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Färdplan för precisionsmedicin i diabetesvården

I en ny gemensam rapport från de amerikanska och europeiska diabetesorganisationerna American Diabetes Association (ADA) och European Association for the Study of Diabetes (EASD) beskrivs den största satsningen någonsin på precisionsmedicin inom diabetes.

Rapporten innehåller en detaljerad översikt av precisionsmedicin och en färdplan för hur precisionsmedicin ska implementeras i diabetesvården.

Precisionsmedicin innebär att diabetesvården ska knytas till den individuella patienten genom att integrera all tillgänglig evidens för den patienten.

– Intentionen är inte att utveckla läkemedel som är unik för varje individ utan att se till att undergrupper i befolkningen behandlas optimalt och därigenom maximera möjligheten till bästa hälsa och minimera risken för onödiga biverkningar och kostnader, säger Paul Franks, professor i genetisk epidemiologi vid Lunds universitet och medansvarig för satsningen Precision Medicine in Diabetes Initiative.

Själva konceptet med precisionsmedicin är inte nytt, det som ändrats radikalt under det senaste decenniet är vår förmåga att karaktärisera och förstå mänskliga biologiska och genetiska variationer, att använda data för att kategorisera sjukdomar och att koppla behandlingsbeslut direkt till specifika sjukdomstillstånd.

Den amerikanska diabetesfederationens, American Diabetes Association (ADA), riktlinjer för diabetesvård från 2020 betonar att "läkare vårdar patienter och inte populationer".

Detta återspeglar att hänsyn tas till individuella skillnader med avseende på exempelvis sociala förhållanden, respons på behandling och samsjuklighet. För att precisionsmedicin ska vara effektiv måste den anpassas till individen.

– Vi arbetar med en långsiktig vision för precisionsmedicin inom diabetes. Det börjar med en utvärdering av själva konceptet som ska staka ut vägen från upptäckt till klinisk implementering. Nya rön kommer så småningom att bli underlag till riktlinjer för sjukvården och påverka diabetesvården i världen, säger Paul Franks.

Rapporten publiceras samtidigt i de vetenskapliga tidskrifterna Diabetes Care och Diabetologia och är en presentation av satsningens uppdrag och mål.

Rapporten innehåller redogörelser och definitioner av alla viktiga delar inom precisionsmedicin vid diabetes; diagnos, prevention, behandling, övervakning och prognos. Den belyser även de områden som är avgörande för att införandet av precision medicin ska lyckas men där det krävs mer forskning.

– Initiativet till satsningen togs av ADA tillsammans med EASD 2018. Målet är att etablera konsensus och skapa en grogrund för implementering av precisionsmedicin för att möjliggöra längre och friskare liv för människor med diabetes, säger Paul Franks.

Detta är den första konsensusrapporten om precisionsmedicin för diabetes. Den tar inte upp vilken roll precisionsmedicin har för de olika följdsjukdomarna till diabetes eftersom detta kommer att presenteras i en framtida rapport.

Den tar heller inte upp utvecklingen inom tekniska hjälpmedel eftersom detta diskuterats i en tidigare rapport. En andra konsensusrapport som väntas bli klar 2022 med fokus på precisionsdiagnostik och precisionsterapier för prevention och behandling.

Länk till publikationen i Diabetes Care:
Precision Medicine in Diabetes: A Consensus Report From the American Diabetes Association (ADA) and the European Association for the Study of Diabetes

Läs abstract och artikeln i sin helhet utan lösenord
27 sidor med pedagogiska boxar, tabeller, figurer som kan laddas ner i powerpoint för egen visning och lectures
https://doi.org/10.2337/dci20-0022

Press release 
Paul Franks, professor i genetisk epidemiologi vid Lunds universitet

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Från artikeln

Consensus Reports

Precision Medicine in Diabetes: A Consensus Report From the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

 
 

Abstract

The convergence of advances in medical science, human biology, data science, and technology has enabled the generation of new insights into the phenotype known as “diabetes.” Increased knowledge of this condition has emerged from populations around the world, illuminating the differences in how diabetes presents, its variable prevalence, and how best practice in treatment varies between populations. In parallel, focus has been placed on the development of tools for the application of precision medicine to numerous conditions.

