Metabolic dysfunction–associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis, is a common condition, affecting an estimated 25% of American adults and up to 90% of people with a BMI of 40 or greater. Until recently, the only FDA-approved MASH therapy was Resmetirom (Rezdiffra), a thyroid hormone receptor-beta (THR-β) partial agonist. On August 15, 2025, the FDA approved Wegovy for MASH based on an interim analysis of the ESSENCE study that compared Wegovy to placebo in 1,197 patients with MASH and fibrosis stage 2 or 3. At 72 weeks, resolution of steatohepatitis without worsening of fibrosis was observed in 63% of Wegovy-treated patients and 34% of placebo-treated patients (P<0.001). A reduction in liver fibrosis without worsening of steatohepatitis occurred in 37% and 22%, respectively (P<0.001). The Wegovy group lost 10.5% of their body weight compared to 2% in the placebo group.

Less than 20% of commercial health insurance plans cover Wegovy for weight loss, so a MASH indication is encouraging since it may increase access. However, a looming question is what criteria will insurance companies require for a MASH diagnosis. In the ESSENCE study, MASH was diagnosed with a liver biopsy, and only patients with stage 2 or 3 fibrosis were enrolled. Prior authorization criteria for Rezdiffra, which has the exact same indication as Wegovy, vary by insurance, but I know some plans require the following: (1) diagnosis by liver biopsy, Fibroscan, or magnetic resonance elastography (MRE), (2) prescribed by a gastroenterologist or hepatologist. Fibroscan is a specialized ultrasound typically found in gastroenterology practices, and MRE is a specific type of MRI that is not widely available. If insurance companies have the same criteria for Wegovy, it will create a significant barrier to access, especially in primary care.

Tirzepatide (Zepbound) has also been shown to improve MASH, and Eli Lilly is in the process of pursuing a MASH indication for it.

• ESSENCE study - Wegovy vs Placebo for MASH, NEJM (2025)
• Resmetirom (Rezdiffra®) review
• SYNERGY-NASH trial - Tirzepatide vs Placebo for MASH, NEJM (2024)
• Article on webpage

Animal-derived thyroid products, including Armour Thyroid, NP Thyroid, WP Thyroid, and Nature-throid, are not FDA-approved to treat hypothyroidism; however, they existed before the Food, Drug, and Cosmetic Act of 1938 and, therefore, were grandfathered into the FDA's list of prescription drug medications without going through the formal approval process. The products are produced from dried, ground thyroid glands, typically from pigs. The FDA contends that due to a lack of safety and efficacy data, these products may be unsafe because of variations in purity and potency and the presence of contaminants. The agency sent letters to manufacturers on August 6, 2025, notifying them of their intent to take action against unapproved animal-derived thyroid medications. The FDA is also encouraging healthcare providers to transition patients from animal-derived products to synthetic levothyroxine.

An estimated 1.5 million Americans receive prescriptions for animal-derived combination products each year. However, all major professional organizations recommend synthetic levothyroxine products (e.g., Synthroid) for treating hypothyroidism. Reasons they are preferred over combination products include:

• Combination products (e.g. Armour Thyroid) have a T4 to T3 ratio of 4:1, while physiologic ratios secreted by the thyroid gland are around 14:1.
• Combination therapy leads to supraphysiologic levels of T3, which may lead to symptoms of thyrotoxicosis
• T3 has a shorter half-life than T4, which can lead to fluctuations in T3 levels, with a peak occurring shortly after dosing
• There is substantially more data from trials on the use of levothyroxine compared to combination therapy

In my experience, patients who are on animal-derived combination products have already tried synthetic levothyroxine and feel that the combination products control their symptoms better. However, blinded studies comparing levothyroxine to combination products have not found a difference in symptom control. Despite this, it can be difficult to change patient perceptions, especially with regard to subjective symptoms. I anticipate significant pushback when trying to switch these patients to levothyroxine products.

• FDA notification on animal-derived thyroid products
• Hypothyroidism review
• Evaluating the effectiveness of combined T4 and T3 therapy or desiccated thyroid versus T4 monotherapy in hypothyroidism: a systematic review and meta-analysis, BMC Endocr Disord (2024)
• Article on webpage

In 2021, the SGLT2 inhibitor empagliflozin (Jardiance) became the first drug FDA-approved to treat heart failure with preserved ejection fraction (HFpEF). Several years later, another SGLT2 inhibitor, dapagliflozin (Farxiga), was approved. Now, Finerenone (Kerendia), a nonsteroidal mineralocorticoid receptor antagonist, has become the third drug and the first non-SGLT2 inhibitor to be approved. Approval was based on results from the FINEARTS-HF Study, where 6016 patients with heart failure and an ejection fraction (EF) of 40% or greater (average EF 53%) were randomized to finerenone or placebo. Over a median follow-up of 32 months, the incidence of the primary composite outcome (total worsening heart failure events and death from cardiovascular causes) was 14.9 events per 100 patient-years in the finerenone group and 17.7 events per 100 patient-years in the placebo group (P=0.007). There was no significant difference in overall mortality. Hyperkalemia was more common in the finerenone group (14.3% vs 6.9%) as was hypotension (18.5% vs 12.4%).

