Oral or injectable semaglutide for the management of type 2 diabetes in routine care: A multicentre observational study comparing matched cohorts.

AIM: To investigate the real-world utilization and comparative clinical outcomes of injectable and oral semaglutide in individuals with type 2 diabetes (T2D) with the aim of enhancing understanding of the practical implications associated with choosing between these formulations. METHODS: New users of oral or injectable semaglutide were selected from a cohort of 14 079 initiators of glucagon-like peptide-1 receptor agonists. Propensity-score matching (PSM) was employed to create balanced groups, ensuring comparability. The analysis encompassed dose exposure, drug persistence, and clinical outcomes, including changes in glycated haemoglobin (HbA1c) and body weight, with up to 18 months' follow-up. RESULTS: We analysed two matched groups of 107 participants each, who comprised on average 63.6% men, aged 64 years, with diabetes duration of approximately 10 years, body mass index of 29 kg/m2 and HbA1c level of 7.7-7.8% (61-62 mmol/mol). The proportion of low, intermediate and high doses were similar with the oral and the injectable formulation. The change in HbA1c was similar between groups (-0.9% / -10 mmol/mol at 18 months) as was the proportion of individuals reaching HbA1c <6.5% (48 mmol/mol). The average change in body weight was similar in the two groups (-3.7 kg with injectable and -3.3 kg with oral at 18 months) but more new users of injectable semaglutide lost ≥5% body weight. Persistence on drug was longer with injectable than with oral semaglutide. CONCLUSION: In a real-world setting, improvements in HbA1c and body weight were similar after initiation of oral or injectable semaglutide. These results may be specific to the features of the matched cohorts under investigation, with limited generalizability to populations with different characteristics.

Long-term benefits of dapagliflozin on renal outcomes of type 2 diabetes under routine care: a comparative effectiveness study on propensity score matched cohorts at low renal risk.

Background: Despite the overall improvement in care, people with type 2 diabetes (T2D) experience an excess risk of end-stage kidney disease. We evaluated the long-term effectiveness of dapagliflozin on kidney function and albuminuria in patients with T2D. Methods: We included patients with T2D who initiated dapagliflozin or comparators from 2015 to 2020. Propensity score matching (PSM) was performed to balance the two groups. The primary endpoint was the change in estimated glomerular filtration rate (eGFR) from baseline to the end of observation. Secondary endpoints included changes in albuminuria and loss of kidney function. Findings: We analysed two matched groups of 6197 patients each. The comparator group included DPP-4 inhibitors (40%), GLP-1RA (22.3%), sulphonylureas (16.1%), pioglitazone (8%), metformin (5.8%), or acarbose (4%). Only 6.4% had baseline eGFR <60 ml/min/1.73 m2 and 15% had UACR >30 mg/g. During a mean follow-up of 2.5 year, eGFR declined significantly less in the dapagliflozin vs comparator group by 1.81 ml/min/1.73 m2 (95% C.I. from 1.13 to 2.48; p < 0.0001). The mean eGFR slope was significantly less negative in the dapagliflozin group by 0.67 ml/min/1.73 m2/year (95% C.I. from 0.47 to 0.88; p < 0.0001). Albuminuria declined significantly in new-users of dapagliflozin within 6 months and remained on average 44.3 mg/g lower (95% C.I. from -66.9 to -21.7; p < 0.0001) than in new-users of comparators. New-users of dapagliflozin had significantly lower rates of new-onset CKD, loss of kidney function, and a composite renal outcome. Results were confirmed for all SGLT2 inhibitors, in patients without baseline CKD, and when GLP-1RA were excluded from comparators. Interpretation: Initiating dapagliflozin improved kidney function outcomes and albuminuria in patients with T2D and a low renal risk. Funding: Funded by the Italian Diabetes Society and partly supported by a grant from AstraZeneca.

Prevalence and risk factors of glomerular hyperfiltration in adults with type 2 diabetes: A population-based study.

