Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner.

Immune cells residing in white adipose tissue have been highlighted as important factors contributing to the pathogenesis of metabolic diseases, but the molecular regulators that drive adipose tissue immune cell remodeling during obesity remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively map all adipose tissue immune populations in both mice and humans during obesity. We describe a novel and conserved Trem2+ lipid-associated macrophage (LAM) subset and identify markers, spatial localization, origin, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream molecular LAM program, leading to adipocyte hypertrophy as well as systemic hypercholesterolemia, body fat accumulation, and glucose intolerance. These findings identify Trem2 signaling as a major pathway by which macrophages respond to loss of tissue-level lipid homeostasis, highlighting Trem2 as a key sensor of metabolic pathologies across multiple tissues and a potential therapeutic target in metabolic diseases.

Developmental origins of metabolic diseases.

Almost 2 billion adults in the world are overweight, and more than half of them are classified as obese, while nearly one-third of children globally experience poor growth and development. Given the vast amount of knowledge that has been gleaned from decades of research on growth and development, a number of questions remain as to why the world is now in the midst of a global epidemic of obesity accompanied by the "double burden of malnutrition," where overweight coexists with underweight and micronutrient deficiencies. This challenge to the human condition can be attributed to nutritional and environmental exposures during pregnancy that may program a fetus to have a higher risk of chronic diseases in adulthood. To explore this concept, frequently called the developmental origins of health and disease (DOHaD), this review considers a host of factors and physiological mechanisms that drive a fetus or child toward a higher risk of obesity, fatty liver disease, hypertension, and/or type 2 diabetes (T2D). To that end, this review explores the epidemiology of DOHaD with discussions focused on adaptations to human energetics, placental development, dysmetabolism, and key environmental exposures that act to promote chronic diseases in adulthood. These areas are complementary and additive in understanding how providing the best conditions for optimal growth can create the best possible conditions for lifelong health. Moreover, understanding both physiological as well as epigenetic and molecular mechanisms for DOHaD is vital to most fully address the global issues of obesity and other chronic diseases.

Western Diet and the Immune System: An Inflammatory Connection.

The consumption of Western-type calorically rich diets combined with chronic overnutrition and a sedentary lifestyle in Western societies evokes a state of chronic metabolic inflammation, termed metaflammation. Metaflammation contributes to the development of many prevalent non-communicable diseases (NCDs), and these lifestyle-associated pathologies represent a rising public health problem with global epidemic dimensions. A better understanding of how modern lifestyle and Western diet (WD) activate immune cells is essential for the development of efficient preventive and therapeutic strategies for common NCDs. Here, we review the current mechanistic understanding of how the Western lifestyle can induce metaflammation, and we discuss how this knowledge can be translated to protect the public from the health burden associated with their selected lifestyle.

Historic obstacles and emerging opportunities in the field of developmental metabolism - lessons from Heidelberg.

The field of developmental metabolism is experiencing a technological revolution that is opening entirely new fields of inquiry. Advances in metabolomics, small-molecule sensors, single-cell RNA sequencing and computational modeling present new opportunities for exploring cell-specific and tissue-specific metabolic networks, interorgan metabolic communication, and gene-by-metabolite interactions in time and space. Together, these advances not only present a means by which developmental biologists can tackle questions that have challenged the field for centuries, but also present young scientists with opportunities to define new areas of inquiry. These emerging frontiers of developmental metabolism were at the center of a highly interactive 2023 EMBO workshop 'Developmental metabolism: flows of energy, matter, and information'. Here, we summarize key discussions from this forum, emphasizing modern developmental biology's challenges and opportunities.

The epithelial barrier: The gateway to allergic, autoimmune, and metabolic diseases and chronic neuropsychiatric conditions.

