What's it Worth? A Journal Club Podcast

S4E4 - Beyond Dopamine: Xanomeline-Trospium in Acute Schizophrenia

Welcome back to What's it Worth! For over 70 years, the treatment of schizophrenia has been synonymous with dopamine D2 receptor blockade—until now. Join your host, Dr. Diana Langworthy, and guest Dr. Alexandra Rola (Psychiatry Clinical Pharmacist and Assistant Professor at Binghamton University) as they dive into the EMERGENT-3 trial. We're dissecting the efficacy and safety of xanomeline-trospium, a first-in-class muscarinic agonist that targets psychosis without the traditional side effects of dopamine antagonists. Is this the breakthrough psychiatry has been waiting for? Let's dive in and see what it's worth! Key Points * Unlike traditional antipsychotics, xanomeline is a dual M1/M4-preferring muscarinic receptor agonist. By pairing it with trospium (a peripheral muscarinic antagonist), the "KarXT" combination aims to deliver CNS antipsychotic effects while minimizing peripheral side effects like nausea and vomiting. * In this 5-week, Phase 3 trial of 256 adults with acute psychosis, xanomeline-trospium demonstrated a statistically significant and clinically meaningful 9.4-point greater reduction in the PANSS total score compared to placebo by week 5. * The study showed significant improvements in both the Positive Syndrome Scale (hallucinations/delusions) and the Negative Syndrome Scale (social withdrawal/apathy), suggesting a more holistic impact on schizophrenia symptoms. * While it avoids dopamine-related side effects, KarXT is associated with cholinergic-driven GI issues; nausea, dyspepsia, and vomiting were the most frequently reported adverse events. * What are the ethics of a placebo controlled trial in acute psychosis when we have proven medications for treatment? Join us for an important conversation about equity and ethics in clinical trials. * Can we treat psychosis without touching a single dopamine receptor? ------> Tune in to find out! References 1. [EPISODE TRIAL] Kaul I, Sawchak S, Walling DP, et al. Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry. 2024;81(8):749-756. doi:10.1001/jamapsychiatry.2024.0785 2. World Medical Association. WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Participants. Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 75th WMA General Assembly, Helsinki, Finland, October 2024. 3. Waltz JA, Pujji SD, Colloca L. Placebo and nocebo phenomena in schizophrenia spectrum disorders: a narrative review on current knowledge and potential future directions. Psychol Med. 2025 Jul 18;55:e199. doi: 10.1017/S0033291725100901. Erratum in: Psychol Med. 2026 Feb 02;56:e37. doi: 10.1017/S0033291726103493. 4. Gara MA, Vega WA, Arndt S, et al. Influence of patient race and ethnicity on clinical assessment in patients with affective disorders. Arch Gen Psychiatry. 2012 Jun;69(6):593-600. doi: 10.1001/archgenpsychiatry.2011.2040. 5. Lawrence RE, Appelbaum PS. Ethics in placebo-controlled, acute treatment trials in schizophrenia: Two rival ethical frameworks. Schizophrenia Research 264 (2024) 372-377. Host Information Dr. Diana R. Langworthy, PharmD, BCPS Clinical Associate Professor, University of Minnesota College of Pharmacy Clinical Pharmacist - Inpatient Internal Medicine, M Health Fairview East Bank Hospital Guest Information Alexandra Rola, PharmD Clinical Assistant Professor, Pharmacy Practice, Binghamton University Psychiatry Clinical Pharmacist

S4E3 - The GLP-1 Battle: Cardiovascular outcomes of Tirzepatide vs. Dulaglutide in the SURPASS-CVOT Trial

