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Introduction: The cumulative impact of metabolic syndrome (MetS) components on micro‐ and macrovascular disease in metabolic dysfunction‐associated steatotic liver disease (MASLD) is unclear. We aimed to determine whether the number of the MetS components increases the risk of micro‐ and macrovascular disease in patients with MASLD. Methods: We performed a retrospective cohort study of electronic medical records using the TriNetX network, a global federated database. The exposure arm was patients with hepatic steatosis (defined via International Classification of Diseases, 10th Revision coding, or modified hepatic steatosis index), and ≥1 MetS components (obesity/central adiposity, insulin resistance, hypertension, or dyslipidaemia), compared with a reference arm of adults without any MetS components or hepatic steatosis. Our propensity score matched (1:1) for confounders with 5 years of follow‐up. Primary outcomes included microvascular (peripheral neuropathy, retinopathy, and nephropathy) and macrovascular (cardiovascular events, cerebrovascular accidents, and peripheral vascular disease) disease. Secondary analyses assessed the impact of additional MetS components on these outcomes, as well as the impact of sex. Results: MASLD, defined by hepatic steatosis and insulin resistance (n = 15 937), carried the highest risk of microvascular disease (HR 13.93 (95% CI 8.55–22.68)), whilst MASLD, defined by hepatic steatosis and hypertension (n = 53 028), carried the highest risk of macrovascular disease (7.23 (6.45–8.13)). MASLD with all MetS components carried greatest risk of both micro‐ (31.20 (28.88–33.70) (n = 462 789)) and macrovascular (8.04 (7.33–8.82) (n = 336 010)) disease. Conclusion: We demonstrate a differential effect of MetS components on micro‐ and macrovascular disease risk in patients with MASLD, with a cumulative impact of multiple MetS on overall risk. The impact of MetS components was most pronounced in women. Aggressive metabolic risk factor management is critical for prevention of micro‐ and macrovascular complications. [ABSTRACT FROM AUTHOR]

Background: The Steno Type 1 Risk Engine (ST1RE) was developed to aid clinical decisions in primary prevention for individuals with type 1 diabetes (T1D), as existing cardiovascular (CV) risk models for the general population and type 2 diabetes tend to underestimate CV risk in T1D. However, the applicability of ST1RE in different populations remains uncertain, as prediction models developed for one population may not accurately estimate risk in another. This study aimed to evaluate the performance of the ST1RE in predicting CV events among ethnically mixed T1D individuals and its association with the progression of microangiopathy complications. Methods: A retrospective survey of 435 adults with T1D who were free of CV events at baseline was assessed by ST1RE and chronic diabetes complications at 5 and 10 years of follow-up. The estimated CV risk rates were compared with the observed rates at 5 and 10 years using statistical analyses, including Receiver Operating Characteristic (ROC) curve analysis, Hosmer-Lemeshow test, Kaplan-Meier curves analysis and Cox-regression models. Results: Among 435 patients (aged 25 years; interquartile range [IQR]: 21–32) with a median T1D duration of 13 years (IQR: 9–18), only 5% were categorized into the high ST1RE group. Within a median follow-up of 9.2 years (IQR 6.0-10.7), 5.5% of patients experienced a CV event (1.6%, 14.9%, and 50% from the low, moderate, and high-risk groups, respectively). The hazard ratios (HRs) for CV events were greater in the high-risk group (HR 52.02; 95% CI 18.60–145.51, p < 0.001) and in the moderate-risk group (HR 8.66; 95% CI 2.90–25.80, p < 0.001) compared to the low-risk group. The ST1RE estimated CV events were similar to the observed at 5 years (3.4% vs. 3.5%; χ2 = 10.12, p = 0.899) and 10 years (6.8% vs. 9.9%; χ2 = 14.80, p = 0.676) of follow-up. The progression of microangiopathies was greater in the high vs. low for retinopathy (p = 0.008), diabetic kidney disease (p < 0.001), peripheral neuropathy (p = 0.021), and autonomic neuropathy (p = 0.008). Conclusions: ST1RE performed well in predicting CV events at 5 and 10 years of follow-up. Moreover, higher ST1RE scores were associated with the progression of microangiopathy complications in this genetically heterogeneous T1D population. [ABSTRACT FROM AUTHOR]

Evidence‐based guidelines provide the premise for the delivery of quality care to preserve health and prevent disabilities and premature death. The systematic gathering of observational, mechanistic and experimental data contributes to the hierarchy of evidence used to guide clinical practice. In the field of diabetes, metformin was discovered more than 100 years ago, and with 60 years of clinical use, it has stood the test of time regarding its value in the prevention and management of type 2 diabetes. Although some guidelines have challenged the role of metformin as the first‐line glucose‐lowering drug, it is important to point out that the cardiovascular‐renal protective effects of sodium‐glucose co‐transporter‐2 inhibitors and glucagon‐like peptide‐1 receptor agonists were gathered from patients with type 2 diabetes, the majority of whom were treated with metformin. Most national, regional and international guidelines recommend metformin as a foundation therapy with emphasis on avoidance of therapeutic inertia and early attainment of multiple treatment goals. Moreover, real‐world evidence has confirmed the glucose‐lowering and cardiovascular‐renal benefits of metformin accompanied by an extremely low risk of lactic acidosis. In patients with type 2 diabetes and advanced chronic kidney disease (estimated glomerular filtration rate 15‐30 mL/min/1.73m2), metformin discontinuation was associated with an increased risk of cardiovascular‐renal events compared with metformin persistence. Meanwhile, it is understood that microbiota, nutrients and metformin can interact through the gut‐brain‐kidney axis to modulate homeostasis of bioactive molecules, systemic inflammation and energy metabolism. While these biological changes contribute to the multisystem effects of metformin, they may also explain the gastrointestinal side effects and vitamin B12 deficiency associated with metformin intolerance. By understanding the interactions between metformin, foods and microbiota, healthcare professionals are in a better position to optimize the use of metformin and mitigate potential side effects. The United Kingdom Prospective Diabetes Study and the Da Qing Diabetes Prevention Program commenced 40 years ago provided the first evidence that type 2 diabetes is preventable and treatable. To drive real‐world impact from this evidence, payors, practitioners and planners need to co‐design and implement an integrated, data‐driven, metformin‐based programme to detect people with undiagnosed diabetes and prediabetes (intermediate hyperglycaemia), notably impaired glucose tolerance, for early intervention. The systematic data collection will create real‐world evidence to bring out the best of metformin and make healthcare sustainable, affordable and accessible. [ABSTRACT FROM AUTHOR]

Evidence‐based guidelines provide the premise for the delivery of quality care to preserve health and prevent disabilities and premature death. The systematic gathering of observational, mechanistic and experimental data contributes to the hierarchy of evidence used to guide clinical practice. In the field of diabetes, metformin was discovered more than 100 years ago, and with 60 years of clinical use, it has stood the test of time regarding its value in the prevention and management of type 2 diabetes. Although some guidelines have challenged the role of metformin as the first‐line glucose‐lowering drug, it is important to point out that the cardiovascular‐renal protective effects of sodium‐glucose co‐transporter‐2 inhibitors and glucagon‐like peptide‐1 receptor agonists were gathered from patients with type 2 diabetes, the majority of whom were treated with metformin. Most national, regional and international guidelines recommend metformin as a foundation therapy with emphasis on avoidance of therapeutic inertia and early attainment of multiple treatment goals. Moreover, real‐world evidence has confirmed the glucose‐lowering and cardiovascular‐renal benefits of metformin accompanied by an extremely low risk of lactic acidosis. In patients with type 2 diabetes and advanced chronic kidney disease (estimated glomerular filtration rate 15‐30 mL/min/1.73m2), metformin discontinuation was associated with an increased risk of cardiovascular‐renal events compared with metformin persistence. Meanwhile, it is understood that microbiota, nutrients and metformin can interact through the gut‐brain‐kidney axis to modulate homeostasis of bioactive molecules, systemic inflammation and energy metabolism. While these biological changes contribute to the multisystem effects of metformin, they may also explain the gastrointestinal side effects and vitamin B12 deficiency associated with metformin intolerance. By understanding the interactions between metformin, foods and microbiota, healthcare professionals are in a better position to optimize the use of metformin and mitigate potential side effects. The United Kingdom Prospective Diabetes Study and the Da Qing Diabetes Prevention Program commenced 40 years ago provided the first evidence that type 2 diabetes is preventable and treatable. To drive real‐world impact from this evidence, payors, practitioners and planners need to co‐design and implement an integrated, data‐driven, metformin‐based programme to detect people with undiagnosed diabetes and prediabetes (intermediate hyperglycaemia), notably impaired glucose tolerance, for early intervention. The systematic data collection will create real‐world evidence to bring out the best of metformin and make healthcare sustainable, affordable and accessible. [ABSTRACT FROM AUTHOR]

