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Objective: To study whether inflammation is associated with and helps predict mortality risk in patients with type 2 diabetes. To explore the intertwined link between inflammation and tryptophan metabolism on death risk., Design: Two prospective cohorts: the aggregate Gargano Mortality Study (1,731 individuals; 872 all-cause deaths) as discovery sample, the Foggia Mortality Study (490 individuals; 256 deaths) as validation sample. Twenty-seven inflammatory markers were measured. Causal mediation analysis and in vitro studies were carried out to explore the link between inflammatory markers and the kynurenine-to-tryptophan ratio (KTR) in shaping mortality risk., Results: Using multivariable stepwise Cox regression analysis, IL-4, IL-6, IL-8, IL-13, RANTES and IP-10, were independently associated with death. An inflammation score (I-score) comprising these six molecules is strongly associated with death in both the discovery and the validation cohorts HR (95%CI) = 2.13 (1.91-2.37) and 2.20 (1.79-2.72), respectively. The I-score improved discrimination and reclassification measures (all P<0.01) of two mortality prediction models based on clinical variables. The causal mediation analysis showed that 28% of the KTR effect on mortality was mediated by IP-10. Studies in cultured endothelial cells showed that 5-Methoxy-tryptophan, an anti-inflammatory metabolite derived from tryptophan, reduces the expression of IP-10, thus providing a functional basis for the observed causal mediation., Conclusions: Adding the I-score to clinical prediction models may help identify individuals who are at greater risk of death. Deeply addressing the intertwined relationship between low-grade inflammation and imbalanced tryptophan metabolism in shaping mortality risk may help discover new therapies targeting patients characterized by these abnormalities., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: The independent role of glomerular filtration rate (GFR) decline in shaping the risk of mortality in people with type 2 diabetes has only been partially addressed., Objective: The objective of the study was twofold: i) to investigate the association between all-cause mortality and eGFR changes over time; ii) to understand whether renal dysfunction mediates the effect of tryptophan metabolism on death risk., Design: Prospective study with an average follow-up of 14.8 years., Setting: Research Hospital., Patients: The aggregate Gargano Mortality Study included 962 patients with type 2 diabetes who had at least three eGFR recordings and at least 1.5 years of follow-up., Interventions: This was an observational study, with no intervention., Main Outcome Measures: Rate of all-cause mortality., Results: Age and sex adjusted annual incident rate of mortality was 2.75 events per 100 person-years. The median annual rate of decline of eGFR was 1.3 ml/min per 1.73 m2 per year (range -3.7; 7.8). The decline of kidney function was strongly and independently associated with the risk of death. Serum kynurenine-to-tryptophan ratio (KTR) was associated with both eGFR decline and all-cause mortality. Causal mediation analysis showed that 24.3% of the association between KTR and mortality was mediated by eGFR decline., Conclusions: In patients with type 2 diabetes, eGFR decline is independently associated with the risk of all-cause mortality and mediates a significant proportion of the association between tryptophan metabolism and death., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

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., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: SGLT2 inhibitors have been shown to reduce hospitalisation in patients with chronic heart failure (CHF). The cardioprotective mechanisms of gliflozins however have not been fully elucidated. The aim of this study was therefore to evaluate the effect of SGLT2 inhibitors on right and left ventricular function in patients with diabetes and HF., Methods: Seventy-eight patients with diabetes and CHF were enroled in the study and followed up; 38 started treatment with SGLT2i, while the remaining 40 continued their previous antidiabetic therapy. All patients underwent conventional, TDI and strain echocardiography in