Pharmacists Can Lead Shift Toward Liver-Protecting Polyagonists

Incretin-based polyagonists have demonstrated the ability to significantly transform liver care, and pharmacists are well-positioned to lead the charge in shifting toward this class of medication in the future, according to JAPhA Pharmacotherapy.¹

“The global obesity epidemic continues to be a significant public health concern, contributing to the escalating prevalence of metabolic comorbidities such as type 2 diabetes (T2D) mellitus, cardiovascular disease (CVD), and metabolic dysfunction-associated steatotic liver disease (MASLD),” wrote the study authors. “MASLD encompasses a spectrum of diseases, ranging from simple steatosis to the more severe form, metabolic dysfunction-associated steatohepatitis (MASH).”

The medical landscape for metabolic liver disease is undergoing a tectonic shift, and pharmacists are being positioned at the forefront of this therapeutic revolution. For decades, clinicians struggled to manage MASLD and its more severe inflammatory form, MASH, with limited pharmacological options.¹

READ MORE: How Pharmacists Can Help Patients Manage MASLD

However, a new class of polyagonists—drugs that target multiple incretin receptors simultaneously—is demonstrating an unprecedented ability to reduce liver fat and reverse histological injury. These agents, which go beyond the capabilities of traditional glucagon-like peptide-1 (GLP-1) receptor agonists, are set to transform the therapeutic landscape, requiring pharmacists to lead the way in personalized therapy and patient adherence.

A Changing Landscape for MASLD Treatment

MASLD now affects nearly 30% of the global population, driven by the twin epidemics of obesity and T2D.^1,2 The shared pathophysiology of these conditions involves insulin resistance, which promotes the accumulation of triglycerides in hepatocytes.¹

Although GLP-1 monotherapies such as semaglutide (Ozempic, Wegovy) have recently gained FDA approval for MASH, the next generation of dual and triple agonists—targeting GLP-1 alongside glucose-dependent insulinotropic polypeptide (GIP) and glucagon—are showing even more potent results. For instance, triple agonists like retatrutide have achieved relative liver fat reductions of up to 82.7% in clinical trials.¹

These multireceptor agents leverage synergistic pathways. With GLP-1 reducing appetite and slowing gastric emptying, GIP enhances lipid metabolism, and glucagon increases energy expenditure.^1-3

The efficacy of these polyagonists is often compared with the results of bariatric surgery, yet they offer a far more scalable solution for the millions suffering from metabolic syndrome.²

Pharmacological optimization, such as fatty acid acylation used in tirzepatide (Mounjaro, Zepbound) and semaglutide, extended the half-life of these peptides, allowing for once weekly dosing.^2,3 Furthermore, GIPs may serve a critical role in mitigating the gastrointestinal adverse effects often associated with GLP-1 therapy, potentially allowing for higher, more effective dosages with better patient tolerability.³

This cellular reprogramming represents a significant advance over older, off-label treatments like vitamin E or pioglitazone, which often carried risks of weight gain or heart failure.¹

The Pharmacist’s Role in Polyagonist Therapies

“With the recent FDA approval of semaglutide for MASH, it is expected that other incretin-based polyagonists (ie, tirzepatide and retatrutide) may soon seek specific indications for MASLD/MASH,” continued the study authors. “Pharmacists are well-positioned to support providers in selecting patient-specific incretin-based therapies and to educate patients on proper use, monitoring effectiveness and maintaining adherence to optimize treatment outcomes.”

Pharmacists are already proving their value in this space through collaborative practice agreements. A retrospective cohort study conducted at outpatient clinics along the US-Mexico border demonstrated that pharmacist-led weight management services resulted in significant reductions in liver enzymes for patients with MASLD.⁴

By optimizing medication regimens and providing intensive education, pharmacists were able to achieve more sustained metabolic and hepatic improvements than standard primary care alone.⁴ As polyagonists become more prevalent, the pharmacist’s role in managing food noise and navigating complex prior authorizations will be essential for long-term treatment success.^1,5

However, the rapid weight loss triggered by these polyagonists introduces new clinical challenges that pharmacists must address. For example, patients may lose 15% to 25% of their lean muscle mass during treatment.⁵

Pharmacists must also counsel patients on precision nutrition, ensuring adequate intake of high-quality protein and micronutrients like vitamin D and magnesium to protect bone density and muscle strength. They also play a vital role in monitoring rare but serious risks, such as gallbladder disease or potential impacts on gastric emptying during anesthesia.^1,2,5

By bridging the gap between innovative science and holistic patient care, pharmacists are uniquely primed to guide patients through the shift toward these life-saving, liver-protecting therapies.^1,4

“Incretin-based polyagonists hold tremendous promise in the management of MASLD and MASH,” concluded the authors of the current study.¹ “Now is the time for pharmacists to lead the way in personalized incretin therapy—helping providers make informed choices and ensuring patients stay engaged, adherent, and successful in their treatment.”

READ MORE: Cardiology Resource Center

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REFERENCES

1. Slaton R, Iranikhah MG, White CW. Beyond GLP-1: the promise of polyagonists in MASLD and MASH—a systematic review of randomized trials. JAPhA Pharmacotherapy. February 27, 2026:100032. https://doi.org/10.1016/j.japhar.2026.100032

2. Anastasiou IΑ, Argyrakopoulou G, Dalamaga M, Kokkinos A. Dual and Triple Gut Peptide Agonists on the Horizon for the Treatment of Type 2 Diabetes and Obesity. An Overview of Preclinical and Clinical Data. Curr Obes Rep. 2025 Apr 11;14(1):34. doi: 10.1007/s13679-025-00623-1.

3. Novikoff A, Müller TD. Pharmacological Advances in Incretin-Based Polyagonism: What We Know and What We Don't. Physiology (Bethesda). 2024 May 1;39(3):142-156. doi: 10.1152/physiol.00032.2023. Epub 2024 Feb 14.

4. Li R, Lunares L, Lambeth KE, et al. Impact of a pharmacist-led weight management service in patients with metabolic dysfunction-associated steatotic liver disease at outpatient clinics on the US-Mexico border. JAPhA Pract Innov. November 8, 2025:100082. https://doi.org/10.1016/j.japhpi.2025.100082

5. UC Davis Health examines systemic impact of GLP-1–based therapies. UC Davis Health. December 5, 2025. Accessed March 16, 2026. https://health.ucdavis.edu/news/headlines/uc-davis-health-examines-systemic-impact-of-glp-1based-therapies/2025/12