#517 DIGEST: Weight regain after weight loss medications, GLP1/GIP comparisons, valacyclovir for Alzheimer’s, and nudges to encourage deprescribing 

March 16, 2026 | By Karly Loy

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Join us as we review and appraise recent practice-changing articles. In this episode, we cover the latest in GLP-1s and GIP agonists for CVD, Type 2 Diabetes, and Obesity, valacyclovir to treat Alzheimer’s, weight regain patterns after medication-induced weight loss, and a deep dive into the data behind deprescribing – and behavioral science to increase deprescribing behavior.  Fill your brain hole with a delicious stack of hotcakes! Featuring Paul Williams (@PaulNWilliamz), Alex Chaitoff (@alexchaitoff), Nora Taranto (@norataranto), & Matt Watto (@doctorwatto).

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Show Segments

• Intro, disclaimer
• GLP-1 + GIPs vs GLP-1s for patients with T2DM and Obesity – SURPASS-CVOT 
• Weight Regain after Weight loss 
• VALAD – Valacyclovir in patients with early Alzheimer’s 
• Nudges to increase Deprescribing 
• Outro

Entrée #1: GLP-1 Updates (Watto) 

Nicholls SJ, et al. Cardiovascular Outcomes with Tirzepatide vs. Dulaglutide in Type 2 Diabetes. N Engl J Med. 2025 Dec 18;393(24):2409-2420. doi: 10.1056/NEJMoa2505928.

Covered by Dr. Joshua Gilman in Digest #73. 

• Background and Significance: GLP-1 receptor agonists have been established as effective treatments for reducing cardiovascular events in high-risk patients with type 2 diabetes (T2DM), and for a number of other indications.  Tirzepatide is a novel dual GIP/GLP-1 agonist that seems to be as or more effective in weight management compared to traditional GLP-1 agonists. However, it was unclear whether these benefits translate into improved cardiovascular outcomes, particularly in patients with established atherosclerotic cardiovascular disease (ASCVD). This study aimed to address this gap by comparing the cardiovascular and weight outcomes of tirzepatide and dulaglutide.
• Study Overview: The SURPASS-CVOT trial was a randomized, double-blind, active-comparator study that evaluated the cardiovascular outcomes of treatment with tirzepatide versus dulaglutide in patients with T2DM and established ASCVD. This study was conducted across 640 sites in 30 countries, a total of 13,165 patients were randomized on a 1:1 basis to receive either weekly subcutaneous tirzepatide (titrated up to 15 mg) or dulaglutide (1.5 mg). The primary outcome was the time to the first occurrence of major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, myocardial infarction, or stroke.
• Key Findings: This was a positive study, confirming the noninferiority of tirzepatide compared to dulaglutide, with MACE occurring in 12.2% of the tirzepatide group compared to 13.1% in the dulaglutide group (hazard ratio of 0.92 (95.3% CI 0.83–1.01)). This met noninferiority criteria (P=0.003) but did not ultimately achieve superiority (P=0.09). Individual components demonstrated similar patterns of safety for cardiovascular death, myocardial infarction, and stroke. Tirzepatide also exhibited a lower rate of all-cause mortality (8.6% vs. 10.2%; HR 0.84). Gastrointestinal adverse events were more common in the tirzepatide group (42.5% vs. 35.9%).
• Critical Appraisal: The trial effectively demonstrates the cardiovascular safety of tirzepatide; however, its active-comparator design presents both strengths and limitations. While it allows for rigorous comparison against a proven cardiovascular risk reducer (dulaglutide), using an active-comparator makes demonstrating superiority with tirzepatide challenging, given the known efficacy of dulaglutide in this space. The noninferiority margin (HR 1.05) was strict, and the study maintained very high follow-up completeness (>99% endpoint ascertainment) which supports its internal validity.  There was a low rate of dropout, which may limit generalizability (given higher real-world discontinuation rates of these agents). Post-randomization treatment differences, such as an increase in SGLT2 inhibitor use in the dulaglutide group, could potentially confound cardiovascular outcome comparisons. Both drugs were safely combined on trial with other anti-hyperglycemic therapy.  Ultimately, both drugs appeared effective in reducing cardiovascular outcomes. 
• Conclusion: In high-risk patients with T2DM and established ASCVD, tirzepatide was found to be noninferior—but not superior—to dulaglutide in preventing major cardiovascular events. These findings are significant as they are likely to lead to a future labeled indication for cardiovascular risk reduction associated with tirzepatide. Further trials will be necessary to assess cardiovascular risk reduction in patients with obesity without T2DM (SURMOUNT-MMO). Ultimately, these indications will likely expand the medications in our toolbox for patients with obesity, diabetes, and ASCVD – though the choice of agent for a particular patient may very well be left to what insurance will cover. 

Additional Reading: 

• SURMOUNT-MMO (Lam, 2025) 
• Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes (Davies, 2025) 

Entrée #2: Weight Regain After Cessation of WMM (Paul) 

West S et al. Weight regain after cessation of medication for weight management: systematic review and meta-analysis. BMJ 392. 

