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Background: Specific ceramides have been identified as risk markers for cardiovascular disease (CVD) years before onset of disease. Treatment with the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide has been shown to induce beneficial changes in the lipid profile and reduce the risk of CVD. Reducing lipotoxic lipids with an antidiabetic drug therapy could be a path towards precision medicine approaches for the treatment of complications to diabetes. In this post-hoc study, an investigation was carried out on the effect of liraglutide on CVD-risk associated ceramides in two randomized clinical trials including participants with type 2 diabetes (T2D)., Methods: This study analyzed plasma samples from two independent randomized placebo-controlled clinical trials. The first trial, Antiproteinuric Effects of Liraglutide Treatment (LirAlbu12) followed a crossover design where 27 participants were treated for 12 weeks with either liraglutide (1.8 mg/d) or placebo, followed by a four-week washout period, and then another 12 weeks of the other treatment. The second clinical trial, Effect of Liraglutide on Vascular Inflammation in Type-2 Diabetes (LiraFlame26), lasted for 26 weeks and followed a parallel design, where 102 participants were randomized 1:1 to either liraglutide or placebo. Heresix prespecified plasma ceramides were measured using liquid chromatography mass spectrometry and assessed their changes using linear mixed models. Possible confounders were assessed with mediation analyses., Results: In the LiraFlame26 trial, 26-week treatment with liraglutide resulted in a significant reduction of two ceramides associated with CVD risk, C16 Cer and C24:1 Cer (p < 0.05) compared to placebo. None of the remaining ceramides showed statistically significant changes in response to liraglutide treatment compared to placebo. Significant changes in ceramides were not found after 12-weeks of liraglutide treatment in the LirAlbu12 trial. Mediation analyses showed that weight loss did not affect ceramide reduction., Conclusions: It was demonstrated that treatment with liraglutide resulted in a reduction in C16 Cer and C24:1 Cer after 26 weeks of treatment. These findings suggest the GLP-1RA can be used to modulate ceramides in addition to its other properties., Trial Registration: Clinicaltrial.gov identifier: NCT02545738 and NCT03449654., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Diabetic kidney disease is a major cause of morbidity and mortality. Dysregulated turnover of collagen type III is associated with development of kidney fibrosis. We investigated whether a degradation product of collagen type III (C3M) was a risk marker for progression of chronic kidney disease (CKD), occurrence of cardiovascular disease (CVD), and mortality during follow up in people with type 2 diabetes (T2D) and microalbuminuria. Moreover, we investigated whether C3M was correlated with markers of inflammation and endothelial dysfunction at baseline., Methods: C3M was measured in serum (sC3M) and urine (uC3M) in 200 participants with T2D and microalbuminuria included in an observational, prospective study at Steno Diabetes Center Copenhagen in Denmark from 2007-2008. Baseline measurements included 12 markers of inflammation and endothelial dysfunction. The endpoints were CVD, mortality, and CKD progression (>30% decline in eGFR)., Results: Mean (SD) age was 59 (9) years, eGFR 90 (17) ml/min/1.73m2 and median (IQR) urine albumin excretion rate 102 (39-229) mg/24-h. At baseline all markers for inflammation were positively correlated with sC3M (p≤0.034). Some, but not all, markers for endothelial dysfunction were correlated with C3M. Median follow-up ranged from 4.9 to 6.3 years. Higher sC3M was associated with CKD progression (with mortality as competing risk) with a hazard ratio (per doubling) of 2.98 (95% CI: 1.41-6.26; p = 0.004) adjusted for traditional risk factors. uC3M was not associated with CKD progression. Neither sC3M or uC3M were associated with risk of CVD or mortality., Conclusions: Higher sC3M was a risk factor for chronic kidney disease progression and was correlated with markers of inflammation., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: DGKR, SHN, FG, and MAK are employees of Nordic Bioscience. Nordic Bioscience is a privately owned, small- to medium-sized enterprise, partly focused on the development of biomarkers. None of the authors received fees, bonuses, or other benefits for the work regarding this article. DGKR, SHN, FG, and MAK holds stocks in Nordic Bioscience. The funder provided support in the form of salaries for DGKR and SHN but did not play any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Outside this work, BJvS is employed by Novo Nordisk, and PR has received institutional grants from Bayer, Novo Nordisk and AstraZeneca and has acted as consultant for Novo Nordisk, Bayer, Astellas, Boehringer Ingelheim, AstraZeneca, Gilead, Merk, Mundipharma, and Sanofi (honoraria to institution). MFM has received lecture fees from Novartis, Sanofi, Boehringer Ingelheim and Baxter. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Poulsen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: To assess cardiac angiogenesis in type 2 diabetes by positron emission tomography (PET) tracer [ 68 Ga]Ga-NODAGA-E[(cRGDyK)] 2 ( 68 Ga-RGD) imaging., Methods: Cross-sectional study including 20 persons with type 2 diabetes and 10 non-diabetic controls (CONs). Primary prespecified outcome was difference in cardiac angiogenesis (cardiac 68 Ga-RGD mean target-to-background ratio [TBR mean ]) between type 2 diabetes and CONs. Secondary outcome was to investigate associations between cardiac angiogenesis and kidney function and other risk factors., Results: Participants with type 2 diabetes had a mean ± SD age of 61 ± 9 years, 30% were women, median (IQR) diabetes duration of 11 (6-19) years and 3 (15%) had a history of cardiovascular disease. The CONs had comparable age and sex distribution to the participants with type 2 diabetes, and none had a history of coronary artery disease. Myocardial flow reserve was lower in type 2 diabetes (2.7 ± 0.6) compared with CONs (3.4 ± 1.2) ( p  = 0.03) and coronary artery calcium score was higher (562 [142-905] vs. 1 [0-150] p  = 0.04). Cardiac 68 Ga-RGD TBR mean was similar in participants with type 2 diabetes (0.89 ± 0.09) and CONs (0.89 ± 0.10) ( p  = 0.92). Cardiac 68 Ga-RGD TBR mean was not associated with estimated glomerular filtration rate, urine albumin creatinine ratio, cardiovascular disease, coronary artery calcium score or baroreflex sensitivity, neither in pooled analyses nor in type 2 diabetes., Conclusions: Cardiac angiogenesis, evaluated with 68 Ga-RGD PET, was similar in type 2 diabetes and CONs. Cardiac angiogenesis was not associated with kidney function or other risk markers in pooled analyses or in analyses restricted to type 2 diabetes., (© 2022 Diabetes UK.)

