Hemogram inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), red-cell distribution width (RDW), and mean platelet volume (MPV) have been associated with type 2 diabetes mellitus (T2DM) and its complications, namely diabetic kidney diseases (DKD). We aimed to develop and validate logistic regression (LR) and CatBoost diagnostic models and study the role of adding these markers to the models.

All individuals who were managed in our secondary care center from March 2020 to December 2023 were identified. After excluding the ineligible patients, train-test splitting, and data preprocessing, two baseline LR and CatBoost-based models were developed using demographic, clinical, and laboratory features. The AUC-ROC of the models with biomarkers (NLR, PLR, RDW, and MPV) was compared to the baseline models. We calculated net reclassification improvement (NRI) and integrated discrimination index (IDI).

One thousand and eleven T2DM patients were eligible. The AUC-ROC of both LR (0.738) and CatBoost (0.715) models was comparable. Adding target inflammatory markers did not significantly change the AUC-ROC in both LR and CatBoost models. Adding RDW to the baseline LR model reclassified 41.7% of patients without DKD, in the cost of misclassification of 38.4% of DKD cases. This change was absent in CatBoost models, and other markers did not achieve improved NRI or IDI.

The basic models with demographical and clinical features had acceptable performance. Adding RDW to the basic LR model improved the reclassification of the non-DKD participants. However, adding other hematological indices did not significantly improve the LR and CatBoost models' performance.

The online version contains supplementary material available at 10.1007/s40200-024-01523-2.

The aim of this study was to develop and validate a prediction model for incident chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM), defined as eGFR < 60 ml/min/1.73m2 and/or urine albumin:creatinine ratio (UACR) > 3 mg/mmol in ≥ 2 consecutive readings ≥ 3 months apart.

Model derivation was performed in the SingHealth Diabetes Registry, including patients aged ≥ 21 years diagnosed with T2DM without pre-existing CKD. External validation was performed in a single-center prospective observational cohort. Cox Proportional Hazard model was created to evaluate predictors associated with time-to-onset of incident CKD. Increasingly parsimonious models were assessed for discrimination and calibration. Models underwent external validation, benchmarking against existing models, and decision curve analysis.

25,142 (59 %) of 42,552 patients in the derivation cohort developed CKD over a median 4.0 years (IQR 2.1-7.7) follow up. An 18-variable model, 12-variable model, and 4-variable model (including age, duration of T2DM, eGFR, and previous non-persistent albuminuria) was developed. The 4-variable model had a C-statistic of 0.78 and good calibration on plots of observed-versus-predicted risk. The 12-variable and 18-variable models performed similarly. In the external validation cohort of 2249 patients, of whom 1035 (46 %) developed incident CKD, the 4-variable model had a C-statistic of 0.87. All models had better discrimination than existing benchmarks. Decision curve analysis of the 4-variable model showed positive net benefit for any threshold probability above 16 % for 2-year and 28 % for 5-year CKD risk.

The 4-variable model for prediction of incident CKD in T2DM demonstrates good performance, predicts both eGFR and albuminuria endpoints, and is simple-to-use. This may guide personalized care, resource allocation and population health.

Using machine learning to construct a prediction model for the risk of diabetes kidney disease (DKD) in the American diabetes population and evaluate its effect.

First, a dataset of five cycles from 2009 to 2018 was obtained from the National Health and Nutrition Examination Survey (NHANES) database, weighted and then standardized (with the study population in the United States), and the data were processed and randomly grouped using R software. Next, variable selection for DKD patients was conducted using Lasso regression, two-way stepwise iterative regression, and random forest methods. A nomogram model was constructed for the risk prediction of DKD. Finally, the predictive performance, predictive value, calibration, and clinical effectiveness of the model were evaluated through the receipt of ROC curves, Brier score values, calibration curves (CC), and decision curves (DCA). In addition, we will visualize it.

A total of 4371 participants were selected and included in this study. Patients were randomly divided into a training set (n = 3066 people) and a validation set (n = 1305 people) in a 7:3 ratio. Using machine learning algorithms and drawing Venn diagrams, five variables significantly correlated with DKD risk were identified, namely Age, Hba1c, ALB, Scr, and TP. The area under the ROC curve (AUC) of the training set evaluation index for this model is 0.735, the net benefit rate of DCA is 2%-90%, and the Brier score is 0.172. The area under the ROC curve of the validation set (AUC) is 0.717, and the DCA curve shows a good net benefit rate. The Brier score is 0.177, and the calibration curve results of the validation set and training set are almost consistent.

The DKD risk nomogram model constructed in this study has good predictive performance, which helps to evaluate the risk of DKD as early as possible in clinical practice and formulate relevant intervention and treatment measures. The visual result can be used by doctors or individuals to estimate the probability of DKD risk, as a reference to help make better treatment decisions.

Chronic kidney disease (CKD) affects individual welfare, healthcare systems and societal progress. Of the multifaceted etiological factors, type 1 diabetes mellitus (T1DM) is a prominent contributor to CKD.

We analysed the global incidence, prevalence, deaths and disability-adjusted life-years (DALYs) with age-standardised rates of CKD due to T1DM (CKD-T1DM) in 2021, stratified by subtype. We calculated the temporal trends in the infirmity burden from 1990 to 2019 using a linear regression model. The age-period-cohort (APC) and Bayesian APC models predicted the prospective burden over the next 25 years. Sensitivity analysis was conducted using Autoregressive Integrated Moving Average and Exponential Smoothing models.

Globally, there were 95 140 incidences, 6 295 711 prevalence cases, 94 020 deaths and 3 875 628 DALYs due to CKD-T1DM. Males and young-to-middle-aged individuals were more likely to be affected by CKD-T1DM. The middle-socio-demographic index regions were at higher risk. A considerable variation in disease burden was observed across the Global Burden of Disease super regions and countries. The number of patients with CKD-T1DM surged globally from 1990 to 2021. The projections indicated a continuous increase until 2046, driven by ageing populations and unmet therapeutic needs in low-resource settings.

CKD-T1DM poses a growing public health threat, necessitating region-specific strategies that address healthcare inequities, promote early screening and prioritise nephroprotective therapies among T1DM populations.

This research aimed to investigate the factors contributing to mortality in patients with type 2 diabetes (T2D) to identify the primary determinants that exacerbate mortality risks in this population.

In this cohort study, 297 T2D patients from an urban Spanish population were monitored over 49 months to assess survival. The study collected sociodemographic and clinical data, including cardiovascular risk factors and initial treatments, to examine their impact on patient survival.