Aim: The use of vitamin K antagonists (VKAs) may increase the risk of peripheral arterial disease (PAD) because vitamin K is a strong inhibitor of medial arterial calcification. Type 2 diabetes (T2D) exposes patients to an increased risk of PAD. We examined how the use of VKAs modulates the risk of incident PAD in people with T2D. Materials and Methods: SURDIAGENE is a French cohort including 1468 patients with T2D with a prospective follow‐up from 2002 to 2015. The primary outcome of the current analysis was the first occurrence of PAD, a composite of lower‐limb amputation (LLA) or lower‐limb revascularization. LLA and lower‐limb revascularization were considered individually as secondary outcomes. Results: During a 7‐year median follow‐up, PAD occurred in 147 (10%) of the 1468 participants. The use of VKAs was not significantly associated with the risk of PAD [multivariable adjusted hazard ratio (HR) 1.42, 95% confidence interval (CI), 0.88‐2.31]. During the study period, LLA and lower‐limb revascularization occurred in 82 (6%) and 105 (7%) participants, respectively. The use of VKAs was significantly associated with increased risk of LLA [multivariable adjusted HR 1.90 (95% CI, 1.04‐3.47)], but not lower‐limb revascularization [multivariable adjusted HR 1.08 (95% CI, 0.59‐1.97)]. Conclusions: In this prospective study, we did not observe any excess risk of PAD requiring lower‐limb revascularization in people with type 2 diabetes using VKAs. However, our data suggest a high risk of LLA in VKA users. Further studies are required to confirm this observation. [ABSTRACT FROM AUTHOR]

Background: Monocytes play a central role in the pathophysiology of cardiovascular complications in type 2 diabetes (T2D) patients through different mechanisms. We investigated diabetes-induced changes in lncRNA genes from T2D patients with cardiovascular disease (CVD), long-duration diabetes, and poor glycemic control. Methods: We performed paired-end RNA sequencing of monocytes from 37 non-diabetes controls and 120 patients with T2D, of whom 86 had either macro or microvascular disease or both. Monocytes were sorted from peripheral blood using flow cytometry; their RNA was purified and sequenced. Alignments and gene counts were obtained with STAR to reference GRCh38 using Gencode (v41) annotations followed by batch correction with CombatSeq. Differential expression analysis was performed with EdgeR and pathway analysis with IPA software focusing on differentially expressed genes (DEGs) with a p-value < 0.05. Additionally, differential co-expression analysis was done with csdR to identify lncRNAs highly associated with diabetes-related expression networks with network centrality scores computed with Igraph and network visualization with Cytoscape. Results: Comparing T2D vs. non-T2D, we found two significantly upregulated lncRNAs (ENSG00000287255, FDR = 0.017 and ENSG00000289424, FDR = 0.048) and one significantly downregulated lncRNA (ENSG00000276603, FDR = 0.017). Pathway analysis on DEGs revealed networks affecting cellular movement, growth, and development. Co-expression analysis revealed ENSG00000225822 (UBXN7-AS1) as the highest-scoring diabetes network-associated lncRNA. Analysis within T2D patients and CVD revealed one lncRNA upregulated in monocytes from patients with microvascular disease without clinically documented macrovascular disease. (ENSG00000261654, FDR = 0.046). Pathway analysis revealed DEGs involved in networks affecting metabolic and cardiovascular pathologies. Co-expression analysis identified lncRNAs strongly associated with diabetes networks, including ENSG0000028654, ENSG00000261326 (LINC01355), ENSG00000260135 (MMP2-AS1), ENSG00000262097, and ENSG00000241560 (ZBTB20-AS1) when we combined the results from all patients with CVD. Similarly, we identified from co-expression analysis of diabetes patients with a duration ≥ 10 years vs. <10 years two lncRNAs: ENSG00000269019 (HOMER3-AS10) and ENSG00000212719 (LINC02693). The comparison of patients with good vs. poor glycemic control also identified two lncRNAs: ENSG00000245164 (LINC00861) and ENSG00000286313. Conclusion: We identified dysregulated diabetes-related genes and pathways in monocytes of diabetes patients with cardiovascular complications, including lncRNA genes of unknown function strongly associated with networks of known diabetes genes. [ABSTRACT FROM AUTHOR]

Aims: To develop and externally validate the LIFE‐T1D model for the estimation of lifetime and 10‐year risk of cardiovascular disease (CVD) in individuals with type 1 diabetes. Materials and Methods: A sex‐specific competing risk‐adjusted Cox proportional hazards model was derived in individuals with type 1 diabetes without prior CVD from the Swedish National Diabetes Register (NDR), using age as the time axis. Predictors included age at diabetes onset, smoking status, body mass index, systolic blood pressure, glycated haemoglobin level, estimated glomerular filtration rate, non‐high‐density lipoprotein cholesterol, albuminuria and retinopathy. The model was externally validated in the Danish Funen Diabetes Database (FDDB) and the UK Biobank. Results: During a median follow‐up of 11.8 years (interquartile interval 6.1–17.1 years), 4608 CVD events and 1316 non‐CVD deaths were observed in the NDR (n = 39 756). The internal validation c‐statistic was 0.85 (95% confidence interval [CI] 0.84–0.85) and the external validation c‐statistics were 0.77 (95% CI 0.74–0.81) for the FDDB (n = 2709) and 0.73 (95% CI 0.70–0.77) for the UK Biobank (n = 1022). Predicted risks were consistent with the observed incidence in the derivation and both validation cohorts. Conclusions: The LIFE‐T1D model can estimate lifetime risk of CVD and CVD‐free life expectancy in individuals with type 1 diabetes without previous CVD. This model can facilitate individualized CVD prevention among individuals with type 1 diabetes. Validation in additional cohorts will improve future clinical implementation. [ABSTRACT FROM AUTHOR]

Aim: Despite the increasing use of combination treatment with sodium‐glucose cotransporter 2 inhibitors and glucagon‐like peptide‐1 receptor agonists, data are limited on the effects of combination treatment on markers of cardiovascular disease. This study aimed to investigate the effect of empagliflozin, semaglutide, and their combination on vascular function. Materials and Methods: In total, 120 patients with type 2 diabetes were randomized into four groups (n = 30 in each) for 32 weeks: placebo, semaglutide, empagliflozin, and their combination. The study had two co‐primary outcomes: change in arterial stiffness and kidney oxygenation. This paper reports on arterial stiffness assessed as carotid‐femoral pulse wave velocity. Secondary outcomes included 24‐h blood pressure (BP), 24‐h central BP, urinary albumin to creatinine ratio and glycaemic control assessed by both continuous glucose monitoring and glycated haemoglobin. Results: The carotid‐femoral pulse wave velocity did not change significantly in any of the groups compared with placebo. Twenty‐four‐hour systolic BP was reduced by 10 mmHg (95% CI 6–14), p <.001 in the combination group, significantly superior to both placebo and monotherapy (p <.05). Combination treatment increased glycaemic time in range from 72% at baseline to 91% at week 32, p <.001, without increasing time below range. The urinary albumin to creatinine ratio decreased by 36% (95% CI 4–57), p =.03 in the combination group compared with placebo. Conclusions: Empagliflozin, semaglutide, or their combination did not reduce arterial stiffness. Combination treatment showed a substantial and clinically important reduction in 24‐h systolic BP compared with either treatment alone. Combination treatment increased glycaemic time in range without increasing the risk of hypoglycaemia. [ABSTRACT FROM AUTHOR]

Aim: To examine the effect of nutritional guidance (NG) provided by a registered dietitian under the direction of a physician on the development of subsequent cardiovascular events in patients with early-stage type 2 diabetes mellitus (T2DM). Materials and methods: This retrospective cohort study used the JMDC claims database to explore patients aged 18 years or older who first met the diagnostic criteria for T2DM at a health checkup between January 2011 and January 2019. The last day of the observation period was set for 28 February, 2021. Exposure was defined as receiving NG within 180 days of diagnosis of T2DM. The primary outcome was a composite endpoint of coronary artery disease (CAD) and cerebrovascular disease, and the secondary outcomes were each event, and time to event was compared. The propensity score weighting method was used for adjusting the distribution of confounding variables. Cox regression was conducted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Overall, 31,378 patients met the eligibility criteria at an annual health checkup. 9.6% received NG (n = 3013). Patients who attended ≥ 1 NG after diagnosis had significantly reduced risk of cardiovascular composite (adjusted HR 0.75, 95% CI 0.58–0.97) and cerebrovascular disease (adjusted HR 0.65, 95% CI 0.47–0.90) during approximately 3.3 years of follow-up. In contrast, no difference was observed for CAD. Conclusions: Receiving NG in early-stage diabetes may reduce the incidence of cardiovascular events, especially cerebrovascular events. [ABSTRACT FROM AUTHOR]

