Supported self-management interventions for patients with musculoskeletal (MSK) conditions may not adequately support those with limited health literacy, leading to inequalities in care and variable outcomes. The aim of this study was to develop a model for inclusive supported self-management intervention(s) for MSK pain that take account of health literacy.A mixed methods study with four work-packages was conducted: work package 1: secondary analysis of existing data to identify potential targets for intervention; work package 2: evidence synthesis to assess effective components of self-management interventions taking into account health literacy; work package 3: views of community members and healthcare professionals (HCPs) on essential components; work package 4: triangulation of findings and an online modified Delphi approach to reach consensus on key components of a logic model.Findings identified targets for intervention as self-efficacy, illness perceptions, and pain catastrophizing. A range of intervention components were identified . Support should be multi-professional using a combination of delivery modes .This research has developed a patient-centred model for a multi-disciplinary, multi-modal approach to supported self-management for patients with MSK pain and varying levels of health literacy. The model is evidence-based and acceptable to both patients and HCPs, with potential for significant impact on the management of MSK pain and for improving patient health outcomes. Further work is needed to establish its efficacy.The online version contains supplementary material available at 10.1186/s12891-023-06452-4. Musculoskeletal (MSK) conditions affect over 17 million people across the UK . The maiHL refers to the personal characteristics and social resources needed for individuals and communities to access, understand, appraise and use information and services to make decisions about health . LimitedLimited HL is associated with poorer health, greater illness and increased healthcare costs –11. PeopHealth services are increasingly delegating the work of managing MSK conditions to patients themselves , yet peoThere is evidence that healthcare professionals (HCPs) find pain management in patients with limited HL challenging . FurtherIn the light of such evidence around the importance of HL and its role in the effective management of MSK pain, there is a need to develop acceptable and useful patient support, educational materials and/or patient resources to better support both such patients and the HCPs working with them –22.The aim of the EASIER (achEs And painS and lIving bEtteR) study was to develop a logic model to explain how a supported self-management intervention could address potential mediators, and lead to improved health outcomes for people who have MSK pain and varying levels of HL.The EASIER study consisted of 4 inter-linked work packages, in a mixed-methods concurrent-sequential design. Work Packages 1, 2 and 3 were conducted concurrently, and the findings were synthesized in work package 4 to produce an evidence-based logic model  by examining factors that influence (moderate) and explain (mediate) the relationship.The study team took a pragmatic approach to selecting the datasets for analysis in work package 1. The studies chosen were readily available internal datasets that members of the EASIER study team had been involved in previously and were familiar with. We analysed data from three existing studies ) including patients presenting with MSK pain in primary care (Keele Aches and Pains Study (KAPS) , TreatmeThe sample size requirement was based on expected power of 0.8, with up to 7 observed variables on expected direct effects (0.1 to 0.45) for a structural equation model (mediation and moderation), requiring 140 to 400 participants for model structure .In KAPS, TAPS and STEMS we examined the association between HL   and MSK The three datasets included valid scale measurement of pain and function outcomes  and SF-Potential confounders accounted for in the analyses were: age; gender; education; employment status; socio-economic status; co-morbidities; living alone; accommodation ownership. Association between HL and pain and function were examined before and after covariate adjustment.The relationship between HL and the outcomes of pain intensity or physical function may be different within different population socio-demographic subgroups. Hence, we examined whether the same socio-demographic variables (given above) moderated any association between HL and pain / function outcome, which may further help in informing the strategy for targeting of any possible intervention.Beyond crude (unadjusted) association, the association of HL with pain intensity and function at final follow-up was analysed using a stepped general linear model, with step 1 adjusting for socio-demographic factors ) and socio-economic status, step 2 additionally adjusting for baseline co-morbidities and mental health status, and step 3 further adjusting for baseline pain duration and corresponding baseline values of the outcome measures (pain and function), to estimate the level of independent association of pain and functional outcome with HL.To examine moderation we modelled the individual interaction effects between each of the baseline socio-demographic / health variables and the HL variable . Since moderator evaluations are generally under-powered relative to main-effects evaluations we report the interactions that give p-values less than 0.1.We conducted a mediation analysis , 30 to iFurther, we conducted moderation analysis to explore factors that affect the strength of the mediation relationships between HL at baseline, the mediators, and outcomes . This analysis (moderated mediation) potentially identifies sub-groups of individuals where mediation affect is increased/decreased, which will help support intervention development.Structural equation modelling (SEM) was used to conduct the mediation analyses. Unstandardised and standardised model coefficients are presented for the indirect effects through mediation and the affiliated p-values. The percent indirect effect through the mediation variables  are presented. The mediation models included age, gender, comorbidity and education/ socio-economic status as covariates.For those mediator variables accounting for at least a quarter (≥ 25%) of the total effect, further evaluation was carried out to assess whether socio-demographic subgroups based on age, gender, education, co-morbidity and socio-economic status, modified the mediation effect.All statistical analyses were carried out using IBM SPSS version24, AMOS and STATA_v15.The objective of WP2 was to summarize evidence from previous trials to identify which types of interventions, or components of interventions, aiming to support self-management of a long-term condition  have been developed specifically for people with limited health literacy and demonstrated to be effective. For example, supported self-management interventions may include components focusing on lifestyle ; pain education, medication management, or mind–body therapy.An evidence synthesis was conducted in accordance with PRISMA  and registered with the International prospective register of systematic reviews (PROSPERO ID: CRD: 42019136424). An experienced information specialist (NC) designed and conducted searches from 2009 until March 2019 in MEDLINE (OVID), EMBASE (OVID), CINAHLPlus (EBSCO), AMED (OVID), PsycINFO (EBSCO) and the Cochrane Library  searches to identify recent systematic reviews of relevant RCTs (past 10 years), and (b) updated searches to identify more recently published relevant individual RCTs. Additional methods for identifying eligible studies included: (i) checking reference lists of included RCTs and systematic reviews; (ii) consulting experts for additional studies; and (iii) citation tracking of key documents/reports or systematic reviews. We included RCTs of any design . All other study designs were excluded .We included studies of supported self-management interventions developed for adults diagnosed with at least one long-term condition (LTC)  and who had been identified with limited HL using a validated measure. Interventions could include components focusing on lifestyle , pain education, medication management, or mind–body therapy. The review included studies conducted in primary care, community care, occupational healthcare or rehabilitation settings, studies conducted in hospital settings were excluded, except for those concerning supported self-management interventions provided at discharge.Eligibility screening of titles and abstracts, then full texts, was conducted by sets of two review authors independently. Disagreements were resolved by discussion or by consulting a third reviewer where necessary. A standardised data extraction form was developed, piloted and used to collect data for analysis. Study-level data were collected on healthcare setting; selection criteria; population characteristics; characteristics of investigated interventions; process measures ; outcome measures; and effect estimates. The TIDIER (Template for Intervention Description and Replication) checklist was used to extract details regarding included interventions . Data exTo ensure we had a comprehensive approach to identifying relevant self-management approaches that are relevant and suitable for people with MSK conditions, we also conducted an umbrella review  which summarised evidence of interventions to support self-management specifically in people with MSK pain, and included a focus on varying levels of health literacy . This woThe objective of WP3 was to examine the experiences of people living with MSK pain, HCPs and experts around self-management of MSK pain, and their views on the most appropriate intervention components that are also suitable for people with varying levels of HL.1. Personal and/or professional experiences around MSK condition self-management.2. Potential targets for intervention for supported self-management and for intervention design identified in WP1.3. Appropriate intervention components and how best to deliver them in primary care for patients with varying levels of HL.This work package explored:A qualitative design was employed comprising 4 focus groups . Focus gIn addition to a topic guide, we used a case vignette focused on a fictional character ‘Robert’ who has MSK pain and may have problems with their HL. The case vignette was introduced as an ‘ice-breaker’ at the start of each focus group to help facilitate and focus the discussion around what can be a sensitive issue for some participants , who have expertise in working in community settings with those with limited HL , experts in HL, and 3rd sector experts working with people with limited HL. Participants were recruited via professional network  hosted by Keele University. Participants were asked to rank the importance of the evidence statements produced from the triangulation of the findings from work packages 2 and 3. The importance of the statements were ranked on a 4-point Likert scale   for each evidence statement across all respondents after each round was decided upon a priori, following a review of the literature , 48. TheFollowing the Delphi, we took the evidence statements with 80% consensus for inclusion and mapped them to the findings of the systematic review and assessed the overall confidence in the evidence by grading them as high, moderate, low or very low using an approach modified from GRADE  methodology .The research team used the agreed components identified through the Delphi to produce a logic model that explains how potential intervention components could address potential mediators, leading to improved health outcomes for people who have MSK pain and varying levels of HL.Involvement was embedded in all stages of the EASIER study. The study concept and design was co-produced with our PPIE members. PPIE members advised on the participant facing documents, the topic guides and the case vignettes for WP3. They were also asked to reflect on the proposed recruitment strategy and location of the focus groups. PPIE input was obtained at an analysis workshop focused on the WP3 data. A final workshop with PPIE members took place to allow them to share their perspectives on the components of interventions that were incorporated into the logic model based on the modified online Delphi.Table Table The moderation analysis  resulted in the identification of 408 unique citations. Screening and full text eligibility assessment removed 398 systematic reviews, leaving 10 for inclusion. From these 10 systematic reviews, 91 unique citations were identified and 10 RCTs (11 papers) were deemed eligible see Fig. a.Fig. 2The search to identify more recently published relevant individual RCTs resulted in the identification of 886 unique citations. Screening and full text eligibility assessment removed 881 RCTs, leaving 5 for inclusion see Fig. b.The characteristics of the studies included are described in Table n = 12) included a range of professional groups who are all directly involved in the care or support of people with MSK pain: 3 third sector workers, 2 GPs, 2 physiotherapists, 1 nurse, 1 occupational therapist, 1 pharmacist, 1 rheumatologist and 1 psychologist. The PFG comprised seven women and 1 man, with a wide range of experience levels (mean: 19 years providing care or support to people with MSK pain).Three focus groups with people with MSK pain from the community (CFG) and one focus group with professional stakeholders (PFG) were conducted, each lasting between 60–120 min. The three CFGs included a total of 17 participants  which comprised 13 women and 4 men with an mean age of 72.2 (SD 13.4) years and included a mix of race/ethnic backgrounds . The PFG sample ‘I think health literacy should be part of undergraduate medical and clinical training as a matter of course.’ (PFG)‘Any intervention needs to be owned and understood by the person to whom it applies. And, in order for somebody to self-manage, they need to understand what the condition is, and what they can do about it, within their context.’ (PFG).‘If we come up with some sort of education, that would be helpful for the wider community in terms of giving them awareness, or giving them any kind of self-management programme to help them with their aches and pains and with their muscles and joints’. (CFG).Both groups highlighted the importance of understanding the concept of HL. In particular, that HCPs should be educated and trained to understand its importance and impact on health, specifically self-management, and consequently its relevance to health care practice and service provision.‘For some [patients], it will be about levels of health literacy. The problem with things like health literacy is, as I’ve said, everything needs to be holistic.’ (PFG)‘It [health literacy] looks at everything from social to psychology to see what they’re picking up in that section. Are they picking up the social aspect? I find that so much more now about people’s pains, understanding and beliefs.’ (PFG).The psychosocial implications of MSK conditions with a particular focus on ageing, social construction of MSK, co-morbidities including mental health and access to services were deemed important when understanding MSK conditions in the context of HL.‘They [doctors] generalise a lot of things and I quite agree with [X] as they (Drs) told [X] to take two times a day. The doctor says, ‘Take this three times a day,’ but they’re not really personally talking about you. They have to go deeper into what works’. (CFG).‘The system is changing and it’s whether everybody in the community fully understands that actually, when it comes to illness, it’s more back on them to be in control of it. Whereas, actually some people just don’t want to be in control. They want to be told’. (PFG).The training needs to address how patients may mask limited HL, and the importance of seeing the patient in the context of their personal, familial and social resources and support was felt to be crucial. HCP training also needs to enable them to acknowledge and understand what the patient/care-giver knows, including their health beliefs and expectations.‘Sometimes you just need somebody to go through, explain and be able to go a bit deeper with them rather than just being given the information.’ (PFG).‘You go to a consultation with a dietician and when you walk out, how much can you retain? Not much, too much information’. (CFG).Use of language and terminology was very important from the perspective of those with MSK pain. Suggestions of how to improve communication with patients to enable them to better retain information included alternative approaches e.g. teach-back, audio and visual aids etc. The importance of non-verbal communication, breaking bad news, and exploring patient health beliefs and expectations were also highlighted in the focus groups.‘It’s also about the relative importance of musculoskeletal conditions compared to other things in terms of training, isn’t it? You only have to look at how diabetes, heart disease and some of these other conditions are prioritised. Of course, the other thing is that most of these people will have five or six other health conditions at the same time. Whilst the priority today might be aches and pains, the priority tomorrow will be diabetes, or blood pressure, or ten other things. I don’t think arthritis has that sense of priority for patients or for healthcare practitioners. We need to set this as priority.’ (PFG).‘They (HCPs) gave you too much information in one day for you to really take in. You can go back another time now and do it again’. (CFG)Both groups agreed that training and education on identifying and responding to reactions of shock, anxiety, denial, guilt, blame is important. Providing timely information and prioritising information at different time points, whilst avoiding information overload, was deemed necessary when considering people with limited HL. Liaison with other providers and providing follow-up were also identified as important components for HCPs to consider.‘I’m starting straight from the beginning of the consultation now. It’s massively changed my practice and I’m tending to not have to give out as much information leaflets and having more time to sit with people in clinic to sort of watch the video ‘Three minutes understanding pain’, especially with the younger chaps that don’t really open up.’ (PFG).‘There are a lot of things that we need to be guided into and educated well about, so then we can take the right steps.' (CFG)To help patients understand their MSK pain the participants of the focus groups agreed that education and support is vital and should be condition-specific, accessible, reliable, and trustworthy. Specific knowledge and understanding of the side effects of analgesics, self-management strategies, sources of information, and relevant services including physiotherapy.‘…less information in a clearer format and signposting people as to where they can get more when they’re ready to receive it.' (PFG)‘Don’t know if it could be something virtual, like webinars. I know people can drop in at times or there are videos they could watch and then people could start talking.’ (PFG)‘I'm talking about videos for treatment, I mean painkillers are great and this study is brilliant when you're getting different peoples, you know, I suppose, that’s one thing where it really would but to me it would be helpful if I could see somebody actually doing the exercises’. (CFG).The participants felt strongly that the way in which information is delivered to patients should be clear and accessible. Some of the suggestions from the groups included pamphlets, videos, pictures, audio clips, on YouTube, in GP surgeries, TV, physiotherapy clinics, and web-based resources; Regular text messages with prompts, updates and reminders were felt to be useful.‘Instead of leaving them and saying, ‘Right, off you go now,’ there’s a floating advisor you can just drop in. You may need to steer that person to that somebody and say, ‘Yeah, watch this video with them.’ (PFG).‘I think a group setting works quite well so like here we've shared ideas between each other, although there is a problem about possibly misinformation, you know, you can feed off other people and say, oh right, yes, well I never thought about that strategy or using a hot water bottle or doing this or doing the other and it may give you ideas that perhaps you hadn’t already thought about. So, meeting together in a group and perhaps have somebody come and show a video let’s say about strategies, I think that would be useful.’ (CFG).The participants provided a range of perspectives on modes of support. Suggestions included a ‘floating’ advisor in GP surgeries to offer on-going support, integrated services, peer-support groups, expert-led support groups, community education sessions to raise awareness of MSK and self-management strategies, expert-moderated internet-based chat groups/forums and social media.Triangulation of the findings resulted in the production of an evidence table. From this, 49 evidence statements across 5 themes  were created and used in the Delphi study , with a wide range of experience levels (average: 15 years proving care or support to people with MSK pain). The sample included different professional groups who are all directly involved in the care or support of people with MSK pain: 9 physiotherapists, 4 GPs, 2 third sector workers, 2 academic researchers, 1 nurse practitioner, 1 occupational therapist, 1 pharmacist, 1 rheumatologist, 1 psychologist and 1 Public Health specialist. The sample comprised of 5 individuals who stated they had expertise in HL.After analyzing the round 1 data, 12 evidence statements reached consensus and were removed from the second  round. The second round was completed by 21 93.3%) participants from round 1 and a further 10 evidence statements reached consensus, which resulted in a total of 22 evidence statements relating to potential components and modes of delivery to include in the logic model , intervention components, delivery modes, outputs and health outcomes see Fig. . Key detSupported self-management interventions are widely used to improve the health of those with MSK pain . Such inThe findings of work package 1  demonstrated that low HL is associated with poorer  pain and function, which was independent in part from other baseline co-factors such as socio-demographic and health-related-factors. This provides further support to the findings of Lacey et al. 2018) who previously used the KAPS data alone to examine the impact of limited HL in a population with MSK pain 18 who pr. HoweverWith regards to targets for intervention, a previous study of chronic pain clinics that served patients with low socioeconomic status found that lower levels of HL were associated with greater catastrophizing and lower pain-related self-efficacy . A systeThe aim of work package 2 (systematic review) was not to estimate the overall effectiveness of self-management interventions as this has been addressed in several previous systematic reviews –71. The The findings from work package 3 (focus groups) also identified a number of intervention components which were deemed important to HCPs and individuals with MSK pain. These components were grouped into 2 overarching themes, 1. HCP education and training, 2. Patient and caregiver education and support. Following the thematic analysis, it was clear that there was significant overlap between the effective components identified in work package 2 (systematic review) and the sub-themes identified in the focus group data .n = 49) which were grouped into 1 of 5 themes .The triangulation of the data from work packages 2 and 3 grouped together the data sources and explored commonalities and divergence. The final evidence table produced from this process included a large number of intervention components and modes of delivery (Evidence statements were produced from the evidence table and were then considered by the stakeholders participating in the Delphi consensus study (work package 4). The majority (69%) of the evidence statements were associated with moderate or high levels of confidence in the evidence when risk of bias was assessed. The Delphi narrowed down the 49 evidence statements to 22 evidence statements, which the group felt should definitely be included in the logic model. At least one evidence statement was selected from each of the themes identified in the triangulation process.To our knowledge, this is the first study to identify key components of supported self-management interventions suitable for individuals with MSK pain and varying levels of HL. We used a mixed methods approach, including both quantitative and qualitative methods. Conducting secondary data analysis of three large data sets was an efficient approach as it allowed us to access relevant data from 3 different studies with a collective large sample size.Incorporating a systematic review enabled us to identify and synthesise all relevant evidence and assess our confidence in the components of interventions and modes of delivery selected for inclusion in the logic model. The focus groups and the Delphi study included a range of important stakeholders including people with MSK pain, multidisciplinary HCPs and third sector workers, therefore gained a wide range of relevant perspectives on what would be important to include in a supported self-management programme and what would be feasible to deliver within primary care. The team worked hard to involve seldom heard voices in the project and specifically approached groups in the community who may experience barriers to accessing services or are under-represented in healthcare decision making. However, there were some limitations surrounding the other samples recruited. For example, the professional focus group included only one male participant and all identified as white British. The participants in the Delphi study represented a better gender mix, but again there was only one participant that was not of white British origin.Some findings that might have been expected to arise in the professional focus group, such as the ways in which promoting patient knowledge of the causes and mechanisms of pain in MSK conditions, were not brought up in the discussions. Factors such as this could be explored in future studies.A key strength of this study was that PPIE was included at each stage of this research, from study conception through to analysis and agreeing the final logic model.This study has enabled us to produce a person-centered, evidenced-based logic model that describes evidence-based intervention targets, effective intervention components and modes of delivery to support self-management and explains how these can lead to improved health outcomes for patients with MSK pain and varying levels of HL.The model is acceptable to both patients and HCPs and has potential for significant impact on the management of MSK pain and for improving patient health outcomes. The next steps are now to draw on this logic model to inform the future refinement and evaluation of new, inclusive supported self-management intervention(s) for MSK pain that can be delivered in primary care.Additional file 1. Details of datasets.Additional file 2. OVID MEDLINE Search strategy.Additional file 3. Case Vignette.Additional file 4. Work package 3 data collection and analysis flowchart.Additional file 5. Evidence statements for Delphi study.Additional file 6. Estimates of association of baseline socio-demographic variables with follow up pain and function outcomes .Additional file 7. Mediation and moderation of mediation of the association between inadequate health literacy and poor pain and function at follow up.Additional file 8. Work package 2 TIDIER checklist.