Of the initial 291 T2D patients, 60.1% were over 65y, with a male majority (53.3%) and average T2D duration of 8.8 years. In the 4-year follow-up, 15.4% of the patients died, predominantly due to cardiovascular disease (33.3%) and cancer (31.1%). In multivariate analysis, age (Hazard Ratio [HR] 1.169, p = 0.002) and body mass index (BMI; HR 0.807, p = 0.039) were identified as potential modulators of such relationships.

The present study reveals that cardiovascular disease, closely followed by cancer, are the leading causes of mortality in a Spanish T2D patients' cohort over a 4-year follow-up. In addition to age - which, as expected, was clearly associated with higher mortality - BMI was inversely associated with mortality, supporting the existence of an obesity paradox in T2D.

Bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical, is widely used in polymers, plasticizers, and food packaging, raising significant concerns for human health. Growing evidence links BPA exposure to cardiovascular diseases, including diabetic cardiomyopathy (DCM), a severe complication of diabetes characterized by myocardial dysfunction. This study employs an integrative approach combining network toxicology and molecular docking to elucidate the molecular mechanisms underlying BPA-induced DCM. Using computational tools such as ADMETlab2.0, ProTox3.0, GeneCards, OMIM, Swiss Target Prediction, and ChEMBL databases, we systematically predicted BPA's potential to induce DCM and constructed comprehensive disease and BPA target libraries. Venn diagram analysis identified 93 potential targets associated with BPA-induced DCM, and a robust BPA regulatory network was established using Cytoscape. Functional enrichment analyses revealed significant involvement of oxidative stress, insulin signaling, and metabolic pathways in BPA toxicity. Molecular docking simulations demonstrated stable binding interactions between BPA and core targets (INS, AKT1, PPARG, STAT3, PPARA, MMP9), with binding energies ranging from -5.3 to -7.5 kcal/mol. Our findings indicate that BPA may induce DCM through key genes and pathways, including cGMP-PKG signaling pathway, insulin signaling pathway, AMPK signaling pathway, and HIF-1 signaling pathway. This study provides a novel theoretical framework for understanding the molecular pathogenesis of BPA-induced DCM and highlights the potential of network toxicology in identifying toxic pathways for uncharacterized environmental compounds. These insights offer potential targets for preventive and therapeutic strategies against BPA-associated cardiovascular complications.

Type 2 diabetes (T2DM) is the leading cause of chronic kidney disease (CKD) worldwide. Identifying clinical and laboratory associations with chronic kidney disease (CKD) in type 2 diabetes (T2DM) can help physicians target modifiable risk factors. In light of limited data from India, the CITE (CKD in Indian T2DM Evaluation) study was conducted.

The multicenter, cross-sectional CITE study included 3,325 patients from 28 centres across India over a three-month period. CKD was defined as a persistent decline in kidney function (eGFR < 60 ml/min/1.73 m² for ≥ 3 months) or an elevated urine albumin-to-creatinine ratio (UACR) in at least two samples. Descriptive statistics summarised patient characteristics, while logistic regression analyses identified significant risk factors for CKD.

The prevalence of CKD in T2DM was 32%, with a median patient age of 59.9 years and 60.72% having a T2DM duration > 10 years. Reduced eGFR (< 60 ml/min/1.73 m²) was associated with older age (OR: 2.47, 95% CI 2.11-2.88, P < 0.001), longer T2DM duration (OR: 2.28, 95% CI 1.77-2.93, P < 0.001), higher HbA1c (OR: 1.039, 95% CI 1.001-1.079, P = 0.046), and elevated SBP (OR: 1.005, 95% CI 1.002-1.009, P = 0.003). Macroalbuminuria (UACR > 300 mg/g) was linked to non-vegetarian diet (OR: 1.95, 95% CI: 1.59-2.40, P < 0.001) and tobacco use (OR: 1.42, 95% CI: 1.17-1.73, P < 0.001). CKD increased comorbidity odds.

The CITE study highlights the prevalence of CKD (32%) in Indian patients with T2DM and identifies clinical and laboratory factors associated with CKD, including age ≥ 60 years, T2DM duration, SBP, HbA1c, tobacco use, non-vegetarian diet, and comorbidities. Longitudinal studies are needed to confirm these associations and evaluate causality.

We aimed to investigate the association between objectively measured physical activity and the presence and development of albuminuria in individuals recently diagnosed with type 2 diabetes at baseline.

This study was based on data from The Danish Centre for Strategic Research in Type 2 diabetes cohort (N = 832). We assessed moderate to vigorous physical activity (MVPA) and sedentary time by 24-hour dual-monitor accelerometry at baseline and 4-years follow-up and investigated the association with albuminuria, defined as urine albumin/creatinine-ratio (UACR) ≥30 mg/g, measured from a urine sample. The odds ratio (OR) for the presence and development of albuminuria were investigated using multiple logistic regressions.

We found an inverse association between baseline MVPA and both presence (OR: 0.82; 95 % CI: 0.69-0.98) and incidence of albuminuria (OR: 0.74; 95 % CI: 0.59-0.94), independent of known confounding factors. However, sedentary time was not significantly associated with increased development of albuminuria. Moreover, neither decrease in MVPA (OR: 0.79; 95 % CI: 0.42-1.49) nor increase in sedentary time (OR: 1.03; 95 % CI: 0.98-1.09) were significantly associated with development of albuminuria from baseline to 4-years follow-up.

Our findings demonstrate an inverse association between baseline MVPA and development of albuminuria in individuals recently diagnosed with type 2 diabetes. An increase in MVPA from baseline to follow-up inferred 21 % lower incidence of albuminuria after 4-years follow-up, albeit insignificant, likely due to the relatively small sample size at follow-up and the lack of larger changes in physical activity.

NCT02015130.

Chronic kidney disease (CKD) due to Type 2Diabetes Mellitus (T2DM) is an increasing health burden in South Asia. This study evaluates the burden, trends, and future projections of CKD from 1990-2021 using Global Burden of Disease (GBD) data and ARIMA modeling.

We analyzed age-standardized rates (ASR) for prevalence, incidence, mortality, and DALYs of CKD due to T2DM in South Asia(India, Pakistan, Bangladesh, Bhutan, Nepal). Join point regression and ARIMAmodels were applied for trend analysis and projections.

From 1990 to 2021, prevalence decreased slightly (e.g. India: 5.4% to 5.2%), while mortality increased (e.g.Pakistan: 33.7 to 42.1 per 100,000). Incidence increased across all countries, with Nepal (1.3% increase) and Bhutan (1.7% increase) showing the highest growth. Projections indicate a continued rise in CKD burden, especially inNepal and India.