AIMS: Glomerular hyperfiltration characterises the earliest stage of diabetic nephropathy and predicts adverse kidney and cardiovascular outcomes. We aimed to assess the prevalence and risk factors of glomerular hyperfiltration in a population-based contemporary cohort of individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: The prevalence of unequivocal glomerular hyperfiltration (defined by an estimated glomerular filtration rate >120 mL/min/1.73 m2 ) and its associated risk factors were identified in a cohort of 202,068 adult patients with T2D receiving specialist care in 2021-2022, whose center-aggregated data were automatically extracted from electronic medical records of 75 diabetes clinics in Italy. RESULTS: Glomerular hyperfiltration was identified in 1262 (0.6%) participants. The prevalence of glomerular hyperfiltration varied widely across centers (0%-3.4%) and correlated with mean center age, HbA1c , body mass index (BMI), and low-density lipoprotein cholesterol. Patients in centers with high glomerular hyperfiltration prevalence (>0.8%) were more often men and had lower age and BMI, but more frequent albuminuria and worse glucose, lipid, and blood pressure control, compared with low-normal prevalence centers. CONCLUSIONS: Unequivocal glomerular hyperfiltration can be identified in up to 3.4% of patients receiving up-to-date specialist diabetes care. Glomerular hyperfiltration prevalence varies across centers and substantially increases with suboptimal control of metabolic risk factors, which would require improved management to mitigate the negative health consequences of this pathological condition.

IDegLira for the real-world treatment of type 2 diabetes in Italy. Final results from the REX observational study.

AIM: The study was designed to generate real-world evidence on IDegLira in the Italian clinical practice in two groups of patients with type 2 diabetes (T2D), switching to IDegLira either from a basal only (basal group) or basal-bolus insulin regimen (BB group). MATERIALS AND METHODS: This was a non-interventional, multicentre, single-cohort, prospective study assessing the long-term glycaemic control in patients with T2D, who switched to IDegLira from a basal insulin ± glucose-lowering medication regimen with or without a bolus insulin component for approximately 18 months, conducted in 28 Italian diabetes centres. The primary endpoint was the change in glycated haemoglobin (HbA1c) levels from baseline to 6 months after IDegLira initiation. RESULTS: The study included 358 patients with a mean age 67.2 years and diabetes duration of 15.7 years. HbA1c significantly decreased from IDegLira start to all study time points in the overall population (basal group -1.19%; BB group -0.60% at the end of observation). Patients achieving HbA1c <7% levels increased from 12.9% (n = 43) to 40.3% (n = 110) at 18 months. Fasting blood glucose and body weight also significantly decreased in both groups, although more in the BB group. Overall, 14.3% of completed patients had an intensification of treatment (mainly in the basal group) and 48.6% had a simplification of treatment (mainly in the BB group). CONCLUSIONS: Switching to IDegLira in a real-world clinical setting is a valid therapeutic option for patients with T2D with inadequate glycaemic control on basal or BB insulin regimen and/or need to simplify their insulin therapy, with specific reasons and therapeutic goals according to different T2D management trajectories.

PACE: randomized, controlled, multicentre, multinational, phase III study of PLX-PAD for critical limb ischaemia in patients unsuitable for revascularization: randomized clinical trial.

BACKGROUND: Revascularization is the primary treatment modality for chronic limb-threatening ischaemia (CLTI), but is not feasible in all patients. PLX-PAD is an off-the-shelf, placental-derived, mesenchymal stromal cell-like cell therapy. This study aimed to evaluate whether PLX-PAD would increase amputation-free survival in people with CLTI who were not candidates for revascularization. METHODS: People with CLTI and minor tissue loss (Rutherford 5) who were unsuitable for revascularization were entered into a randomized, parallel-group, placebo-controlled, multinational, blinded, trial, in which PLX-PAD was compared with placebo (2 : 1 randomization), with 30 intramuscular injections (0.5 ml each) into the index leg on days 0 and 60. Planned follow-up was 12-36 months, and included vital status, amputations, lesion size, pain and quality-of-life assessments, haemodynamic parameters, and adverse events. RESULTS: Of 213 patients enrolled, 143 were randomized to PLX-PAD and 70 to placebo. Demographics and baseline characteristics were balanced. Most patients were Caucasian (96.2%), male (76.1%), and ambulatory (85.9%). Most patients (76.6%) reported at least one adverse event, which were mostly expected events in CLTI, such as skin ulcer or gangrene. The probability of major amputation or death was similar for placebo and PLX-PAD (33 and 28.6% respectively; HR 0.93, 95% c.i. 0.53 to 1.63; P = 0.788). Revascularization and complete wound healing rates were similar in the two groups. A post hoc analysis of a subpopulation of 121 patients with a baseline haemoglobin A1c level below 6.5% showed improved 12-month amputation-free survival (HR 0.46, 0.21 to 0.99; P = 0.048). CONCLUSION: Although there was no evidence that PLX-PAD reduced amputation-free survival in the entire study population, benefit was observed in patients without diabetes mellitus or whose diabetes was well controlled; this requires confirmation in further studies. Trial registration: NCT03006770 (http://www.clinicaltrials.gov); 2015-005532-18 (EudraCT Clinical Trials register - Search for 2015-005532-18).