Since the 1960 s, our health has been compromised by exposure to over 350,000 newly introduced toxic substances, contributing to the current pandemic in allergic, autoimmune and metabolic diseases. The "Epithelial Barrier Theory" postulates that these diseases are exacerbated by persistent periepithelial inflammation (epithelitis) triggered by exposure to a wide range of epithelial barrier-damaging substances as well as genetic susceptibility. The epithelial barrier serves as the body's primary physical, chemical, and immunological barrier against external stimuli. A leaky epithelial barrier facilitates the translocation of the microbiome from the surface of the afflicted tissues to interepithelial and even deeper subepithelial locations. In turn, opportunistic bacterial colonization, microbiota dysbiosis, local inflammation and impaired tissue regeneration and remodelling follow. Migration of inflammatory cells to susceptible tissues contributes to damage and inflammation, initiating and aggravating many chronic inflammatory diseases. The objective of this review is to highlight and evaluate recent studies on epithelial physiology and its role in the pathogenesis of chronic diseases in light of the epithelial barrier theory.

Emerging Roles and Therapeutic Applications of Arachidonic Acid Pathways in Cardiometabolic Diseases.

Cardiometabolic disease has become a major health burden worldwide, with sharply increasing prevalence but highly limited therapeutic interventions. Emerging evidence has revealed that arachidonic acid derivatives and pathway factors link metabolic disorders to cardiovascular risks and intimately participate in the progression and severity of cardiometabolic diseases. In this review, we systemically summarized and updated the biological functions of arachidonic acid pathways in cardiometabolic diseases, mainly focusing on heart failure, hypertension, atherosclerosis, nonalcoholic fatty liver disease, obesity, and diabetes. We further discussed the cellular and molecular mechanisms of arachidonic acid pathway-mediated regulation of cardiometabolic diseases and highlighted the emerging clinical advances to improve these pathological conditions by targeting arachidonic acid metabolites and pathway factors.

Genetic disorders of cellular trafficking.

Cellular trafficking is essential to maintain critical biological functions. Mutations in 346 genes, most of them described in the last 5 years, are associated with disorders of cellular trafficking. Whereas initially restricted to membrane trafficking, the recent detection of many diseases has contributed to the discovery of new biological pathways. Accordingly, we propose to redesign this rapidly growing group of diseases combining biological mechanisms and clinical presentation into the following categories: (i) membrane trafficking (including organelle-related); (ii) membrane contact sites; (iii) autophagy; (iv) cytoskeleton-related. We present the most recently described pathophysiological findings, disorders and phenotypes. Although all tissues and organs are affected, the nervous system is especially vulnerable.

Epigenetics of Early Cardiometabolic Disease: Mechanisms and Precision Medicine.

Epigenetics has transformed our understanding of the molecular basis of complex diseases, including cardiovascular and metabolic disorders. This review offers a comprehensive overview of the current state of knowledge on epigenetic processes implicated in cardiovascular and metabolic diseases, highlighting the potential of DNA methylation as a precision medicine biomarker and examining the impact of social determinants of health, gut bacterial epigenomics, noncoding RNA, and epitranscriptomics on disease development and progression. We discuss challenges and barriers to advancing cardiometabolic epigenetics research, along with the opportunities for novel preventive strategies, targeted therapies, and personalized medicine approaches that may arise from a better understanding of epigenetic processes. Emerging technologies, such as single-cell sequencing and epigenetic editing, hold the potential to further enhance our ability to dissect the complex interplay between genetic, environmental, and lifestyle factors. To translate research findings into clinical practice, interdisciplinary collaborations, technical and ethical considerations, and accessibility of resources and knowledge are crucial. Ultimately, the field of epigenetics has the potential to revolutionize the way we approach cardiovascular and metabolic diseases, paving the way for precision medicine and personalized health care, and improving the lives of millions of individuals worldwide affected by these conditions.

Efficacy, tolerability and pharmacokinetics of survodutide, a glucagon/glucagon-like peptide-1 receptor dual agonist, in cirrhosis.