Introduction: Diabetes, chronic kidney disease (CKD) and cardiovascular disease (CVD) are cardiometabolic diseases that remain amongst the leading causes of morbidity and premature mortality. Here, we review the current understanding of how anti-inflammatory intervention via inhibition of the pro-inflammatory but pleiotropic cytokine interleukin (IL) 6 may benefit patients with these or related diseases or complications., Areas Covered: Based on a PubMed literature search, this review integrates and contextualizes evidence regarding the clinical utility of anti-IL-6 intervention in the treatment of cardiometabolic diseases, as well as of the associated condition nonalcoholic hepatosteatosis., Expert Opinion: Evidence implicates the pro-inflammatory effects of IL-6 in the pathophysiology of diabetes, CKD and CVD. Thus, targeting the IL-6 pathway holds a therapeutic potential in these cardiometabolic disorders. However, because IL-6 has multiple homeostatic roles, antagonizing this cytokine may be associated with side effects, such as increased risk of infection as seen with other anti-inflammatory drugs. Additional studies are required to establish the benefit-risk profile of anti-IL-6 intervention in the cardiometabolic diseases, whilst also considering alternative interventions such as lifestyle changes. IL-6 is also elevated in NASH, but the clinical usefulness of targeting IL-6 in this hepatic disorder remains largely unexplored.