Circulating haematopoietic stem cells and long-term outcomes of COVID-19.

BACKGROUND AND AIMS: An acute depletion of circulating haematopoietic stem/progenitor cells (HSPCs) occurs during COVID-19, especially among patients with a poorer disease course. We herein examined whether HSPCs levels at hospital admission for COVID-19 predict 1-year mortality and the long-COVID syndrome. MATERIALS AND METHODS: Patients hospitalized for COVID-19 in an infectious disease ward were consecutively enrolled. Circulating HSPC levels were assessed by flow cytometry as cells expressing CD34 and/or CD133. Follow-up was performed for 12 months after hospitalization through the review of electronic medical records and demographic local registers. RESULTS: The study included 100 patients, 36 of whom reported symptoms of long-COVID and 20 died during follow-up. The reduction of 1-SD of HSPCs was associated with a 3- to 5-fold increase in the risk of 1-year mortality. Age, admission hyperglycaemia, C-reactive protein peak, liver enzymes, the need of high-flow oxygen and/or invasive ventilation were predictors of mortality at univariate analysis. Among pre-existing comorbidities, coronary heart disease and chronic kidney disease, but not diabetes, were associated with 1-year mortality. In multivariate analyses, HSPCs remained significantly associated with 1-year mortality independently of confounders. The development of pneumonia an in-hospital treatment with glucocorticoids and convalescent plasma were associated with long-COVID symptoms at follow-up. HSPCs, diabetes and other comorbidities were not predictors of long-COVID. CONCLUSIONS: In a cohort of patients hospitalized for COVID-19, lower HSPC levels at the time of admission were independent predictors of 1-year mortality. However, COVID-19 severity, but not HSPC level, was significantly associated with the development of long-COVID symptoms.

Recent developments in targets for ischemic foot disease.

Diabetes is a key risk factor for ischaemic foot disease, which causes pain, tissue loss, hospital admission, and major amputation. Currently, treatment focuses on revascularisation, but many patients are unsuitable for surgery and revascularisation is frequently unsuccessful. The authors describe recent research in animal models and clinical trials investigating novel medical targets for ischaemia, including theories about impaired wound healing, animal models for limb ischaemia and recent randomised controlled trials testing novel medical therapies. Novel targets identified in animal models included stimulating mobilisation of CD34+ progenitor cells through upregulating oncostatin M or microRNA-181, downregulating tumour necrosis factor superfamily member 14, or activating the Wingless pathway. Within the ischaemic limb vasculature, upregulation of apolipoprotein L domain containing 1, microRNA-130b or long noncoding RNA that enhances endothelial nitric oxide synthase expression promoted limb blood supply recovery, angiogenesis, and arteriogenesis. Similarly, administration of soluble guanylate cyclase stimulators riociguat or praliciguat or 3-ketoacyl-CoA thiolase inhibitor trimetazidine promoted blood flow recovery. Translating pre-clinical findings to patients has been challenging, mainly due to limitations in clinically translatable animal models of human disease. Promising results have been reported for administering plasmids encoding hepatocyte growth factor or intra-arterial injection of bone marrow derived cells in small clinical trials. It remains to be seen whether these high resource therapies can be developed to be widely applicable. In conclusion, an ever-expanding list of potential targets for medical revascularisation is being identified. It is hoped that through ongoing research and further larger clinical trials, these will translate into new broadly applicable therapies to improve outcomes.

