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Abstract BACKGROUNDWomen are increasingly choosing to delay childbirth, and those with low ovarian reserves indicative of primary ovarian insufficiency are at risk for sub- and infertility and also the early onset of menopause. Experimental strategies that promise to extend the duration of ovarian function in women are currently being developed. One strategy is to slow the rate of loss of existing primordial follicles (PFs), and a second is to increase, or ‘boost’, the number of autologous PFs in the human ovary. In both cases, the duration of ovarian function would be expected to be lengthened, and menopause would be delayed. This might be accompanied by an extended production of mature oocytes of sufficient quality to extend the fertile lifespan. OBJECTIVE AND RATIONALEIn this work, we consider how slowing physiological ovarian aging might improve the health and well-being of patients, and summarize the current state-of-the-art of approaches being developed. We then use mathematical modeling to determine how interventions are likely to influence the duration of ovarian function quantitatively. Finally, we consider efficacy benchmarks that should be achieved so that individuals will benefit, and propose criteria that could be used to monitor ongoing efficacy in different patients as these strategies are being validated. SEARCH METHODSCurrent methods to estimate the size of the ovarian reserve and its relationship to the timing of the menopausal transition and menopause were compiled, and publications establishing methods designed to slow loss of the ovarian reserve or to deliver additional ovarian PFs to patients were identified. OUTCOMESWe review our current understanding of the consequences of reproductive aging in women, and compare different approaches that may extend ovarian function in women at risk for POI. We also provide modeling of primordial reserve decay in the presence of therapies that slow PF loss or boost PF numbers. An interactive online tool is provided that estimates how different interventions would impact the duration of ovarian function across the natural population. Modeling output shows that treatments that slow PF loss would need to be applied as early as possible and for many years to achieve significant delay of menopause. In contrast, treatments that add additional PFs should occur as late as possible relative to the onset of menopause. Combined approaches slowing ovarian reserve loss while also boosting numbers of (new) PFs would likely offer some additional benefits in delaying menopause. WIDER IMPLICATIONSExtending ovarian function, and perhaps the fertile lifespan, is on the horizon for at least some patients. Modeling ovarian aging with and without such interventions complements and helps guide the clinical approaches that will achieve this goal. REGISTRATION NUMBERNot applicable. 

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. 

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. 

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.