such endpoints are considered “likely to predict clinical benefit” and therefore have been the primary basis of drug approvals with the U.S. Food and Drug Administration. The trials of Resmetirom, Tirzepatide, and Semaglutide have all used such endpoints, and DEAN did the same in assessing the efficacy of dapagliflozin.   These biopsy outcomes – along with improvement in other metabolic endpoints –  highlight dapagliflozin as a new potential therapy to improve steatohepatitis and liver fibrosis, regardless of the presence of diabetes or obesity.  Limitations include a young, male, and somewhat homogenous population with a relatively small sample size and limited major adverse liver outcomes (e.g. progression to cirrhosis or hepatocellular carcinoma).  But this SGLT2 inhibitor may very well be worth adding to the MASH toolbox in coming years. 

Read The Study Here!

Digestifs

Before you go….
we’ve got a few nibbles!

Consolidate your learning with a Quiz!  

This week on The Curbsiders: In Episode 488, we bring the Digest to your earholes! Take a listen to get deeper dives into several of the articles covered in Digests 64 – 66, and hear the hot takes and hot cakes from the Digest crew, as well as Matt and Paul. It’s a tasty one!

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The Curbsiders Digest

Issue 66

Editor in Chief: Nora Taranto MD

Banner: Kate Grant  MBChB, DipGUMed

Jennifer DeSalvo,  Josh Gilman, Laura Glick, Alyssa Mancini, and Nora Taranto report no disclosures. Kate Grant reports no disclosures. 
 

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