Welcome back to What's it Worth! In this episode, your host Dr. Diana Langworthy is joined by Mia Lussier, PharmD, MS, Clinical Assistant Professor at Binghamton University and ambulatory care specialist, to dissect the results of the SURPASS-CVOT trial . As the first large-scale trial directly comparing a dual GLP-1/GIP agonist to a proven GLP-1 receptor agonist for cardiovascular outcomes, we ask: is tirzepatide officially the champion of metabolic and cardiovascular health? Join us for an evidence detective session as we evaluate the clinical worth of these findings Key Points * SURPASS-CVOT was an active-comparator, double-blind trial that randomized 13,299 patients with Type 2 Diabetes and established ASCVD to receive either tirzepatide (up to 15 mg) or dulaglutide (1.5 mg) once weekly . * Tirzepatide met its primary end point of noninferiority to dulaglutide for MACE (cardiovascular death, MI, or stroke) with a hazard ratio of 0.92. However, it did not achieve statistically significant superiority for this composite outcome (P=0.09) * While CV outcomes were noninferior, tirzepatide showed superior metabolic benefits, including a -1.66 percentage point reduction in A1c (vs. -0.88 with dulaglutide) and an 11.6% reduction in total body weight (vs. 4.8% with dulaglutide). * In a pre-specified secondary analysis of high-risk CKD patients, tirzepatide significantly slowed the decline of eGFR compared to dulaglutide, showing a difference of 3.17 ml/min/1.73m² over 36 months. * Both agents had similar overall adverse event rates * Was dulaglutide 1.5 mg weekly the best comparator vs tirzepatide for cardiovascular outcomes? ---> Tune in to find out! References 1. [EPISODE TRIAL] Nicholls SJ, Pavo I, Bhatt DL, et al. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes. N Engl J Med. 2025;393(24):2409-2420. doi: 10.1056/NEJMoa2505928. 2. Gerstein H, Colhoun H, Dagenais G et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. The Lancet, 2019; 394, 121-130. 3. Pratley RE, Aroda VR, Lingvay I, et al. SUSTAIN 7 investigators. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol. 2018 Apr;6(4):275-286. doi: 10.1016/S2213-8587(18)30024-X. Epub 2018 Feb 1. PMID: 29397376. 4. Marson SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with Type 2 Diabetes. N Engl J Med 2016;375:1834-1844. Join the Conversation Subscribe [https://whatsitworthpodcast.substack.com/] to the What's it Worth? Podcast on Substack If you want to get new episode alerts, bonus content, and continue reflecting on what studies like this mean for real clinicians and real patients—head over to the What's it Worth? substack. Have a study you'd like us to decode on a future episode? Email whatsitworthpodcast@gmail.com or share how you're navigating evidence in practice—I love hearing how clinicians and learners think through uncertainty. Host Information Dr. Diana R. Langworthy, PharmD, BCPS Clinical Associate Professor, University of Minnesota College of Pharmacy Clinical Pharmacist - Inpatient Internal Medicine, M Health Fairview East Bank Hospital Guest Information Mia Lussier, PharmD, MS Clinical Assistant Professor, Pharmacy Practice, Binghamton University Ambulatory Care Specialist