Aims: To investigate to what extent multiple risk marker improvements confer lower risk of cardiovascular and kidney complications in a contemporary type 2 diabetes population., Materials and Methods: Post-hoc analysis of the LEADER (n = 8638; median follow-up 3.8 years) and SUSTAIN 6 (n = 3040; median follow-up 2.1 years) cardiovascular outcome trials. Participants were those with baseline and year-1 assessment of at least one of the parameters of interest; we pooled the liraglutide-/semaglutide- and placebo-treated groups and categorized them by number of risk markers with clinically relevant improvements after 1 year of study participation. We investigated risk of major adverse cardiovascular events (MACE), expanded MACE, cardiovascular death and nephropathy. Predefined clinically relevant changes: body weight loss ≥5%; reductions in: glycated haemoglobin ≥1%, systolic blood pressure ≥5 mmHg and low-density lipoprotein cholesterol ≥0.5 mmol/L; estimated glomerular filtration rate change ≥0 ml/min/1.73 m 2 and urinary albumin-to-creatinine ratio change ≥30% of baseline value. Cox regression analysed risk of outcomes adjusted for baseline risk marker levels and treatment group and stratified by trial., Results: Participants with two, three, or four or more improved risk markers versus participants with no risk marker improvement had reduced risk of expanded MACE [hazard ratio (95% confidence interval) 0.80 (0.67-0.96); 0.80 (0.66-0.97); 0.82 (0.66-1.02)], cardiovascular death [0.66 (0.45-0.96), 0.67 (0.45-0.99), 0.60 (0.38-0.94)] and nephropathy [0.71 (0.52-0.97), 0.48 (0.34-0.68), 0.43 (0.29-0.65)]., Conclusions: In persons with type 2 diabetes, improvements in ≥2 risk markers conferred cardiovascular risk reduction versus none or one improved risk marker. The nephropathy risk decreased with improvement in more risk markers. These findings stress the importance of multifactorial interventions targeting all risk markers., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: The trimethylamine N-oxide (TMAO) pathway is related to intestinal microbiota and has been associated to risk of cardiovascular disease (CVD). We investigated associations between four plasma metabolites in the TMAO pathway and risk of all-cause mortality, CVD and deterioration in renal function in individuals with type 2-diabetes (T2D) and albuminuria., Materials and Methods: Plasma concentrations of TMAO, choline, carnitine, and betaine were measured by liquid chromatography-tandem mass spectrometry at baseline in 311 individuals with T2D and albuminuria. Information on all-cause mortality and fatal/non-fatal CVD during follow-up was obtained from registries. The association of each metabolite, and a weighted sum score of all four metabolites, with the endpoints were examined. Serum creatinine was measured at follow-up visits and the renal endpoint was defined as eGFR-decline of ≥30%. Associations were analysed using proportional hazards models adjusted for traditional risk factors., Results: Baseline mean(SD) age was 57.2(8.2) years and 75% were males. Follow-up was up to 21.9 years (median (IQR) follow-up 6.8 (6.1-15.5) years for mortality and 6.5 (5.5-8.1) years for CVD events). The individual metabolites and the weighted sum score were not associated with all-cause mortality (n = 106) or CVD (n = 116) (adjusted p≥0.09). Higher choline, carnitine and the weighted sum score of the four metabolites were associated with higher risk of decline in eGFR (n = 106) (adjusted p = 0.001, p = 0.03 and p<0.001, respectively)., Conclusions: In individuals with T2D and albuminuria, higher choline, carnitine and a weighted sum of four metabolites from the TMAO pathway were risk markers for deterioration in renal function during long-term follow-up. Metabolites from the TMAO pathway were not independently related to risk of all-cause mortality or CVD., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: PR reports having given lectures for Astra Zeneca, Bayer, Novo Nordisk and Boehringer Ingelheim, and has served as a consultant for AbbVie, Astra Zeneca, Bayer, Eli Lilly, Boehringer Ingelheim, Astellas, Gilead, Mundipharma, Vifor, and Novo Nordisk, all fees given to Steno Diabetes Center Copenhagen. SAW, TWH, BJvS, TSA and PR own stocks in Novo Nordisk A/S and TSA in Zealand Pharma A/S. Z.W. and S.L.H. are named as coinventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics, and have the right to receive royalty payment for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland Heart Lab, Quest Diagnostics and Proctor & Gamble. S.L.H. also reports having been paid as a consultant from Proctor & Gamble, and having received research funds from Proctor & Gamble and Roche. Novo Nordisk A/S provided support in the form of salaries for authors SAW, JO and BJvS. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors report no conflicts of interest.

Epicardial adipose tissue (EAT) and pericardial adipose tissue (PAT) are metabolically active fat depots implicated in cardiovascular disease, and EAT has potential as a novel cardiac risk factor, suitable as a target for interventions. The objective of this systematic review and meta-analysis was to investigate the evidence whether EAT and PAT volume can be reduced by weight-loss interventions (exercise, diet, bariatric surgery or pharmaceutical interventions). A systematic literature search identified 34 studies that were included in the qualitative synthesis (exercise, n = 10, diet, n = 5, bariatric surgery, n = 9 and pharmaceutical interventions, n = 10). Of the 34 studies, 10 reported sufficient data to be included in the meta-analysis. The meta-analysis was only conducted for changes in EAT volume, since only few controlled studies reported changes in PAT (n = 3) or total cardiac adipose tissue volume (n = 1). A significant pooled effect size (ES) for reduction in EAT volume was observed following weight-loss interventions as compared with control interventions (ES = -0.89, 95% CI: -1.23 to -0.55, P < 0.001). When comparing the effect of exercise training versus control on EAT volume reduction, there was a significant pooled ES favouring exercise training (ES: -1.11, 95% CI: -1.57 to -0.65, P < 0.001). Similarly, the ES of pharmaceutical versus control interventions on EAT volume reduction was significant, favouring pharmaceutical interventions (ES: -0.79, 95% CI: -1.37 to -0.21, P < 0.0072). In conclusion, this systematic review and meta-analysis provides evidence that exercise, diet, bariatric surgery and pharmaceutical interventions can reduce cardiac adipose tissue volume., (©2020 World Obesity Federation.)