CK2ß Regulates Hematopoietic Stem Cell Biology and Erythropoiesis.

The Ser-Thr kinase CK2 plays important roles in sustaining cell survival and resistance to stress and these functions are exploited by different types of blood tumors. Yet, the physiological involvement of CK2 in normal blood cell development is poorly known. Here, we discovered that the ß regulatory subunit of CK2 is critical for normal hematopoiesis in the mouse. Fetal livers of conditional CK2ß knockout embryos showed increased numbers of hematopoietic stem cells associated to a higher proliferation rate compared to control animals. Both hematopoietic stem and progenitor cells (HSPCs) displayed alterations in the expression of transcription factors involved in cell quiescence, self-renewal, and lineage commitment. HSPCs lacking CK2ß were functionally impaired in supporting both in vitro and in vivo hematopoiesis as demonstrated by transplantation assays. Furthermore, KO mice developed anemia due to a reduced number of mature erythroid cells. This compartment was characterized by dysplasia, proliferative defects at early precursor stage, and apoptosis at late-stage erythroblasts. Erythroid cells exhibited a marked compromise of signaling cascades downstream of the cKit and erythropoietin receptor, with a defective activation of ERK/JNK, JAK/STAT5, and PI3K/AKT pathways and perturbations of several transcriptional programs as demonstrated by RNA-Seq analysis. Moreover, we unraveled an unforeseen molecular mechanism whereby CK2 sustains GATA1 stability and transcriptional proficiency. Thus, our work demonstrates new and crucial functions of CK2 in HSPC biology and in erythropoiesis.

Deep-learning-based natural-language-processing models to identify cardiovascular disease hospitalisations of patients with diabetes from routine visits' text.

Writing notes is the most widespread method to report clinical events. Therefore, most of the information about the disease history of a patient remains locked behind free-form text. Natural language processing (NLP) provides a solution to automatically transform free-form text into structured data. In the present work, electronic healthcare records data of patients with diabetes were used to develop deep-learning based NLP models to automatically identify, within free-form text describing routine visits, the occurrence of hospitalisations related to cardiovascular disease (CVDs), an outcome of diabetes. Four possible time windows of increasing level of expected difficulty were considered: infinite, 24 months, 12 months, and 6 months. Model performance was evaluated by means of the area under the precision recall curve, as well as precision, recall, and F1-score after thresholding. Results showed that the proposed NLP approach was successful for both the infinite and 24-month windows, while, as expected, performance deteriorated with shorter time windows. Possible clinical applications of tools based on the proposed NLP approach include the retrospective filling of medical records with respect to a patient's CVD history for epidemiological and research purposes as well as for clinical decision making.

Clinical Features, Cardiovascular Risk Profile, and Therapeutic Trajectories of Patients with Type 2 Diabetes Candidate for Oral Semaglutide Therapy in the Italian Specialist Care.

INTRODUCTION: This study aimed to address therapeutic inertia in the management of type 2 diabetes (T2D) by investigating the potential of early treatment with oral semaglutide. METHODS: A cross-sectional survey was conducted between October 2021 and April 2022 among specialists treating individuals with T2D. A scientific committee designed a data collection form covering demographics, cardiovascular risk, glucose control metrics, ongoing therapies, and physician judgments on treatment appropriateness. Participants completed anonymous patient questionnaires reflecting routine clinical encounters. The preferred therapeutic regimen for each patient was also identified. RESULTS: The analysis was conducted on 4449 patients initiating oral semaglutide. The population had a relatively short disease duration (42% < 5 years), and a minority (15.6%) had a history of cardiovascular events. Importantly, oral semaglutide was started in subjects with various disease durations and background therapies. Notably, its initiation was accompanied by de-prescription of sulfonylureas, pioglitazone, DPP-4 inhibitors, and insulin. Choice of oral semaglutide was influenced by patient profiles and ongoing glucose-lowering regimens. Factors such as younger age, higher HbA1c, and ongoing SGLT-2 inhibitor therapy drove the choice of oral semaglutide with the aim of improving glycemic control. Projected glycemic effectiveness analysis revealed that oral semaglutide could potentially lead HbA1c to target in > 60% of patients, and more often than sitagliptin or empagliflozin. CONCLUSION: The study supports the potential of early implementation of oral semaglutide as a strategy to overcome therapeutic inertia and enhance T2D management.