It is well known that the multiple factors contributing to the pathogenesis of type 2 diabetes (T2D) confer an increased risk of developing cardiovascular disease (CVD). Although the relationship between hyperglycaemia and increased microvascular risk is well established, the relative contribution of hyperglycaemia to macrovascular events has been strongly debated, particularly owing to the failure of attempts to reduce CVD risk through normalizing glycaemia with traditional therapies in high‐risk populations. The debate has been further fuelled by the relatively recent discovery of the cardioprotective properties of glucagon‐like peptide‐1 receptor agonists and sodium‐glucose cotransporter‐2 inhibitors. Further, as guidelines now recommend individualizing glycaemic targets, highlighting the importance of achieving glycated haemoglobin (HbA1c) goals safely, the previously observed negative influences of intensive therapy on CVD risk might not present if trials were repeated using current‐day treatments and individualized HbA1c goals. Emerging longitudinal data illuminate the overall effect of excess glucose, the impacts of magnitude and duration of hyperglycaemia on disease progression and risk of CVD complications, and the importance of glycaemic control at or early after diagnosis of T2D for prevention of complications. Herein, we review the role of glucose as a modifiable cardiovascular (CV) risk factor, the role of microvascular disease in predicting macrovascular risk, and the deleterious impact of therapeutic inertia on CVD risk. We reconcile new and old data to offer a current perspective, highlighting the importance of effective, early treatment in reducing latent CV risk, and the timely use of appropriate therapy individualized to each patient's needs. [ABSTRACT FROM AUTHOR]

The role of diabetes in developing microvascular and macrovascular complications has been subject to extensive research. Despite multiple observational and genetic studies, the causal inference of diabetes (and associated risk factors) on those complications remains incomplete. In this review, we focused on type 2 diabetes, as the major form of diabetes, and investigated the evidence of causality provided by observational and genetic studies. We found that genetic studies based on Mendelian randomization provided consistent evidence of causal inference of type 2 diabetes on macrovascular complications; however, the evidence for causal inference on microvascular complications has been somewhat limited. We also noted high BMI could be causal for several diabetes complications, notable given high BMI is commonly upstream of type 2 diabetes and the recent calls to target weight loss more aggressively. We emphasize the need for further studies to identify type 2 diabetes components that mostly drive the risk of those complications. Even so, the genetic evidence summarized broadly concurs with the need for a multifactorial risk reduction approach in type 2 diabetes, including addressing excess adiposity. [ABSTRACT FROM AUTHOR]

Background: It is not clear whether pre-existing macrovascular complications (ischemic heart disease, stroke or peripheral artery disease) are associated with health outcomes in people with diabetes mellitus hospitalized for COVID-19. Methods: We conducted cohort studies of adults with pre-existing diabetes hospitalized for COVID-19 infection in the UK, France, and Spain during the early phase of the pandemic (between March 2020—October 2020). Logistic regression models adjusted for demographic factors and other comorbidities were used to determine associations between previous macrovascular disease and relevant clinical outcomes: mortality, intensive care unit (ICU) admission and use of invasive mechanical ventilation (IMV) during the hospitalization. Output from individual logistic regression models for each cohort was combined in a meta-analysis. Results: Complete data were available for 4,106 (60.4%) individuals. Of these, 1,652 (40.2%) had any prior macrovascular disease of whom 28.5% of patients died. Mortality was higher for people with compared to those without previous macrovascular disease (37.7% vs 22.4%). The combined crude odds ratio (OR) for previous macrovascular disease and mortality for all four cohorts was 2.12 (95% CI 1.83–2.45 with an I2 of 60%, reduced after adjustments for age, sex, type of diabetes, hypertension, microvascular disease, ethnicity, and BMI to adjusted OR 1.53 [95% CI 1.29–1.81]) for the three cohorts. Further analysis revealed that ischemic heart disease and cerebrovascular disease were the main contributors of adverse outcomes. However, proportions of people admitted to ICU (adjOR 0.48 [95% CI 0.31–0.75], I2 60%) and the use of IMV during hospitalization (adjOR 0.52 [95% CI 0.40–0.68], I2 37%) were significantly lower for people with previous macrovascular disease. Conclusions: This large multinational study of people with diabetes mellitus hospitalized for COVID-19 demonstrates that previous macrovascular disease is associated with higher mortality and lower proportions admitted to ICU and treated with IMV during hospitalization suggesting selective admission criteria. Our findings highlight the importance correctly assess the prognosis and intensive monitoring in this high-risk group of patients and emphasize the need to design specific public health programs aimed to prevent SARS-CoV-2 infection in this subgroup. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the cardiovascular (CV) efficacy of liraglutide and semaglutide in patients with type 2 diabetes (T2D) and peripheral artery disease (PAD). Materials and Methods: LEADER and SUSTAIN 6 trials investigated subcutaneous liraglutide (≤1.8 mg/day) and semaglutide (0.5 or 1.0 mg/week), respectively, versus placebo in patients with T2D and high CV risk (median follow‐up: 3.8 and 2.1 years, respectively). The primary outcome was a composite of CV death, non‐fatal myocardial infarction or non‐fatal stroke (major adverse CV event [MACE]) according to the presence of PAD at baseline. Results: Overall, 1184/9340 (12.7%) patients in LEADER and 460/3297 (14.0%) in SUSTAIN 6 had PAD at baseline. Patients with PAD were at an ~35% increased risk of MACE versus those without (LEADER: hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.17‐1.58; SUSTAIN 6: HR 1.33, 95% CI 0.94‐1.83). The effects of both therapies on MACE were consistently beneficial in patients with PAD (liraglutide: HR 0.77, 95% CI 0.58‐1.01; semaglutide: 0.61, 0.33‐1.13) and without (liraglutide: HR 0.89, 95% CI 0.79‐1.00; semaglutide: HR 0.77, 95% CI 0.58‐1.01; Pinteraction =.34 for liraglutide and.49 for semaglutide). Absolute risk reductions for MACE were higher in patients with PAD (liraglutide: 4.13%‐point, 95% CI −0.15‐8.42; semaglutide: 4.63%‐point, 95% CI −0.58‐9.84) versus without (liraglutide:1.42%‐point, 95% CI −0.03‐2.87; semaglutide: 1.90%‐point, 95% CI 0.00‐3.80). Conclusion: Both liraglutide and semaglutide reduce MACE with consistent CV efficacy regardless of PAD status. [ABSTRACT FROM AUTHOR]

Vascular complications are the leading cause of morbidity and mortality among patients with type 2 diabetes mellitus (T2DM). These vascular abnormalities result in a chronic hyperglycemic state, which influences many signaling molecular pathways that initially lead to increased oxidative stress, increased inflammation, and endothelial dysfunction, leading to both microvascular and macrovascular complications. Endothelial dysfunction represents the initial stage in both types of vascular complications; it represents "mandatory damage" in the development of microvascular complications and only "introductory damage" in the development of macrovascular complications. Increasing scientific evidence has revealed an important role of the Wnt pathway in the pathophysiology of the vascular wall. It is well known that the Wnt pathway is altered in patients with T2DM. This review aims to be an update of the current literature related to the Wnt pathway molecules that are altered in patients with T2DM, which may also be the cause of damage to the vasculature. Both microvascular complications (retinopathy, nephropathy, and neuropathy) and macrovascular complications (coronary artery disease, cerebrovascular disease, and peripheral arterial disease) are analyzed. This review aims to concisely concentrate all the evidence to facilitate the view on the vascular involvement of the Wnt pathway and its components by highlighting the importance of exploring possible therapeutic strategy for patients with T2DM who develop vascular pathologies. [ABSTRACT FROM AUTHOR]

Purpose: To investigate and compare how patients with diabetes mellitus and doctors rate the importance of outcomes used as part of composite endpoints in clinical diabetes trials. Secondly, to compare the ratings of outcomes between patients with low and high education. Methods: Using a pre-piloted questionnaire, patients with diabetes and doctors working with diabetes were asked to rate the importance of 36 different outcomes commonly used in trials assessing intervention effects in patients with diabetes. The respondents were asked to rate individual outcomes as being either critical, of major importance, of moderate importance, or of minor importance. Results: The study population consisted of 139 patients with a mean age of 56.6 years and an average duration of diabetes for 13.6 years and 45 doctors with a mean time of practice of 19.6 years. There was no difference between patients' and doctors' rating of risk of mortality and non-fatal myocardial infarction, and percutaneous coronary intervention (all p-values > 0.34). Non-fatal stroke, admission for heart failure or angina was perceived more severely by patients compared to doctors (all p-values < 0.03). Patients rated risk of foot-ulcers, amputations and quality of life as more important compared to doctors (p-values < 0.01). Conclusion: The current study suggest that patients and doctors weigh some diabetic outcomes used as part of composite endpoints in clinical diabetes trials differently. These findings call for more studies on patient reported outcomes and patient education for improved personal care. Highlights: • We performed this study to assess how patients and practicing physicians rate the importance of outcomes commonly used in diabetes trials. • We found that patients and doctors rate the importance of some outcomes used in clinical diabetes trials differently. • These findings suggest that shared decision making is pivotal when taking clinical decisions and that future diabetes studies incorporate end points relevant to both patients and clinicians and do not combine end points which are not equally important. [ABSTRACT FROM AUTHOR]