Aims: Lipoprotein(a)(Lp(a)) has emerged as an independent risk marker for cardiovascular disease (CVD) in the general population and among persons with existing CVD. We investigated associations between serum Lp(a)concentrations and renal function decline, incident CVD and all-cause mortality in individuals with type 2 diabetes (T2D) and microalbuminuria., Methods: Prospective study including 198 individuals with T2D, microalbuminuria and no CVD. Yearly p-creatinine was measured after baseline in 176 of the participants. The renal endpoint was defined as decline in eGFR of >30% from baseline. CVD events and mortality were tracked from national registries. Cox regression analyses were applied both unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDL-cholesterol, smoking, HbA 1c , creatinine and urinary albumin creatinine ratio (UAER))., Results: Baseline mean (SD) age was 59 (9)years, eGFR 89 (17) mL/min/1.73 m 2 , 77% were male, and median [IQR] UAER was 103 [38-242] mg/24-h. Median Lp(a)was 8.04 [3.42-32.3] mg/dL. Median follow-up was 6.1 years; 38 CVD events, 26 deaths and 43 renal events were recorded. For each doubling of baseline Lp(a), the following hazard ratios (95% confidence intervals) were found before and after adjustment respectively: 0.98 (0.84-1.15) and 1.01 (0.87-1.18) for decline in eGFR > 30%, 0.96 (0.81-1.13) and 0.99 (0.82-1.18) for CVD events, 1.04 (0.85-1.27) and 1.06 (0.87-1.30) for all-cause mortality., Conclusions: In this cohort of individuals with T2D and microalbuminuria, the baseline concentration of Lp(a)was not a risk marker for renal function decline, CVD events or all-cause mortality., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Cardiac fat is a cardiovascular biomarker but its importance in patients with type 2 diabetes is not clear. The aim was to evaluate the predictive potential of epicardial (EAT), pericardial (PAT) and total cardiac (CAT) fat in type 2 diabetes and elucidate sex differences., Methods: EAT and PAT were measured by echocardiography in 1030 patients with type 2 diabetes. Follow-up was performed through national registries. The end-point was the composite of incident cardiovascular disease (CVD) and all-cause mortality. Analyses were unadjusted (model 1), adjusted for age and sex (model 2), plus systolic blood pressure, body mass index (BMI), low-density lipoprotein (LDL), smoking, diabetes duration and glycated hemoglobin (HbA 1c ) (model 3)., Results: Median follow-up was 4.7 years and 248 patients (191 men vs. 57 women) experienced the composite end-point. Patients with high EAT (> median level) had increased risk of the composite end-point in model 1 [Hazard ratio (HR): 1.46 (1.13; 1.88), p = 0.004], model 2 [HR: 1.31 (1.01; 1.69), p = 0.038], and borderline in model 3 [HR: 1.32 (0.99; 1.77), p = 0.058]. For men, but not women, high EAT was associated with a 41% increased risk of CVD and mortality in model 3 (p = 0.041). Net reclassification index improved when high EAT was added to model 3 (19.6%, p = 0.035). PAT or CAT were not associated with the end-point., Conclusion: High levels of EAT were associated with the composite of incident CVD and mortality in patients with type 2 diabetes, particularly in men, after adjusting for CVD risk factors. EAT modestly improved risk prediction over CVD risk factors.

Aims/hypothesis: The study aimed to evaluate toe-brachial index (TBI) and ankle-brachial index (ABI) as determinants of incident cardiovascular disease (CVD) and all-cause mortality in people with type 2 diabetes and microalbuminuria., Methods: This was a prospective study including 200 participants. Unadjusted and adjusted (traditional risk factors and additional inclusion of N-terminal pro-brain natriuretic peptide [NT-proBNP] and coronary artery calcification) Cox regression models were performed. C statistics and relative integrated discrimination improvement (rIDI) evaluated risk prediction improvement., Results: Median follow-up was 6.1 years; 40 CVD events and 26 deaths were recorded. Lower TBI was associated with increased risk of CVD (HR per 1 SD decrease: 1.55 [95% CI 1.38, 1.68]) and all-cause mortality (1.41 [1.22, 1.60]) unadjusted and after adjustment for traditional risk factors (CVD 1.50 [1.27, 1.65] and all-cause mortality 1.37 [1.01, 1.60]). Lower ABI was a determinant of CVD (1.49 [1.32, 1.61]) and all-cause mortality (1.37 [1.09, 1.57]) unadjusted and after adjustment for traditional risk factors (CVD 1.44 [1.23, 1.59] and all-cause mortality 1.39 [1.07, 1.60]). After additional adjustment for NT-proBNP and coronary artery calcification, lower TBI remained a determinant of CVD (p = 0.023). When TBI was added to traditional risk factors, the AUC increased significantly for CVD, by 0.063 (95% CI 0.012, 0.115) from 0.743 (p = 0.016), but not for all-cause mortality; adding ABI did not improve the AUC significantly. The rIDI for TBI was 46.7% (p < 0.001) for CVD and 46.0% (p = 0.002) for all-cause mortality; for ABI, the rIDI was 51.8% (p = 0.004) for CVD and 53.6% (p = 0.031) for all-cause mortality., Conclusions/interpretation: Reduced TBI and ABI were associated with increased risk of CVD and all-cause mortality, independent of traditional risk factors in type 2 diabetes, and improved prognostic accuracy.