CKD due to T2DM is increasing, emphasizing the need for targeted interventions.

Cardiovascular-kidney-metabolic (CKM) syndrome reflects the interplay among metabolic risk factors, chronic kidney disease, and cardiovascular disease (CVD). While the hemoglobin glycation index (HGI) has demonstrated prognostic value for cardiovascular events, its clinical utility remains unexplored in early-stage CKM syndrome.

Participants with early-stage CKM syndrome (stage 0-3) were recruited from the China Health and Retirement Longitudinal Study (CHARLS) database. Using k-means clustering analysis, the participants were classified according to the values of HGI measured at baseline and 3 years later, respectively. The primary outcome was self-reported CVD during the follow-up of at least 3 years. Extreme gradient boosting (XGBoost) algorithm was applied, with the Shapley additive explanation (SHAP) method used to determine feature importance. Multivariable logistics proportional regression analysis the association between HGI and CVD, and restricted cubic spline (RCS) regression assessed potential nonlinear relationships.

A total of 4676 eligible participants were included in the final analysis, with 944 (20.19%) progressed to CVD within 10 years. Among the baseline clinical features, HGI ranked the second for the impact on the occurrence of CVD. According to the changes of HGI values, the participants were clustered into 4 classes. Compared to the class 1 with lower level of HGI, higher risk of CVD was observed in class 3 (adjusted OR: 1.34, 95% CI: 1.06-1.69, P = 0.013) and class 4 (adjusted OR: 1.65, 95% CI: 1.01-2.45, P = 0.025) with higher and rapidly increasing level of HGI. RCS analysis showed cumulative HGI and the risk of CVD were linearly related (P for nonlinearity = 0.967). Subgroup analyses confirmed the stability of the association. Additionally, the SHAP plot revealed that HGI were the more important features than traditional risk factors such as FBG for predicting CVD.

HGI is associated with an elevated risk of CVD in participants with early-stage CKM syndrome. HGI can serve as an independent biomarker for guiding clinical decision-making and managing patient outcomes.

Investigating the causes of death in individuals with diabetes compared with those without is essential for understanding diabetes care. However, methods for identifying individuals with diabetes within populations vary. We conducted a comparison of these groups under identical conditions, analyzing differences in causes and age at death, and assessing how different identification methods influence these outcomes.

This study used the clinical records of inpatients who died at the National Center for Global Health and Medicine from September 1, 2010, to December 31, 2020. Individuals with or without diabetes were defined using prescriptions and laboratory data. The cause of death was determined by the name of the primary illness provided by the attending physician at the time of death. Individuals with diabetes were stratified by different definitions, and their age at death was compared.

In Individuals with diabetes, males accounted for 67.6%, and in those without diabetes, 57.0%. The mean age at death was 75.0 ± 11.8 and 73.8 ± 16.0 years, respectively. Malignant neoplasia was the most common cause of death in both groups, with a higher frequency in individuals with diabetes (36.9% vs 31.0%). Age at death of individuals with diabetes differed by up to 1.5 years, depending on the definitions.

Direct comparisons suggested that malignant neoplasia was the leading cause of death, and individuals with diabetes had a higher mean age at death. The method used to identify diabetes influenced these outcomes, emphasizing the importance of careful consideration in mortality studies.

To verify the influence of glucagon-like peptide-1 receptor agonists (GLP-1 RA) on renal function parameters in type 2 diabetes based on well-known randomized controlled trials (RCTs).

PubMed, Cochrane, Web of Science, Embase, and grey literature were searched for RCTs published until December 24, 2024. The quality of the RCTs was assessed using the Cochrane risk-of-bias tool. Weighted mean differences (WMD) and 95% confidence intervals (CIs) were calculated for continuous variables using meta-analysis. The primary outcomes were composite renal function parameters, including serum creatinine (Cr) levels, estimated glomerular filtration rate (eGFR), urinary albumin excretion (UAE), and urinary albumin-to-creatinine ratio (UACR).

Pooled data from 24 studies revealed that GLP-1 RA positively influenced renal outcomes in the type 2 diabetes group to some extent compared with that in the control group. GLP- 1 RA decreased serum creatinine levels (WMD=-0.10, 95%CI -0.19 to -0.01, I2 = 33%, P < 0.05), eGFR(WMD = 0.54, 95% CI 0.19 to 0.90, I2 = 27%, P < 0.05), UAE (WMD=-11.92, 95% CI - 23.50 to - 0.33, I2 = 0%, P < 0.05) and UACR (WMD: -1.01 mg/g, 95% CI:-1.68, -0.34, I2 = 15%, P < 0.05) in the type 2 diabetes group.

GLP-1 RA treatment significantly elevated eGFR, decreased the UACR, and positively influenced renal function outcomes in the type 2 diabetes group.

Not applicable.

Type 2 diabetes (T2D) is the leading cause of chronic kidney disease (CKD) and is a risk factor for progression to end-stage kidney disease and cardiovascular morbidity and mortality. Despite pharmacologic treatment, residual risk of disease progression and adverse outcomes remains substantial. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist (MRA) approved in the United States for use in patients with CKD associated with T2D. The present review focuses on finerenone use, including its pharmacologic basis, indication and eligibility, and practical aspects of incorporation into routine clinical practice (particularly primary care). Results from the two placebo-controlled phase 3 clinical trials of finerenone (plus maximum tolerated dose of a renin-angiotensin-aldosterone system inhibitor) in patients with CKD associated with T2D showed a significantly lower risk of CKD progression and cardiovascular events with finerenone versus placebo. These effects of finerenone were applicable across the broad spectrum of patient participants, including those with baseline comorbidities such as a history of heart failure or a history of atherosclerotic cardiovascular disease. We also compare finerenone to steroidal MRAs and discuss the relevance of ongoing and recently completed clinical trials of finerenone in other patient groups, which could expand finerenone use further to a broader spectrum of patients.

