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
Incretin mimetics for weight loss forgive nonadherence
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
- PAR ID:
- 10590471
- Publisher / Repository:
- Wiley-Blackwell
- Date Published:
- Journal Name:
- Diabetes, Obesity and Metabolism
- Volume:
- 27
- Issue:
- 8
- ISSN:
- 1462-8902
- Format(s):
- Medium: X Size: p. 4109-4117
- Size(s):
- p. 4109-4117
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
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
-
ImportanceScreening with low-dose computed tomography (CT) has been shown to reduce mortality from lung cancer in randomized clinical trials in which the rate of adherence to follow-up recommendations was over 90%; however, adherence to Lung Computed Tomography Screening Reporting & Data System (Lung-RADS) recommendations has been low in practice. Identifying patients who are at risk of being nonadherent to screening recommendations may enable personalized outreach to improve overall screening adherence. ObjectiveTo identify factors associated with patient nonadherence to Lung-RADS recommendations across multiple screening time points. Design, Setting, and ParticipantsThis cohort study was conducted at a single US academic medical center across 10 geographically distributed sites where lung cancer screening is offered. The study enrolled individuals who underwent low-dose CT screening for lung cancer between July 31, 2013, and November 30, 2021. ExposuresLow-dose CT screening for lung cancer. Main Outcomes and MeasuresThe main outcome was nonadherence to follow-up recommendations for lung cancer screening, defined as failing to complete a recommended or more invasive follow-up examination (ie, diagnostic dose CT, positron emission tomography–CT, or tissue sampling vs low-dose CT) within 15 months (Lung-RADS score, 1 or 2), 9 months (Lung-RADS score, 3), 5 months (Lung-RADS score, 4A), or 3 months (Lung-RADS score, 4B/X). Multivariable logistic regression was used to identify factors associated with patient nonadherence to baseline Lung-RADS recommendations. A generalized estimating equations model was used to assess whether the pattern of longitudinal Lung-RADS scores was associated with patient nonadherence over time. ResultsAmong 1979 included patients, 1111 (56.1%) were aged 65 years or older at baseline screening (mean [SD] age, 65.3 [6.6] years), and 1176 (59.4%) were male. The odds of being nonadherent were lower among patients with a baseline Lung-RADS score of 1 or 2 vs 3 (adjusted odds ratio [AOR], 0.35; 95% CI, 0.25-0.50), 4A (AOR, 0.21; 95% CI, 0.13-0.33), or 4B/X, (AOR, 0.10; 95% CI, 0.05-0.19); with a postgraduate vs college degree (AOR, 0.70; 95% CI, 0.53-0.92); with a family history of lung cancer vs no family history (AOR, 0.74; 95% CI, 0.59-0.93); with a high age-adjusted Charlson Comorbidity Index score (≥4) vs a low score (0 or 1) (AOR, 0.67; 95% CI, 0.46-0.98); in the high vs low income category (AOR, 0.79; 95% CI, 0.65-0.98); and referred by physicians from pulmonary or thoracic-related departments vs another department (AOR, 0.56; 95% CI, 0.44-0.73). Among 830 eligible patients who had completed at least 2 screening examinations, the adjusted odds of being nonadherent to Lung-RADS recommendations at the following screening were increased in patients with consecutive Lung-RADS scores of 1 to 2 (AOR, 1.38; 95% CI, 1.12-1.69). Conclusions and RelevanceIn this retrospective cohort study, patients with consecutive negative lung cancer screening results were more likely to be nonadherent with follow-up recommendations. These individuals are potential candidates for tailored outreach to improve adherence to recommended annual lung cancer screening.more » « less
-
Abstract ObjectivesEpileptiform activity (EA) worsens outcomes in patients with acute brain injuries (e.g., aneurysmal subarachnoid hemorrhage [aSAH]). Randomized trials (RCTs) assessing anti-seizure interventions are needed. Due to scant drug efficacy data and ethical reservations with placebo utilization, RCTs are lacking or hindered by design constraints. We used a pharmacological model-guided simulator to design and determine feasibility of RCTs evaluating EA treatment. MethodsIn a single-center cohort of adults (age >18) with aSAH and EA, we employed a mechanistic pharmacokinetic-pharmacodynamic framework to model treatment response using observational data. We subsequently simulated RCTs for levetiracetam and propofol, each with three treatment arms mirroring clinical practice and an additional placebo arm. Using our framework we simulated EA trajectories across treatment arms. We predicted discharge modified Rankin Scale as a function of baseline covariates, EA burden, and drug doses using a double machine learning model learned from observational data. Differences in outcomes across arms were used to estimate the required sample size. ResultsSample sizes ranged from 500 for levetiracetam 7 mg/kg vs placebo, to >4000 for levetiracetam 15 vs. 7 mg/kg to achieve 80% power (5% type I error). For propofol 1mg/kg/hr vs. placebo 1200 participants were needed. Simulations comparing propofol at varying doses did not reach 80% power even at samples >1200. InterpretationOur simulations using drug efficacy show sample sizes are infeasible, even for potentially unethical placebo-control trials. We highlight the strength of simulations with observational data to inform the null hypotheses and assess feasibility of future trials of EA treatment.more » « less
-
Abstract BackgroundCancer-care complexity heightens communication challenges between health care providers and patients, impacting their treatment adherence. This is especially evident upon hospital discharge in patients undergoing surgical procedures. Digital health tools offer potential solutions to address communication challenges seen in current discharge protocols. We aim to explore the usability and acceptability of an interactive health platform among discharged patients who underwent oncology-related procedures. MethodsA 4-week exploratory cohort study was conducted. Following hospital discharge, a tablet equipped with an integrated Personal Virtual Assistant (PVA) system was provided to patients who underwent oncology-related procedures. The PVA encompasses automated features that provide personalized care plans, developed through collaboration among clinicians, researchers, and engineers from various disciplines. These plans include guidance on daily specific assignments that were divided into 4 categories: medication intake, exercise,symptom surveys, and postprocedural specific tasks. The aim was to explore the acceptability of the PVA by quantification of dropout rate and assessing adherence to each care plan category throughout the study duration. The secondary aim assessed acceptability of the PVA through a technology acceptance model (TAM) questionnaire that examined ease of use, usefulness, attitude toward use, and privacy concerns. ResultsIn total, 17 patients were enrolled. However, 1 (5.8%) patient dropped out from the study after 3 days due to health deterioration, leaving 16/17 (94.2%) completing the study (mean age 54.5, SD 12.7, years; n=9, 52% Caucasian; n=14, 82% with a gynecological disease; n=3, 18% with a hepatobiliary disease). At the study end point, adherence to care plan categories were 78% (SD 25%) for medications, 81% (SD 24%) for exercises, 61% (SD 30%) for surveys, and 58% (SD 44%) for specific tasks such as following step-by step wound care instructions, managing drains, administering injectable medications independently, and performing pelvic baths as instructed. There was an 80% patient endorsement (strongly agree or agree) across all TAM categories. ConclusionThis study suggests the potential acceptability of the PVA among patients discharged after oncology-related procedures, with a dropout rate of less than 6% and fair-to-good adherence to tasks such as medication intake and exercise. However, these findings are preliminary due to the small sample size and highlight the need for further research with larger cohorts to validate and refine the system.more » « less