Background: Individuals with type 2 diabetes mellitus (T2DM) have an increased risk for developing macrovascular disease (MVD) manifested by atherosclerosis. Phenotypically and functionally different monocyte subsets (classical; CD14++CD16−, non-classical; CD14+CD16++, and intermediate; CD14++CD16+) including pro-angiogenic monocytes expressing Tie2 (TEMs) can be identified. Here we investigated monocyte heterogeneity and its association with T2DM and MVD. Methods: Individuals with (N = 51) and without (N = 56) T2DM were recruited and allocated to "non-MVD" or "with MVD" (i.e., peripheral or coronary artery disease) subgroups. Blood monocyte subsets were quantified based on CD14, CD16 and Tie2 expression levels. Plasma levels of Tie2-ligands angiopoietin-1 and angiopoietin-2 were determined using ELISA. Carotid endarterectomy samples from individuals with (N = 24) and without (N = 22) T2DM were stained for intraplaque CD68+ macrophages (inflammation) and CD34+ (angiogenesis), as plaque vulnerability markers. Results: Monocyte counts were similar between individuals with T2DM and healthy controls (non-diabetic, non-MVD). Non-classical monocytes were reduced (p < 0.05) in T2DM, whereas the percentage of TEMs within the intermediate subset was increased (p < 0.05). T2DM was associated with increased angiopoietin-1 (p < 0.05) and angiopoietin-2 (p = 0.0001) levels. Angiopoietin-2 levels were higher in T2DM individuals with MVD compared with non-MVD (p < 0.01). Endarterectomized plaques showed no differences in macrophage influx and microvessel number between individuals with and without T2DM. Conclusions: Monocyte subset distribution is altered in T2DM with reduced non-classical monocytes and increased TEM percentage in the intermediate monocyte subset. Increased angiopoietin-2 levels together with increased frequency of TEMs might promote plaque vulnerability in T2DM which could however not be confirmed at tissue level in advanced atherosclerotic lesions. [ABSTRACT FROM AUTHOR]

Aim: To assess the efficacy and safety of sotagliflozin in patients with type 2 diabetes. Methods: We searched Medline, Embase, the Cochrane Library, and grey literature sources up to August 2021 for randomized controlled trials (RCTs) that compared sotagliflozin with placebo or other antidiabetic agents in patients with type 2 diabetes. Our primary outcome was change in HbA1c from baseline. We additionally assessed three secondary efficacy and 15 safety outcomes. We synthesized data using weighted mean differences (WMDs) and odds ratios (ORs), along with 95% confidence intervals (CIs). Results: We included 11 RCTs comprising 16 411 subjects in the meta‐analysis. Compared with placebo, sotagliflozin reduced HbA1c (WMD −0.42%, 95% CI −0.56 to −0.29), body weight (WMD −1.33 kg, 95% CI −1.57 to −1.09), and systolic blood pressure (WMD −2.44 mmHg, 95% CI −2.81 to −2.07). No difference was evident against other active comparators. Sotagliflozin reduced myocardial infarction (OR 0.72, 95% CI 0.54 to 0.97) and heart failure (OR 0.68, 95% CI 0.58 to 0.79) compared with placebo, and had a neutral effect on all‐cause mortality, cardiovascular mortality, and stroke. Treatment with sotagliflozin was safe regarding the incidence of serious adverse events, hypoglycaemia, and diabetic ketoacidosis. Nevertheless, it was associated with an increased incidence of diarrhoea, genital infections, and volume depletion events. Conclusions: Sotagliflozin reduces blood glucose, body weight, and systolic blood pressure, and demonstrates a beneficial effect on heart failure and myocardial infarction. Its overall safety profile is comparable with other sodium‐glucose co‐transporter‐2 inhibitors. [ABSTRACT FROM AUTHOR]

Aims: A diabetic foot ulcer (DFU) is associated with increased cardiovascular risk and mortality, independently of ulcer etiology (ischemic, neuro-ischemic or neuropathic). Ankle–brachial index (ABI) is the most commonly used test when diagnosing peripheral macrovascular disease and is a well-known marker for increased cardiovascular risk. Transcutaneous oxygen pressure (TcPO2) is considered to better evaluate microvascular function and has in previous studies shown correlations with both wound healing and survival. The aim of this study was to evaluate the combined impact of a low TcPO2 (<30 mmHg) and a pathological ABI (<0.9 or ≥1.4) on three-year mortality in patients with DFU. Methods: Type 2 diabetes patients aged <90 years, with at least one DFU who underwent vascular assessment with ABI and TcPO2 were screened for participation. The primary endpoint was mortality after three years, assessed from the National Death Registry in Sweden. Results: The study enrolled 235 participants with a median age of 76 years. Individuals with either an abnormally high or low ABI in combination with a low TcPO2 had the worst survival rates, with three-year mortality of 54%, compared to 42% in those with one abnormal variable (either ABI or TcPO2), and 21% in those with normal ABI and TcPO2. Conclusions: Combining ABI and TcPO2 when risk stratifying DFU patients seems to provide additional predictive information, not only concerning ulcer healing and limb salvage, but also on survival. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to detect macrovascular findings in systemic sclerosis (SSc) by means of color Doppler ultrasonography (CDUS) and to evaluate the relationship between the laboratory and clinical findings in the setting of the disease. Methods: This was a cross‐sectional study. Eighty‐eight patients were included in the study. CDUS examinations of the bilateral carotid, vertebral, and peripheral arteries were performed. The presence of macrovascular involvement was investigated and recorded, and its relationships with the clinical, laboratory, and cardiovascular risk factors were evaluated. Results: An atheromatous plaque was found in 67.7% of the 1936 arteries examined by CDUS. Of these 1936 arteries, 37.4% demonstrated a narrowing of the intraluminal diameter. On the other hand, the carotid intima‐media thickness (CIMT) was found to have increased in 55.7% of the patients. This increase was found to be statistically correlated with disease duration, the modified Rodnan Skin Thickness Score, and the Medsger Disease Activity Score. But no relation existed with the disease subtype, age, or cardiovascular risk factors. Arterial occlusion was detected in 10 patients. An association was found between the CIMT values and arterial occlusion. Conclusions: In this study, we examined the arteries by means of CDUS, and we detected structural alterations in the peripheral and carotid arteries. We witnessed that these macrovascular changes had a close association with certain features of SSc. We think there is a need for broader prospective studies in order to evaluate the contribution of these factors to the macrovascular changes stated in the article. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is associated with high morbidity and mortality from microvascular and macrovascular disease with considerable economic cost to society. Islet cell transplantation (ICT) is a treatment option recommended by National Institute for Health and Care Excellence (NICE) for people with debilitating hypoglycaemia due to type 1 diabetes, including those with renal failure where kidney transplantation may also be indicated. The primary aim of ICT is to improve glycaemic control, reduce severe hypoglycaemia, stabilise glycaemic variability and restore awareness of hypoglycaemia where this is compromised. Insulin independence, although not a primary aim, should also be considered a therapeutic goal. The impact ICT has on the progression of microvascular and macrovascular diabetes complications is derived from small studies and has not been examined in large clinical trials. Lifelong immunosuppression, which is necessary to avoid transplant rejection, has adverse effects on lipid metabolism, hypertension and renal function, which must also be considered. In this review, we discuss the role of ICT in type 1 diabetes management and the available evidence with respect to microvascular and macrovascular disease progression post‐transplantation. We conclude that, following ICT, microvascular complications including retinopathy and neuropathy are stabilised or improved. Effects on nephropathy can be complicated by coexisting kidney transplantation and the impact of immunosuppression, the latter leading to an early decline in renal function; however, there is evidence to suggest stable renal outcomes in the long term. Short‐term studies have demonstrated a positive impact of ICT on surrogate markers of macrovascular disease; however, long‐term studies and trials in this area are lacking. [ABSTRACT FROM AUTHOR]

Aims: For relatively old patients with diabetes, current guidelines recommend adjustment of glycaemic goals based on patients' cognitive function, or coexisting chronic illnesses. However, the evidence which supports the efficacy and safety of intensive glucose lowering in older patients with diabetes is scarce. The objective of the present study was to compare the efficacy and safety of intensive glucose lowering in patients with type 2 diabetes stratified by age (<65 and ≥ 65 years), and examine whether the effects differ according to patients' characteristics in the older patient group. Materials and Methods: The effects of intensive glucose lowering (to a target glycated haemoglobin [HbA1c] concentration of ≤48 mmol/mol [6.5%]) on major clinical outcomes were evaluated by Cox regression models according to subgroups defined by baseline age of <65 or ≥ 65 years in the ADVANCE trial (n = 11 140). Results: Over a median follow‐up of 5 years, intensive glucose lowering significantly decreased the risk of the composite of major macrovascular and microvascular events (hazard ratio 0.90, 95% confidence interval 0.82‐0.98), with no heterogeneity in the effects across age subgroups (p for heterogeneity = 0.44). Relative effects on all‐cause death, cardiovascular death, and components of major vascular events were also similar (P for heterogeneity ≥0.06), except for severe hypoglycaemia, which was of greater risk for patients aged <65 years. Absolute benefits and harms were broadly consistent across subgroups. Among patients aged ≥65 years, randomized treatment effects did not differ significantly across different levels of cognitive function or coexisting chronic illnesses. Conclusions: Our results suggest that an intensive glycaemic control strategy to reduce HbA1c to 48 mmol/mol (6.5%) provided broadly similar benefits and harms and may be recommended for older, as well as younger, patients. [ABSTRACT FROM AUTHOR]