Aims: In subjects with type 2 diabetes (DM), poor glycemic control, and advanced chronic kidney disease (CKD), the kidney benefit of the reduction of glycated hemoglobin (HbA1c) is not well established. Methods: In a retrospective cohort, we included patients with DM, CKD grade 3b-5, and HbA1c > 9% to evaluate the risk of developing major adverse kidney events (MAKE) defined as the start of kidney replacement therapy (KRT), ≥ 25% or ≥ 40% decline in the glomerular filtration rate (eGFR) from baseline, and death; patients were divided according to the HbA1c levels at the end of the follow-up into the following groups: > 75 mmol/mol (≥ 9.0%), 74-64 mmol/mol (8.9%-8.0%), 64-53 mmol/mol (7.9%-7.0%), and < 52 mmol/mol (< 7.0%). We described their characteristics and analyzed their risks, adjusting for confounding variables. Results: From 2015 to 2023, 111 patients were included. In 46 patients (41.4%), the HbA1c at the end of follow-up (60 months) was still > 75 mmol/mol (≥ 9%), and each patient had a mean of 4.9 HbA1c measurements. The mean age was 59 years, and 46% were male; the baseline eGFR was 25 mL/min/1.73 m2. MAKE occurred in 67% of cases. In a multivariate analysis, the risk of MAKE was not associated with the HbA1c groups, nor was it associated with any of the MAKE components individually, nor in certain subgroups. When evaluating the magnitude of percentage changes in HbA1 with the initiation of KRT, we did not find any association. Conclusions: With advanced CKD and poor glycemic control, changes in HbA1c during long follow-up are not associated with MAKE or its individual components.

Novel therapies are emerging for the prevention of chronic kidney disease (CKD) progression in patients with type 2 diabetes (T2D). Within the FOUNTAIN platform (NCT05526157; EUPAS48148), this real-world study aimed to characterize cohorts of adults with CKD and T2D starting therapy with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in Europe, Japan, and the United States (US) during 2012-2021.

This multinational, multicohort study was conducted in five data sources: the Danish National Health Registers (DNHR) (Denmark), PHARMO Data Network (PHARMO) (The Netherlands), Valencia Health System Integrated Database (VID) (Spain), Japan Chronic Kidney Disease Database Extension (J-CKD-DB-Ex) (Japan), and Optum's de-identified Clinformatics® Data Mart Database (CDM) (US). Eligible patients had T2D (defined by data source-specific algorithms) and CKD (based on diagnosis codes, estimated glomerular filtration rate values, and/or urine albumin-to-creatinine ratio) and initiated an GLP-1 RA during 2012-2021. Baseline demographic, lifestyle, and clinical characteristics were analyzed, and treatment patterns were described.

Study cohorts included 18,929 GLP-1 RA initiators in DNHR; 476 in PHARMO; 11,798 in VID; 329 in J-CKD-DB-Ex; and 70,158 in CDM. Across cohorts, mean age ranged from 66.1 years in J-CKD-DB-Ex to 67.9 years in CDM, and between 46.6% (PHARMO) and 59.6% (J-CKD-DB-Ex) of patients were men. There was a steady increase in GLP-1 RA initiators from 2012 (when 1.6-4.8% of GLP-1 RA initiators started therapy) to 2019 (when 19.8-31.5% started therapy). The median duration of initial treatment with a GLP-1 RA ranged from 2.3 months (PHARMO) to 12.4 months (VID). At 1-year follow-up, between 52% (CDM) and 78% (DNHR) of patients were receiving treatment. Findings suggested that GLP-1 RA use was independent of CKD severity.

During 2012-2021, GLP-1 RA use steadily increased across multinational cohorts of patients with T2D and CKD, and persistence with treatment was high. GLP-1 use was independent of CKD severity.

Glucagon-like peptide 1 (GLP-1) receptor agonists improve cardiac and kidney outcomes in patients with diabetes; however, their efficacy in individuals with reduced estimated glomerular filtration rate (eGFR) is uncertain. This study evaluated the effects of GLP-1 receptor agonists on kidney and cardiovascular (CV) outcomes in patients with chronic kidney disease (CKD).

Systematic review and meta-analysis of randomized controlled trials (RCTs) reported through May 25, 2024.

Adult participants in RCTs with baseline eGFR<60mL/min/1.73m2.

RCTs including adults (≥18 years old) with varying degrees of kidney function, including individuals with CKD characterized by a baseline eGFR of<60mL/min/1.73m2, that compared GLP-1 receptor agonists with control treatments with respect to a composite kidney outcome, all-cause mortality, or a composite CV disease outcome. From among 212 screened studies, 12 trials involving that included participants with baseline eGFR<60mL/min/1.73m2 were included.

Two independent investigators extracted the data.

Pooled odds ratios (ORs) for composite kidney outcome, all-cause mortality, and composite CV outcome were estimated using random-effects models. Evidence certainty was assessed using the GRADE system.

The analyses included 17,996 RCT participants with baseline eGFR<60mL/min/1.73m2. GLP-1 receptor agonists were significantly associated with a reduced risk of the composite kidney outcome (OR, 0.85 [95% CI, 0.77-0.94]; P=0.001) with low heterogeneity (I2<0.01%). GLP-1 receptor agonists were also associated with a reduced the risk of a>30% eGFR decline (OR, 0.78; P=0.004), a>40% decline (OR, 0.76; P=0.01), and a>50% decline (OR, 0.72; P<0.001). Risk of all-cause mortality was also lower in the GLP-1 receptor agonist group (OR, 0.77 [95% CI, 0.60-0.98], P=0.03), though there was high heterogeneity (I2=71.6%). Composite CV outcomes were also lower with the use of a GLP-1 receptor agonist (OR, 0.86 [95% CI, 0.74-0.99], P=0.03; I2=40.3%). Sensitivity analyses restricted to human GLP-1 backbone agents showed enhanced benefits.

Inconsistent kidney outcome definitions, focus on diabetic populations in most studies, and potential publication bias.

GLP-1 receptor agonists improved kidney and CV outcomes, and survival in patients with CKD enrolled in an array of clinical trials.

Registered at PROSPERO with identification number CRD42023449059.

Glucagon-like peptide 1 (GLP-1) receptor agonists reduce body weight and improve glycemic control. They also have been shown to protect the heart and kidney in people with diabetes. However, the extrapolation of these findings to those with chronic kidney disease (CKD) is uncertain. This study meta-analyzed data from clinical trials focusing on patients with CKD and noted that GLP-1 receptor agonists may slow kidney disease progression and lower the risk of heart disease, stroke, and death. These findings suggest that GLP-1 receptor agonists offer multiple kidney and cardiovascular benefits to people with CKD.

Both glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular, kidney, and survival outcomes in patients with type 2 diabetes; however, the comparative effectiveness of these drugs in a real-world setting remains unclear.

Retrospective cohort study.

79,047 patients with type 2 diabetes and an eGFR <60 mL/min/1.73 m2 between 2016 and 2021 from the Taiwan's national health database.