an ambulatory setting, at the beginning and after 3 months of therapy with SGLT2i., Results: After 3 months of therapy with SGLT2i, echocardiographic parameters assessing both left and right ventricular dimensions and function were found as significantly improved in patients switching to SGLT2i than control group: LVEF (45 ± 9% vs. 40 ± 8%, p < 0.001), LVEDD (54 ± 6.5 vs. 56 ± 6.5 mm, p < 0.01), GLS (-13 ± 4% vs. -10 ± 3%, p < 0.001), TAPSE (21 ± 3 vs. 19 ± 3 mm, p < 0.001), RV S' (12.9 ± 2.5 vs 11.0 ± 1.9 cm/sec, p < 0.001) and PAsP (24 ± 8 vs. 31 ± 9 mmHg, p < 0.001). Also mitral (1.0 ± 0.5 vs. 1.3 ± 0.5, p < 0.01) and tricuspid regurgitation (1.0 ± 0.5 vs. 1.3 ± 0.5, p < 0.01) improved after SGLT2i therapy. Changes were not statistically significant in patients not treated with SGLT2i (p n.s. in all cases)., Conclusions: In a real-world scenario, treatment with SGLT2i in patients with CHF and diabetes is associated with an improvement in both left and right ventricular function assessed at echocardiography. These data may explain potential anti-remodelling effects of gliflozins., (© 2023 The Authors. Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Background and Aims: The CHA 2 DS 2 -VASc score estimates the risk of cardioembolism in patients with atrial fibrillation (AF). It also predicts vascular events and death in different clinical settings, even in the absence of AF. The R 2 CHA 2 DS 2 -VASc score, obtained by adding the glomerular filtration rate to CHA 2 DS 2 -VASc, shows a higher prediction ability for new events and all-cause mortality. The present study aims to assess whether the addition of albuminuria to R 2 CHA 2 DS 2 -VASc score further improves its discrimination ability in predicting all-cause mortality in a sample of high cardiovascular risk population., Methods and Results: Prospective, monocentric, observational study, evaluating a subset of 737 subjects consecutively undergoing to coronary angiography at Coronary Unit of Scientific Institute "Casa Sollievo della Sofferenza" from June 2016 to December 2018. The presence of albuminuria was significantly associated with all-cause mortality (p < 0.0001). Any one-point increase of Alb-R 2 CHA 2 DS 2 -VASc score increased mortality of about 1.5-fold (adjusted HR 1.49; 95%CI: 1.37-1.63; p < 0.0001). Considering tertiles of Alb-R 2 CHA 2 DS 2 -VASc, the third tertile showed a 9.5-fold increased risk of mortality (HR 9.52; 95% CI: 5.15-17.60, p < 0.001). Comparing the two scores, the Alb-R 2 CHA 2 DS 2 -VASc score (C-statistic = 0.751; 95%CI: 0.69-0.81) outperformed the R 2 -CHA 2 DS 2 -VASc score (C-statistic = 0.736; 95%CI: 0.68-0.961) in predicting mortality (delta C-statistic = 0.015; 95%CI: 0.001-0.029). The better prediction ability of the Alb-R 2 CHA 2 DS 2 -VASc score was also proven by an IDI of 0.024 (p < 0.0001) and a relative IDI of 24.11% (p < 0.0001), with an NRI = 0.608 (p < 0.00001)., Conclusions: The addition of albuminuria to R 2 CHA 2 DS 2 -VASc significantly and independently predicts the risk of all-cause mortality in a sample of high CV risk patients. Moreover, Alb-R 2 CHA 2 DS 2 -VASc outperforms R 2 CHA 2 DS 2 -VASc., Competing Interests: Declaration of competing interest The authors declare they have no conflict of interest. The results presented in this article have not been published previously in whole or in part., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Alterations of endothelial function, inflammatory activation, and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway are involved in the pathophysiology of heart failure. Metabolic alterations have been studied in the myocardium of heart failure (HF) patients; alterations in ketone body and amino acid/protein metabolism have been described in patients affected by HF, as well as mitochondrial dysfunction and other modified metabolic signaling. However, their possible contributions toward cardiac function impairment in HF patients are not completely known. Recently, sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have emerged as a new class of drugs designed to treat patients with type 2 diabetes (T2D), but have also been shown to be protective against HF-related events and CV mortality. To date, the protective cardiovascular effects of these drugs