Aim: The effect of the weekly exendin‐based glucagon‐like peptide‐1 receptor agonist efpeglenatide on cardiovascular (CV) outcomes in high‐risk patients with type 2 diabetes (T2DM) with and without chronic kidney disease (CKD) is unknown. Materials and methods: People with T2DM and glycated haemoglobin >7%, ≥18 years old with previous CV disease, or ≥50 years old with CKD [defined as an estimated glomerular filtration rate (eGFR) of 25–59.9 mL/min/1.73 m2], and one or more additional CV risk factors were recruited. Participants were randomized in a 1:1:1 ratio, stratified by current, intended or neither current nor intended use of a sodium‐glucose cotransporter‐2 (SGLT2) inhibitor to receive weekly injections of efpeglenatide (4 mg or 6 mg) or masked placebo. The primary outcome is a major adverse CV event defined as non‐fatal myocardial infarction, non‐fatal stroke or CV death. Secondary outcomes include a composite kidney outcome (new onset macroalbuminuria with an increase from baseline of ≥30%, sustained 40% decrease in eGFR, renal replacement therapy, or sustained eGFR <15 mL/min/1.73 m2). The trial will continue until ≥330 participants have had a major adverse CV event outcome and the sample size was based on accruing enough outcomes to detect non‐inferiority of efpeglenatide versus placebo. Results: Recruitment of 4076 participants (33% women, mean age 64.5 years) occurred between 11 May 2018 and 25 April 2019 at 344 sites in 28 countries. Mean baseline glycated haemoglobin was 8.9% (1.5), 31.6% had an eGFR <60 mL/min/1.73 m2, 89.5% had previous CV disease and 15.0% were on an SGLT2 inhibitor. Conclusions: The results of the AMPLITUDE O trial will inform the use of exendin‐based glucagon‐like peptide‐1 receptor agonist to people with T2DM and high CV risk, with and without CKD, in the presence and absence of an SGLT2 inhibitor. [ABSTRACT FROM AUTHOR]

The randomized, double-blind, cardiovascular outcomes trials LEADER (NCT01179048) and SUSTAIN 6 (NCT01720446) showed cardiovascular risk reduction in patients with type 2 diabetes treated with liraglutide and semaglutide, respectively, compared with placebo. This post hoc analysis examined the impact of microvascular disease at baseline on cardiovascular outcomes in these trials, and the efficacy of liraglutide (1.8 mg) and once-weekly semaglutide (0.5-1.0 mg) in patients with and without microvascular disease. In total, 9340 patients from LEADER and 3297 patients from SUSTAIN 6 were included in this analysis; of these, 5761 and 2356 had a history of microvascular disease at baseline and 3835 and 1640 had a history of both microvascular and macrovascular disease, respectively. Patients with microvascular disease were shown to have an increased risk of major adverse cardiovascular events compared with patients without microvascular disease (hazard ratio [95% confidence interval] in LEADER: 1.15 [1.03; 1.29], P = .0136; SUSTAIN 6: 1.56 [1.14; 2.17], P = .0064). Liraglutide and semaglutide consistently reduced cardiovascular risk in patients with and without microvascular disease. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to evaluate the interrelationship between the micro- and macrovasculature. Methods: This is a cross-sectional study that examined SSc patients and fibromyalgia (FM) patients as controls. We assessed forearm peripheral vascular status and nailfold capillaroscopy. We evaluated the association between nailfold capillaroscopy pattern of microvasculopathy reflected as microangiopathy evolution score and macrovascular changes in the forearm vessels examined by color Doppler ultrasound. We assessed relevant clinical and laboratory data, as well as intima-media thickness (IMT) and internal diameter (ID) in the radial and ulnar arteries in millimeters, and calculated the ratio IMT\ID peak systolic velocity and end-diastolic velocity were used for the calculation of the resistance index. Results: We examined 73 patients: 50 patients with SSc and 23 patients with FM. Ten patients with SSc had arterial occlusions compared to 1 among FM patients (p = 0.082). The SSc group had a statistically significantly higher mean IMT to ID ratio (p < 0.001). There was no correlation between microangiopathy evolution score for both hands, RI, or mean IMT/ID ratio. Total microangiopathy evolution score was not associated with arterial occlusions. Conclusions: Our study demonstrated a high prevalence of macrovascular disease in SSc; no correlation was found between microvasculopathy and macrovascular disease, suggesting that different pathogenic mechanisms might operate in different vessels size. Key Points • This study demonstrated a high prevalence of macrovascular arterial forearm disease in systemic sclerosis patients. • This study found no correlation between capillaroscopic microangiopathy evolution score (MES) and macrovascular abnormalities. • Our findings suggest that different pathogenic mechanisms might operate in different vessels size. [ABSTRACT FROM AUTHOR]

Aims: To examine the manifestation of cardiovascular or renal disease (CVRD) in patients with type 2 diabetes (T2D) initially free from CVRD as well as the mortality risks associated with these diseases. Methods: Patients free from CVRD were identified from healthcare records in England, Germany, Japan, the Netherlands, Norway and Sweden at a fixed date. CVRD manifestation was defined by first diagnosis of cardiorenal disease, or a stroke, myocardial infarction (MI) or peripheral artery disease (PAD) event. The mortality risk associated with single CVRD history of heart failure (HF), chronic kidney disease (CKD), MI, stroke or PAD was compared with that associated with CVRD‐free status. Results: Of 1 177 896 patients with T2D, 772 336 (66%) were CVRD‐free and followed for a mean of 4.5 years. A total of 137 081 patients (18%) developed a first CVRD manifestation, represented by CKD (36%), HF (24%), stroke (16%), MI (14%) and PAD (10%). HF or CKD was associated with increased cardiovascular and all‐cause mortality risk: hazard ratio (HR) 2.02 (95% confidence interval [CI] 1.75–2.33) and HR 2.05 (95% CI 1.82–2.32), respectively. HF and CKD were separately associated with significantly increased mortality risks, and the combination was associated with the highest cardiovascular and all‐cause mortality risk: HRs 3.91 (95% CI 3.02–5.07) and 3.14 (95% CI 2.90–3.40), respectively. Conclusion: In a large multinational study of >750 000 CVRD‐free patients with T2D, HF and CKD were consistently the most frequent first cardiovascular disease manifestations and were also associated with increased mortality risks. These novel findings show these cardiorenal diseases to be important and serious complications requiring improved preventive strategies. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes (T2D) are at an increased risk of cardiovascular disease (CVD). Cardiovascular risk in these patients should be considered as a continuum, and comprehensive treatment strategies should aim to target multiple disease risk factors. Large‐scale clinical trials of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors have shown an impact on cardiovascular outcomes, including heart failure hospitalization and cardiovascular death, which appears to be independent of their glucose‐lowering efficacy. Reductions in major cardiovascular events appear to be greatest in patients with established CVD, particularly those with prior myocardial infarction, but are independent of heart failure or renal risk. Most large‐scale trials of SGLT2 inhibitors predominantly include patients with T2D with pre‐existing CVD and high cardiovascular risk at baseline, limiting their applicability to patients typically observed in clinical practice. Real‐world evidence from observational studies suggests that there might also be beneficial effects of SGLT2 inhibitors on heart failure hospitalization and all‐cause mortality in various cohorts of lower risk patients. The most common adverse events reported in clinical and observational studies are genital infections; however, the overall risk of these events appears to be low and easily managed. Similar safety profiles have been reported for elderly and younger patients. There is still some debate regarding the safety of canagliflozin in patients at high risk of fracture and amputation. Outstanding questions include specific patterns of cardiovascular protection according to baseline risk. [ABSTRACT FROM AUTHOR]

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial was a landmark randomized controlled clinical trial in 11 140 type 2 diabetic patients from 215 centers in 20 countries with a two‐by‐two factorial design. In the blood pressure‐lowering arm, patients were treated using a fixed combination of the ACE‐inhibitor, perindopril, and the thiazide‐like diuretic, indapamide, or placebo, whereas in the glucose‐lowering arm, the intervention compared the sulphonylurea gliclazide plus other glucose‐lowering drugs, targeting a glycated hemoglobin value of 6.5% or less, with standard glucose control. Primary end‐points were major macro‐ and microvascular events in both arms. This review gives an overview of the results of the primary randomized trial, results from observational follow‐up studies, and results of several biomarker studies and discusses the perspectives of these data in the context of recent major outcome trials for current medical treatment. [ABSTRACT FROM AUTHOR]