Covered by Dr. Alyssa Mancini in Digest #74. 

• Background and Significance: With the growing prevalence of obesity, weight management medications (WMMs) have gained significant attention. Among these, incretin agents like semaglutide, dulaglutide, and tirzepatide are frequently discussed. However, understanding what happens after stopping these medications is critical, especially given that many patients discontinue their use after several months to a year. 
• Study Overview: This systematic review and meta-analysis included 37 studies with a total of 9,341 participants, focusing on the effects of discontinuing various WMMs and examining the rates of weight regain as well as changes in cardiometabolic parameters.
• Key Findings: The analysis demonstrated an average monthly weight regain of 0.4 kg after cessation of any WMM. Notably, the rate increased to 0.8 kg for the newer incretin mimetics, with projections suggesting a return to baseline weight within approximately 1.7 years for any WMM, and 1.5 years for newer incretin mimetics. The return to baseline was mirrored in cardiometabolic parameters which improved with weight loss and then approached baseline after WMM discontinuation, indicating that the improvements seen during treatment may also regress after medication has been discontinued. Behavioral support provided during WMM treatment did not affect the rate of weight re-gain after treatment discontinuation. 
• Critical Appraisal: The findings suggest that weight management medications might need to be part of a comprehensive, long-term strategy, with discussions about therapy involving the real possibility of long-term use. The physiologic challenges after discontinuation mirror challenges with discontinuation of therapy for other chronic disease treatments such as blood pressure management. Patients will likely derive the most benefit from ongoing, long-term use – though it remains unclear (and will be interesting to see) whether or not re-initiation of these medications if and when weight re-gain or cardiometabolic factors worsen is as effective as the first exposure.  Regardless, this data should inform discussions with patients at medication initiation, to ensure that patients fully understand that these medications may be long-term ones. 
• Conclusion: The study highlights the significant challenges surrounding the sustainability of weight loss following WMM cessation.  

Entrée #3: Valacyclovir for Alzheimer’s (Nora) 

Devanand DP, et al. Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: The VALAD Randomized Clinical Trial. JAMA. 2026 Feb 10;335(6):511-522. doi: 10.1001/jama.2025.21738. PMID: 41405855; PMCID: PMC12712832.

Covered by Dr. Beth “Garbs” Gasperlin in Digest #74. 

• Background and Significance: The VALAD trial investigated whether valacyclovir, an antiviral used to treat herpes simplex virus infections, could improve cognitive outcomes in patients with early Alzheimer’s disease (AD). The underlying hypothesis was that latent HSV might contribute to neurodegenerative processes associated with AD. Why would we think valacyclovir – an antiviral used for Herpes Simplex – or HSV–infection (and Varicella)– would be useful in treating Alzheimer’s (AD)? Well, HSV is a neurotropic virus that can cause both cold sores and genital infections, and that the majority of adults have been infected with by older age.  After initial infection, HSV becomes latent in the trigeminal ganglion and then can enter and remain in parts of the brain that may contribute to neurodegenerative conditions such as Alzheimer’s.  In animal models, HSV-1 infection in neurons triggers accumulation of amyloid β-protein and phosphorylated tau, neuropathologic features of Alzheimer’s – and autopsy evaluation of pts with AD have demonstrated that a large proportion of amyloid plaques contain HSV-1 DNA. Anti-viral medications have been shown in cell culture to reduce the accumulation of HSV-1 and also abnormal protein accumulation. Several observational studies in humans have also looked at the risk of AD by HSV status, finding that seropositive individuals have a higher odds of having AD–with conflicting results in these observational studies around whether anti-viral use is associated with a decreased risk of AD. Enter VALAD, the first placebo-controlled randomized trial testing whether the use of valacyclovir, an antiviral medication, can improve cognitive outcomes in patients with early AD and positive antibodies for HSV-1 or HSV-2 (indicating prior infection). 
• Study Overview: This study enrolled 120 individuals diagnosed with either probable Alzheimer’s disease or mild cognitive impairment with positive Alzheimer’s biomarkers, all of whom had positive serology for HSV (either IgG or IgM, majority IgG). Participants were randomized to receive either 4 g/day of valacyclovir or a placebo and followed for 78 weeks, focusing on cognitive outcomes measured through standardized assessment scales.
• Key Findings: The study was ultimately a negative study, in which those receiving valacyclovir experienced a greater decline in cognitive function compared to the placebo group. Specifically, the least-squares mean change in the Alzheimer’s Disease Assessment Scale Cognitive Subscale scores indicated a deterioration of 10.9 points in the valacyclovir group versus 6.9 in the placebo group, with statistical significance (p = 0.01). Secondary outcomes also mirrored this trend, raising concerns about the treatment’s safety and efficacy.
• Critical Appraisal: The study’s results challenge the premise that targeting viral infections may have a beneficial effect on cognitive decline in AD patients. But it remains unclear whether or not the timing of valacyclovir treatment in this study was the right window to target, given valacyclovir causes viral suppression but typically not full clearance, and given that Alzheimer’s is a disease many years in the making. Whether or not preventing HSV infection – or treating it earlier, prior to cognitive symptom development – might help remains unclear.  Valacyclovir can also cause neurotoxicity in and of itself, so it is possible this “benign” treatment isn’t quite as harmless as expected. The results raise more questions about the complex mechanisms underlying cognitive decline in AD and suggest that, despite the associations noted between viral infections and Alzheimer’s in observational studies, treating patients with valacyclovir after Alzheimer’s development does not appear to improve disease trajectory–and may in fact worsen it. 
• Conclusion: The VALAD trial contributes valuable data to the discussion surrounding Alzheimer’s treatment strategies, underscoring the complexity of neurodegenerative diseases. Patients experienced greater cognitive worsening with valacyclovir. Whether or not a different approach to antiviral treatment timing or prevention strategies might lead to different results remains unclear. 