This Consensus Report presents the American Diabetes Association (ADA) Precision Medicine in Diabetes Initiative in partnership with the European Association for the Study of Diabetes (EASD), including its mission, the current state of the field, and prospects for the future. Expert opinions are presented on areas of precision diagnostics and precision therapeutics (including prevention and treatment), and key barriers to and opportunities for implementation of precision diabetes medicine, with better care and outcomes around the globe, are highlighted. Cases where precision diagnosis is already feasible and effective (i.e., monogenic forms of diabetes) are presented, while the major hurdles to the global implementation of precision diagnosis of complex forms of diabetes are discussed. The situation is similar for precision therapeutics, in which the appropriate therapy will often change over time owing to the manner in which diabetes evolves within individual patients.

This Consensus Report describes a foundation for precision diabetes medicine, while highlighting what remains to be done to realize its potential. This, combined with a subsequent, detailed evidence-based review (due 2022), will provide a roadmap for precision medicine in diabetes that helps improve the quality of life for all those with diabetes

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Rationale for Precision Medicine in Diabetes

The practice of medicine centers on the individual. From the beginning, the physician has examined the patient suffering from illness, ascertained his/her signs and symptoms, related them to the medical knowledge available at the time, recognized patterns that fit a certain category and, based on the practical wisdom accumulated via empirical trial and error, applied a given remedy that is best suited to the situation at hand. Thus, the concept of precision medicine, often defined as providing the right therapy for the right patient at the right time, is not novel. What has changed radically is our ability to characterize and understand human biological variation through 1) assessment of the genetic and metabolic state, 2) leveraging data to inform disease categories, and 3) science-guided preventive and treatment decisions tailored to specific pathological conditions. Coupling these with detailed information about lifestyle and environment, available through digital devices and technologies that collect those measures, as well as data abstracted from electronic medical records, present unparalleled opportunities to optimize diabetes medicine.

Diabetes mellitus is diagnosed by the presence of hyperglycemia that is higher than a threshold blood glucose concentration which predisposes to microvascular end-organ complications. However, hyperglycemia is the end product of numerous pathophysiological processes that often emerge over many years and converge on the inability of the pancreatic β-cells to secrete enough insulin to meet the demands of target tissues. In clinical practice, absolute insulin deficiency can be detected from the autoimmune destruction of β-cells in type 1 diabetes (T1D), which represents ∼10% of all diabetes cases. Making the diagnosis of T1D is critical for survival, given the therapeutic requirement of exogenous administration of insulin. However, less commonly, hyperglycemia might derive from an inherited or de novo loss of function in a single gene (e.g., monogenic diabetes, comprising 2–3% of all diabetes diagnosed in children or young adults). Diabetes can also appear after pancreatitis or organ transplantation, during pregnancy, or as a result of cystic fibrosis. Most individuals with diabetes, however, are likely to be diagnosed with type 2 diabetes (T2D), which includes defects in one or (more often) multiple physiological pathways (e.g., β-cell insufficiency, fat accumulation or miscompartmentalization, inflammation, incretin resistance, dysfunctional insulin signaling).

Our modern capacity to comprehensively interrogate diverse axes of biology has facilitated the approach of studying an individual to infer general principles, from which a discrete treatment plan is selected. These axes include developmental/metabolic context, genomic variation, chromatin signals that mark genes as active or repressed in tissues, expressed transcripts, biomarkers of disease, and increased knowledge of lifestyle/environmental risk factors. Parallel advances in computational power and analytical methods required to appropriately interrogate “big data” are driving insights that may radically transform the practice of medicine. Yet, at this time, the individual physician often lacks the time and training needed to incorporate these insights into medical decision making. Thus, the translation of the rapidly accumulating new knowledge into practice requires careful evaluation and translational strategies involving specialist training, education, and policy considerations.

The failure to adequately understand the diverse molecular and environmental processes that underlie diabetes and our inability to identify the pathophysiological mechanisms that trigger diabetes in individual patients limit our ability to prevent and treat the disease. Public health strategies have struggled to slow the epidemic, even in countries with the greatest financial and scientific resources. Pharmacological therapies, comprising 12 different drug classes currently approved by the U.S. Food and Drug Administration (FDA), may, at best, control blood glucose and modify disease course but do not provide a cure or result in the remission of disease. Moreover, these agents are sometimes prescribed based on nonmedical considerations (cost, side effects, patient preference, or comorbidities), which may overlook the biological mechanism. Thus, more people are developing diabetes worldwide and have disease progressing to complications, incurring a significant health care burden and cost.