BACKGROUND & AIMS: Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated survodutide in people with cirrhosis. METHODS: This multinational, non-randomized, open-label, phase 1 clinical trial initially evaluated a single subcutaneous (s.c.) dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight/obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) and maximal plasma concentration (Cmax). Subsequently, people with overweight/obesity with or without cirrhosis and Child-Pugh class A or B received once-weekly s.c. doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH/cirrhosis-related endpoints explored. RESULTS: In the single-dose cohorts (n = 41), mean AUC0-∞ and Cmax were similar in those with cirrhosis compared with healthy individuals (90% confidence intervals for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and ≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment. CONCLUSIONS: Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis. Clinical trial number; ClinicalTrials.gov identifier: NCT05296733. IMPACT AND IMPLICATIONS: Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH-including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted.

Longitudinal Outcomes Associated With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Meta-analysis of 129 Studies.

BACKGROUND & AIMS: The progression of metabolic dysfunction-associated steatotic liver disease (MASLD) has been found to manifest in a series of hepatic and extrahepatic complications. A comprehensive meta-analysis of the longitudinal outcomes associated with MASLD has yet to be conducted. METHODS: To investigate the longitudinal outcomes associated with MASLD, Medline and Embase databases were searched to identify original studies that evaluated the longitudinal risks of incident clinical outcomes among MASLD patients compared with non-MASLD individuals. DerSimonian Laird random-effects meta-analysis was performed. Pooled effect estimates were calculated, and heterogeneity among studies was evaluated. RESULTS: One hundred twenty-nine studies were included in the meta-analysis. Meta-analysis revealed a significant increase in the risk of cardiovascular outcomes (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.27-1.60; P < .01), various metabolic outcomes such as incident hypertension (HR, 1.75; 95% CI, 1.46-2.08; P < .01), diabetes (HR, 2.56; 95% CI, 2.10-3.13; P < .01), pre-diabetes (HR, 1.69; 95% CI, 1.22-2.35; P < .01), metabolic syndrome (HR, 2.57; 95% CI, 1.13-5.85; P = .02), chronic kidney disease (HR, 1.38; 95% CI, 1.27-1.50; P < .01), as well as all cancers (HR, 1.54; 95% CI, 1.35-1.76; P < .01) among MASLD patients compared with non-MASLD individuals. By subgroup analysis, MASLD patients with advanced liver disease (HR, 3.60; 95% CI, 2.10-6.18; P < .01) were also found to be associated with a significantly greater risk (P = .02) of incident diabetes than those with less severe MASLD (HR, 1.63; 95% CI, 1.0-2.45; P = .02) when compared with non-MASLD. CONCLUSIONS: The present study emphasizes the association between MASLD and its clinical outcomes including cardiovascular, metabolic, oncologic, and other outcomes. The multisystemic nature of MASLD found in this analysis requires treatment targets to reduce systemic events and end organ complications.

The Multifunctional Family of Mammalian Fatty Acid-Binding Proteins.

Fatty acid-binding proteins (FABPs) are small lipid-binding proteins abundantly expressed in tissues that are highly active in fatty acid (FA) metabolism. Ten mammalian FABPs have been identified, with tissue-specific expression patterns and highly conserved tertiary structures. FABPs were initially studied as intracellular FA transport proteins. Further investigation has demonstrated their participation in lipid metabolism, both directly and via regulation of gene expression, and in signaling within their cells of expression. There is also evidence that they may be secreted and have functional impact via the circulation. It has also been shown that the FABP ligand binding repertoire extends beyond long-chain FAs and that their functional properties also involve participation in systemic metabolism. This article reviews the present understanding of FABP functions and their apparent roles in disease, particularly metabolic and inflammation-related disorders and cancers.

Which surrogate insulin resistance indices best predict coronary artery disease? A machine learning approach.