Finerenone blocks aldosterone receptors, similar to spironolactone, an inexpensive aldosterone antagonist that has been available for decades. Spironolactone, which is FDA-approved for heart failure with reduced ejection fraction (HFrEF), has also been studied in HFpEF. In the TOPCAT study, which enrolled 3445 patients with heart failure and an EF ≥ 45% (median EF 56%), spironolactone was not superior to placebo for a composite of CVD events; however, it did significantly reduce heart failure hospitalizations. The trial was plagued by discordant data in certain geographic regions (Russia, Georgia), and post-hoc analyses have found that when these regions were excluded, spironolactone significantly improved the primary outcome. The ACC 2023 HFpEF guidelines recommend spironolactone in some patients. Other drugs, including Entresto, Wegovy, and Zepbound, have demonstrated improvements in HFpEF outcomes in clinical trials but have not received FDA approval for the condition.

Finerenone is the third drug and only non-SGLT2 inhibitor approved for HFpEF. Providers should note that finerenone dosing recommendations for HFpEF, which are based on GFR and potassium levels, differ from those used in diabetic kidney disease. For patients who cannot afford finerenone, spironolactone likely offers similar benefits. Potassium levels should be monitored closely with either drug.

• Finerenone review
• HFpEF treatment recommendations
• Article on webpage

Currently, resmetirom (Rezdiffra®), a thyroid hormone receptor beta partial agonist, is the only FDA-approved medication for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), formally known as nonalcoholic steatohepatitis or fatty liver disease. MASH is a progressive liver condition with an estimated global prevalence of 4 to 6%. Its strong association with obesity has prompted researchers to evaluate the effects of weight-loss GLP therapies, specifically semaglutide and tirzepatide, on MASH pathology. A 72-week interim analysis from a placebo-controlled semaglutide study (N=800) in MASH patients with stage 2 or 3 fibrosis was recently published. The analysis found that semaglutide (2.4 mg) caused resolution of steatohepatitis without worsening of fibrosis in 62.9% of patients, compared to 34.3% in the placebo group (p<0.001). A reduction in liver fibrosis without worsening of steatohepatitis occurred in 36.8% and 22.4%, respectively (p<0.001). Semaglutide-treated patients lost 10.5% of their body weight compared to 2.0% with placebo (p<0.001). As expected, gastrointestinal adverse events were more frequent in the semaglutide group.

These results are consistent with a previous 52-week study (N=190) involving tirzepatide, where MASH resolution without worsening of fibrosis was observed in 62% of tirzepatide-treated patients (15 mg) and 10% of placebo-treated patients (p<0.001). Weight loss in this study was 15.6% and 0.8%, respectively.

While results from different studies are not comparable linearly, nothing in resmetirom's pivotal trial suggests that it is superior to semaglutide or tirzepatide. Furthermore, it does not cause weight loss, giving it no benefit in other obesity-related conditions. Resmetirom also has drug interactions and requires lab monitoring, while GLP-1 therapies generally do not. The effects of these drugs on long-term clinical outcomes like cirrhosis and liver failure are being evaluated in ongoing studies. MASH indications for semaglutide and tirzepatide are likely forthcoming.

• Semaglutide vs Placebo for MASH, NEJM (2025)
• Tirzepatide vs Placebo for MASH, NEJM (2024)
• Resmetirom (Rezdiffra®) review
• Article on webpage

Three GLP-1 drugs, Zepbound (tirzepatide), Wegovy (semaglutide), and Saxenda (liraglutide), are currently approved for weight loss. Zepbound and Wegovy have demonstrated superior weight loss (16% to 22%) compared to Saxenda (8%), making them two of the most discussed medications in decades. Now, they have been compared head-to-head in an open-label trial, where 751 overweight, nondiabetic adults were randomized to Zepbound (target dose 10 mg or 15 mg/week) or Wegovy (target dose of 1.7 mg or 2.4 mg/week). The primary outcome, percent change in weight from baseline to week 72, was -20.2% with Zepbound and -13.7% with Wegovy (p<0.001). Key secondary outcomes, including average weight loss (50 lbs vs 33 lbs) and the proportion of participants achieving a weight reduction of 20% or more (48% vs 27%), also favored Zepbound. Side effects, including nausea (44% vs 44%), constipation (28% vs 29%), diarrhea (24% vs 23%), and vomiting (15% vs 21%), were similar between groups and mainly occurred during the therapy titration phase. Drug discontinuation due to adverse events was slightly higher in the Wegovy group (6.1% vs 8%).

These results corroborate findings from placebo-controlled studies, which showed that both drugs are highly effective, but Zepbound is superior. Patients sometimes ask me if one of the two has fewer side effects, and I can now confidently say they are similar in that regard. For those who are unaware, current cash pricing for both drugs is detailed below.

• 2.5 mg: $349 per month
• 5 mg: $499 per month
• 7.5 mg: $499 per month
• 10 mg: $499 per month

Wegovy cash pay: Novo Nordisk now offers all doses of Wegovy for $499/month through their online mail-order pharmacy NovoCare Pharmacy. Wegovy is available from other pharmacies for $650/month with the Wegovy savings card.

• Zepbound vs Wegovy for Weight Loss in Obese Adults, NEJM (2025)
• Zepbound review
• Wegovy review
• Article on webpage