There are, however, several reasons for hope. First, diabetes caused by single gene defects can be characterized and targeted therapies are particularly effective (1,2). Second, islet autoantibody biomarkers and genomic risk have clarified autoimmune diabetes from other forms of the disease (3,4), thereby facilitating immune intervention trials and preonset monitoring to reduce risk of severe complications and aiding in detection of environmental triggers (5). Third, multiple biomarkers and genetic variants have been shown to alter risk of T2D, revealing previously unsuspected biological pathways and providing new targets. Fourth, T2D has been shown to be a complex combination of multiple conditions and processes, defined by process-specific subgroups in which individuals with extreme burdens of risk in particular pathways reside and for whom a specific therapeutic approach may be optimal (6). Finally, the tools, resources, and data now exist to determine the biological and lifestyle/environmental predictors of drug response, as measured by a variety of clinical outcomes (7).

The Road to Implementation

Advances in science allow for generation of large-scale biological and physiological data that can be harnessed for precision diagnostic (Fig. 2), therapeutic (Fig. 3), and prognostic (Fig. 4) purposes. Programs are needed to train, foster, and retain individuals with biological and data science expertise who will contribute to precision diabetes medicine efforts. Furthermore, clinicians, scientists, and regulators must collaborate to develop standards and safeguards for protecting the accumulated “precise” data, which in some instances may lead to unintended and sensitive revelations, on individuals in a secure manner across populations and across countries. Worldwide differences in prevalence of the forms of diabetes necessitates inclusion of currently understudied populations for the development of precision diagnostics and therapeutics. As a result, the precise subtype of diabetes a particular individual is diagnosed with may vary in different populations based on subtype frequency or genetic or dietary or lifestyle differences.

The communication strategy used by the interventionalist and the patient’s perception of risk may be important factors contributing to the successful implementation of precision diabetes medicine. Both personal and societal barriers may exist to the implementation of precision prevention across geographic regions and countries. Discussions with global and regional regulatory agencies will be needed to determine the level of evidence needed for approval and adoption of precision diagnostics and therapeutics. The development of tools and strategies to synthesize patient data and facilitate shared decision making will be needed to translate evidence for precision diabetes medicine into individualized diabetes care, accounting for patient preferences and behaviors, health literacy, and socioeconomic considerations. Pragmatic studies of decision-support systems utilizing rich information in these health care systems, particularly those with biobank-linked electronic health care records, are needed to guide implementation of precision diabetes medicine into clinical practice and to generate the much needed cost-efficacy data for broader adoption.

 

Summary and Future Perspectives

Precision diabetes medicine has found a firm foothold in the diagnosis and treatment of monogenic diabetes, while the application of precision medicine to other types of diabetes is at this time aspirational, rather than standard of care. The ability to integrate the diagnosis of monogenic diabetes into routine clinical care is one example where diagnostics are essential and meet many of the characteristics of the ideal test. Despite an excellent diagnostic paradigm, there are no known avenues for prevention in monogenic diabetes, although careful monitoring in presymptomatic variant carriers may lead to early detection of diabetes and rapid treatment.

Future precision diabetes medicine approaches are likely to include diagnostic algorithms for defining diabetes subtypes in order to decide the best interventional and therapeutic approaches. The scope and potential for precision treatment in diabetes is vast, yet deep understanding is lacking. It will be imperative to determine when and how the application of therapeutics in precision diabetes medicine improves outcomes in a cost-effective fashion.

There are many important stakeholders whose engagement will be necessary for the implementation of precision diabetes medicine to succeed (Fig. 5). Progress in translating advances in biology and technology will be governed by the identification, accurate measurement, and scalable deployment of agents for diagnosis and therapy, so broad stakeholder engagement is essential. It is crucial that precision approaches are available to the full diversity of human populations and societal contexts, such that precision diabetes medicine does not widen health disparity but achieves the greatest benefits to all individuals and society as a whole. Highly functional partnerships with patient representatives and public organizations will be required to reap the benefits of precision diabetes medicine.











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