Treatment with GLP1RA or treatment with SGLT2i.

Initiation of kidney replacement therapy (KRT) and all-cause mortality.

Propensity score matching was performed to balance baseline characteristics between the groups. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for each outcome, using an intention-to-treat approach.

14,182 (7,091 initiating GLP1RA and 7,091 initiating SGLT2i) from the original cohort of 79,047 individuals were included in the propensity score-matched analysis. With a median follow-up duration of 2.5 years, people initiating GLP1RA had a higher risk of requiring KRT compared to those initiating SGLT2i (HR: 1.39, 95% CI: 1.19-1.63). Although tests of interaction were not statistically significant, stratified analyses suggested possibly greater differences between the two drugs among patients with eGFR <45 mL/min/1.73 m2 or urine albumin-to-creatinine ratio >300 mg/g. Overall mortality did not differ between treatment groups.

Nonrandomized treatment selection.

Patients receiving SGLT2i demonstrated lower rates of progression to KRT compared to those receiving GLP1RA. These findings may inform the choice of these therapies in the setting of chronic kidney disease and type 2 diabetes.

The effectiveness of vitamin D supplementation in the progression of diabetic kidney disease (DKD) remains controversial. Our review tries to provide a comprehensive summary of all the relevant articles in the area to assess the association of vitamin D deficiency with the development of DKD and the effect of vitamin D supplementation on the progression of DKD.

PubMed, Embase, Scopus, Cochrane Library and Web of Science were accessed from inception till June 2024 to obtain all the relevant meta-analyses assessing the function of vitamin D in the onset and prognosis of DKD. The summary data were extracted by two independent reviewers. A Measurement Tool to Assess Systematic Reviews (AMSTAR) 2 tool was used for the assessment of the methodological quality of the included meta-analyses.

A total of 4579 articles were obtained from 5 databases in the initial search, of which 8 meta-analyses were included for the evidence synthesis. The methodological quality of the retrieved articles ranged from critically low to high. Serum vitamin D levels were significantly correlated with the prevalence of DKD. The review suggested that vitamin D supplementation could help in reducing proteinuria. However, no such changes were observed in other renal function parameters of DKD patients following vitamin D supplementation.

The current evidence indicates that vitamin D supplementation could be beneficial in reducing proteinuria among DKD patients.PROSPERO registration number: CRD42022375194.

The Cardiovascular Event Risk Test (CERT1) score derived from plasma ceramides has been applied clinically for cardiovascular risk assessment.

To study whether plasma ceramides predict risk of mortality in patients with type 2 diabetes.

In a prospective study that included 1903 outpatients with type 2 diabetes in a regional hospital and a primary care facility in Singapore, plasma ceramides (d18:1/16:0, d18:1/18:0, d18:1/24:0, d18:1/24:1) were measured by mass spectrometry and CERT1 score was calculated accordingly. Main outcomes were all-cause and cause-specific mortality.

During a median of 9.3 years of follow-up, 252 death events were identified. Compared to those with low score (≤ 2), participants with a high CERT1 score (≥ 7) had 1.86-fold (95% CI, 1.30-3.65) increased risk for all-cause death after adjustment for cardiorenal risk factors, including estimated glomerular filtration rate and albuminuria. As continuous variable, 1-unit increment in CERT1 was associated with 8% increased risk for all-cause death (adjusted hazard ratio [HR] 1.08 [1.04-1.13]). Adding CERT1 onto Risk Equations for Complications Of type 2 Diabetes (RECODe) mortality risk engine significantly improved prediction of 10-year risk of all-cause death (area under the curve, 0.810 to 0.823, delta 0.013 [0.005-0.022]). The association between CERT1 and noncardiovascular death remained significant (adjusted HR 2.12 [1.32-3.42]), whereas its association with cardiovascular death became nonsignificant after adjustment for kidney measurements (adjusted HR 1.41 [0.78-2.56]).

CERT1 score predicts mortality risk independent of clinical cardiorenal risk factors. Further studies are warranted to elucidate the mechanistic linkage between ceramide and mortality, especially noncardiovascular mortality.

To describe temporal changes in the characteristics of medication-initiator cohorts in persons with chronic kidney disease (CKD) and type 2 diabetes (T2D).

Adults with CKD and T2D initiating sodium-glucose cotransporter-2 inhibitors (SGLT-2i) or glucagon-like peptide-1 receptor agonists (GLP-1RA) were identified in the Japan Chronic Kidney Disease Database Extension in each of the two study periods (Period I: 1 January 2014-30 June 2021; Period II: 1 July 2021-31 December 2022). For each cohort, baseline characteristics and the standard mean differences (SMD) between periods I and II were assessed.

During study periods I and II, 1157 and 1122 SGLT-2i, and 329 and 369 GLP-1RA new users were identified, respectively. All four cohorts had similar age, sex and comorbidity patterns, with a mean age spanning 66.1-69.5 years and 60%-70% being male. More than 80% of persons had hypertension and 60% had congestive heart failure. In the SGLT-2i cohorts, we observed a decrease in prior metformin and dipeptidyl peptidase-4 inhibitor use (SMD ≥0.5 and <0.8), and an increase in the number of persons with no T2D medications other than insulin between periods (SMD >0.8). In the GLP-1RA cohorts, there was a medium decrease in persons using insulin.

With the introduction of new treatments and emerging evidence supporting cardio-renal protective effects in people with CKD and T2D, notable changes in baseline treatment were observed in the medication-initiator cohort characteristics. These findings suggest the earlier use of cardio-renal protective medications in the course of T2D.

The efficacy and safety of finerenone (a nonsteroidal mineralocorticoid receptor antagonist) versus placebo were assessed according to different changes in estimated glomerular filtration rate (eGFR) using data from FIDELITY, a pooled individual-level analysis of two clinical trials.

Patients had chronic kidney disease (eGFR of 25 ml/min/1.73 m2 or greater) and type 2 diabetes with optimized renin-angiotensin system blockade. Risk of composite cardiovascular and composite kidney outcomes was analyzed by baseline eGFR change at month one in the total population and by treatment group.