in patients with and without T2D are not completely understood and several mechanisms have been proposed. In this review, we discuss on vascular and metabolic effects of SGLT2i and GLP-1 in HF patients., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: An "obesity paradox" for mortality has been shown in chronic disorders such as diabetes, and attributed to methodological bias, including the use of body mass index (BMI) for obesity definition. This analysis investigated the independent association of BMI versus surrogate measures of central adiposity with all-cause mortality in individuals with type 2 diabetes., Methods: The Renal Insufficiency And Cardiovascular Events Italian Multicentre Study is a prospective cohort study that enrolled 15,773 patients in 19 Italian centres in 2006-2008. Exposures were BMI and the surrogate measures of central adiposity waist circumference (WC), waist-to-height ratio (WHtR), and A Body Shape Index (ABSI). Vital status was retrieved on 31 October 2015 for 15,656 patients (99.3%), RESULTS: Age- and sex-adjusted hazard ratios and 95% confidence intervals were significantly higher in BMI-based underweight (1.729 [1.193-2.505), P = 0.004), moderately obese (1.214 [1.058-1.392), P = 0.006) and severely obese (1.703 [1.402-2.068), P < 0.0001), lower in overweight (0.842 [0.775-0.915), P < 0.0001) and similar in mildly obese (0.950 [0.864-1.045), P = 0.292), compared to normal-weight individuals. When further adjusting for smoking, physical activity (PA), and comorbidities, risk was lower also in mildly obese versus normal-weight patients. The BMI-mortality relationship did not change after sequentially excluding ever smokers, individuals with comorbidities, and those died within two years from enrollment and when analyzing separately participants below and above the median age. Conversely, a paradox relationship was observed among inactive/moderately inactive, but not moderately/highly active patients. Mortality risk adjusted for age, gender, smoking, PA and comorbidities was significantly higher in the highest tertile of WC (1.279 [1.089-1.501], P = 0.003), WHtR (1.372 [1.165-1.615], P < 0.0001), and ABSI (1.263 [1.067-1.495], P = 0.007) versus the lowest tertile. However, risk was lower in the intermediate versus lowest tertile for WC (0.823 [0.693-0.979], P = 0.028), similar for WHtR, and higher, though not significantly, for ABSI., Conclusions: An "overweight paradox" remained after controlling for age, smoking, and comorbidities, arguing against a collider bias or reverse causation. However, it could be partly explained by confounding from PA level, possibly through its impact on lean mass and cardiorespiratory fitness. No obesity paradox was observed with WHtR and especially ABSI, which predicted mortality risk associated with central adiposity better than WC. Trial registration ClinicalTrials.gov, NCT00715481, 15 July, 2008., (© 2022. The Author(s).)

Purpose: The use of sodium-glucose-cotransporter-type-2 inhibitors (SGLT2i) was associated in previous studies with an improved vascular function in non-human experimental models. We therefore sought to evaluate possible changes in endothelial function assessed by flow-mediated dilation (FMD) in patients with chronic heart failure (CHF) and type-2 diabetes mellitus (T2DM), switching from other oral hypoglycemic agents to SGLT2i in an observational study., Methods: Twenty-two consecutive outpatients with CHF and T2DM were enrolled after switching to SGLT2i therapy, and compared with 23 consecutive controls from the same registry comparable for principal clinical characteristics. In all patients, endothelial function was assessed by FMD at baseline and after 3 months of follow-up., Results: Three months of therapy with SGLT2i were associated with a statistically significant improvement in endothelial function (19.0 ± 5.7% vs 8.5 ± 4.1%, p &lt; 0.0001); baseline levels of FMD were comparable between groups (p n.s.). Therapy with SGLT2i was significantly associated to improved FMD levels even at multivariable stepwise regression analysis (p &lt; 0.001)., Conclusions: Switch to SGLT2i in patients with CHF and T2DM was associated in an observational non-randomized study with an improved endothelial function., (© 2021. The Author(s).)