BACKGROUND: Various surrogate markers of insulin resistance have been developed, capable of predicting coronary artery disease (CAD) without the need to detect serum insulin. For accurate prediction, they depend only on glucose and lipid profiles, as well as anthropometric features. However, there is still no agreement on the most suitable one for predicting CAD. METHODS: We followed a cohort of 2,000 individuals, ranging in age from 20 to 74, for a duration of 9.9 years. We utilized multivariate Cox proportional hazard models to investigate the association between TyG-index, TyG-BMI, TyG-WC, TG/HDL, plus METS-IR and the occurrence of CAD. The receiver operating curve (ROC) was employed to compare the predictive efficacy of these indices and their corresponding cutoff values for predicting CAD. We also used three distinct embedded feature selection methods: LASSO, Random Forest feature selection, and the Boruta algorithm, to evaluate and compare surrogate markers of insulin resistance in predicting CAD. In addition, we utilized the ceteris paribus profile on the Random Forest model to illustrate how the model's predictive performance is affected by variations in individual surrogate markers, while keeping all other factors consistent in a diagram. RESULTS: The TyG-index was the only surrogate marker of insulin resistance that demonstrated an association with CAD in fully adjusted model (HR: 2.54, CI: 1.34-4.81). The association was more prominent in females. Moreover, it demonstrated the highest area under the ROC curve (0.67 [0.63-0.7]) in comparison to other surrogate indices for insulin resistance. All feature selection approaches concur that the TyG-index is the most reliable surrogate insulin resistance marker for predicting CAD. Based on the Ceteris paribus profile of Random Forest the predictive ability of the TyG-index increased steadily after 9 with a positive slope, without any decline or leveling off. CONCLUSION: Due to the simplicity of assessing the TyG-index with routine biochemical assays and given that the TyG-index was the most effective surrogate insulin resistance index for predicting CAD based on our results, it seems suitable for inclusion in future CAD prevention strategies.

A cross-sectional time series of cardiometabolic health education format preferences across sociodemographic groups.

AIMS: Health education is integral to cardiometabolic disease (CMD) management. This study aimed to assess whether and how education preferences have changed over time, and whether trends differ by sociodemographic characteristics (education status, age, ethnicity, and sex). METHODS: A cross-sectional questionnaire was deployed across five counties in the East Midlands, UK between 2017 and 2022 to adults with CMD (type 2 diabetes, cardiovascular disease or cerebrovascular disease). Respondent demographic data were collected alongside health education preferences. Statistical analyses ascertained whether demographic characteristics influenced preferences. The distribution of preferences over time was charted to identify trends. RESULTS: A total of 4301 eligible responses were collected. Face-to-face one-to-one education was preferred (first choice for 75.1% of participants) but popularity waned over the five-year period. Trends were similar amongst demographic groups. Online education showed a U-shaped trend: In 2017, 44% of respondents ranked it as acceptable, peaking at 53% in 2019, but declining again, to below base line, 43%, by 2022. This modality was more popular with participants aged younger than 65 years, but popularity in people older than 65 years increased over the study period. The popularity of printed information also declined over time across all demographic groups except those of South Asian ethnicity, for whom it remained static. CONCLUSIONS: The overwhelming preference for face-to-face one-to-one health education from a doctor or nurse highlights the importance of preserving access to this modality, even in the face of current NHS pressures and trends towards digitalisation. Trends are changing, and should continue to be monitored, including between different sociodemographic groups.

Growth differentiation factor 15 is not modified after weight loss induced by liraglutide in South Asians and Europids with type 2 diabetes mellitus.