A “living” approach to clinical practice guidelines is when the identification, appraisal and synthesis of evidence is maintained and repeated at an agreed frequency, with a clear process for when and how new evidence is to be incorporated. The value of a living approach to guidelines was emphasised during the COVID-19 pandemic when health professionals and policymakers needed to make decisions regarding patient care in the context of a nascent but rapidly evolving evidence base. In this perspective, we draw on our recent experience developing Australian and international living guidelines and reflect on the feasibility of applying living guideline methods and processes to a lifecycle approach to health technology assessment (HTA). We believe the opportunities and challenges of adopting a living approach in HTA fall into five key themes: identification, appraisal and synthesis of evidence; optimising the frequency of updates; embedding ongoing multi-stakeholder engagement; linking the emergence of new evidence to reimbursement; and system capacity to support a living approach. We acknowledge that the suitability of specific living approaches to HTA will be heavily influenced by the type of health technology, its intended use in the health system, local reimbursement pathways, and other policy settings. But we believe that the methods and processes applied successfully to guideline development to manage evidentiary uncertainty could be applied in the context of HTA and reimbursement decision-making to help manage similar sources of uncertainty. Health Technology Assessment (HTA) is a multidisciplinary process that uses explicit methods to determine the value of a health technology at different points in its lifecycle, for the purpose of informing decision-making that promotes an equitable, efficient, and high-quality health system  It is a HTA is often reactive, occurring at a single point in time following initial regulatory approval or in response to regulatory changes  . Full HTA lifecycle approach is even more relevant as agencies around the world are faced with assessing new, rapidl evolving classes of health technology, such as cell and gene therapies . In thisThe core methods for literature searching, evidence appraisal and synthesis are similar for living and partial updating of traditional (static) guidelines, but living guidelines involve a frequent and explicit approach to keeping the guidelines up-to-date. This approach includes frequent surveillance for newly published clinical studies, the prospective, ongoing incorporation of those studies into the evidence base, and the use of pre-agreed triggers for updating the corresponding evidence-based recommendations  The critThe most tangible benefit of a living approach to guidelines is that evidence-based recommendations for clinical care retain their trustworthiness by remaining up-to-date. A less tangible (but no less important) benefit of a living approach is the way it changes the context for decision making: the knowledge that a decision can be revisited soon  means that Guideline Development Panel members are more likely to make a decision on a recommendation in the face of uncertain evidence, rather than make no decision.Though intended for different purposes and audiences, HTA and clinical practice guidelines share core components, particularly those related to methods for the surveillance, appraisal, synthesis, and contextualisation of clinical and patient evidence . Best prHowever, there are important differences between HTA and guidelines. These differences arise from the fact that HTA has a broader scope than guidelines, is undertaken by industry as well as by government and non-profit organisations, is less transparent because of the inclusion of unpublished clinical data and commercially sensitive pricing information, and needs to comply with local regulatory and reimbursement pathways. This means that it is more straight-forward to change a guideline recommendation than it is to change an HTA decision. It also means that it cannot be assumed that the methods and processes applied in living guidelines are directly transferable to all HTA in all settings.Despite the differences, HTA and guideline development are interdependent activities that draw from the same knowledge base: HTA often relies on guidelines to define current treatment pathways and comparators; and guidelines need to be cognisant of the regulatory and reimbursement status of treatments they recommend. The need for harmonisation of HTA and guidelines  is an important area of health services research and has been described by others, but is not the focus of the current article . Early mWe see a number of opportunities and challenges for adopting a living guideline approach in HTA . The livSimilar and additional factors are likely to determine the frequency with which HTA literature searches can be updated, including a combination of the capacity of HTA teams to undertake more frequent searching, and the frequency with which the respective decision-making entities can meet to adjudicate on the new evidence. One issue to be mindful of is that the frequency of updating decisions does not outpace the ability of the health system to respond. The frequency of guideline recommendation revisions is effectively limited by the ability of healthcare providers to modify local protocols and standards for care. However, the frequency of reimbursement revisions will be limited by the frequency at which decision-makers can consider updates, and the frequency with which pricing and supply contracts between industry and payers can be varied.As is for guidelines, it is unlikely that all HTA questions will be suitable for a living approach. Given the organisational changes that would be required to support a living approach to HTA, agencies may wish to focus on technologies that promise a high benefit-to-risk ratio, where the usual levels of RCT evidence are not available and where the cost implications are significant , or where the pace of technological innovation is very high  or the policy context is changing rapidly . In these situations, it should be possible to adopt a concept known as early multi-stakeholder dialogue, which is a prospective or intentional approach to HTA where manufacturers, healthcare providers, clinicians and payers pre-agree i) the measures of most relevance for the technology and the population(s) of interest, and ii) how the pricing of the technology will vary based on those measures . Any nonConditional marketing authorization pathways or lifecycle approaches to HTA have been introduced for cancer drugs and for digital health technologies . These pA living approach to HTA could decrease research waste and duplication of effort. The sharing of evidence summaries already happens in clinical practice guidelines , and theIn this perspective we have discussed the aspects of HTA that are most amenable to a living approach and where living guideline evidence translation methods or processes can be transferred to HTA. We also highlight what, in our view, is needed to support a transition to living HTA .Box 1 What is needed to optimise the impact and reliability of a living approach to HTA.1. Development and/or testing of methods for the continuous updating of non-RCT evidence.2. Pilot studies for different technologies for different clinical purposes, to understand what works, what does not work, and why, and the importance of context .3. Agreement on the HTA scenarios where a living approach is likely to optimise market access, defined as a combination of shorter time to market, with acceptable mitigation of safety risk to patients, and acceptable cost and cost-effectiveness.4. Agreement on the policy levers that will be required to support partial or full disinvestment if technologies do not live up to their promise.5. Practical guidance on the organisational and resourcing requirements for living HTA, and how to transition from reactive HTA at a single point in time to responsive HTA throughout the life-cycle of a technology.The iterative nature of a living process allows for more nuance in the face of uncertainty, and a willingness to support innovation at early stages, knowing that decisions will be revisited and revised as new evidence emerges. It could give decision-makers comfort in making early conditional decisions for a technology/service, instead of what might otherwise be a “no” decision in the face of uncertainty. The “secret sauce” of a living guideline approach is the organisational infrastructure and collaborative culture that needs to be put in place to support it. It requires a commitment on the part of the guideline developer to provide ongoing funding to resource continuous evidence review activities, and a standing Guideline Development Panel to deliberate on new evidence as and when it emerges. Although a lot of HTA activity is undertaken as ‘one off’ evidence reviews, it should be possible for industry and HTA agencies to re-orient some  of their resources to a framework that supports the ongoing incorporation of new data . There is also additional efficiency to be gained by aligning the methods and timing for living guidelines and lifecycle HTA.before living approaches are implemented, and finding a balance between policy levers that “push”  and “pull”  towards a living approach.HTA agencies are under increased pressure to provide patients with early access to promising health technologies, while accounting for the often-incomplete picture of clinical and economic impact of a new treatment during its initial technology assessment. Often, the evidence available at the time of the first HTA is limited, and decision uncertainty may be reduced with longer term data from trials, observational and registry data. At the level of evidence review methods, further innovation and testing of living methods is required for study designs other than RCTs and for non-intervention questions, particularly given the drive for HTA to rely more on innovative clinical trial designs . Living HTA could expand the approaches employed by living guidelines in two key ways: By 1) including pricing/cost considerations in the prioritisation criteria for living topics, and 2) exploring how living searches for economic and epidemiological data could feed in to economic evaluations and budget impact analyses. The policy challenges of adopting a living approach in HTA are more significant than for a living approach to guidelines: the benefits of earlier patient access to treatments need to be balanced against the potential for making “wrong” decisions—reimbursing technologies that do not end up being as safe, effective and/or cost-effective as anticipated. This highlights the importance of developing trust between stakeholders The introduction of the living approach may result in the ability to create a more harmonious and streamlined process between both HTA and guidelines. In this perspective we have illustrated the HTA domains where living guideline evidence translation methods or processes are directly transferable to HTA, additional aspects of HTA where a living approach is likely to be suitable (but where methods and processes still need to be developed); and aspects of HTA that are unlikely to be suitable for a living approach. However, our experience is limited by primarily conducting living guidelines and HTAs in an Australian context. Pilot case studies are needed that 1) describe the experience of introducing different living methods or processes within different HTA scenarios, 2) determine benefits and challenges of these approaches, 3) further develop methods for those areas of living methods that are specific to HTA, such as economic analysis, and 4) place these experiences within the local policy context so that broader themes can be identified regarding the suitability of living methods and processes for HTA in different countries.