Aim: To investigate the associations of blood pressure variability (BPV), expressed as long‐term (visit‐to‐visit) and short‐term (ambulatory blood pressure monitoring [ABPM] and home blood pressure monitoring [HBPM]) and all‐cause mortality, major adverse cardiovascular events (MACEs), extended MACEs, microvascular complications (MiCs) and hypertension‐mediated organ damage (HMOD) in adult patients with type 2 diabetes. Materials and methods: PubMed, Medline, Embase, Cinahl, Web of Science, ClinicalTrials.gov and grey literature databases were searched for studies including patients with type 2 diabetes, at least one variable of BPV (visit‐to‐visit, HBPM, ABPM) and evaluation of the incidence of at least one of the following outcomes: all‐cause mortality, MACEs, extended MACEs and/or MiCs and/or HMOD. The extracted information was analyzed using random effects meta‐analysis and meta‐regression. Results: Data from a total of 377 305 patients were analyzed. Systolic blood pressure (SBP) variability was associated with a significantly increased risk of all‐cause mortality (HR 1.12, 95% CI 1.04–1.21), MACEs (HR 1.01, 95% CI 1.04–1.17), extended MACEs (HR 1.07, 95% CI 1.03–1.11) and MiCs (HR 1. 12, 95% CI 1.01–1.24), while diastolic blood pressure was not. Associations were mainly driven from studies on long‐term SBP variability. Qualitative analysis showed that BPV was associated with the presence of HMOD expressed as carotid intima‐media thickness, pulse wave velocity and left ventricular hypertrophy. Results were independent of mean blood pressure, glycaemic control and serum creatinine levels. Conclusions: Our results suggest that BPV might provide additional information rather than mean blood pressure on the risk of cardiovascular disease in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aim: To investigate the associations of blood pressure variability (BPV), expressed as long‐term (visit‐to‐visit) and short‐term (ambulatory blood pressure monitoring [ABPM] and home blood pressure monitoring [HBPM]) and all‐cause mortality, major adverse cardiovascular events (MACEs), extended MACEs, microvascular complications (MiCs) and hypertension‐mediated organ damage (HMOD) in adult patients with type 2 diabetes. Materials and methods: PubMed, Medline, Embase, Cinahl, Web of Science, ClinicalTrials.gov and grey literature databases were searched for studies including patients with type 2 diabetes, at least one variable of BPV (visit‐to‐visit, HBPM, ABPM) and evaluation of the incidence of at least one of the following outcomes: all‐cause mortality, MACEs, extended MACEs and/or MiCs and/or HMOD. The extracted information was analyzed using random effects meta‐analysis and meta‐regression. Results: Data from a total of 377 305 patients were analyzed. Systolic blood pressure (SBP) variability was associated with a significantly increased risk of all‐cause mortality (HR 1.12, 95% CI 1.04–1.21), MACEs (HR 1.01, 95% CI 1.04–1.17), extended MACEs (HR 1.07, 95% CI 1.03–1.11) and MiCs (HR 1. 12, 95% CI 1.01–1.24), while diastolic blood pressure was not. Associations were mainly driven from studies on long‐term SBP variability. Qualitative analysis showed that BPV was associated with the presence of HMOD expressed as carotid intima‐media thickness, pulse wave velocity and left ventricular hypertrophy. Results were independent of mean blood pressure, glycaemic control and serum creatinine levels. Conclusions: Our results suggest that BPV might provide additional information rather than mean blood pressure on the risk of cardiovascular disease in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objetive: to determine the relationship between limited joint mobility (LJM) of the hand and the presence of atheroma plaques in the carotid arteries of patients with type 2 diabetes mellitus (DM2). Material and methods: 80 patients with DM2, in two groups (40 with LJM and 40 without LJM), between 40 and 80 years. LJM was diagnosed with a positive prayer maneuver. Using B-mode ultrasonography of the carotid arteries, atheromatous plaques were classified according to the Gray-Weale Scale. Results: There was no significant difference in age and sex between both groups. The LJM group had longer illness time. The values of VLDL cholesterol, urea and creatinine were significantly higher in the LJM group. Both groups of patients had the same type of treatment for diabetes, high blood pressure and anti-dyslipidemic. LJM was associated with a greater number of atheromas. Type I, II and III carotid plaques were more frequent in patients with LJM. Conclusions: patients with DM2 and with LJM have a greater number of atheroma plaques in the carotid arteries than patients without LJM. [ABSTRACT FROM AUTHOR]

Aims: Latent autoimmune diabetes in adults (LADA) is diagnosed in up to 12% of adults with clinically diagnosed type 2 diabetes (T2D). LADA tends to have healthier cardiovascular (CV) risk profiles than T2D, but it remains uncertain whether the risk of CV events differs between the two. We examined the risk of CV events in patients enrolled in the United Kingdom Prospective Diabetes Study (UKPDS) according to LADA status. Materials and methods: Diabetes autoantibodies (AAb) were measured in 5062 UKPDS participants. The incidence of major adverse CV events (MACE), defined as CV death, non‐fatal myocardial infarction or non‐fatal stroke, was compared in those with LADA (≥1 AAb test positive) and those without LADA (AAb negative). Results: There were 567 participants (11.2%) with LADA. Compared with participants with T2D, they were younger, with higher mean HbA1c and HDL‐cholesterol values, and with lower body mass index and total cholesterol and systolic blood pressure values (all P < 0.01). After a median (25th, 75th percentile) 17.3 (12.6–20.7) years of follow‐up, MACE occurred in 157 (17.4 per 1000 person‐years) participants with LADA and in 1544 (23.5 per 1000 person‐years) participants with T2D (HR, 0.73; 95% confidence interval [CI], 0.62–0.86; P < 0.001). However, after adjustment for confounders, this difference was no longer significant (HRadj, 0.90; 95% CI, 0.76–1.07; P = 0.22). Conclusions: In adults thought to have newly diagnosed T2D, the long‐term risk of MACE was lower in those with LADA. However, this did not differ after adjustment for traditional CV risk factors, suggesting that measurement of AAb in addition to traditional CV risk factors will not aid in stratification of CV risk in clinically diagnosed T2D. [ABSTRACT FROM AUTHOR]

The prevalence of heart failure (HF) in patients with type 2 diabetes (T2DM) is debatable and no data exist concerning the diagnostic value of mid‐regional pro‐atrial natriuretic peptide (MR‐proANP). We aimed to identify HF prevalence and evaluate the diagnostic value of MR‐proANP in outpatients followed in two specialized diabetes clinics. HF was pre‐defined as HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). The prevalence of HFrEF and HFpEF was 2.4% and 17.5%, respectively. An MR‐proANP <60 pmol/L ruled out HFrEF in the total population (n = 806) and in patients reporting dyspnea (n = 311) with a sensitivity of 94.7% and 87.5%, a negative predictive value of 99.7% and 99.0%, a specificity of 39.5% and 33.0%, and a positive predictive value of 3.6% and 3.3%, respectively. In a multivariable model including age, sex, T2DM duration, albuminuria, uncontrolled systolic blood pressure, abnormal electrocardiogram and ischaemic heart disease for diagnosis of HF in patients reporting dyspnea, adding MR‐proANP increased the area under the curve from 0.69 to 0.78 (P < 0.001). In conclusion, HFrEF was rare among outpatients with T2DM. MR‐proANP rules out HFrEF and contributes independent information relevant to diagnosis of HF in patients reporting dyspnea. [ABSTRACT FROM AUTHOR]

Background/Objective: Adolescents with type 1 diabetes have early macrovascular changes (increased intima‐media thickness [IMT]) and early retinal changes that predict clinical disease in adulthood. We hypothesized that early changes in the macrovascular and retinal microvascular beds develop in parallel before retinopathy develops. We therefore aimed to investigate the relationship between changes in atherosclerosis (carotid and aortic IMT) and retinal vascular geometry cross‐sectionally and longitudinally in adolescents with type 1 diabetes. Methods: Ninety adolescents with type 1 diabetes (41 boys, aged 13.6 ± 3.5 years) who were enrolled in a randomized controlled trial had evaluations at baseline; 41 randomized to placebo were also investigated at 12 months for carotid and aortic IMT using ultrasound and retinal vascular geometry was measured from retinal photographs. Results: There were significant associations between thicker mean/maximum carotid IMT and wider retinal arteriolar and venular calibers; for every 0.1 mm increase in mean carotid IMT, retinal arteriolar caliber increased by 7.90 μm (95% confidence interval [CI] 4.50, 11.30, P < 0.0001) and venular caliber by 9.61 μm (95% CI 4.16, 15.06, P = 0.0008). Increased mean aortic IMT was associated with increased arteriolar tortuosity (2.61, 95% CI 0.50, 4.71, P = 0.02). Conclusions: The early changes of atherosclerosis are associated with retinal microvascular changes in adolescents with type 1 diabetes. This supports parallel adverse changes in the macro and microvascular circulations from early adolescence in type 1 diabetes, and highlights the importance of early intervention. [ABSTRACT FROM AUTHOR]

Aims: Patients with type 2 diabetes have a high risk of cardiovascular disease (CVD). Central obesity has been particularly associated with this risk relationship. We aimed to evaluate waist to height ratio (WHtR) as a predictor of risk in such patients. Methods: WHtR was evaluated as a predictor of the risk of CVD and mortality amongst 11 125 participants with type 2 diabetes in the ADVANCE and ADVANCE‐ON studies, and was compared with body mass index (BMI), waist circumference and waist hip ratio (WHR). Primary outcome was a composite of death from CVD, non‐fatal myocardial infarction or non‐fatal stroke. Secondary outcomes were myocardial infarction, stroke, cardiovascular death and death from any cause. Cox models were used, with bootstrapping to compare associations between anthropometric measures for the primary outcome. Results: Median follow‐up time was 9.0 years. There was a positive association between WHtR and adverse outcomes. The hazard ratio (HR) (confidence interval), per SD higher WHtR, was 1.16 (1.11‐1.22) for the primary endpoint, with no heterogeneity by sex or region, but a stronger effect in individuals aged 66 years or older. The other 3 anthropometric measurements showed similar associations, although there was evidence that WHtR marginally outperformed BMI and WHR. Based on commonly used BMI cut‐points, the equivalent WHtR cut‐points were estimated to be 0.55 and 0.6, with no evidence of a difference across subgroups. Conclusions: In patients with diabetes, WHtR is a useful indicator of future adverse risk, with similar effects in different population subgroups. [ABSTRACT FROM AUTHOR]