Glucagon-like peptide-1 receptor (GLP-1R) agonists induce weight loss in patients with type 2 diabetes mellitus (T2DM), but the underlying mechanism is unclear. Recently, the mechanism by which metformin induces weight loss could be explained by an increase in growth differentiation factor 15 (GDF15), which suppresses appetite. Therefore, we aimed to investigate whether the GLP-1R agonist liraglutide modifies plasma GDF15 levels in patients with T2DM. GDF15 levels were measured in plasma samples obtained from Dutch Europids and Dutch South Asians with T2DM before and after 26 weeks of treatment with daily liraglutide (n = 44) or placebo (n = 50) added to standard care. At baseline, circulating GDF15 levels did not differ between South Asians and Europids with T2DM. Treatment with liraglutide, compared to placebo, decreased body weight, but did not modify plasma GDF15 levels in all patients, or when data were split by ethnicity. Also, the change in plasma GDF15 levels after treatment with liraglutide did not correlate with changes in body weight or HbA1c levels. In addition, the dose of metformin used did not correlate with baseline plasma GDF15 levels. Compared to placebo, liraglutide treatment for 26 weeks does not modify plasma GDF15 levels in Dutch Europid or South Asian patients with T2DM. Thus, the weight loss induced by liraglutide is likely explained by other mechanisms beyond the GDF15 pathway. HIGHLIGHTS: What is the central question of this study? Growth differentiation factor 15 (GDF15) suppresses appetite and is increased by metformin: does the GLP-1R agonist liraglutide modify plasma GDF15 levels in patients with type 2 diabetes mellitus (T2DM)? What is the main finding and its importance? Plasma GDF15 levels did not differ between South Asians and Europids with T2DM and were not modified by 26 weeks of liraglutide in either ethnicity. Moreover, there was no correlation between the changes in plasma GDF15 levels and dosage of metformin administered, changes in body weight or HbA1c levels. The appetite-suppressing effect of liraglutide is likely exerted via pathways other than GDF15.

New insights of DsbA-L in the pathogenesis of metabolic diseases.

Metabolic diseases, such as obesity, diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD), are abnormal conditions that result from disturbances of metabolism. With the improvement of living conditions, the morbidity and mortality rates of metabolic diseases are steadily rising, posing a significant threat to human health worldwide. Therefore, identifying novel effective targets for metabolic diseases is crucial. Accumulating evidence has indicated that disulfide bond A oxidoreductase-like protein (DsbA-L) delays the development of metabolic diseases. However, the underlying mechanisms of DsbA-L in metabolic diseases remain unclear. In this review, we will discuss the roles of DsbA-L in the pathogenesis of metabolic diseases, including obesity, diabetes mellitus, and NAFLD, and highlight the potential mechanisms. These findings suggest that DsbA-L might provide a novel therapeutic strategy for metabolic diseases.

Liver transplantation and primary liver cancer in porphyria.

The porphyrias are a heterogeneous group of metabolic disorders that result from defects in heme synthesis. The metabolic defects are present in all cells, but symptoms are mainly cutaneous or related to neuropathy. The porphyrias are highly relevant to hepatologists since patients can present with symptoms and complications that require liver transplantation (LT), and some porphyrias are associated with a high risk for primary liver cancer (PLC). Among the cutaneous porphyrias, erythropoietic protoporphyria (EPP) can lead to cholestatic liver failure where LT cures the liver disease but not the porphyria. In acute porphyria (AP), neurotoxic porphyrin precursors are produced in the liver and LT is a curative treatment option in patients with recurrent severe neuropathic attacks. Patients with AP, mainly acute intermittent porphyria, have a significantly increased risk for PLC that warrants surveillance and adequate follow-up of high-risk groups. LT is well established in both EPP with liver failure and AP with recurrent attacks, but most transplant centres have little porphyria experience and cooperation between transplant hepatologists, and porphyria experts is important in the often-difficult decisions on timing and management of comorbid conditions.

Discovery and characterization of a new class of NAD+-independent SIRT1 activators.

The activity of sirtuin 1 (SIRT1, a member of the NAD+-dependent deacetylases family) decreases during aging as NAD+ levels naturally decline, thus increasing the risk of several age-associated diseases. Several sirtuin-activating compounds (STACs) have been developed to counteract the age-associated reduction in SIRT1 activity, and some of them are currently under development in clinical trials. STACs induce SIRT1 activation, either through allosteric activation of the enzyme in the presence of NAD+, or by increasing NAD+ levels by inhibiting its degradation or by supplying a key precursor in biosynthesis. In this study, we have identified (E)-2'-des-methyl sulindac analogues as a novel class of STACs that act also in the absence of NAD+, a peculiar behavior demonstrated through enzymatic and mass spectrometry experiments, both in vitro and in cell lines. The activation of the SIRT1 pathway was confirmed in vivo through gene expression and metabolomics analysis. Our data suggest that these compounds could serve as candidate leads for a novel therapeutic strategy aimed at addressing a key metabolic deficiency that may contribute to metabolic and age-associated diseases.