The past decade has seen the increasing influence and relevance of real-world data (RWD) and real-world evidence (RWE) in healthcare decision making. The value added by RWD/RWE has prompted the pharmaceutical industry to develop high performing systems and practices to harness the power of evidence generated at the global level. However, this worldwide transformation provides outstanding opportunities to support capability building within local affiliates and to impact key country-level stakeholders through resulting evidence. Therefore, we present an Evidence Blueprint Initiative, which links the global and local  skills, and furthermore addresses the opportunities and gaps in evidence generation capabilities at the local level. Cross-functional experts were recruited at the local, regional, and global level to define best practices. A framework was developed to characterize the foundational expertise needed and to assess markets’ existing capabilities. Subsequently, targeted roadmaps were developed and implemented to build capabilities in specific areas within each affiliate. The impact from the Blueprint is encouraging, resulting in improved local evidence plans, established evidence teams, enhanced RWD use and strategic implementation of patient centric science in local affiliates. The success of the Blueprint resides in empowering affiliates to realise their local evidence generation ambitions and to match them to their local context. It strengthens and expands the ties between various parts of the organisation and the external environment while building fit-for-future evidence capabilities from local affiliates. As a reReal World Data (RWD) refers to local healthcare information that is routinely collected in hospital registries, electronic healthcare records (EHR), patient and disease registries and health insurance databases  and is oWith an increased role of RWD/E in the drug development process, beginning from pre-clinical to post-approval phases , RWD andIn order to address local challenges, we present a modular framework for how to ‘glocally’ address opportunities and support local affiliates in building their integrated end-to-end evidence generation capabilities, positively impacting healthcare. This framework is designed for markets of all sizes and maturity levels in evidence generation, considering varied data environment and opportunities. Additionally, it factors in existing best practices and potential barriers at the local level. The modular framework has been leveraged across AstraZeneca affiliates to build fit-for-purpose evidence capabilities through comprehensive local self-assessment and the development of country-specific roadmaps for capability building. This initiative could therefore be an opportunity for other organizations striving to further establish the industry as a collaborative partner to positively impact healthcare through enhanced RWE generation capabilities and utilization of local RWD.The Evidence Blueprint initiative was split into two phases: a framework development phase, and a subsequent framework implementation phase  were engaged to catalogue best practices and define the various levels of maturity across the different core areas of evidence generation. As the framework was setup to develop internal ways of working, no external experts were engaged during initial development. The framework is comprehensive and considers key processes, tools and documents, people, Key Performance Indicators (KPIs) and stakeholders/communications. As each core area was developed independently, there was a subsequent centrally coordinated review to harmonize the defined levels of maturity for each area to ensure a high level of continuity across the Blueprint framework.The Blueprint forms the basis of the capability assessments across local affiliates, whereby an evaluation of current and desired maturity is evaluated, and an evidence capability roadmap is created to provide short-, mid- and long-term goals, actions, and critical success factors.for local affiliates and driven by local affiliates, however, the process of implementing the framework is supported by a core Blueprint team from AstraZeneca global Medical Affairs, responsible for defining the step approach and alignment on expectations . This is done jointly between the core team and key representatives of the local affiliate, most commonly the Medical Director and Evidence Generation Lead.The Blueprint Initiative is versus desired maturity level with regards to key processes, tools and documents, people, KPIs, and stakeholders/communications, The self-assessment of evidence capability maturity is performed by a cross-functional team from the local affiliates. Typical functions that participate in the assessment are Country Medical Director, Medical Evidence Leads, Medical Advisors/Therapeutic Area Leads, Market Access, and a Commercial representation. However, this may differ depending on country set up. Each core capability is assessed based on current Following this assessment, a workshop is hosted for the local cross-functional team to align on strategies and jointly develop an evidence capability roadmap. The generated roadmap outlines the short-, mid- and long-term goals, actions, and critical success factors to enable the local affiliate to reach their desired maturity for the selected capability areas. The discussions and roadmap creation is driven by the local affiliate, with moderation provided by the global Blueprint core team. The global core team supports the process by sharing learnings from previous workshops; however, the direction and decisions are made by the local affiliate.An outcome of the workshop is for the local affiliate to appoint a designated change lead that oversees the execution of the roadmap. The successes, learnings and roadblocks are shared with the global team in a follow-up call  but also informally with other local affiliates, contributing to the ever-growing knowledge sharing network that has been established as a result of the Blueprint Initiative.The Blueprint Initiative has proven to be a hugely valuable approach that has enhanced the evidence generation capabilities across local affiliates. As a result of embarking on the Blueprint Initiative, local affiliates gain an in-depth understanding of their current capabilities by identifying areas of strength, and areas where there is room to improve to become leaders in evidence generation. An actionable plan to reach the desired capability level is developed as local affiliates define their own objectives and evidence generation ambitions in a cross-functional group. In this section we will present an overview of the rollout and highlight specific impacts of the initiative. Overall, the Blueprint has proven highly beneficial in understanding the level of intrinsic skills and capabilities necessary to generate the appropriate evidence at the right time to the right stakeholder.Since 2021, ten local affiliates across Europe, North America, and Asia-Pacific have joined the Blueprint Initiative. The first ten countries had varying degrees of evidence generation capability maturity, broad geographical spread, and represented a variety of healthcare system archetypes. The local affiliates also represented different types of data infrastructure, highlighting differences in data collected across the markets.Following the completion of the initiative by the first wave of 10 local affiliates, other markets have started to proactively express an interest to understand how they can also implement the Blueprint Initiative. Through the AstraZeneca company network, the impacts of the initiative have been circulated, creating a strong appetite among other affiliates for taking part in this evidence generation-empowering initiative, highlighting the importance of ‘glocal’ initiatives.Since the launch of the Evidence Blueprint in 2021, there have been vast and important improvements in local evidence capabilities in participating markets. The key improvements to capabilities are summarised in The Blueprint has also prompted local affiliates to adjust their evidence resourcing and role descriptions, improving local capacity and expertise. In a medium-sized central European market, the Blueprint played a key role in reigniting a collective belief in the importance of RWE and potential for the future, which led to increased RWE resource allocation, with specific expertise added in biostatistics and dedicated therapeutic area roles. In both previously mentioned markets, regular cross functional RWE sessions have been introduced, enabling better communication and more visibility within the therapeutic areas. This has led to better evidence strategy and evidence generation as an outcome.Transforming patient care has taken centre-stage in catalysing RWD, and the Blueprint Initiative has played a pivotal role in embedding patient centricity in local evidence generation. Across local affiliates, there has been an emphasis on establishing collaboration forums with local patient societies and patient advocacy experts. In a North American market, for example, dedicated training materials are being created in collaboration with internal AstraZeneca Patient Engagement experts to educate local stakeholder on how best to engage with Patient Advocacy Groups (PAGs) on evidence generation. As a result, PAGS can be increasingly involved in more aspects of the study process, such as reviewing of study protocols. For example, a top European local affiliate is learning first-hand how to take their feedback into consideration throughout the lifecycle of a study by inviting third party patient association representatives to evidence planning workshops. Overall, this has led to new qualitative studies being developed across markets to capture patient experience.The Blueprint has also prompted greater awareness of the regional data landscape for affiliates, establishing new data partnerships in key disease areas based on the evidence gaps identified by the VTs. Local affiliates, such as the top 4 EU market mentioned in the previous paragraph, conducted a review of their data supply in the context of local evidence needs. Findings were leveraged to continue support of data platforms and databases consortiums to integrate data for local evidence generation studies. This has resulted in targeted external partnerships to broaden access to data across primary, secondary, and tertiary cases. Across markets, processes have been established to better link evidence needs and data supply, e.g., implementation of local data sources to medical field staff to enhance customer interactivities, with a more frequent review of evidence needs via cross functional forums. Additionally, with increased patient centricity and improved data partnerships, local affiliates have expressed a wish to further evolve the use of data with patients. The evolved uses of data include engaging with patients/PAGs by leveraging the evidence to educate patients on how to advocate for themselves using evidence, e.g., in interactions with physicians.Data governance is often concurrently managed by various functions, e.g., medical, commercial, and epidemiology. Following the Blueprint Initiative, some local affiliates have established dedicated data governance committees to ensure better visibility and safety of the data being accessed by the various cross functional partners. The data governance committees have allowed for reduced duplication of efforts and improved accountability in whom should be leading the analysis of specific data assets and also improved already robust data safety processes. This has resulted in more targeted external strategic engagement and made it possible to improve the enterprise strategy for data access and use across the affiliate. In addition to improvements locally, the data governance committee helps educate global functions on regional difference in data access.While the overall success of the Blueprint has been confirmed in the engagement with local affiliates throughout the programme, a few common challenges were observed across markets. There was not always complete alignment on the overall long-term evidence strategy. It was therefore important to ensure that the Blueprint roadmaps were developed to complement and advance the overall strategic objectives of the cross-functional evidence generation teams.Additionally, a challenge that was encountered for some local affiliates was limited previous opportunities to benchmark their current capabilities within evidence generation. To pre-empt this challenge, we ensured that the framework was designed in collaboration with representative local affiliate SMEs to ensure that the defined levels of maturity would resonate across markets and reflect the full range of evidence capability levels. This means that the framework can be used to build capabilities from emerging markets to markets with strong capabilities in place already.Additionally, through discussions during the benchmarking process, we were able to ensure that the local affiliates had a unified perspective on their current capability maturity, to successfully plan for building the capability regardless of current maturity.As the role of global medical affairs is only acting as a catalyst in supporting evidence generation capability growth, a challenge has been the heterogenous nature of local affiliates and their needs. The team has had to adapt the timeline of the process and the level of support required depending on the maturity and skillsets of the local affiliates. The key to successful adaptation by the global team is to understand the current state of the local affiliate and also to pre-empt the needs and support required. An example of this is from one of the largest Asian markets, where additional support was provided from the global team in generating buy-in across the local affiliate, e.g., through support with material tailoring and messaging development, or jointly presenting the opportunities and success stories for the leadership team at the local affiliate.We acknowledge that a limitation of the current approach is that the data-points in the framework and in the outcomes are subjective. Nonetheless, we believe the framework is completely fit-for-purpose to align subjective data with local strategies for evidence capability building and not to compare across local affiliates.The Blueprint is considered a living and evolving programme. As local affiliates share their experiences and feedback, the process and framework are updated and extended. The updates are related to both fine-tuning of the existing modules as well as extending the framework to additional modules to ensure it mirrors the ever-changing evidence generation landscape. As a future direction, we are considering the value of inviting external experts/stakeholders to comment on the framework to make sure capabilities developed are fit for their needs, e.g., PAGs to provide input on PRO/Patient centric evidence module. At the request of local affiliates and in line with broader strategic aims, a new module is planned to support the use of evidence in customer interactions in the field to drive medical practice change improving healthcare. Feedback received has also helped in fuelling other initiatives, such as a new global online repository that is under development. The support for the repository partly comes from the Blueprint and will be a “one stop shop” for materials that support evidence capabilities across the company. Additional initiatives that have emerged out of the Blueprint is an informal “matching” of local affiliates of different capability maturity, that can help complement and support each other with evidence generation initiatives.After implementing the framework across 10 local affiliates, with many more underway, the strength in this initiative lies in “glocal” collaboration. With feedback and updates from a wide group of stakeholders, a positive feedback loop has been created that further strengthens the framework, improving the usefulness of the tool in building evidence capabilities across countries. We are certain that similar approaches within other pharma companies would be successful, but we also believe that similar approaches could be leveraged in non-profit settings with a global and local organisation to improve the impact of evidence generated.In this publication, we have outlined a framework for how global healthcare companies can work to develop local affiliates in building their integrated end-to-end evidence generation capabilities, as well as the impact this framework has had. Since evidence and data should underpin all impactful medical activities, the ability to generate local impact on healthcare providers, patients, payers, and regulators is expected to be a crucial strategic driver for medical affairs now and into the future. The Blueprint framework offers a structured, fit-for-purpose approach for local capability building in the increasingly important field of RWE generation.