Of 12,798 patients, 25.1% had a >10% eGFR decline, 31.2% had a >0-10% decline, 26.8% had a 0-10% increase, and 16.8% had a >10% increase after one month of treatment. Factors associated with acute eGFR decline included higher baseline urine albumin-to-creatinine ratio, eGFR, systolic blood pressure, diuretic or beta-blocker use, and finerenone use. Finerenone significantly reduced composite cardiovascular and kidney outcomes overall and had similar beneficial effect across eGFR subgroups of >10% decline, >0-10% decline, 0-10% increase, and >10% increase for composite cardiovascular (hazard ratio [95% Confidence Interval] of 0.74 [0.61-0.90], 0.87 [0.73-1.04], 1.06 [0.87-1.28], and 0.78 [0.61-0.99], respectively) and kidney outcomes (0.67 [0.53-0.85], 0.78 [0.61-1.01], 0.56 [0.40-0.77], and 0.75 [0.50-1.14], respectively) (P interaction 0.048 and 0.23, respectively). When modeled as a continuous variable, finerenone reduced the risk of cardiovascular and kidney outcomes, irrespective of acute eGFR change (P interaction 0.58 and 0.36, respectively).

The cardiovascular and kidney benefits of finerenone were not modified by an acute eGFR change after drug initiation.

Diabetic kidney disease (DKD) is a significant risk factor for End-Stage Renal Disease, with a high global incidence and mortality rate. Hyperglycemia in DKD induces inflammation, contributing to glomerular hyperfiltration, fibrosis, and impaired renal function. Current therapies, including SGLT2 inhibitors, ACE inhibitors, and ARBs, show limited efficacy. Autologous dendritic cells (DCs) offer potential anti-inflammatory effects by reducing cytokine activity and fibrosis biomarkers.

A quasi-experimental pretest-post-test design was conducted involving 29 DKD patients. Baseline blood and urine samples were collected for MMP-9, TGF-β, and Doppler ultrasound (PSV, EDV) measurements. The subjects received subcutaneous injections of autologous DCs, and follow-up measurements were conducted four weeks after treatment. The statistical analyses included paired t-tests, Wilcoxon signed-rank tests, and linear regression.

After treatment, there were a significant decrease in PSV (from 47.1 ± 23.87 cm/s to 27.85 ± 20.53 cm/s, p = 0.044) and a significant increase in EDV (from 13 ± 5.32 cm/s to 15.7 ± 12.55 cm/s, p = 0.039). A strong correlation was observed between the TGF-β and MMP-9 levels (p = 0.001). Linear regression analysis showed reduced MMP-9 influence on the TGF-β after treatment, suggesting potential fibrosis reduction. Gender and UACR subgroup analyses revealed significant PSV and EDV improvements in females and the microalbuminuria group.

Autologous dendritic cell therapy significantly improved renal hemodynamics and showed potential to reduce fibrosis by modulating TGF-β and MMP-9 levels in DKD patients, warranting further investigation.

Background/Objectives: The current study aims to estimate the frequency of abnormal renal status (ARS, defined as chronic kidney disease (CKD) diagnosis in electronic medical records or current albuminuria) in people with newly diagnosed diabetes mellitus (DM), to determine the associated risk factors, and to evaluate the level of compliance with good clinical practice recommendations. Methods: Cross-sectional study with 1030 adults diagnosed with DM in the last 4 years. Anthropometric, clinical, analytical, and lifestyle variables were collected. Multivariate analyses were performed to determine the factors associated with ARS. Results: Hypercholesterolaemia, metabolic syndrome, hypertension, obesity, hypertriglyceridaemia, and cardiovascular disease (CVD) were the most prevalent comorbidities. ARS was present in 11.5% of patients. The variables associated with ARS were male sex (OR: 1.78; 95% CI, 1.16-2.75), age ≥70 years (OR: 2.96; 95% CI: 1.92-4.56), hypertension (OR: 1.59; 95% CI: 1.03-2.44), CVD (OR: 1.73; 95% CI: 1.03-2.90), and hemoglobin A1c (HbA1c) ≥8% (OR: 2.26; 95% CI, 1.19-4.27). Among patients with hypertension and albuminuria, 80% received angiotensin-converting enzyme inhibitors (ACE inhibitor) or an angiotensin receptor blocker (ARB), compared to 60% of those with albuminuria without hypertension. The 42.4% patients with ARS were treated with sodium-glucose cotransporter type 2 inhibitors (SGLT2i) and 72% with statins, but only 31.5% achieved the target low density lipoproteins cholesterol (LDLc) < 70 mg/dL. Conclusions: ARS in newly diagnosed patients with DM is less common than described in the literature, but risk factors for its development are highly prevalent. Adherence to good clinical practice recommendations was poor, especially in LDL cholesterol targets and the use of SGLT2i.

The relationship between initial changes in estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR), and their independent association with clinical outcomes in type 2 diabetes (T2D) patients receiving sodium-glucose cotransporter 2 inhibitors (SGLT2is), remains unclear.

This study aimed to investigate the association between initial changes in eGFR and UACR with consequent cardiovascular and kidney outcomes in an Asian population with T2D following SGLT2i treatment in a real-world setting.

Using a large multicenter medical database in Taiwan, we analyzed 8222 T2D patients with baseline and 3-month follow-up eGFR and UACR measurements, receiving SGLT2is between June 1, 2016, and December 31, 2021. We assessed risks of major adverse renal events (MARE), major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF), and all-cause mortality using a Cox proportional hazards model.

After 3 months of SGLT2i treatment, patients were categorized based on early changes in eGFR (no decline, 0%-10% decline, > 10% decline) and UACR (no reduction, 0%-30% reduction, > 30% reduction). Among those with no initial eGFR decline (40.9%), 19.8% had no initial UACR reduction, 8.4% had 0% to 30% reduction, and 12.7% had greater than 30% reduction. For those with greater than 10% initial eGFR decline (21.5%), 6.5% had no UACR reduction, 4.3% had 0% to 30% reduction, and 10.7% had greater than 30% reduction. Patients with greater than 10% initial eGFR decline but no UACR reduction showed higher risks of MARE (adjusted HR [aHR]: 2.34; 95% CI, 1.32-4.15), MACE (aHR: 1.83; 95% CI, 1.01-3.29), and HHF/cardiovascular death (aHR: 1.93; 95% CI, 1.05-3.55) compared to those with modest early eGFR decline and UACR reduction.

T2D patients experiencing profound early eGFR decline without concordant UACR reduction while on SGLT2is represent a high-risk subgroup with worse clinical outcomes. These findings suggest the need for closer monitoring and potentially more aggressive therapeutic strategies for this patient population.