The application of organoid models in research into metabolic diseases.

Metabolic diseases have become a major threat to human health worldwide as a result of changing lifestyles. The exploration of the underlying molecular mechanisms of metabolic diseases and the development of improved therapeutic methods have been hindered by the lack of appropriate human experimental models. Organoids are three-dimensional in vitro models of self-renewing cells that spontaneously self-organize into structures similar to the corresponding in vivo tissues, recapitulating the original tissue function. Off-body organoid technology has been successfully applied to disease modelling, developmental biology, regenerative medicine, and tumour precision medicine. This new generation of biological models has received widespread attention. This article focuses on the construction process and research progress with regard to organoids related to metabolic diseases in recent years, and looks forward to their prospective applications.

Comparative analysis of gene and disease selection in genomic newborn screening studies.

Genomic newborn screening (gNBS) is on the horizon given the decreasing costs of sequencing and the advanced understanding of the impact of genetic variants on health and diseases. Key to ongoing gNBS pilot studies is the selection of target diseases and associated genes to be included. In this study, we present a comprehensive analysis of seven published gene-disease lists from gNBS studies, evaluating gene-disease count, composition, group proportions, and ClinGen curations of individual disorders. Despite shared selection criteria, we observe substantial variation in total gene count (median 480, range 237-889) and disease group composition. An intersection was identified for 53 genes, primarily inherited metabolic diseases (83%, 44/53). Each study investigated a subset of exclusive gene-disease pairs, and the total number of exclusive gene-disease pairs was positively correlated with the total number of genes included per study. While most pairs receive "Definitive" or "Strong" ClinGen classifications, some are labeled as "Refuted" (n = 5) or "Disputed" (n = 28), particularly in genetic cardiac diseases. Importantly, 17%-48% of genes lack ClinGen curation. This study underscores the current absence of consensus recommendations for selection criteria for target diseases for gNBS resulting in diversity in proposed gene-disease pairs, their coupling with gene variations and the use of ClinGen curation. Our findings provide crucial insights into the selection of target diseases and accompanying gene variations for future gNBS program, emphasizing the necessity for ongoing collaboration and discussion about criteria harmonization for panel selection to ensure the screening's objectivity, integrity, and broad acceptance.

Repurposing empagliflozin in individuals with glycogen storage disease Ib: A value-based healthcare approach and systematic benefit-risk assessment.

Off-label repurposing of empagliflozin allows pathomechanism-based treatment of neutropenia/neutrophil-dysfunction in glycogen storage disease type Ib (GSDIb). From a value-based healthcare (VBHC) perspective, we here retrospectively studied patient-reported, clinical and pharmacoeconomic outcomes in 11 GSDIb individuals before and under empagliflozin at two centers (the Netherlands [NL], Austria [AT]), including a budget impact analysis, sensitivity-analysis, and systematic benefit-risk assessment. Under empagliflozin, all GSDIb individuals reported improved quality-of-life-scores. Neutrophil dysfunction related symptoms allowed either granulocyte colony-stimulating factor cessation or tapering. Calculated cost savings per patient per year ranged between € 6482-14 190 (NL) and € 1281-41 231 (AT). The budget impact analysis estimated annual total cost savings ranging between € 75 062-225 716 (NL) and € 37 697-231 790 (AT), based on conservative assumptions. The systematic benefit-risk assessment was favorable. From a VBHC perspective, empagliflozin treatment in GSDIb improved personal and clinical outcomes while saving costs, thereby creating value at multiple pillars. We emphasize the importance to reimburse empagliflozin for GSDIb individuals, further supported by the favorable systematic benefit-risk assessment. These observations in similar directions in two countries/health care systems strongly suggest that our findings can be extrapolated to other geographical areas and health care systems.