Background: To evaluate symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) as risk markers of cardiovascular disease, all-cause mortality and deterioration in renal function in a well characterised type 2 diabetic population with microalbuminuria and without symptoms of coronary artery disease., Methods: 200 participants followed for 6.1 years. SDMA and ADMA were measured at baseline. Endpoints included (1) composite cardiovascular endpoint (n = 40); (2) all-cause mortality (n = 26); and (3) decline in eGFR of >30% (n = 42). Cox models were unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDL-cholesterol, smoking, HbA 1c , creatinine and urinary albumin excretion rate). To assess if SDMA or ADMA improved risk prediction beyond traditional risk factors we calculated c statistics and relative integrated discrimination improvement (rIDI). C statistic (area under the curve) quantifies the model's improved ability to discriminate events from non-events. rIDI quantifies the increase in separation of events and non-events on a relative scale., Results: Higher SDMA was associated with increased risk of all three endpoints (unadjusted: p ≤ 0.001; adjusted: p ≤ 0.02). Higher ADMA was associated with all-cause mortality (unadjusted: p = 0.002; adjusted: p = 0.006), but not cardiovascular disease or decline in eGFR (p ≥ 0.29).The c statistic was not significant for any of the endpoints for either SDMA or ADMA (p ≥ 0.10). The rIDI for SDMA was 15.0% (p = 0.081) for the cardiovascular endpoint, 52.5% (p = 0.025) for all-cause mortality and 48.8% (p = 0.007) for decline in eGFR; for ADMA the rIDI was 49.1% (p = 0.017) for all-cause mortality., Conclusion: In persons with type 2 diabetes and microalbuminuria higher SDMA was associated with incident cardiovascular disease, all-cause mortality and deterioration in renal function. Higher ADMA was associated with all-cause mortality. SDMA and ADMA significantly improved risk prediction for all-cause mortality, and SDMA for deterioration in renal function beyond traditional risk factors.

We assessed the effects of liraglutide treatment on five cardiovascular risk biomarkers, reflecting different pathophysiology: tumour necrosis factor (TNF)-α; soluble urokinase plasminogen activator receptor (suPAR); mid-regional pro-adrenomedullin (MR-proADM); mid-regional pro-atrial natriuretic peptide (MR-proANP); and copeptin, in people with type 2 diabetes with albuminuria. In a randomized, double-blind, placebo-controlled, crossover trial we enrolled people with type 2 diabetes and persistent albuminuria (urinary albumin-to-creatinine ratio [UACR] >30 mg/g) and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m 2 . Participants received liraglutide (1.8 mg/d) and matched placebo for 12 weeks, in random order. The primary endpoint was change in albuminuria; this was a prespecified sub-study. A total of 32 participants were randomized, of whom 27 completed the study. TNF-α level was 12% (95% confidence interval [CI] 3; 20) lower after liraglutide treatment compared with placebo (P = .012); MR-proADM level was 4% (95% CI 0; 8) lower after liraglutide treatment compared with placebo (P = .038), and MR-proANP level was 13% (95% CI 4; 21) lower after liraglutide treatment compared with placebo (P = .006). In the present study, we showed anti-inflammatory effects of liraglutide treatment, reflected in reductions in levels of TNF-α and MR-proADM, while the reduction in MR-proANP levels may represent a clinically relevant benefit with regard to heart failure., (© 2017 John Wiley & Sons Ltd.)

Aims/hypothesis: We evaluated two urinary biomarkers reflecting different aspects of renal pathophysiology as potential determinants of incident cardiovascular disease (CVD), all-cause mortality and a reduced estimated GFR (eGFR) in patients with type 2 diabetes and microalbuminuria but without clinical features of coronary artery disease., Methods: In a prospective study of 200 patients, all received multifactorial treatment. Baseline measurements of urinary hepatocyte growth factor (HGF) and adiponectin were available for 191 patients. Cox models were adjusted for sex, age, LDL-cholesterol, smoking, HbA1c, plasma creatinine, systolic BP and urinary AER (UAER). The pre-defined endpoint of chronic kidney disease progression was a decline in the eGFR of >30% during follow-up. HRs per 1 SD increment of log-transformed values are presented., Results: Patients had a mean ± SD age of 59 ± 9 years with a median (interquartile range) UAER of 103 (39-230) mg/24 h. During a median 6.1 years of follow-up, there were 40 incident CVD events, 26 deaths and 42 patients reached the pre-defined chronic kidney disease progression endpoint after 4.9 years (median). Higher urinary HGF was a determinant of CVD in unadjusted (HR 1.9 [95% CI 1.3, 2.8], p = 0.001) and adjusted (HR 2.0 [95% CI 1.2, 3.2], p = 0.004) models, and of all-cause mortality in unadjusted (HR 2.3 [95% CI 1.3, 3.9], p = 0.003) and adjusted (HR 2.5 [95% CI 1.3, 4.8], p = 0.005) models. A higher adiponectin level was associated with CVD in unadjusted (HR 1.4 [95% CI 1.0, 1.9], p = 0.04) and adjusted (HR 1.4 [95% CI 1.1, 2.3], p = 0.013) models, and with a decline in the eGFR of >30% in unadjusted (HR 1.6 [95% CI 1.2, 2.2], p = 0.008) and adjusted (HR 1.5 [95% CI 1.1, 2.2], p = 0.007) models., Conclusions/interpretation: In patients with type 2 diabetes and microalbuminuria receiving multifactorial treatment, higher urinary HGF was associated with incident CVD and all-cause mortality, and higher adiponectin was associated with CVD and deterioration in renal function.