Aims: Ankle-brachial index (ABI) is the most commonly used test when diagnosing peripheral vascular disease and is considered a marker for cardiovascular risk. Transcutaneous oxygen pressure (TcPO2), a test associated with microvascular function, has in several studies shown better correlation with diabetic foot ulcer (DFU) healing. Whether a low TcPO2 could be a marker for mortality in the high-risk population of DFU patients has not been evaluated before. The aim of this study was to evaluate the predictive value of TcPO2 in comparison with ABI and toe blood pressure (TBP) on 1-year mortality in type 2 diabetes patients with DFU.Methods: Type 2 diabetes patients aged ≤ 90 years, with one DFU who attended our multidisciplinary DFU-unit during year 2013-2015 and were screened with TcPO2, ABI and TBP were retrospectively evaluated. One-year mortality was assessed from the national death register in Sweden.Results: A total of 236 patients (30% women) with a median age of 76 (69-82) years were evaluated in this study. Within 1 year, 14.8% of the patients died. TcPO2 < 25 mmHg was associated with a higher 1-year mortality compared with TcPO2 ≥ 25 mmHg (27.7 vs. 11.6%, p = 0.003). TBP and ABI did not significantly influence 1-year mortality. In a Cox regression analysis adjusted for confounders, TcPO2 was independently predicting 1-year mortality with a hazard ratio for TcPO2 < 25 mmHg of 2.8 (95% CI 1.34-5.91, p = 0.006).Conclusions: This study indicates that a low TcPO2 is an independent prognostic marker for 1-year mortality among patients with type 2 diabetes and DFU. [ABSTRACT FROM AUTHOR]

A primary goal of the treatment of type 2 mellitus is the prevention of morbidity and mortality associated with cardiovascular disease; however, anti‐hyperglycaemic drugs have the capacity to cause deleterious effects on the circulation, a risk that is not adequately reflected by the endpoints selected for emphasis in large‐scale clinical trials that are designed to evaluate cardiovascular safety. The primary endpoint of the large‐scale studies mandated by regulatory authorities focuses only on 3 to 4 events that depict only a limited view of the circulatory system. One of the most serious adverse effects of many glucose‐lowering drugs is new‐onset or worsening heart failure. Most antidiabetic drugs can aggravate heart failure because they exert anti‐natriuretic actions, and possibly, adverse effects on the myocardium. In addition, certain anti‐hyperglycaemic agents may worsen peripheral vascular disease and trigger cardiac arrhythmias that may lead to sudden death. Initiation of treatment with antidiabetic medications may also cause deterioration of the function of the kidneys, retina and peripheral nerves, which are typically regarded as reflecting microvascular disease. The current confusion about the cardiovascular effects of glucose‐lowering drugs may be exacerbated by conceptual uncertainties about the classification of large and small vessel disease in determining the clinical course of diabetes. Physicians should not be falsely reassured by claims that a new treatment appears to have passed a narrowly defined regulatory test. The management of people with diabetes often carries with it the risk of important cardiovascular consequences, even for drugs that do not overtly increase the risk of myocardial infarction or stroke. [ABSTRACT FROM AUTHOR]

Aims: To determine whether baseline metabolic syndrome (MetS) modifies the effect of intensive blood pressure control on cardiovascular (CV) outcomes, and whether the effects varied by race/ethnicity. Methods: We performed post hoc analyses among non‐Hispanic black, non‐hispanic white and Hispanic participants, with and without MetS, in the Systolic Blood Pressure Intervention Trial (SPRINT), who were randomized to a systolic blood pressure (SBP) target of <120 mm Hg (intensive group, N = 4544) or an SBP target of <140 mm Hg (standard group, N = 4553). The median follow‐up was 3.26 years. The primary outcome was the composite of the first occurrence of myocardial infarction, stroke, heart failure, non‐myocardial infarction acute coronary syndrome or CV death. Results: Overall, 3521/9097 participants (38.7%) met the criteria for MetS at baseline. Baseline characteristics were similar in the two SBP target groups within each MetS subgroup, except body mass index was slightly higher in the standard arm of the MetS subgroup (33.3 ± 5.6 vs 33.0 ± 5.3 kg/m2; P < .01), but were similar across treatment arms in the non‐MetS subgroup. The hazard ratio for the primary outcome was similarly reduced in participants with or without baseline MetS: 0.75 (95% confidence interval [CI] 0.57, 0.96) and 0.71 (95% CI 0.57, 0.87), respectively (adjusted P value for treatment by subgroup interaction = .98). Similarly, there was no evidence of treatment × MetS subgroup interaction for all‐cause mortality (adjusted interaction P value = .98). The findings were also similar across race/ethnic subgroups. Conclusions: In this analysis the CV benefit of intensive SBP control did not differ among participants by baseline MetS status, regardless of race/ethnicity. [ABSTRACT FROM AUTHOR]

Aims: To investigate the risk of Chinese females versus males for non-fatal coronary heart disease (CHD) due to long exposure to type 2 diabetes mellitus (T2DM).Methods: 223,612 Chinese patients with T2DM were recruited from China in 2012. Binary logistic regression analysis was performed to obtain odds ratios (OR) of females versus males for non-fatal CHD. Additive interaction was used to test whether female gender and long exposure to T2DM (≥15 years) had a synergistic effect for non-fatal CHD. Significant relative excess risk due to interaction (RERI > 0), attributable proportion due to interaction (AP > 0) or synergy index (SI > 1) suggest a significant additive interaction.Results: More females than males with T2DM had non-fatal CHD (11.3% versus 10.6%, P < .0001). Females had slightly higher risk of non-fatal CHD since 5-10 years of diabetic duration and the effect size became larger since 15 years and onwards. Overall effect of females versus males for non-fatal CHD was 1.04 (95% CI: 1.01-1.08) among patients with <15 years of duration while the effect size increased to 1.17 (95% CI: 1.07-1.28) among patients with ≥15 years of duration. Using males with <15 years of duration as the reference, females with ≥15 years of duration were at 1.82-fold (95% CI: 1.70-1.95) non-fatal CHD risk while males with ≥15 years of duration were only at 1.56 (95% CI: 1.45-1.68) fold non-fatal CHD risk, with significant additive interaction (all three measures < 0.05).Conclusions: Long exposure to T2DM imparted a larger risk of non-fatal CHD to Chinese females than to Chinese males. [ABSTRACT FROM AUTHOR]

Aim: Limited joint mobility (LJM) of hand, which is one of a complication of diabetic hand, has a close association with diabetic microangiopathy. However, it remains to be elucidated about the relationships between LJM of hand and subclinical atherosclerosis in patients with type 2 diabetes. Therefore, we conducted a cross-sectional study to evaluate the relationships between LJM of hand and carotid intima-media thickness (IMT) and plaque score in patients with type 2 diabetes.Methods: We evaluated the relationships between LJM of hand, and carotid IMT and plaque score, evaluated by carotid ultrasound examination, in 341 consecutive patients with type 2 diabetes. LJM of hand was diagnosed using a 'prayer sign' or 'table test'.Results: LJM of hand was present in 72 patients. Carotid IMT and plaque score were higher in patients with LJM of hand than those in patients without (1.45±0.66vs. 1.14±0.68mm, P=0.013 and 8.0±5.3vs. 5.4±4.8mm, P<0.001). Multivariate linear regression analysis revealed that LJM of hand was positively correlated with plaque score (β=0.423, P=0.043) after adjusted for age, sex, durations of diabetes, body mass index, hemoglobin A1c, creatinine, uric acid, smoking, hypertension and dyslipidemia.Conclusions: Our results demonstrate a relation between LJM of hand and subclinical atherosclerosis, especially plaque score, in patients with type 2 diabetes. Diagnosis of diabetic hand is simple and non-invasive, and thus is a useful method for assessment of subclinical atherosclerosis in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Microvascular disease is associated with a high risk of macrovascular events in patients with type 2 diabetes, but the impact of macrovascular disease on the risk of microvascular events remains unknown. We sought to evaluate the respective effects of prior microvascular and macrovascular disease on the risk of major outcomes, including microvascular events, in these patients. Methods: Participants in the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) trial (n = 11,140) and the ADVANCE-ON post-trial study (n = 8494) were categorized into 4 groups at baseline: dual absence of microvascular or macrovascular disease (n = 6789), presence of microvascular disease alone (n = 761), macrovascular disease alone (n = 3196), and both (n = 394). Outcomes were all-cause mortality, major macrovascular events (MACE), and major clinical microvascular events. Results: All-cause mortality, MACE, and major clinical microvascular events occurred in 2265 (20%), 2166 (19%), and 807 (7%) participants respectively, during a median follow-up of 9.9 (inter-quartile interval 5.6-10.9) years. The adjusted hazard ratios [95% CI] of death, MACE, and major clinical microvascular events were each greater in patients with baseline microvascular disease (1.43 [1.20-1.71], 1.64 [1.37-1.97], and 4.74 [3.86-5.82], respectively), macrovascular disease (1.43 [1.30-1.57], 2.04 [1.86-2.25], and 1.26 [1.06-1.51]) or both (2.01 [1.65-2.45], 2.92 [2.40-3.55], and 6.30 [4.93-8.06]) compared with those without these conditions. No interaction was observed between baseline microvascular and macrovascular disease for these events. The addition of microvascular disease (change in c-statistic [95% CI] 0.005 [0.002-0.008], p = 0.02) or macrovascular disease (0.005 [0.002-0.007], p < 0.0001) considered separately or together (0.011 [0.007-0.014], p < 0.0001) improved the discrimination and the classification (integrated discrimination improvement (IDI): 0.013 [0.010-0.016], p < 0.001; net reclassification improvement (NRI): 0.021 [0.011-0.032], p < 0.001) of the risk of all-cause mortality. Microvascular disease improved discrimination (0.009 [0.003-0.014]) and classification (IDI: 0.008 [0.006-0.010]; NRI: 0.011 [0.001-0.020]) of MACE. Baseline macrovascular disease modestly enhanced IDI (0.002 [0.001-0.002]) and NRI (0.041 [0.002-0.087]), but not discrimination, of major clinical microvascular events. Conclusions: Microvascular and macrovascular disease are independently associated with the 10-year risk of death, MACE, and major clinical microvascular events in patients with type 2 diabetes. The coexistence of these conditions was associated with the highest risks. [ABSTRACT FROM AUTHOR]

