An official website of the United States government
Abstract AimsTo discover alternative dosing regimens of incretin mimetics that simultaneously reduce costs and maintain weight loss efficacy. As a secondary objective, we used our results to explore how allocating a limited incretin mimetics budget could affect public health on a national scale. Materials and MethodsWe used mathematical modelling and simulation of semaglutide and tirzepatide to investigate dosing regimens which have not yet been studied clinically. For semaglutide, we used a recent pharmacokinetic (PK) and pharmacodynamic (PD) model. For tirzepatide, we used a recent PK model and modelled PD by reparameterizing the semaglutide PD model to fit tirzepatide clinical data. ResultsReducing dose frequency does not commensurately reduce weight loss. For example, merely switching from one dose per week (q1wk) to one dose every 2 weeks (q2wk) maintains roughly 75% of the weight loss. Furthermore, if the decrease in dose frequency involves an appropriate increase in dose size, then approximately 100% of the weight loss is maintained. In addition, we compared offering incretin mimetics to (1) a fraction of obese US adults with q1wk dosing versus (2) twice as many obese US adults with q2wk dosing. Though scenarios (1) and (2) require the same budget, our analysis suggests that (2) reduces national obesity and mortality to a much greater degree. ConclusionOur study highlights the potential utility of alternative dosing regimens of incretin mimetics. Compared with standard once‐weekly dosing, costs can be halved and weight loss maintained. These cost‐saving results have implications for patients, physicians, insurers, and governments.
more »
« less
Less frequent dosing of GLP ‐1 receptor agonists as a viable weight maintenance strategy
Abstract ObjectiveIncretin mimetics are revolutionizing obesity treatment, but high prices and supply shortages limit patient access. Some clinicians have suggested less frequent dosing as an off‐ramping strategy to maintain weight loss, but this approach lacks published evidence regarding its weight loss efficacy. We aim to provide such clinical evidence and to rationalize these results with mathematical modeling. MethodsWe present a real‐world case series of two patients who took their incretin mimetic less frequently than recommended. We complement this case report with a pharmacokinetic‐pharmacodynamic model of virtual patients that simulates long‐term weight change with semaglutide and tirzepatide administered at various frequencies. ResultsBoth real‐world and virtual patients maintained significant weight loss under reduced dosing frequencies. Our results indicate that reducing frequency does not commensurately reduce efficacy. The majority of weight loss persists even when patients wait 2, 3, or perhaps even 4 weeks between doses. ConclusionsOur findings support the hypothesis that less frequent administration of incretin mimetics can be a viable and cost‐saving long‐term weight maintenance strategy in conjunction with sustained lifestyle modification. Further research is warranted to validate the effectiveness of this off‐label approach, define optimal dosing regimens to meet individual patient needs, and evaluate the cost–benefit implications.
more »
« less
- PAR ID:
- 10593092
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Obesity
- Volume:
- 33
- Issue:
- 7
- ISSN:
- 1930-7381
- Format(s):
- Medium: X Size: p. 1232-1236
- Size(s):
- p. 1232-1236
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract AimsGLP‐1 and GIP‐GLP‐1 agonists have emerged as potent weight‐loss medications. These incretin mimetics often have low patient adherence, and as with any medication, clinically meaningful efficacy requires adequate adherence. But what constitutes “adequate” adherence for incretin mimetics? The purpose of this paper is to address this question. Materials and MethodsWe use mathematical modelling and stochastic simulation to investigate the weight loss efficacy of incretin mimetics under imperfect adherence. We use validated pharmacokinetic and pharmacodynamic models of semaglutide and tirzepatide and assume that simulated patients randomly miss doses. ResultsWe find that semaglutide and tirzepatide forgive nonadherence, meaning that strong weight loss efficacy persists despite missed doses. For example, taking 80% of the prescribed doses yields around 90% of the weight loss achieved under perfect adherence. Taking only 50% of the prescribed doses yields nearly 70% of the weight loss of perfect adherence. Furthermore, such nonadherence causes only small fluctuations in body weight, assuming that patients do not typically miss more than several consecutive doses. ConclusionIncretin mimetics are powerful tools for combating obesity, perhaps even if patients can consistently take only half of their prescribed doses. The common assumption that significant weight loss requires at least 80% adherence needs revision.more » « less