Improved prediction of long-term kidney outcomes in people with type 2 diabetes by levels of circulating haematopoietic stem/progenitor cells.

AIM/HYPOTHESIS: We examined whether prediction of long-term kidney outcomes in individuals with type 2 diabetes can be improved by measuring circulating levels of haematopoietic stem/progenitor cells (HSPCs), which are reduced in diabetes and are associated with cardiovascular risk. METHODS: We included individuals with type 2 diabetes who had a baseline determination of circulating HSPCs in 2004-2019 at the diabetes centre of the University Hospital of Padua and divided them into two groups based on their median value per ml of blood. We collected updated data on eGFR and albuminuria up to December 2022. The primary endpoint was a composite of new-onset macroalbuminuria, sustained ≥40% eGFR decline, end-stage kidney disease or death from any cause. The analyses were adjusted for known predictors of kidney disease in the population with diabetes. RESULTS: We analysed 342 participants (67.8% men) with a mean age of 65.6 years. Those with low HSPC counts (n=171) were significantly older and had a greater prevalence of hypertension, heart failure and nephropathy (45.0% vs 33.9%; p=0.036), as evidenced by lower eGFR and higher albuminuria at baseline. During a median follow-up of 6.7 years, participants with high vs low HSPC counts had lower rates of the composite kidney outcome (adjusted HR 0.69 [95% CI 0.49, 0.97]), slower decline in eGFR and a similar increase in albuminuria. Adding the HSPC information to the risk score of the CKD Prognosis Consortium significantly improved discrimination of individuals with future adverse kidney outcomes. CONCLUSIONS/INTERPRETATION: HSPC levels predict worsening of kidney function and improve the identification of individuals with type 2 diabetes and adverse kidney outcomes over and beyond a clinical risk score.

Safety of sodium-glucose cotransporter 2 inhibitors in elderly patients with type 2 diabetes: A meta-analysis of randomized controlled trials.

AIM: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are particularly effective in preventing adverse outcomes of heart failure and chronic kidney disease, which are highly prevalent in the elderly. Here, we aimed to access the safety of SGLT2i in elderly patients with type 2 diabetes. MATERIALS AND METHODS: We performed a meta-analysis of randomized controlled trials (RCTs) reporting safety outcomes of the elderly (≥65 years) patients with type 2 diabetes, randomized to an SGLT2i or placebo. We recorded the incidence of acute kidney injury, volume depletion, genital tract infections, urinary tract infections, bone fractures, amputations, diabetic ketoacidosis, hypoglycaemia and drug discontinuation, by group of treatment. RESULTS: Of the 130 RCTs screened, only six reported data on elderly patients. In total, 19 986 patients were included. The SGLT2i discontinuation rate was approximately 20%. The risk of acute kidney injury was significantly lower among SGLT2i users compared with placebo [risk ratio (RR) 0.73; 95% CI 0.62-0.87]. SGLT2i were associated with a six-fold increased risk of genital tract infections (RR 6.55; 95% CI 2.09-20.5). The rate of amputations was increased only among canagliflozin users (RR 1.94, 95% CI 1.25-3). The risk of fractures, urinary tract infection, volume depletion, hypoglycaemia and diabetic ketoacidosis was similar between SGLT2i and placebo. CONCLUSIONS: SGLT2is were well tolerated in the elderly. However, older patients are underrepresented in most RCTs and a call for action is need to favour clinical trials reporting safety outcomes stratified by age.

The cardio-renal-metabolic connection: a review of the evidence.

Type 2 diabetes (T2D), cardiovascular disease (CVD) and chronic kidney disease (CKD), are recognized among the most disruptive public health issues of the current century. A large body of evidence from epidemiological and clinical research supports the existence of a strong interconnection between these conditions, such that the unifying term cardio-metabolic-renal (CMR) disease has been defined. This coexistence has remarkable epidemiological, pathophysiologic, and prognostic implications. The mechanisms of hyperglycemia-induced damage to the cardio-renal system are well validated, as are those that tie cardiac and renal disease together. Yet, it remains controversial how and to what extent CVD and CKD can promote metabolic dysregulation. The aim of this review is to recapitulate the epidemiology of the CMR connections; to discuss the well-established, as well as the putative and emerging mechanisms implicated in the interplay among these three entities; and to provide a pathophysiological background for an integrated therapeutic intervention aiming at interrupting this vicious crosstalks.