Emerging evidence suggests the complex interactions between gut microbiota and bile acids, which are crucial end products of cholesterol metabolism. Cholestatic liver disease is characterized by dysfunction of bile production, secretion, and excretion, as well as excessive accumulation of potentially toxic bile acids. Given the importance of bile acid homeostasis, the complex mechanism of the bile acid–microbial network in cholestatic liver disease requires a thorough understanding. It is urgent to summarize the recent research progress in this field. In this review, we highlight how gut microbiota regulates bile acid metabolism, how bile acid pool shapes the bacterial community, and how their interactions contribute to the pathogenesis of cholestatic liver disease. These advances might provide a novel perspective for the development of potential therapeutic strategies that target the bile acid pathway. In recent years, the contribution of gut microbes to health and disease has gained increasing recognition ,2. DiverClostridium difficile infection, and tumors . Th. Th39]. lic acid .Primary BAs synthesized in the liver or absorbed into the enterohepatic circulation are actively transported to the bile canaliculus by the bile salt export pump (BSEP) or multidrug resistance-associated protein 2 (MRP2) ,44,45. FBAs achieve intercellular communication through various receptors. BAs can directly activate nuclear receptors, such as FXR, pregnane X receptor (PXR), constitutive androstane receptor (CAR), and vitamin D receptor (VDR), as well as a few G protein-coupled receptors (GPCRs), including TGR5 and sphingosine-1-phosphate receptor 2 (S1PR2) ,50.N-terminal kinas-dependent pathway, thereby inhibiting BA synthesis in the liver [FXR is the major receptor for both free and conjugated BAs, and is highly expressed in hepatocytes and the intestine . The acthe liver ,53. Convhe liver . Additiohe liver ,56,57, ahe liver , therebyTGR5 is a type of BA-specific GPCR and is expressed in the intestinal epithelium, liver sinusoid endothelium, liver macrophages, and Kupffer cells ,60. The Gut microbiota is considered a crucial factor in BA homeostasis and substantially affects the chemical properties of BAs. In detail, gut microbiota has been shown to alter the composition of the BA pool through dehydrogenation, dihydroxylation, and desulfurization under the action of various enzymes.BSH gene [The first step in secondary BA metabolism is the hydrolysis of the amide bond by BSH. BSH, an intracellular enzyme encoded by the BSH gene , is a meBSH gene ,68. BSH BSH gene ,70.Clostridium, Bifidobacterium, Lactobacillus, Bacteroidetes, and Enterococcus. The presence of BSH has also been demonstrated in the archaea of the human intestine [BSH has been identified in various microbial species across multiple phyla, including ntestine . The amintestine .Bacteroidetes, Eubacillus, Clostridium, Bifidobacterium, Lactobacillus, Streptococcus peptidis, and Escherella [12ɑ-HSDH, 7ɑ-HSDH, 3ɑ-HSDH, and 3β-HSDH, have also been reported [Humans produce BAs that contain alpha-oriented hydroxyl groups, and gut microbiota can facilitate the biotransformation of these BAs into harmful hydrophobic BAs, such as DCA. Pyridine nucleotide-dependent HSDHs can reversibly oxidize the 3-, 7-, and 12-hydroxyl groups of CA by producing oxo-BA intermediates, thereby facilitating the generation of more hydrophilic and less harmful BAs. The BA-recognizing HSDH enzyme exhibits regional and stereo-specific properties and can modify the hydroxyl group of steroid nuclei . To datecherella ,75,76. Greported ,78.bai gene cluster [bai belong to the Ruminococcus genus. In Clostridium, the operons baiA–J of the bai gene have been sequenced, and the enzyme encoded by the bai gene has been identified. In detail, BA 7α-HSDH is encoded by the baiE gene, and 7β-HSDH may be encoded by the baiI gene [Using 7α-dehydroxylase, bacteria in the colon convert primary BAs CA and CDCA to DCA and LCA, respectively , both of cluster . Most ofaiI gene ,79,83,84Clostridium and Gastrococcus. However, the role of gut microbiota in esterification and desulfurization remains unclear [Esterified BAs may account for more than 25% of the total BA content in feces. The esterification of BAs makes these molecules more hydrophobic and insoluble and results in the reduction of their concentration in feces . The bac unclear .The gut microbiota is involved in the transformation of BAs and the regulation of BA reabsorption. Intestinal microbiota not only participate in the decoupling, dehydrogenation, and dehydroxylation of BAs, but also negatively regulate BA synthesis through the FXR–FGF15/19 pathway . BAs areBacteroides fragilis in the intestine was decreased, and the levels of BA mandeoxycholic acid (GUDCA) were increased. These alterations, coupled with the inhibition of FXR signaling in the intestine, suggest that manipulation of the B. fragilis–GUDCA–intestinal FXR axis may ameliorate metabolic dysfunction. In addition, another study involving hamsters fed a 60% high-fat diet (HFD) and treated with antibiotics showed that increased levels of intestinal TMCA and decreased secondary BA levels, attributable to the loss of intestinal microbiota [Sayin et al. analyzed the composition of the BA pool of the entire enterohepatic system of sterile and conventionally fed (CONV-R) mice and validated that CONV-R mice exhibited significantly decreased levels of muricholic acid but not CA . Intesticrobiota , result Ctenopharyngodon idellus has been shown to cause more fluctuations in the composition of biliary BAs [The size and diversity of the BA pool can affect the intestinal microbiota. Studies have shown that CA can alter the composition of gut microbiota in rats at the phylum level and lead to an increase in the number of Firmicutes and a decrease in the number of Bacteroidetes . Compareiary BAs . Primaryiary BAs .BAs have toxic effects on the gut microbiome. In addition to harming bacterial cell membranes, BAs can also affect protein conformation, resulting in protein misfolding or denaturation; additionally, they can induce DNA damage and activate DNA repair-related enzymes, as well as generate oxygen free radicals, thereby causing oxidative stress . Intesti-/- and wild-type mice [The effect of BAs on the composition of intestinal microbiota can also be modulated by FXR. Through FXR, BAs can upregulate the expression of inducible nitric oxide synthase and the expression and secretion of interleukin 18, thereby preventing the proliferation of intestinal microorganisms . Inagakiype mice . The intype mice . Animal ype mice .CLD is a type of hepatobiliary disease caused by immunological, genetic, and environmental factors, among others , whereinClostridium and an increase in the abundance of Lactobacillus [Haemophilus, Veillonella, and Clostridium. UDCA treatment has been found to alter the composition of gut microbiota and partially improve the dysbacteriosis in patients with PBC [PBC is an autoimmune liver disease characterized by the presence of antimitochondrial antibodies and the progressive destruction of interlobular bile ducts . There abacillus . Patientwith PBC .Veillonella and Klebsiella, and positively correlated with microorganisms rich in healthy individuals, such as Faecalibacterium and Oscillospira. Following UDCA treatment, patients exhibit decreased levels of taurine-bound BAs, significantly increased levels of taurine-metabolizing bacteria Bilophila spp., and significantly decreased levels of FGF19 in the serum [The gut microbiota imbalance in PBC is associated with changes in the BA pool. The abundance of intestinal microbes in patients with PBC treated with UCDA varies according to bilirubin levels . PBC is he serum .In PBC, BAs can promote liver regeneration by activating the FXR and TGR5 pathways . The actPSC is a chronic CLD and is characterized by biliary inflammation and periductal fibrosis . PSC is Enterococcus, Fusobacterium, and Lactobacillus, independent of IBD or UDCA treatment. Furthermore, an operational classification unit of Enterococcus has been found to be positively correlated with elevated serum alkaline phosphatase (ALP) levels, indicating the severity of the disease [Enterococcus in the bile of patients with PSC is closely associated with the concentration of toxic secondary BA TCA [Ruminococcus and Fusobacterium bacteria is increased, and the abundance of Dorea, Veillonella, Lachnospira, Blautia, and Roseburia bacteria is reduced; additionally, a specific correlation between microbiota and BA content in feces has been elucidated [Patients with PSC exhibit a decrease in the diversity of gut microbiota, with a significant increase in the abundance of  disease . The abuy BA TCA . The risy BA TCA . The comucidated .-/- mice and patients with PSC, Lachnospiraceae in feces are negatively correlated with the clinical severity of PSC, whereas Enterococcus faecalis and Enterobacteriaceae are positively correlated with the clinical severity of PSC. The inhibition of ileal BA transport alleviates antibiotic-induced progression of liver disease and reduces the total content of BA in the serum and liver [Prevotella in PSC has been reported to enhance the FXR signaling pathway, leading to improvements in cholestasis and liver fibrosis [In a PSC mouse model, the absence of intestinal microbiota has been shown to aggravate hepatobiliary diseases . The imbnd liver . In a gend liver . Intervefibrosis .Biliary obstruction typically refers to the obstruction of the biliary system , which rFaecalibacterium, Lachnospira, and Roseburia is decreased. Moreover, the diversity of biliary bacteria in patients with gallstones is significantly higher than that of intestinal bacteria, with most of the intestinal bacterial operational classification units being detected in the biliary tract. Similarly, another study revealed that in the feces of patients with gallstones, the total concentration of BAs is higher, microbial diversity is lower, the abundance of Roseburia is decreased, and the abundance of Oscillospira is increased [A study involving 29 patients with gallstones and 38 normal individuals  revealedncreased . FurtherRuminococcus_1 was observed to be increased [Wu et al. simulated the processes of biliary obstruction, drainage, and bile reinfusion in a mouse model and found that, despite the occurrence of biliary obstruction, mice continued to produce secondary BAs, and their levels were increased in both the liver and serum. Following 12 days of biliary obstruction, the abundance of ncreased . In anotncreased . Desulfoncreased .In general, in CLD, gut microbiota affects disease progression by interacting with BAs. Drugs that affect BA metabolism or alter intestinal microbiota may be used for the treatment of these diseases. A better understanding of the relationship between diseases and intestinal microorganisms is crucial for developing treatment strategies.Lactobacillus rhamnosus GG (LGG) was shown to inhibit liver BA synthesis and enhance BA excretion by activating the intestinal FXR–FGF15 signaling pathway, thereby preventing liver injury and fibrosis in mice [mdr2-/-) mice [Traditional interventions aimed at gut microbiota include prebiotics, probiotics, antibiotics, and fecal microbiome transplantation (FMT) . Probiot in mice . Additio in mice  and chol in mice . In an a in mice . The exp/-) mice . Other pThe activation of FXR inhibits the synthesis of BAs in hepatocytes, increases the efflux of BAs from hepatocytes, thereby reducing the exposure of hepatocytes to BAs, and has become a key therapeutic target for cholestasis . At presNon-steroidal FXR agonists are currently topics of intense research, with many related drugs having been developed. Cilofexor is an effective non-steroidal FXR agonist. A new phase II trial (NCT02943460) involving 52 patients with PSC who were treated with cilofexor for 96 weeks showed that cilofexor improved liver biochemistry and biomarkers of cholestasis; specifically, the treatment led to a reduction in the levels of γ-glutamyl transpeptidase (GGT), alanine aminotransaminase (ALT), aspartate aminotransferase (AST), and other indicators ,126. BesIn recent years, bezafibrate, a PPARα agonist, elafibranor, a PPARα/δ agonist, seladelpar, a PPARδ agonist, and saroglitazar, a PPARα/γ agonist, have been investigated for the treatment of CLD. Several studies have demonstrated that the combination of UDCA and bezafibrate, a type of fibrate, can improve biochemical measures and long-term outcomes in patients with PBC ,130. ImpAnalogs of FGF19, such as NGM282 , have been developed; FGF19 is expressed in the terminal ileum, reaches the liver through the intestinal-hepatic circulation, and binds to the FGFR4/βKlotho receptor complex . AldaferIn addition to the popular drugs described in the previous sections, many other types of drugs exist. A variety of PXR agonists exists, such as rifampicin, which is an effective human PXR agonist. Currently, the use of rifampicin and the PPAR agonist bezafibrate for the treatment of pruritus in patients with PBC and PSC has been supported by empirical evidence . FXR/TGRIn recent years, the pharmacological properties of traditional Chinese medicine have been extensively studied. Traditional Chinese medicines targeting BA metabolic pathways have gradually emerged. For example, lignans, which are bioactive components isolated from Schisandrae chinensis Fructus, have been elucidated to play protective roles by activating the PXR signaling pathway in cholestatic liver injury .The interaction between BAs and gut microbiota is associated with the progression and prognosis of CLD. The relationship among them is not one-way, but highly intertwined in a network. Much remains to be discovered about the specific mechanisms by which the gut microbiota and BAs are involved in pathophysiological processes. Treatments targeting BA signaling pathways and gut microbiota have proved successful, but more research is needed to further explore new therapeutic targets and the molecular mechanisms of symptoms remission in CLD, and more clinical trial evidence is needed.


The aim of our study was to investigate associations of spleen volume with blood count markers and lipid profile in the general population.Cross-sectional data from 1,106 individuals aged 30–90 years from the population-based Study of Health in Pomerania (SHIP-START-2) were analyzed. Blood count markers included red blood cell (RBC) counts, hemoglobin, platelet count, and white blood cell (WBC) counts. Lipid profile included total-cholesterol, high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) as well as triglycerides. Linear regression models adjusted for age, sex, body height, and weight were used to associate standardized spleen volume with blood counts and lipid profile markers.β = 0.05; 95% confidence interval [CI] = 0.03 to 0.08) and hemoglobin  but inversely with platelet count  and WBC . Furthermore, spleen volume showed inverse associations with total cholesterol , HDL-C , and LDL-C . There was no significant association of spleen volume with triglycerides.Spleen volume was positively associated with RBC (Our study showed that the spleen volume is associated with markers of the blood count and lipid profile in the general population. The spleen is the second largest lymphoid organ in the body and consists of the two parts, white and red pulp . While tThere are several studies from selected populations or animal models describing associations between spleen size and blood parameters. Spleen function regulates the abundance of circulating platelets, and it has been shown that splenectomized individuals are prone to thromboembolism . One stuThere is limited knowledge regarding the association of spleen volume with lipid markers. An experimental study conducted in splenectomized rats suggests that the spleen may alter circulating lipid levels . While aPrevious literature on the effects of the spleen on blood count and lipid levels mostly focused on splenectomized patients or animal models , 13, 14.This study is based on data from the second follow-up of the population-based Study of Health in Pomerania (SHIP-START) conducted in Northeast Germany. At baseline of SHIP-START, 6,267 eligible subjects were randomly selected from population registries. Of those, 4,308 individuals were examined between 1997 and 2001 (response 68.8%). In the present analyses, we used data from the second follow-up of SHIP-START-2, in which 2,333 individuals aged 30–93 years were examined between 2008 and 2012. All participants gave an informed written consent, and both studies followed the recommendations of the Declaration of Helsinki and were approved by the Ethics Committee of the University of Greifswald.Of the 2,333 individuals participating in SHIP-START-2, 1,306 underwent the MRI examination. After exclusion of 197 individuals with missing data in the spleen sequence and three individuals with a splenectomy, the study population consisted of 1,106 individuals.Fasting blood samples were collected from the cubital vein of participants in the supine position between 7 am and 1 pm All samples were either analyzed immediately or stored at − 80°C. Serum lipids  were measured in serum using the Dimension Vista 500 analytical system . Glucose levels were measured using a hexokinase method . Measurements of the blood count including RBC, hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), platelet count, and WBC were determined at maximum two hours after obtaining sample in anticoagulated whole blood on the Sysmex platform XE 5000 .All participants were asked to bring all of their medications to the examination center. Medication data were obtained online using the IDOM software (online drug-database leaded medication assessment) and categorized according to the Anatomical Therapeutical Chemical (ATC) classification index. Lipid-lowering medication was defined by the ATC code C10.2/s, 400 mm2/s, and 800 mm2/s. The acquisition was gated using a prospective acquisition correction technique and following imaging parameters: repetition/echo time = 4,140/72 [ms], field of view = 284 × 379 [mm2], a matrix of 192 × 115, a voxel size of 2.0 × 2.0 × 6.0 [mm], a slice gap of 1.2 [mm], a flip angle of 90°, and a bandwidth of 1,735 Hz/Pixel. Quantitative image analysis of all b-800 images was performed by one observer after training, and interobserver certification was computed together with a radiology resident with 5 years of abdominal MRI experience. Mean interobserver variability was 1.30%  in a random subsample of 20 images. The volume calculation was performed by summation of each contoured spleen slice areas with the slice thickness plus slice gap by MeVisLab®-Software  after conversion of the acquired DICOM data to the NIfTI standard (Neuroimaging Informatics Technology Initiative)  using a 12-channel phased-array surface coil with subjects in a supine position. The isotropic diffusion-weighted imaging was performed using a spin-echo-based echo-planar imaging sequence. Imaging series with different diffusion weightings  were acquired using b-values of 50 mmP < 0.05 was considered as statistically significant. All analyses were conducted with Stata 16.1 .Stratified by spleen volume, data were expressed as median (25th and 75th percentiles) for continuous data and as absolute numbers (percentages) for categorical data. Associations of spleen volume with markers of blood count and lipid profile were calculated by regression models. Linear regression was applied to continuous outcomes and logistic regression to dichotomous outcomes. All models were adjusted for age, sex, body height, and body weight. To account for the drop-out from the main examinations in SHIP-START-2 to the MRI examinations, we calculated inverse probability weights by logistic regression with participation at the MRI examinations as outcome and health-related markers from the main examinations as explanatory variables. These weights were used in all regression analyses. A In multivariable linear regression models adjusted for age, sex, body height, and weight, we found significant associations of spleen volume with blood count markers  to d. WeAfter adjustment for age, sex, body height, and weight, spleen volume was inversely associated with total cholesterol and LDL-cholesterol in the whole population as well as in males and females . Spleen In sensitivity analyses, we excluded individuals using lipid lowering medication, which did not change our results.To the best of our knowledge, there is no study that investigated associations of MRI-derived spleen volume with markers of blood count and lipid metabolism in the general population. We demonstrated positive associations of spleen volume with RBC and hemoglobin, while spleen volume was inversely associated with MCH, MCV, platelet count, and WBC. These associations were consistent in the whole population as well as in males and females except for MCH, where we observed no significant association in females. Regarding lipids, we showed that spleen volume was inversely associated with total cholesterol, LDL-cholesterol, and