Accurate and rapid monitoring of the glucose concentration in blood is essential for the prevention and treatment of diabetes. However, existing glucose sensors still have room for improvement in terms of sensitivity, selectivity, and stability. Benefiting from the fully exposed metal sites and uniform coordination environment, single-atom catalysts (SACs) have exhibited unique electrochemical sensing performances and received extensive attention in blood glucose detection. A growing number of researches have focused on the close connection between structural regulation of SACs and high efficiency glucose sensing. In this review, we start from the development of sensing devices, function materials related to glucose detection and electrochemical glucose sensing mechanisms. Then, the superiorities of SACs and a variety of SACs-based glucose sensors are proposed. The interact models between the single-atom active species and the reactants (including enzymatic and non-enzymatic environment) will be highlighted. Finally, the precise and large-scale synthesis, followed by the exploration of sensing mechanism, and concluding with opportunities and challenges of SACs in electrochemical glucose detection are outlined.

The American Heart Association defined cardiovascular-kidney-metabolic (CKM) syndrome as a novel multi-stage disorder. We examined the associations of CKM stages with premature mortality and the role of social determinants of health (SDOHs).

A prospective cohort study.

A nationally representative sample of US adults from NHANES 1999-2018.

CKM included 5 stages (stages 0-4), reflecting progressive pathophysiology. Premature mortality (deaths before 75 years) were ascertained via linkage to the National Death Index with follow-up until 2019. Cox proportional-hazards models adjusted for age, sex, race/ethnicity, medical history, and other confounding factors were used to calculate the hazard ratios (HR) and 95% CIs for CKM-mortality associations.

Among 27,909 participants (mean age 49.7 years, 49.0% females), 1762 premature deaths occurred over a median follow-up of 8.3 years. Compared with stage 0, the adjusted HRs for all-cause premature mortality at CKM stages 1-4 were 0.88 (95% CI 0.66-1.17), 1.31 (0.99-1.73), 1.94 (1.31-2.87), and 2.19 (1.61-2.98), respectively. For CVD premature mortality, the adjusted HRs for CKM stages 1-4 were 1.12 (0.46-2.72), 1.74 (0.71-4.28), 3.93 (1.53-10.12), and 6.48 (2.95-14.20), respectively. Among adults at CKM stages 3-4, unfavorable SDOHs, particularly not living with a partner, low family income, lack of private health insurance, unemployment, or ≥2 cumulative SDOHs (4.16, 95% CI 3.35-5.18) were associated with increased all-cause premature mortality. Among those at CKM stages 0-2, unfavorable SDOHs were also related to increased premature mortality.

CKM stages 3-4, but not stages 1-2, were associated with increased risks of premature mortality compared with stage 0. The risks were increased by unfavorable SDOHs across CKM stages.

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease worldwide. Endothelin-1 (ET-1) is a potent vasoconstrictor secreted by vascular endothelial cells, actively involved in the pathophysiology of numerous cardiovascular diseases. Based on the differential downstream effects of ET-1 binding to its two distinct types of receptors (ETA/ETB) within the kidney, selective ETA receptor blockade has been long proposed as a promising treatment modality for DKD.

This review aims to examine the available evidence base for the use of ERAs in the treatment of DKD, by critically reappraising available landmark trials and discussing their possible position in the context of current treatment of this disease.

Despite early enthusiasm and widespread expectations, endothelin receptor antagonists (ERAs) faded into obscurity following the release of the first randomized controlled trials (RCTs). More recent RCTs using different compounds have re-introduced ERAs as a promising treatment in the growing pharmaceutical armamentarium of DKD. While the future of DKD management will be based on a more personalized approach, new, robust evidence from appropriately designed RCTs is eagerly anticipated to clearly define the role of ERAs in DKD.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), affecting over 40% of patients with diabetes. DKD progression involves fibrosis and damage to glomerular and tubulointerstitial regions, with mitochondrial dysfunction playing a critical role. Impaired mitochondria lead to reduced adenosine triphosphate (ATP) production, damaged mitochondria accumulation, and increased reactive oxygen species (ROS), contributing to renal deterioration. Maintaining mitochondrial quality control (MQC) is essential for preventing cell death, tissue injury, and kidney failure. Recent clinical trials show that enhancing MQC can alleviate DKD. However, current treatments cannot halt kidney function decline, underscoring the need for new therapeutic strategies. Mitochondrial-targeted drugs show potential; however, challenges remain because of adverse effects and unclear mechanisms. Future research should aim to comprehensively explore therapeutic potential of MQC in DKD. This review highlights the significance of MQC in DKD treatment, emphasizing the need to maintain mitochondrial quality for developing new therapies.

To examine the isotemporal substitution association of replacing moderate-to-vigorous physical activity (MVPA) with other behaviors on the prevalence of chronic kidney disease (CKD) among Chinese adults with type 2 diabetes mellitus (T2DM).

This study included 5421 adults with T2DM from the National Metabolic Management Centre Ningbo Branch. Data on physical activity, sedentary behavior, and sleep were collected using a standardized questionnaire through face-to-face interviews. Isotemporal substitution models were employed to evaluate the associations of reallocating time from other behaviors to MVPA with the risk of CKD.

Substitution of 30 min per day of sleeping or sitting with MVPA was associated with a lower CKD prevalence (OR: 0.87 for sleep substitution; 0.90 for sitting substitution). Among individuals with inadequate MVPA levels (less than 150 min per week), the association of replacing 30 min of sleeping, sitting, or low-intensity physical activity with MVPA was particularly strong, cutting the risk of CKD by more than 60%. Stratified analysis among participants with inadequate MVPA revealed that the association of reallocating time to MVPA with lower CKD prevalence were predominantly observed among men, individuals with prolonged sleep duration (sleep duration more than 7.5 h per day), and those with better glycemic control (HbA1c levels below 7%).

This study revealed that replacing sleep or sedentary time with MVPA was associated with a lower prevalence of CKD among Chinese adults with T2DM, especially those with low MVPA. Incorporating MVPA into daily routines is potentially beneficial for improving renal health in people with T2DM.

Diabetic kidney disease (DKD) makes up nearly half of all chronic kidney disease cases and is a major cause of mortality for people with diabetes. However, the study of the association of longitudinal Chinese visceral adiposity index (CVAI) with DKD is still missing.

This prospective cohort study included 7874 diabetes patients from the Kailuan study. These participants had complete repeated waist circumference, body mass index, triglycerides and high-density lipoprotein cholesterol measurements that formed the continuous CVAI records. DKD was defined by increased proteinuria or decreased estimated glomerular filtration rate (eGFR), preceded by diabetes. Cox proportional hazard regression models were used to examine the associations between baseline and cumulative CVAI and the risk of DKD.