Additional Reading: 

• Pilot study of valacyclovir in patients with schizophrenia (2012) 
• VZV Vaccination and risk of dementia (2025) 

Entrée #4: EHR Alerts to Deprescribe (Alex) 

Lauffenburger JC et al. Electronic Health Record Intervention and Deprescribing for Older Adults: A Randomized Clinical Trial. JAMA. 2026 Jan 29:e2526967. doi: 10.1001/jama.2025.26967. Epub ahead of print. PMID: 41609788; PMCID: PMC12856743.

Covered by Dr. Alex Chaitoff in Digest #74.

• Background and Significance: With an increasing number of older adults on polypharmacy (over 5 medications), adverse drug events pose significant risks, especially in this vulnerable population. Adverse medication events lead to millions of healthcare visits per year, and older adults are especially susceptible to adverse medication events that can land people in the hospital. Deprescribing—proactively stopping medications that are no longer beneficial—has emerged as a strategy to improve patient outcomes and reduce harm. 
• Study Overview: This study employed a cluster-randomized trial design to test whether electronic health record (EHR)-integrated behavioral nudges could promote the deprescribing of potentially inappropriate medications (PIMs), particularly targeting benzodiazepines, Z-drugs, and anticholinergics. Primary care physicians (PCPs) who had prescribed PIMs to older adults were randomized into three groups: a precommitment intervention, a boostering intervention, and a usual care group. The precommitment intervention involved a sequential strategy that first prompted a clinician to commit to a “soft” action with a patient—e.g. discussing medication risks with the patient. They were then prompted to consider the “hard” action of actual deprescribing at subsequent visits. The boostering was a reinforcement strategy that provided clinicians an initial notification to deprescribe during a patient encounter, followed by repeated automated reminders sent during subsequent visits and to their electronic inboxes to ensure the goal remained top-of-mind.  
• Key Findings: Among the 1,146 patients (mean age 73.6 years), those in the precommitment intervention group and the boostering intervention group experienced 40% and 26% higher rates of deprescribing events, respectively, compared to the usual care cohort. Absolute differences in deprescribing rates ranged from 6.5% to 10.4%, indicating a meaningful impact to the interventions. However, there was no significant improvement in any clinical outcomes with the boostering or precommitment interventions (and in fact the patients in the intervention arms had more cumulative lorazepam milligram equivalents prescribed) . 
• Critical Appraisal: While the findings highlight the effectiveness of behavioral nudges, they also raise important questions about the definition of successful deprescribing. There are obvious tradeoffs to spending time to deprescribe in a visit–versus focusing on addressing other health gaps. The burden of EHR nudges on clinicians – and the challenges of figuring out which health goal is the most important to nudge about – should also not be ignored. Many previous deprescribing trials focus on the act of stopping medications without adequately assessing downstream impacts on patient satisfaction, clinical outcomes, or quality of life.  This study does much the same,  and prompts a discussion about whether the goal should be merely achieving deprescribing or ensuring that it translates into better health outcomes for the patients. 
• Conclusion: The trial illustrates the potential of EHR-based nudges to influence prescribing behavior positively; however, further research is needed to understand the long-term benefits of deprescribing, especially regarding patient health and wellbeing. The implications of such interventions may guide future healthcare practices in managing polypharmacy among older adults.

Additional Reading: 

• EMPOWER
• SHED-Meds
• OPTICA

Links

Links are included in the show notes above.

Goals

Listeners will review recent practice-changing articles and medical news.

Learning objectives

After listening to this episode listeners will…

1. Compare the efficacy between tirzepatide and dulaglutide for CV outcomes in patients with diabetes. 
2. Decide whether to prescribe valacyclovir for patients with Alzheimer’s.  
3. Discuss how behavioral health can be helpful to guide deprescribing. 

Disclosures

The Curbsiders report no relevant financial disclosures. 

Citation

Taranto E, Chaitoff A, Williams PN, Watto MF. “#514 DIGEST: Weight regain after weight loss medications, GLP1/GIP comparisons, valacyclovir for Alzheimer’s, and nudges to encourage deprescribing  ”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list March 16, 2026.