Circulating Long Noncoding RNA Signatures Associate With Incident Diabetes in Older Adults: A Prospective Analysis From the VITA Cohort Study.

OBJECTIVE: Long noncoding RNAs (lncRNAs) are involved in diabetogenesis in experimental models, yet their role in humans is unclear. We investigated whether circulating lncRNAs associate with incident type 2 diabetes in older adults. RESEARCH DESIGN AND METHODS: A preselected panel of lncRNAs was measured in serum of individuals without diabetes (n = 296) from the Vienna Transdanube Aging study, a prospective community-based cohort study. Participants were followed up over 7.5 years. A second cohort of individuals with and without type 2 diabetes (n = 90) was used to validate our findings. RESULTS: Four lncRNAs (ANRIL, MIAT, RNCR3, and PLUTO) were associated with incident type 2 diabetes and linked to hemoglobin A1c trajectories throughout the 7.5-year follow-up. Similar results (for MIAT and PLUTO also in combined analysis) were obtained in the validation cohort. CONCLUSIONS: We found a set of circulating lncRNAs that independently portends incident type 2 diabetes in older adults years before disease onset.

Loss of Hematopoietic Cell-Derived Oncostatin M Worsens Diet-Induced Dysmetabolism in Mice.

Innate immune cells infiltrate growing adipose tissue and propagate inflammatory clues to metabolically distant tissues, thereby promoting glucose intolerance and insulin resistance. Cytokines of the IL-6 family and gp130 ligands are among such signals. The role played by oncostatin M (OSM) in the metabolic consequences of overfeeding is debated, at least in part, because prior studies did not distinguish OSM sources and dynamics. Here, we explored the role of OSM in metabolic responses and used bone marrow transplantation to test the hypothesis that hematopoietic cells are major contributors to the metabolic effects of OSM. We show that OSM is required to adapt during the development of obesity because OSM concentrations are dynamically modulated during high-fat diet (HFD) and Osm-/- mice displayed early-onset glucose intolerance, impaired muscle glucose uptake, and worsened liver inflammation and damage. We found that OSM is mostly produced by blood cells and deletion of OSM in hematopoietic cells phenocopied glucose intolerance of whole-body Osm-/- mice fed a HFD and recapitulated liver damage with increased aminotransferase levels. We thus uncovered that modulation of OSM is involved in the metabolic response to overfeeding and that hematopoietic cell-derived OSM can regulate metabolism, likely via multiple effects in different tissues.

Hematopoietic Stem Cells and Metabolic Deterioration in Alström Syndrome, a Rare Genetic Model of the Metabolic Syndrome.

Alström syndrome (AS) is a rare genetic disease caused by ALMS1 mutations, characterized by short stature, and vision and hearing loss. Patients with AS develop the metabolic syndrome, long-term organ complications, and die prematurely. We explored the association between AS and a shortage of hematopoietic stem/progenitor cells (HSPCs), which is linked to metabolic diseases and predicts diabetic complications. We included patients with AS at a national referral center. We measured HSPCs with flow cytometry at baseline and follow-up. We followed patients up to January 2022 for metabolic worsening and end-organ damage. We evaluated HSPC levels and mobilization as well as bone marrow histology in a murine model of AS. In 23 patients with AS, we found significantly lower circulating HSPCs than in healthy blood donors (-40%; P = .002) and age/sex-matched patients (-25%; P = .022). Longitudinally, HSPCs significantly declined by a further 20% in patients with AS over a median of 36 months (interquartile range 30-44). Patients with AS who displayed metabolic deterioration over 5.3 years had lower levels of HSPCs, both at baseline and at last observation, than those who did not deteriorate. Alms1-mutated mice were obese and insulin resistant and displayed significantly reduced circulating HSPCs, despite no overt hematological abnormality. Contrary to what was observed in diabetic mice, HSPC mobilization and bone marrow structure were unaffected. We found depletion of HSPCs in patients with AS, which was recapitulated in Alms1-mutated mice. Larger and longer studies will be needed to establish HSPCs shortage as a driver of metabolic deterioration leading to end-organ damage in AS.