Background: The CHA 2 DS 2 -VASc score, widely used to estimate cardioembolic risk in patients with atrial fibrillation (AF), appears to be useful also in predicting vascular adverse events and death in different sets of patients without AF. The R 2 CHA 2 DS 2 -VASc score, which includes renal impairment, allows a better prediction of death and thromboembolism in patients without AF. The aims of our study were to assess, in a large sample of patients at high cardiovascular (CV) risk, (i) the correlation between CHA 2 DS 2 -VASc and R 2 CHA 2 DS 2 -VASc with all-cause mortality, and (ii) to compare the performances of CHA 2 DS 2 -VASc and R 2 CHA 2 DS 2 -VASc in predicting all-cause mortality., Methods: In this single-centre prospective observational study, conducted at the Research Hospital 'Casa Sollievo della Sofferenza' between June 2016 and December 2018, 1017 CV patients at high risk of undergoing coronary angiography were enrolled., Results: CHA₂DS₂-VASc and R 2 CHA 2 DS 2 -VASc scores significantly associated with all-cause mortality. For each one-point increase in CHA 2 DS 2 -VASc or R 2 CHA 2 DS 2 -VASc scores, mortality increased by almost 1.5-fold. The R 2 CHA 2 DS 2 -VASc score (C-statistic = 0.71; 95% CI = 0.65-76) outperformed the CHA 2 DS 2 -VASc score (C-statistic = 0.66; 95% CI = 0.61-0.71) in predicting 4-year mortality (delta C-statistic = 0.05; 95% CI = 0.02-0.07). The better predictive ability of the R-CHA 2 DS 2 -VASc score was also demonstrated by an IDI = 0.027 (95% CI = 0.021-0.034, p < .00001) and a relative IDI = 62.8% (95% CI = 47.9%-81.3%, p < .00001). The R 2 CHA 2 DS 2 -VASc score correctly reclassified the patients with a NRI = 0.715 (95% = 0.544-0.940, p < .00001)., Conclusions: The CHA₂DS₂-VASc and R 2 CHA 2 DS 2 -VASc scores are useful predictors of all-cause mortality in subjects at high CV risk, with the R 2 CHA 2 DS 2 -VASc score being the best performer., (© 2022 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Aim: This study investigated whether rare, deleterious variants in monogenic diabetes-genes are associated with early-onset type 2 diabetes (T2D)., Methods: A nested case-control study was designed from 9712 Italian patients with T2D. Individuals with age at diabetes onset ≤35 yrs (n = 300; cases) or ≥65 yrs (n = 300; controls) were selected and screened for variants in 27 monogenic diabetes-genes by targeted resequencing. Rare (minor allele frequency-MAF <1%) and possibly deleterious variants were collectively tested for association with early-onset T2D. The association of a genetic risk score (GRS) based on 17 GWAS-SNPs for T2D was also tested., Results: When all rare variants were considered together, each increased the risk of early-onset T2D by 65% (allelic OR =1.64, 95% CI: 1.08-2.48, p = 0.02). Effects were similar when the 600 study participants were stratified according to their place of recruitment (Central-Southern Italy, 182 cases vs. 142 controls, or Rome urban area, 118 vs. 158, p for heterogeneity=0.53). Progressively less frequent variants showed increasingly stronger effects in the risk of early-onset T2D for those with MAF <0.001% (OR=6.34, 95% CI: 1.87-22.43, p = 0.003). One unit of T2D-GRS significantly increased the risk of early-onset T2D (OR 1.09, 95% CI: 1.01-1.18; p = 0.02). This association was stronger among rare variants carriers as compared to non-carriers (p = 0.02)., Conclusion: Rare variants in monogenic-diabetes genes are associated with an increased risk of early-onset T2D, and interact with common T2D susceptibility variants in shaping it. These findings might help develop prediction tools to identify individuals at high risk of developing T2D in early adulthood., Competing Interests: Declaration of Competing Interest No potential conflicts of interest relevant to this article were reported., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Greater efforts are needed to overcome the worldwide reported low achievement of LDL-c targets. This survey aimed to dissect whether and how the physician-based evaluation of patients with diabetes is associated with the achievement of LDL-c targets., Methods: This cross-sectional self-reported survey interviewed physicians working in 67 outpatient services in Italy, collecting records on 2844 patients with diabetes. Each physician reported a median of 47 records (IQR 42-49) and, for each of them, the