HDL-cholesterol. These associations were independent of age, sex, body height, and weight.Similar to our findings, a previous study conducted in small group of healthy individuals also found positive associations of spleen volume with hemoglobin and RBC as well as inverse associations of spleen volume with platelet count and lymphocytes percentage . A compaThe underlying mechanisms for the association of spleen volume with the blood counts are largely unclear. In hematopoietic cancers, larger spleen volume can be associated with extramedullary hematopoiesis and systemic inflammation. However, in healthy individuals, extramedullary hematopoiesis is neither present to a relevant extent nor responsible for higher spleen size. Recent reports, however, have indicated the presence of clonal somatic aberrations that increase with age , mediateOur results showed that a lower spleen volume was associated with higher lipid levels. Similar to our findings, previous results from rat models also showed a change in lipid levels after splenectomy –12. For The spleen is considered a reservoir for lipid and lipoprotein lipase enzymes and is responsible for the storage and transportation of lipids . An incrThe large number of individuals recruited in a population-based setting is one of the strengths of our study. We used MRI as a standardized method for the estimation of spleen volume. The limitation of our study is the cross-sectional design, which did not allow us to draw casual inference. Likewise, as indicated earlier, the SHIP-cohort investigated in this analysis has not been investigated for the presence of clonal hematopoiesis, which is a frequent finding in individuals above the age of 60 . Clonal Our study showed that the spleen volume is associated with markers of the blood count and lipid profile. A larger spleen volume was associated with higher levels of RBC and hemoglobin, but with a lower platelet count, a lower WBC, and lower lipid levels. Further studies are warranted to validate and explain our findings.


The objective of this study was to provide recommendations regarding effectiveness, safety, optimal starting dose, optimal maintenance dose range, and target fasting plasma glucose of five basal insulins  in insulin‐naïve adult patients with type 2 diabetes in the Asia‐Pacific region. Based on evidence from a systematic review, we developed an Asia‐Pacific clinical practice guideline through comprehensive internal review and external review processes. We set up and used clinical thresholds of trivial, small, moderate, and large effects for different critical and important outcomes in the overall certainty of evidence assessment and balancing the magnitude of intervention effects when making recommendations, following GRADE methods . The AGREE  and RIGHT  guideline reporting checklists were complied with. After the second‐round vote by the working group members, all the recommendations and qualifying statements reached over 75% agreement rates. Among 44 contacted external reviewers, we received 33 clinicians' and one patient's comments. The overall response rate was 77%. To solve the four research questions, we made two strong recommendations, six conditional recommendations, and two qualifying statements. Although the intended users of this guideline focused on clinicians in the Asia‐Pacific region, the eligible evidence was based on recent English publications. We believe that the recommendations and the clinical thresholds set up in the guideline can be references for clinicians who take care of patients with type 2 diabetes worldwide. HighlightsThis is a systematic review‐based clinical practice guideline. After internal and external review, two strong recommendations, six conditional recommendations, and one qualifying statement were made for insulin‐naive adult patients with type 2 diabetes. Although the guideline authors came from the Asia‐Pacific region, the eligible evidence was based on recent English publications. The recommendations and the clinical thresholds set up in the guideline can be used as references for clinicians worldwide. Many T2DM patients eventually require injectable glucose‐lowering therapy, such as glucagon‐like peptide‐1 receptor agonist or insulin when a combination of rally administered antihyperglycemic agents (OHAs) fails to maintain the desired glycemic targets. Among the various insulin options, basal insulin is recommended at the initiation of insulin therapy.Q1. What are the differences in the effectiveness and safety among the five basal insulin preparations after the initiation of insulin therapy in the target population?Q2. What are the optimal starting doses (U/kg/day) and time of administration (morning versus bedtime) of five basal insulins?Q3. Among the target population, what is the optimal maintenance dose (U/kg/day) that achieves target fasting plasma glucose (FPG)?1c) level  in the target population?Q4. After initiation of any of the five basal insulins, what range of the target FPG can lead to the ideal glycated hemoglobin (HbA1.11c > 7%) on OHAs.Nonpregnant adults with T2DM who are unable to achieve target glycemic goals , drafting recommendations, an internal review by the working group, and an external review by external reviewers who were nominated by the working group members. The GRADE methodology  was used to assess the certainty of evidence and make recommendations.2.11c and incidence of any, nocturnal, and severe hypoglycemia were rated as “critical” outcomes; time in range, FPG control, cost‐effectiveness, weight gain, and patient‐reported outcomes were rated as “important” outcomes. When making recommendations, we placed more emphasis on the effects and certainty of evidence of the critical outcomes.Glycemic control as measured by HbA2.21c (%), which was stated as 0.5%.Based on the GRADE guidance,2.3The core group drafted the recommendations. The clinical experts in the working group reviewed, commented, and voted on the recommendations independently. The core group then revised the recommendations based on the working group's opinion. The revised recommendations were voted by the working group again until each recommendation reached an agreement of more than 75%.2.4Each of the clinical experts from the core and working groups selected three potential external reviewers who can read English and are either intended users of basal insulin or patients with T2DM using basal insulin. The drafted clinical practice guideline and two brief online questionnaires (one for clinicians and one for patients) were sent to the external reviewers. We used the questionnaire templates for external reviewers from the Program in Evidence‐based Care program of McMaster University in Canada.33.1The core group held five online meetings (2–5 h/meeting) to discuss the evidence from the systematic review, answer 12 methodological questions  for each recommendation based on the GRADE approach, and draft the first recommendation document.3.2The first online survey with eight recommendations and eight qualifying statements was sent out to the clinical experts in the working group to vote on 13 September 2022  insulin B for any outcome, insulin A is always treated as the numerator and insulin B as the denominator in the GRADEpro software.3.53.5.12),Appendix Table 1c < 7.0% at 6 months and fewer hypoglycemic events at 3 and 6 months but more nocturnal hypoglycemia <3.9 mmol/L at 3 months. The results of other critical outcomes at 3 or 6 months are similar between two groups, such as HbA1c change and nocturnal hypoglycemia<3.0 mmol/L at 3 months; severe hypoglycemia, nocturnal hypoglycemia<3.0 mmol/L, and nocturnal hypoglycemia<3.9 mmol/L at 6 months, etc. One subgroup analysis showed that patients <65 years old or ≥ 65 years old might have consistent results with the overall patients. Another subgroup analysis (n = 365) showed that for patients with estimated glomerular filtration rate (eGFR) of 60–90 mL/min/1.73m2, glargine U‐300 might result in more nocturnal hypoglycemia events but fewer hypoglycemia events (<3.0 mmol/L); for patients with eGFR of <60 mL/min/1.73m2, glargine U‐300 demonstrated greater HbA1c reduction with potential more nocturnal hypoglycemia (<3.0 mmol/L) at 6 months. However, we do not make recommendations based on subgroup analysis from one study. We call on more high‐quality future research to clarify this point. The prices for both insulins are similar in some countries but may be different in other countries. Additionally, they are unavailable in some areas of certain countries. We did not find evidence for cost‐effectiveness. Based on eligible evidence and clinical experience, we made the following recommendation:The overall certainty of evidence was low because based on the GRADE handbook, for one comparison, if the evidence of one critical outcome has a low certainty, the overall certainty of evidence is low.Appendix Table 1c < 7% at 6 and 12 months .The overall certainty of the evidence was low. Compared with glargine U‐100, detemir probably results in fewer patients having hypoglycemia<3.0 mmol/L at 6 and 12 months (moderate effects), but slightly more patients having nocturnal hypoglycemia<3.0 mmol/L at 6 months  and fewer patients achieving HbAAppendix Table Appendix Table 1c<7.0%. However, when generic degludec U‐100 or glargine U‐300 is unavailable, both glargine U‐300 and degludec U‐100 are more expensive than glargine U‐100. Thus, it may affect equity and acceptability. Based on eligible evidence and clinical experience, we made the following recommendation.The overall certainty of the evidence was low. Compared with glargine U‐100, degludec U‐100 may lead to less severe hypoglycemia (moderate effect) and nocturnal hypoglycemia ; Glargine U‐300 may lead to less hypoglycemia (large effect) and nocturnal hypoglycemia (large effect), with more patients achieving HbAAppendix Table Appendix Table Appendix Table 1c < 7%, a reduction in hypoglycemia, and a large reduction in nocturnal hypoglycemia. There is no eligible evidence to compare degludec U‐100 with NPH. From the indirect evidence  between degludec U‐100 and glargine U‐100,The overall certainty of evidence was low. Compared with NPH, glargine U‐300 or detemir may result in a large reduction in hypoglycemia and nocturnal hypoglycemia; glargine U‐100 may result in an increase in patients achieving HbA3.5.2Appendix Table The overall certainty of evidence was low. Because this eligible RCT had a sample size of only 44 (one group had 32 patients and another group had 12 patients), we do not make