-
Abstract BackgroundWe hypothesized that alemtuzumab use is safe in pediatric kidney transplant recipients (KTRs) with equivalent long‐term outcomes compared to other induction agents. MethodsUsing pediatric kidney transplant recipient data in the UNOS database between January 1, 2000, and June 30, 2022, multivariate logistic regression, multivariable Cox regression, and survival analyses were utilized to estimate the likelihoods of 1st‐year and all‐time hospitalizations, acute rejection, CMV infection, delayed graft function (DGF), graft loss, and patient mortality among recipients of three common induction regimens (ATG, alemtuzumab, and basiliximab). ResultsThere were no differences in acute rejection or graft failure among induction or maintenance regimens. Basiliximab was associated with lower odds of DGF in deceased donor recipients (OR 0.77 [0.60–0.99],p = .04). Mortality was increased in patients treated with steroid‐containing maintenance (HR 1.3 [1.005–1.7]p = .045). Alemtuzumab induction correlated with less risk of CMV infection than ATG (OR 0.76 [0.59–0.99],p = .039). Steroid‐containing maintenance conferred lower rate of PTLD compared to steroid‐free maintenance (HR 0.59 [0.4–0.8]p = .001). Alemtuzumab was associated with less risk of hospitalization within 1 year (OR 0.79 [0.67–0.95]p = .012) and 5 years (HR 0.54 [0.46–0.65]p < .001) of transplantation. Steroid maintenance also decreased 5 years hospitalization risk (HR 0.78 [0.69–0.89]p < .001). ConclusionsPediatric KTRs may be safely treated with alemtuzumab induction without increased risk of acute rejection, DGF, graft loss, or patient mortality. The decreased risk of CMV infections and lower hospitalization rates compared to other agents make alemtuzumab an attractive choice for induction in pediatric KTRs, especially in those who cannot tolerate ATG.more » « less
-
IntroductionDigital twins of patients are virtual models that can create a digital patient replica to test clinical interventionsin silicowithout exposing real patients to risk. With the increasing availability of electronic health records and sensor-derived patient data, digital twins offer significant potential for applications in the healthcare sector. MethodsThis article presents a scalable full-stack architecture for a patient simulation application driven by graph-based models. This patient simulation application enables medical practitioners and trainees to simulate the trajectory of critically ill patients with sepsis. Directed acyclic graphs are utilized to model the complex underlying causal pathways that focus on the physiological interactions and medication effects relevant to the first 6 h of critical illness. To realize the sepsis patient simulation at scale, we propose an application architecture with three core components, a cross-platform frontend application that clinicians and trainees use to run the simulation, a simulation engine hosted in the cloud on a serverless function that performs all of the computations, and a graph database that hosts the graph model utilized by the simulation engine to determine the progression of each simulation. ResultsA short case study is presented to demonstrate the viability of the proposed simulation architecture. DiscussionThe proposed patient simulation application could help train future generations of healthcare professionals and could be used to facilitate clinicians’ bedside decision-making.more » « less
-
PURPOSECirculating tumor DNA (ctDNA) assays are promising tools for the prediction of cancer treatment response. Here, we build a framework for the design of ctDNA biomarkers of therapy response that incorporate variations in ctDNA dynamics driven by specific treatment mechanisms. These biomarkers are based on novel proposals for ctDNA sampling protocols, consisting of frequent sampling within a compact time window surrounding therapy initiation—which we hypothesize to hold valuable prognostic information on longer-term treatment response. METHODSWe develop mathematical models of ctDNA kinetics driven by tumor response to several therapy classes and use them to simulate randomized virtual patient cohorts to test candidate biomarkers. RESULTSUsing this approach, we propose specific biomarkers, on the basis of ctDNA longitudinal features, for targeted therapy and radiation therapy. We evaluate and demonstrate the efficacy of these biomarkers in predicting treatment response within a randomized virtual patient cohort data set. CONCLUSIONThis study highlights a need for tailoring ctDNA sampling protocols and interpretation methodology to specific biologic mechanisms of therapy response, and it provides a novel modeling and simulation framework for doing so. In addition, it highlights the potential of ctDNA assays for making early, rapid predictions of treatment response within the first days or weeks of treatment and generates hypotheses for further clinical testing.more » « less