Background: We evaluated markers of inflammation and endothelial dysfunction and their associations with incident cardiovascular disease (CVD), all-cause mortality and progression of coronary artery calcium (CAC) in patients with type 2 diabetes (T2D) and microalbuminuria but without known coronary artery disease (CAD)., Methods: Prospective study including 200 patients receiving multifactorial treatment. Markers of inflammation (TNF-ɑ, sICAM-1, sICAM-3, hsCRP, SAA, IL-1β, IL-6, IL-8) and endothelial dysfunction (thrombomodulin, sVCAM-1, sICAM-1, sICAM-3, sE-selectin, sP-selectin) were measured at baseline. Adjustment included traditional CVD risk factors, and full adjustment additionally NT-proBNP and CAC. The "SQRT method" assessed CAC progression after 5.8years, and cut-point was an annualised difference >2.5., Results: Occurrence of CVD (n=40) and all-cause mortality (n=26) was traced after 6.1years. In adjusted and fully adjusted Cox models, TNF-ɑ was a determinant of CVD and all-cause mortality (p≤0.007). Further, in adjusted and fully adjusted logistic regression, TNF-ɑ was related to CAC progression (p≤0.042). Of the other biomarkers, sICAM-3 and thrombomodulin were also associated with both endpoints (p≤0.046), IL-1β with CVD endpoints (p=0.021), and sVCAM-1 and sICAM-1 with all-cause mortality (p≤0.005). Higher composite z-scores including all markers of inflammation and endothelial dysfunction were associated with CVD and all-cause mortality (p≤0.008)., Conclusions: In patients with T2D and microalbuminuria without known CAD and receiving multifactorial treatment, biomarkers of inflammation and endothelial dysfunction were independently associated with CVD, all-cause mortality and CAC progression. Especially TNF-ɑ was a robust determinant, even after adjusting for NT-proBNP and CAC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: In patients with type 2 diabetes, cardiovascular disease (CVD) is the major cause of morbidity and mortality. We evaluated the combination of NT-proBNP and coronary artery calcium score (CAC) for prediction of combined fatal and non-fatal CVD and mortality in patients with type 2 diabetes and microalbuminuria (>30 mg/24-h), but without known coronary artery disease. Moreover, we assessed the predictive value of a predefined categorisation of patients into a high- and low-risk group at baseline., Methods: Prospective study including 200 patients. All received intensive multifactorial treatment. Patients with baseline NT-proBNP > 45.2 ng/L and/or CAC ≥ 400 were stratified as high-risk patients (n = 133). Occurrence of fatal- and nonfatal CVD (n = 40) and mortality (n = 26), was traced after 6.1 years (median)., Results: High-risk patients had a higher risk of the composite CVD endpoint (adjusted hazard ratio [HR] 10.6 (95 % confidence interval [CI] 2.4-46.3); p = 0.002) and mortality (adjusted HR 5.3 (95 % CI 1.2-24.0); p = 0.032) compared to low-risk patients. In adjusted continuous analysis, both higher NT-proBNP and CAC were strong predictors of the composite CVD endpoint and mortality (p ≤ 0.0001). In fully adjusted models mutually including NT-proBNP and CAC, both risk factors remained associated with risk of CVD and mortality (p ≤ 0.022). There was no interaction between NT-proBNP and CAC for the examined endpoints (p ≥ 0.31)., Conclusions: In patients with type 2 diabetes and microalbuminuria but without known coronary artery disease, NT-proBNP and CAC were strongly associated with fatal and nonfatal CVD, as well as with mortality. Their additive prognostic capability holds promise for identification of patients at high risk.

To help ensure an expanded healthy lifespan for as many people as possible worldwide, there is a need to prevent or manage a number of prevalent chronic diseases directly and indirectly closely related to aging, including diabetes and obesity. Glucagon‐like peptide 1 receptor agonists (GLP‐1 RAs) have proven beneficial in type 2 diabetes, are amongst the few medicines approved for weight management, and are also licensed for focused cardiovascular risk reduction. In addition, strong evidence suggests several other beneficial effects of the pleiotropic peptide hormone, including anti‐inflammation. Consequently, GLP‐1 RAs are now in advanced clinical development for the treatment of chronic kidney disease, broader cardiovascular risk reduction, metabolic liver disease and Alzheimer's disease. In sum, GLP‐1 RAs are positioned as one of the pharmacotherapeutic options that can contribute to addressing the high unmet medical need characterising several prevalent aging‐related diseases, potentially helping more people enjoy a prolonged healthy lifespan. [ABSTRACT FROM AUTHOR]