physician specified its perceived cardiovascular risk, LDL-c targets, and the suggested refinement in lipid-lowering-treatment (LLT). These physician-based evaluations were then compared to recommendations from EAS/EASD guidelines., Results: Collected records were mostly from patients with type 2 diabetes (94%), at very-high (72%) or high-cardiovascular risk (27%). Physician-based assessments of cardiovascular risk and of LDL-c targets, as compared to guidelines recommendation, were misclassified in 34.7% of the records. The misperceived assessment was significantly higher among females and those on primary prevention and was associated with 67% lower odds of achieving guidelines-recommended LDL-c targets (OR 0.33, p < 0.0001). Peripheral artery disease, target organ damage and LLT-initiated by primary-care-physicians were all factors associated with therapeutic-inertia (i.e., lower than expected probability of receiving high-intensity LLT). Physician-suggested LLT refinement was inadequate in 24% of overall records and increased to 38% among subjects on primary prevention and with misclassified cardiovascular risk., Conclusions: This survey highlights the need to improve the physicians' misperceived cardiovascular risk and therapeutic inertia in patients with diabetes to successfully implement guidelines recommendations into everyday clinical practice., (© 2022. The Author(s).)

Context: Type 2 diabetes (T2D) shows a high mortality rate, partly mediated by atherosclerotic plaque instability. Discovering novel biomarkers may help identify high-risk patients who would benefit from more aggressive and specific managements. We recently described a serum resistin and multicytokine inflammatory pathway (REMAP), including resistin, interleukin (IL)-1β, IL-6, IL-8, and TNF-α, that is associated with cardiovascular disease., Objective: We investigated whether REMAP is associated with and improves the prediction of mortality in T2D., Methods: A REMAP score was investigated in 3 cohorts comprising 1528 patients with T2D (409 incident deaths) and in 59 patients who underwent carotid endarterectomy (CEA; 24 deaths). Plaques were classified as unstable/stable according to the modified American Heart Association atherosclerosis classification., Results: REMAP was associated with all-cause mortality in each cohort and in all 1528 individuals (fully adjusted hazard ratio [HR] for 1 SD increase = 1.34, P < .001). In CEA patients, REMAP was associated with mortality (HR = 1.64, P = .04) and a modest change was observed when plaque stability was taken into account (HR = 1.58; P = .07). REMAP improved discrimination and reclassification measures of both Estimation of Mortality Risk in Type 2 Diabetic Patients and Risk Equations for Complications of Type 2 Diabetes, well-established prediction models of mortality in T2D (P < .05-< .001)., Conclusion: REMAP is independently associated with and improves predict all-cause mortality in T2D; it can therefore be used to identify high-risk individuals to be targeted with more aggressive management. Whether REMAP can also identify patients who are more responsive to IL-6 and IL-1β monoclonal antibodies that reduce cardiovascular burden and total mortality is an intriguing possibility to be tested., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: The rate of all-cause mortality is twofold higher in type 2 diabetes than in the general population. Being able to identify patients with the highest risk from the very beginning of the disease would help tackle this burden., Methods: We tested whether ENFORCE, an established prediction model of all-cause mortality in type 2 diabetes, performs well also in two independent samples of patients with early-stage disease prospectively followed up., Results: ENFORCE's survival C-statistic was 0.81 (95%CI: 0.72-0.89) and 0.78 (95%CI: 0.68-0.87) in both samples. Calibration was also good. Very similar results were obtained with RECODe, an alternative prediction model of all-cause mortality in type 2 diabetes., Conclusions: In conclusion, our data show that two well-established prediction models of all-cause mortality in type 2 diabetes can also be successfully applied in the early stage of the disease, thus becoming powerful tools for educated and timely prevention strategies for high-risk patients., (© 2021. Springer-Verlag Italia S.r.l., part of Springer Nature.)