S4E2 - The Kidney Formula Conundrum: Navigating eCrCl vs. eGFR in DOAC Dosing

Welcome back to What's it Worth! Join your hosts, Dr. Diana Langworthy and guest Dr. Rachel Khan (Associate Professor at VCU School of Pharmacy), as they navigate the murky waters of renal function assessment in anticoagulant users. This episode dissects a critical insight from the ORBIT-AF II registry: the variability in DOAC (NOAC) dose eligibility when labs use newer kidney estimates . While clinical trials used Cockcroft-Gault (eCrCl), modern labs often report eGFR (MDRD or CKD-EPI), leading to a "renal identity crisis" for clinicians . We're putting on our EBP detective hats to explore why these formulas disagree—and what that means for your patients. Let's dive in and see what it's worth! Key Points * The Gold Standard Gap: Landmark DOAC trials and product monographs almost exclusively use Cockcroft-Gault (eCrCl) for dosing, yet clinical labs have moved toward automated eGFR reporting . * Formula Discordance: In the ORBIT-AF II cohort, agreement between eCrCl and eGFR was high overall (~93%), but declined in patients with established chronic kidney disease (CKD) . * The "Misclassification" Mystery: Up to 42% of CKD patients could be classified for a different dose depending on which formula is used, with rivaroxaban showing the highest rates of variability . * The Interpretive Challenge: While the study noted an association between formula-driven "undertreatment" and worse outcomes, we discuss the critical limitations—such as the lack of BSA-adjusted eGFR data—that make it difficult to conclude that eGFR is directly leading us to miss our target doses. * Is your patient truly underdosed, or are we just using the wrong yardstick? ------> Tune in to find out! References 1. [EPISODE TRIAL] Yao RJR, Holmes DN, Andrade JG, et al. Variability in Nonvitamin K Oral Anticoagulant Dose Eligibility and Adjustment According to Renal Formulae and Clinical Outcomes in Patients With Atrial Fibrillation With and Without Chronic Kidney Disease: Insights From ORBIT-AF II. J Am Heart As soc. 2023 Mar 21;12(6):e026605. doi: 10.1161/JAHA.122.026605. 2. St Peter WL, Bzowyckyj AS, Anderson-Haag T, et al; Moving forward from Cockcroft-Gault creatinine clearance to race-free estimated glomerular filtration rate to improve medication-related decision-making in adults across healthcare settings: A consensus of the National Kidney Foundation Workgroup for Implementation of Race-Free eGFR-Based Medication-Related Decisions. Am J Health Syst Pharm. 2025 Jun 11;82(12):644-659. 3. Möller E, McIntosh JF, Van Slyke DD. STUDIES OF UREA EXCRETION. II: Relationship Between Urine Volume and the Rate of Urea Excretion by Normal Adults. J Clin Invest. 1928 Dec;6(3):427-65. doi: 10.1172/JCI100206. PMID: 16693839; PMCID: PMC434761. 4. U.S. Food and Drug Administration (FDA). Pharmacokinetics in Patients with Impaired Renal Function — Study Design, Data Analysis, and Impact on Dosing and Labeling: Guidance for Industry. March 2024. Accessed December 2025. Contact Information Podcast email: whatsitworthpodcast@gmail.com Host Information Dr. Diana R. Langworthy, PharmD, BCPS Clinical Associate Professor, University of Minnesota College of Pharmacy Clinical Pharmacist - Inpatient Internal Medicine, M Health Fairview East Bank Hospital Guest Information Dr. Rachel Khan, PharmD, BCPS Associate Professor, VCU School of Pharmacy Clinical Pharmacist - Internal Medicine, VCUHS

S4E1 | Asking Better Questions of Evidence in 2026

In this brief 2026 season opener, host Diana Langworthy, PharmD, BCPS pauses to acknowledge the weight of the moment—particularly here in Minnesota—where uncertainty, fear, and harm are being felt in very real ways across communities. This episode is not about policy analysis or debate. It's a reflection on what it means to hold space for thinking, teaching, and care when the world feels unstable—and why asking good questions, slowing down our reasoning, and practicing intellectual humility still matter in healthcare education and clinical practice. Diana also shares how What's It Worth? will move forward this season, and how the podcast, Substack (whatsitworthpodcast.substack.com), and future TikTok (Diana the Pharm.D.etective - @whatsitworthrx) content will work together as connected—but distinct—spaces for evidence critique, reflection, and public-facing curiosity.

S3E14 | Defending Evidence in a Broken Trust Environment

Welcome back What's it Worth? listeners. This episode steps away from traditional trial critique. It's a year-end reflection on what it means to practice evidence-based healthcare at a moment when trust in science, institutions, and clinicians is eroding—and when evidence itself is increasingly being misused to create fear rather than understanding. This episode is for frontline healthcare professionals and future providers who feel the weight of that shift and are asking how to respond without becoming part of a polarized conversation. The answer, I believe, is not louder certainty—but better questions. As we move into the next year, evidence-based practice will require more than knowing the literature. It will require clinicians who are willing to defend evidence with transparent communication, clarity, humility, and compassion—and who can help patients ask not just "Is there a study?" but "What's it worth?" Learn more and continue the conversation: Substack: https://whatsitworthpodcast.substack.com/ Email: whatsitworthpodcast@gmail.com