Mannose Receptor Deficiency Impacts Bone Marrow and Circulating Immune Cells during High Fat Diet Induced Obesity.

The mannose receptor C-type 1 (Mrc1) is a C-type lectin receptor expressed on the immune cells and sinusoidal endothelial cells (ECs) of several tissues, including the bone marrow (BM). Parallel to systemic metabolic alterations and hematopoietic cell proliferation, high-fat diet (HFD) feeding increases the expression of Mrc1 in sinusoidal ECs, thus calling for the investigation of its role in bone marrow cell reprogramming and the metabolic profile during obesity. Mrc1-/- mice and wild-type (WT) littermates were fed an HFD (45% Kcal/diet) for 20 weeks. Weight gain was monitored during the diet regimen and glucose and insulin tolerance were assessed. Extensive flow cytometry profiling, histological, and proteomic analyses were performed. After HFD feeding, Mrc1-/- mice presented impaired medullary hematopoiesis with reduced myeloid progenitors and mature cells in parallel with an increase in BM adipocytes compared to controls. Accordingly, circulating levels of neutrophils and pro-inflammatory monocytes decreased in Mrc1-/- mice together with reduced infiltration of macrophages in the visceral adipose tissue and the liver compared to controls. Liver histological profiling coupled with untargeted proteomic analysis revealed that Mrc1-/- mice presented decreased liver steatosis and the downregulation of proteins belonging to pathways involved in liver dysfunction. This profile was reflected by improved glucose and insulin response and reduced weight gain during HFD feeding in Mrc1-/- mice compared to controls. Our data show that during HFD feeding, mannose receptor deficiency impacts BM and circulating immune cell subsets, which is associated with reduced systemic inflammation and resistance to obesity development.

Management of type 2 diabetes with a treat-to-benefit approach improved long-term cardiovascular outcomes under routine care.

BACKGROUND: Results of cardiovascular outcome trials enabled a shift from "treat-to-target" to "treat-to-benefit" paradigm in the management of type 2 diabetes (T2D). However, studies validating such approach are limited. Here, we examined whether treatment according to international recommendations for the pharmacological management of T2D had an impact on long-term outcomes. METHODS: This was an observational study conducted on outpatient data collected in 2008-2018 (i.e. prior to the "treat-to-benefit" shift). We defined 6 domains of treatment based on the ADA/EASD consensus covering all disease stages: first- and second-line treatment, intensification, use of insulin, cardioprotective, and weight-affecting drugs. At each visit, patients were included in Group 1 if at least one domain deviated from recommendation or in Group 2 if aligned with recommendations. We used Cox proportional hazard models with time-dependent co-variates or Cox marginal structural models (with inverse-probability of treatment weighing evaluated at each visit) to adjust for confounding factors and evaluate three outcomes: major adverse cardiovascular events (MACE), hospitalization for heart failure or cardiovascular mortality (HF-CVM), and all-cause mortality. RESULTS: We included 5419 patients, on average 66-year old, 41% women, with a baseline diabetes duration of 7.6 years. Only 11.7% had pre-existing cardiovascular disease. During a median follow-up of 7.3 years, patients were seen 12 times at the clinic, and we recorded 1325 MACE, 1593 HF-CVM, and 917 deaths. By the end of the study, each patient spent on average 63.6% of time in Group 1. In the fully adjusted model, being always in Group 2 was associated with a 45% lower risk of MACE (HR 0.55; 95% C.I. 0.46-0.66; p < 0.0001) as compared to being in Group 1. The corresponding HF-CVM and mortality risk were similar (HR 0.56; 95%CI 0.47-0.66, p < 0.0001 and HR 0.56; 95% C.I. 0.45-0.70; p < 0.0001. respectively). Sensitivity analyses confirmed these results. No single domain individually explained the better outcome of Group 2, which remained significant in all subgroups. CONCLUSION: Managing patients with T2D according to a "treat-to-benefit" approach based international standards was associated with a lower risk of MACE, heart failure, and mortality. These data provide ex-post validation of the ADA/EASD treatment algorithm.