Aims: To assess cardiac angiogenesis in type 2 diabetes by positron emission tomography (PET) tracer [68Ga]Ga‐NODAGA‐E[(cRGDyK)]2 (68Ga‐RGD) imaging. Methods: Cross‐sectional study including 20 persons with type 2 diabetes and 10 non‐diabetic controls (CONs). Primary prespecified outcome was difference in cardiac angiogenesis (cardiac 68Ga‐RGD mean target‐to‐background ratio [TBRmean]) between type 2 diabetes and CONs. Secondary outcome was to investigate associations between cardiac angiogenesis and kidney function and other risk factors. Results: Participants with type 2 diabetes had a mean ± SD age of 61 ± 9 years, 30% were women, median (IQR) diabetes duration of 11 (6–19) years and 3 (15%) had a history of cardiovascular disease. The CONs had comparable age and sex distribution to the participants with type 2 diabetes, and none had a history of coronary artery disease. Myocardial flow reserve was lower in type 2 diabetes (2.7 ± 0.6) compared with CONs (3.4 ± 1.2) (p = 0.03) and coronary artery calcium score was higher (562 [142–905] vs. 1 [0–150] p = 0.04). Cardiac 68Ga‐RGD TBRmean was similar in participants with type 2 diabetes (0.89 ± 0.09) and CONs (0.89 ± 0.10) (p = 0.92). Cardiac 68Ga‐RGD TBRmean was not associated with estimated glomerular filtration rate, urine albumin creatinine ratio, cardiovascular disease, coronary artery calcium score or baroreflex sensitivity, neither in pooled analyses nor in type 2 diabetes. Conclusions: Cardiac angiogenesis, evaluated with 68Ga‐RGD PET, was similar in type 2 diabetes and CONs. Cardiac angiogenesis was not associated with kidney function or other risk markers in pooled analyses or in analyses restricted to type 2 diabetes. [ABSTRACT FROM AUTHOR]

Heart failure (HF) remains one of the cardiovascular diseases (CVDs) associated with a high unmet medical need due to high morbidity and mortality rates and lack of efficacious interventions. HF is closely related to cardiometabolic diseases such as diabetes, obesity and chronic kidney disease, and strategies that address most or all these intertwined conditions are desirable. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are approved for type 2 diabetes (T2D), and some are also indicated for reduction of the risk of atherosclerotic CVD in T2D and for weight management. As we summarise in this concise review, preliminary evidence suggests that the cardioprotective benefits of GLP-1 RAs may also extend to HF. The most robust clinical evidence arguably originates from the large cardiovascular outcomes trials (CVOTs) completed for most GLP-1 RAs, of which the latest showed a significant relative risk reduction (RRR) of 39% (HR) with once-weekly efpeglenatide on HF requiring hospitalisation, corroborating a meta-analysis which found a significant RRR across eight GLP-1 RA CVOTs of 11%. Further, although incompletely described, multiple studies are available to provide insights into the mechanistic underpinnings, which appear to be associated mostly with indirect cardioprotective benefits owing to the ability of GLP-1 RAs to address hyperglycaemia, and reduce body weight, and, amongst others, inflammation. In sum, current evidence positions GLP-1 RAs as a potential cardioprotective strategy in HF, with HF with preserved ejection fraction emerging as the clinically most relevant phenotype for the drug class, especially when occurring in people with obesity with and without diabetes. [ABSTRACT FROM AUTHOR]

Objective: A post hoc analysis to investigate the association between 1-year changes in albuminuria and subsequent risk of cardiovascular and renal events.Research Design and Methods: LEADER was a randomized trial of liraglutide up to 1.8 mg/day versus placebo added to standard care for 3.5-5 years in 9,340 participants with type 2 diabetes and high cardiovascular risk. We calculated change in urinary albumin-to-creatinine ratio (UACR) from baseline to 1 year in participants with >30% reduction (n = 2,928), 30-0% reduction (n = 1,218), or any increase in UACR (n = 4,124), irrespective of treatment. Using Cox regression, risks of major adverse cardiovascular events (MACE) and a composite nephropathy outcome (from 1 year to end of trial in subgroups by baseline UACR [<30 mg/g, 30-300 mg/g, or ≥300 mg/g]) were assessed. The analysis was adjusted for treatment allocation alone as a fixed factor and for baseline variables associated with cardiovascular and renal outcomes.Results: For MACE, hazard ratios (HRs) for those with >30% and 30-0% UACR reduction were 0.82 (95% CI 0.71, 0.94; P = 0.006) and 0.99 (0.82, 1.19; P = 0.912), respectively, compared with any increase in UACR (reference). For the composite nephropathy outcome, respective HRs were 0.67 (0.49, 0.93; P = 0.02) and 0.97 (0.66, 1.43; P = 0.881). Results were independent of baseline UACR and consistent in both treatment groups. After adjustment, HRs were significant and consistent in >30% reduction subgroups with baseline micro- or macroalbuminuria.Conclusions: A reduction in albuminuria during the 1st year was associated with fewer cardiovascular and renal outcomes, independent of treatment. Albuminuria monitoring remains an important part of diabetes care, with great unused potential. [ABSTRACT FROM AUTHOR]