There is a positive association between the CVAI level, whether baseline or cumulative, and the incidence of DKD among diabetic patients (p for log-rank tests <0.001). Compared to low CVAI level, the high baseline CVAI level was positively associated with the risk of DKD (HR: 1.24, 95% CI: 1.09-1.42), as well as the high cumulative CVAI level (HR: 1.62, 95% CI: 1.29-2.04). In addition, the assumption of linearity for the positive associations between both baseline (P-nonlinear = 0.264, p for overall <0.001) and cumulative (P-nonlinear = 0.765, p for overall <0.001) CVAI with incident DKD was satisfied.

Higher baseline and cumulative CVAI are associated with a higher risk of DKD. This finding suggests the health benefits of low levels of CVAI and the importance of its regular surveillance among individuals with diabetes.

Periodontitis is a ubiquitous chronic inflammatory disease affecting the supporting tissues of the teeth and is a major cause of multiple tooth loss. Despite being preventable, periodontitis and dental caries are responsible for more years lost to disability than any other human condition. The most severe form of periodontitis affects 1 billion individuals, and its prevalence is increasing globally. Periodontitis arises from a dysregulated and hyperactive inflammatory response to dysbiosis in the periodontal microbiome. This response has systemic effects associated with premature mortality and elevated risk of several systemic non-communicable diseases (NCDs), including atheromatous cardiovascular disease, type 2 diabetes and chronic kidney disease (CKD). This risk association between periodontitis and NCDs is independent of their shared common risk factors, suggesting that periodontitis is a non-traditional risk factor for NCDs such as CKD. As periodontitis progresses, the immune cells and mediators underpinning its pathophysiology leak into the systemic circulation through the ulcerated oral mucosal lining, inducing in a systemic inflammatory profile that closely mirrors that observed in patients with CKD. The relationship between periodontitis and CKD seems to be bi-directional, but large-scale intervention studies are required to clarify causality and could lead to new care pathways for managing each condition as an exposure for the other.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder and its concurrent presence with chronic kidney disease (CKD) is a significant concern. Glycerol kinase (GK) and glycerol 3-phosphate shuttle enzymes (cGPDH and mGPDH) facilitate the regulation of endogenous glucose production in many cell lines. This research investigates the functions of GK, cGPDH, and mGPDH in HEK293 cells. Standard protocols were employed to assess enzyme activity, mRNA- and protein-expression, glucose uptake, and production. Homology modeling and molecular docking were employed to elucidate interactions of genistein and metformin with these enzymes. The secondary structures of GK, cGPDH and mGPDH and the thermal stability of cGPDH and mGPDH were analyzed by CD spectra. Genistein inhibited GK activity by 40%, while metformin decreased cGPDH and mGPDH activity by 58% and 55%, respectively, in HEK293 cells. Nonetheless, the expression levels of mRNA and protein remained unaltered. Genistein and metformin inhibited HEK293 glucose production by 0.46-fold and 0.63-fold, respectively. Genistein reduced glucose uptake by 0.26-fold, while metformin increased it by 0.51-fold. Genistein allosterically interacted with GK with a CDocker energy of -27.71, while metformin interacted with Gln295 and Lys296 of the catalytic loop of cGPDH and the FAD+ binding domain of mGPDH, yielding CDocker energies of -11.12 and -13.34, respectively. This study indicated the role of genistein and metformin on GK, cGPDH, and mGPDH in HEK293 cells.

Patients with type 2 diabetes mellitus (T2DM) predominantly experience mortality due to cardiovascular diseases (CVD), particularly in low- and middle-income nations. Among these, heart failure (HF) is the most severe cardiovascular complication in terms of prognosis and management. Despite advancements in individualized glycemic control and cardiovascular risk management, including the development of novel glucose- and lipid-lowering agents, the prevalence of HF in T2DM patients remains persistently high. This indicates that factors beyond hyperglycemia significantly contribute to the heightened risk of HF associated with T2DM. This review examines critical factors influencing CVD risk in T2DM, particularly the roles of reduced heart rate variability (HRV), a marker of autonomic dysfunction, and chronic inflammation, both of which play pivotal roles in HF pathogenesis. Recent evidence highlights the potential of vagus nerve activation to modulate these risk factors, underscoring its capacity to reduce T2DM-related cardiovascular complications. Specifically, we discuss the therapeutic promise of transcutaneous auricular vagus nerve stimulation (taVNS) as a non-invasive intervention to enhance vagal tone, decrease systemic inflammation, and improve cardiovascular outcomes in T2DM. By addressing the interplay among HRV, microvascular disease, and inflammation, this review provides a comprehensive perspective on the potential utility of taVNS in managing HF in T2DM.

Cardiovascular Autonomic Neuropathy (CAN) is one of the most devastating complications of Diabetes Mellitus (DM) and presents high morbidity and mortality. Its association with diabetic kidney disease (DKD) worsens the condition even further. CAN diagnosis remains a challenge and is being based on reflex tests which are laborious, risky and difficult to perform. Heart Rate Variability (HRV) tests has been suggested as having high utility in diagnosing CAN, but this issue remains controversial. The aim is to evaluate the sensitivity and specificity of HRV tests to diagnose CAN in patients with type 2 diabetes mellitus (T2DM) and DKD with severely increased albuminuria. This is a cross-sectional study in patients with T2DM and DKD with severely increased albuminuria. A total of 48 subjects were recruited and underwent laboratory and neuropathy assessment. The diagnosis of CAN was first confirmed in 75% (36/48) of patients based on cardiovascular autonomic reflex tests (CARTs). HRV tests (VLF, LF, TP and SDNN) differed between groups with and without CAN (212 vs. 522 ms2, p = 0.024; 57 vs. 332 ms2, p = 0.025; 359.5 vs. 2733 ms2, p = 0.007; 20 vs. 48 ms, p = 0.012), respectively. The best cut-off points based on ROC curve were < 1,117 ms2, < 152.5 ms2, < 1,891 ms2 and < 46.5 ms, respectively. VLF and TP reached highest sensitivity values (97% and 92%) and F1 Score of 90%, while LF had best specificity (75%) and TP had best accuracy (85%). Our best model of serial algorithm using VLF as first screening test and TP in sequency obtained a sensitivity of 97% and accuracy of 90%, reducing in 90% the need to perform CARTs. Our findings suggest that it is possible to achieve high sensitivity and accuracy using an algorithm with VLF and TP parameters analyzed in series. It could enable a simpler and early diagnosis, avoiding CARTs complications.