a recommendation based on the results of this trial.Appendix Table The overall certainty of the evidence was low. This paper was not a peer‐reviewed journal publication, and it was published as a pharmaceutical report with no authors indicated. Thus, we do not make a recommendation based on it.3.5.3Appendix Table The overall certainty of the evidence was low. The results are consistent with that under 3.5.1 when detemir bedtime injection was compared with NPH bedtime injection. That is, detemir may result in better hypoglycemia and nocturnal hypoglycemia outcomes. Therefore, we do not make an additional recommendation.Appendix Table 1c < 7%, a reduction in hypoglycemia. Hence, we do not make an additional recommendation.The overall certainty of the evidence was low. The results are consistent with that under 3.5.1 when glargine U‐100 bedtime injection was compared with NPH bedtime injection. That is, glargine U‐100 may result in an increase in patients who achieved HbA3.5.4Appendix Table The overall certainty of the evidence was low. Based on the above magnitude of effects, there is insufficient evidence to make a recommendation for this comparison.Appendix Table 1c < 7% and reduce nocturnal hypoglycemia events. Thus, if patients can accept morning injection, it may be a better choice. Based on eligible evidence and clinical experience, we made the following recommendation.The overall certainty of the evidence was low. For glargine U‐100, morning injection may increase the number of patients who achieved HbA3.63.6.1There is no eligible RCT to compare the different initial doses for glargine U‐300, degludec U‐100, or NPH to control blood glucose with acceptable side effects for adult patients with T2DM who require basal insulin therapy. Among the 35 included RCTs in our systematic review, eight RCTs indicated that the initial dose for glargine U‐300 was 0.20 U/kg/day,One RCT with 60 patients carried out in Turkey compared the initial dose of 0.12 U/kg/day once daily with 0.12 U/kg/day twice daily for detemir.One RCT with 892 patients carried out in China compared the initial dose of glargine U‐100 0.2 U/kg/day with glargine U‐100 0.3 U/kg/day.3.6.2The working group members made the following consensus conditional recommendation based on the data from eligible publications and clinical experience. Considering the simplicity of practical applications, we suggested the same range of initial doses for any of the five basal insulins. In clinical practice, clinicians and patients should use independent medical judgment in the context of individual clinical circumstances.3.73.7.1There is no eligible RCT to compare the different initial doses for any of five insulins to lead to a satisfactory control of FPG in adult patients with T2DM who require basal insulin therapy. Among the 35 included RCTs in our systematic review, seven RCTs indicated that the range of the end point dose for glargine U‐300 was from 0.34 to 0.62 U/kg/day at bedtime administration3.7.21c) should also be taken into consideration. The 2022 American Diabetes Association guideline stated that when the basal dose is more than 0.5 U/kg/day, overbasalization needs to be evaluated.There is insufficient evidence regarding the optimal maintenance dose range that can lead to a satisfactory control of FPG. Factors associated with the decision of the initial dose in addition to age and renal function  without a big tradeoff of patients who experienced hypoglycemia  and nocturnal hypoglycemia . Controlling hyperglycemia and preventing hypoglycemia are always tradeoffs. Thus, whether raising the lower boundary of the target FPG can reduce hypoglycemia risk without compromising glycemic control should be further investigated. Although this evidence is from glargine U‐100, the working group members believe it can be applied to any four basal insulin regimens. The 2022 American Diabetes Association guideline stated that the expected range of time in range is from 3.9 to 10 mmol/L for continuous glucose monitoring.The overall certainty of the evidence was low. For glargine U‐100, compared with 3.9 < FPG≤5.6 mmol/L, 3.9 < FPG≤6.1 mmol/L may result in more patients achieving HbA3.9We summarized these recommendations in Table 4As we had summarized from the available clinical evidence, compared with NPH, in addition to longer long‐acting time, basal insulin analogs also have more flattened pharmacokinetic and pharmacodynamic profiles that are attributable to less hypoglycemic risk, especially nocturnal hypoglycemia. But because all basal insulin analogs have peaks and troughs in their blood glucose lowering effects, the hypoglycemic risk of that insulin preparation might be different if the insulin were administered at a different time of the day . Although we found 35 eligible papers after a systematic literature search, to date, there is insufficient evidence to conduct a direct comparison between detemir and glargine U‐300 or degludec U‐100 at bedtime. Additionally, there is insufficient direct evidence to compare the effectiveness and safety among glargine U‐300, degludec U‐100, glargine U‐100, and detemir injected in the morning. Although some researchers indicated that the mean 24‐h glucose curves were smooth for the glargine U‐300 group irrespective of morning or evening injection in patients with T1DM,1c < 7.0% at 12 months  in the glargine U‐300 group. Because the point estimate of 54 is higher than our clinical threshold of the moderate effect (50 patients/1000), its upper boundary of 95% CI was 127, which was higher than the clinical threshold of the large effect (>100 patients/1000), and its lower boundary of the 95% CI was 5 fewer, which was lower than the clinical threshold of small effect (30 patients/1000) to favor glargine U‐100, we can consider that it may be clinically significant favoring degludec U‐100 even though it was not statistically significant. A few external reviewers disagreed with our recommendations largely because they considered statistical significance rather than clinical significance for the result of an outcome. Thus, setting up clinical thresholds is a very important step in developing clinical practice guidelines. This point is emphasized in the current GRADE publication.It should be noted that clinical significance is different from statistical significance.In clinical practice, every patient has his/her own individual conditions . Thus, the recommendations and qualifying statements in this guideline should be used only as references. Clinicians should make the appropriate modifications when implementing them for each patient. Additionally, when the evidence with continuous glucose monitoring is available, these recommendations may be changed.We understand that with low certainty of evidence, different working group members may make different recommendations regarding wording and strength based on their context. Thus, keeping the process of developing this guideline transparent, we hope that users will more easily be able to implement any of the recommendations in their daily clinical practice based on their individual contexts. Future high‐quality research is called to investigate the issues discussed and fill gaps in knowledge.5First, the cost‐effectiveness of the five basal insulins was not assessed because of the lack of evidence that met our study selection criteria. In addition, different countries may need the country‐specific cost‐efficacy analysis owing to the availability of these five basal insulins. Second, we did not recruit patient representatives in the working group and found only one patient representative as an external reviewer due to the time limitation. Thus, the patients' values may not be reflected in our recommendations sufficiently. Third, due to the time limitation, the working group was unable to include several large countries in the Asia‐Pacific region, such as India, the Philippines, etc., and were unable to get more external reviewers to complete the online survey, which may limit this study's generalizability.6When new evidence changes any of the recommendations, this guideline will be updated by the authors as soon as possible.Linong Ji, Yingying Luo, Jun Xia, and Xiaomei Yao conceived and designed this study. Zhan Zhao and Chenchen Xu conducted the database search and reviewed the reference lists of articles included in the screening. Zhan Zhao and Chenchen Xuperformed the initial screening and review of full texts for eligibility and inclusion. Zhan Zhao and Chenchen Xuextracted the data and completed the quality assessments. Xiaomei Yaoresolved any conflicts in the quality assessments. Zhan Zhao prepared the tables, and conducted the data analysis. Linong Ji, Xiaomei Yao, and Yingying Luo conducted data interpretation, led group discussions, and drafted the first draft of the manuscript. All authors approved the project plan and reviewed and revised the final manuscript before submission.Sponsored by the Chinese Geriatric Endocrine Society. The Chinese Geriatric Endocrine Society is a not‐for‐profit organization that accepts donations and support from communities and industries. All work done by the authors is editorially independent of the Chinese Geriatric Endocrine Society.Within the past 4 years, Yong Mong Bee and Daisuke Yabe have received consulting remuneration from a commercial entity or other organization with an interest related to subjectiveness of the meeting or work; SiewPheng Chan, Margaret McGill, Daisuke Yabe, or their research teams have received support from a commercial entity or other organization with an interest related to subjectiveness of the meeting or work respectively; Siew Pheng Chan also has received nonmonetary support valued at more than US $1000 . Ketut Suastika received an honorarium for a scientific symposium or webinar on basal insulin from several pharmaceutical companies, which were events collaborated with the Indonesia Society of Endocrinology. Alice Pik Shan Kong received research grants and/or speaker honoraria from Abbott, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli‐Lilly, Kyowa Kirin, Merck Serono, Nestle, Novo‐Nordisk, Pfizer, and Sanofi. Khue Nguyen Thy received an honorarium for the chair in scientific meetings from Servier, Boehringer Ingelheim, and Eisai. Linong Ji has received consulting and lecture fees from Eli Lilly, Novo Nordisk, Merck, Bayer, Sanofi‐Aventis, Roche, MSD, Metronics AstraZeneca, Boehinger Ingelheim, and Abbott. Other authors declare no competing interest.Appendix S1. Supplementary Information.Click here for additional data file.