Objectives: Two biomarkers, growth differentiation factor 15 (GDF-15) and fibroblast growth factor 23 (FGF-23)), reflecting different aspects of renal pathophysiology, were evaluated as determinants of decline in estimated glomerular filtration rate (eGFR), incident cardiovascular disease (CVD) and all-cause mortality in patients with type 2 diabetes (T2D) and microalbuminuria, but without clinical cardiac disease. Materials and methods: Prospective study including 200 T2D patients. The predefined endpoint of chronic kidney disease (CKD) progression: A decline in eGFR of >30% at any time point during follow-up. Hazard ratios (HR) are provided per 1 SD increment of log2-transformed values. Results: Mean (± SD) age was 59 ± 9 years, eGFR 91.1 ± 18.3 ml/min/1.73m2 and median (IQR) UAER 103 (39–230) mg/24-h. During a median 6.1 years follow-up, 40 incident CVD events, 26 deaths and 42 patients reached the CKD endpoint after median 4.9 years. Higher GDF-15 was a determinant of decline in eGFR >30% and all-cause mortality in adjusted models (HR 1.7 (1.1–2.5); p = 0.018 and HR 1.9 (1.2–2.9); p = 0.003, respectively). Adding GDF-15 to traditional risk factors improved risk prediction of decline in renal function (relative integrated discrimination improvement (rIDI) = 30%; p = 0.037). Higher FGF-23 was associated with all-cause mortality in adjusted models (HR 1.6 (1.1–2.2); p = 0.011) with a rIDI of 30% (p = 0.024). Conclusions: In patients with T2D and microalbuminuria, higher GDF-15 and FGF-23 were independently associated with all-cause mortality and higher GDF-15 improved risk prediction of decline in kidney function and higher FGF-23 of all-cause mortality, beyond traditional risk factors, but not independently of GDF-15. [ABSTRACT FROM AUTHOR]

Background: LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of CV Outcome Results) results demonstrated cardiovascular benefits for patients with type 2 diabetes mellitus at high cardiovascular risk on standard of care randomized to liraglutide versus placebo. The effect of glucagon-like peptide-1 receptor agonist liraglutide on cardiovascular events and all-cause mortality in patients with type 2 diabetes mellitus and chronic kidney disease is unknown. Liraglutide's treatment effects in patients with and without kidney disease were analyzed post hoc.Methods: Patients were randomized (1:1) to liraglutide or placebo, both in addition to standard of care. These analyses assessed outcomes stratified by baseline estimated glomerular filtration rate (eGFR; <60 versus ≥60 mL/min/1.73 m2) and baseline albuminuria. The primary outcome (composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and secondary outcomes, including all-cause mortality and individual components of the primary composite outcome, were analyzed using Cox regression.Results: Overall, 2158 and 7182 patients had baseline eGFR <60 or ≥60 mL/min/1.73 m2, respectively. In patients with eGFR <60 mL/min/1.73 m2, risk reduction for the primary composite cardiovascular outcome with liraglutide was greater (hazard ratio [HR], 0.69; 95% CI, 0.57-0.85) versus those with eGFR ≥60 mL/min/1.73 m2 (HR, 0.94; 95% CI, 0.83-1.07; interaction P=0.01). There was no consistent effect modification with liraglutide across finer eGFR subgroups (interaction P=0.13) and when analyzing eGFR as a continuous variable (interaction P=0.61). Risk reductions in those with eGFR <60 versus ≥60 mL/min/1.73 m2 were as follows: for nonfatal myocardial infarction, HR, 0.74; 95% CI, 0.55-0.99 versus HR, 0.93; 95% CI, 0.77-1.13; for nonfatal stroke, HR, 0.51; 95% CI, 0.33-0.80 versus HR, 1.07; 95% CI, 0.84-1.37; for cardiovascular death, HR, 0.67; 95% CI, 0.50-0.90 versus HR, 0.84; 95% CI, 0.67-1.05; for all-cause mortality, HR, 0.74; 95% CI, 0.60-0.92 versus HR, 0.90; 95% CI, 0.75-1.07. Risk reduction for the primary composite cardiovascular outcome was not different for those with versus without baseline albuminuria (HR, 0.83; 95% CI, 0.71-0.97; and HR, 0.92; 95% CI, 0.79-1.07, respectively; interaction P=0.36).Conclusions: Liraglutide added to standard of care reduced the risk for major cardiovascular events and all-cause mortality in patients with type 2 diabetes mellitus and chronic kidney disease. These results appear to apply across the chronic kidney disease spectrum enrolled.Clinical Trial Registration: URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT01179048. [ABSTRACT FROM AUTHOR]