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, LDLcholesterol, smoking, HbA1c, 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. [ABSTRACT FROM AUTHOR]

Background: Vascular calcification (VC) is common in type 2 diabetes, and is associated with cardiovascular complications. Recent preclinical data suggest that metformin inhibits VC both in vitro and in animal models. However, metformin's effects in patients with diabetic VC have not previously been characterized. The present study investigated the association between metformin use and lower-limb arterial calcification in patients with type 2 diabetes and high cardiovascular risk. Methods: The DIACART cross-sectional cohort study included 198 patients with type 2 diabetes but without severe chronic kidney disease. Below-the-knee calcification scores were assessed by computed tomography and supplemented by colour duplex ultrasonography. Data on anti-diabetic drugs were carefully collected from the patients' medical records and during patient interviews. Biochemical and clinical data were studied as potential confounding factors. Results: Metformin-treated patients had a significantly lower calcification score than metformin-free patients (mean ± standard deviation: 2033 ± 4514 and 4684 ± 9291, respectively; p = 0.01). A univariate analysis showed that metformin was associated with a significantly lower prevalence of severe below-the-knee arterial calcification (p = 0.02). VC was not significantly associated with the use of other antidiabetic drugs, including sulfonylureas, insulin, gliptin, and glucagon like peptide-1 analogues. A multivariate logistic regression analysis indicated that the association between metformin use and calcification score (odds ratio [95% confidence interval] = 0.33 [0.11-0.98]; p = 0.045) was independent of age, gender, tobacco use, renal function, previous cardiovascular disease, diabetes duration, neuropathy, retinopathy, HbA1c levels, and inflammation. Conclusions: In patients with type 2 diabetes, metformin use was independently associated with a lower below-theknee arterial calcification score. This association may contribute to metformin's well-known vascular protective effect. Further prospective investigations of metformin's potential ability to inhibit VC in patients with and without type 2 diabetes are now needed to confirm these results. [ABSTRACT FROM AUTHOR]

Objective: To assess health outcomes and the economic burden of hypoglycemia in older patients with type 2 diabetes initiating basal insulin (BI).Research Design and Methods: Medicare Advantage claims data were extracted for patients with type 2 diabetes initiating BI and patients were stratified into two groups: those with medically attended hypoglycemia during the first year of BI treatment (HG group) and those without (non-HG group). Main outcome measures were hospitalization, mortality, healthcare utilization and costs 1 year before and 1 year after BI initiation.Results: Of 31,035 patients included (mean age 72 years [SD 9.2]), 3066 (9.9%; HG group) experienced hypoglycemia during 1 year post-BI initiation. After adjustment for demographic, comorbidity and medication history, hypoglycemia was associated with risk of hospitalization (HR 1.59; 95% CI: 1.53-1.65) and death (HR 1.50; 95% CI: 1.40-1.60). Healthcare utilization was higher pre-index and showed greater increases post-BI initiation in the HG vs. the non-HG group. Per-patient healthcare costs were substantially higher for the HG group than the non-HG group, both pre-index ($54,057 vs. $30,249, respectively) and post-BI initiation ($75,398 vs. $27,753, respectively).Conclusions: Based on available claims data, hypoglycemia during the first year of BI treatment is associated with risk of hospitalization or death in older people, increasing healthcare utilization and costs. Due to the observational nature of this study, causality cannot be attributed, and further prospective studies into the effect of hypoglycemia on health outcomes in this population are warranted. [ABSTRACT FROM AUTHOR]

Aims To analyse depression in German type 2 diabetes patients with or without diabetes complications. Methods Longitudinal data from nationwide general practices in Germany (n = 1,202) were analysed. People initially diagnosed with type 2 diabetes (2004–2013) were identified and 90,412 patients were included (age: 65.5 years, SD: 11.7). The main outcome measure was the first diagnosis of depression (ICD 10: F32, F33) within ten years after index date in patients with and without diabetes complications. Cox proportional hazards models were used to adjust for confounders. Results At baseline, most patients had diabetes complications and 6.4% of them had private insurance. Ten years after type 2 diabetes diagnosis, 30.3% of patients showed symptoms of depression. The prevalence of depression was higher in women than in men (33.7% versus 26.8%), in patients with high HbA1c levels (31.3% when Hb1Ac ≥ 9 versus 27.5% when HbA1c < 7) and in patients with diabetes complications (37.7% when there were more than two complications versus 29.1% when there were no complications). Women and patients without private health insurance were at a higher risk of developing depression. Retinopathy, neuropathy, nephropathy, coronary heart disease, stroke and HbA1c levels higher than 7 were also positively associated with depression. Conclusions Diabetes complications and high HbA1c levels had a substantial impact on depression in primary care patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims To conduct a 10-year, observational follow-up of patients completing PROactive to investigate whether trends of cardiovascular benefit with pioglitazone and imbalances in specific malignancies persisted over time. Methods Macrovascular endpoints and malignancies were compared based on original randomization to pioglitazone or placebo and 'any' versus 'no' pioglitazone use for bladder and prostate cancer. Results Of 4873 patients completing the PROactive trial, 74% entered the follow-up. During follow-up (mean 7.8 years), there were no statistically significant differences in the primary [all-cause mortality, myocardial infarction ( MI), cardiac intervention, stroke, major leg amputation, leg revascularization] or main secondary (death, MI, stroke) endpoints for subjects originally randomized to pioglitazone and placebo, except for leg amputations during follow-up [4.1% pioglitazone, 5.6% placebo; hazard ratio 0.74, 95% confidence interval ( CI) 0.55-0.99; p = 0.046]. During follow-up, the incidence of total malignancies was similar between groups; bladder cancer was reported in 0.8% of patients (n = 14) in the pioglitazone versus 1.2% (n = 21) in the placebo group [relative risk ( RR) 0.65, 95% CI 0.33-1.28], and prostate cancer was reported in 44 men (3.7%) in the pioglitazone versus 29 men (2.5%) in the placebo group ( RR 1.47, 95% CI 0.93-2.34). Conclusions The trends of macrovascular benefits of pioglitazone compared with placebo during PROactive did not persist in the absence of continued pioglitazone during this 10-year follow-up. Trends of decreased bladder cancer and increased prostate cancer were observed in the pioglitazone group during follow-up; however, these imbalances should be interpreted with caution because of the limitations of the observational study design. [ABSTRACT FROM AUTHOR]

Aims To formulate a combined cardiovascular risk score in diabetes that could be useful both to physicians and healthcare funders. Methods Data were derived from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Observational ( ADVANCE-ON) study, a randomized controlled trial (mean duration 5 years) with a post-randomization follow-up (mean 4.9 years), that included 11 140 high-risk patients with diabetes. The outcome analysed was the occurrence of either fatal or non-fatal macrovascular or renal disease. A Cox regression model was used to determine weightings in the risk score. The resultant score was recalibrated to each of three major global regions, as covered by the ADVANCE-ON study. Results Over a median of 9.9 years, 1145 patients experienced at least one component of the combined outcome event. The resultant score, the AD-ON risk score, incorporated 13 demographic or clinical variables. Its discrimination was modest [c-statistic = 0.668 (95% confidence interval 0.651, 0.685)] but its calibration was excellent (predicted and observed risks coincided well, within disparate global regions). In terms of the integrated discrimination improvement index, its performance was marginally superior, over a 10-year risk horizon, to existing risk scores in clinical use, from a restricted version of the same data, for macrovascular and renal disease separately. Conclusions The AD-ON risk score has advantages over the existing vascular risk scores in diabetes that used data from the original ADVANCE trial, which treat macrovascular and renal diseases separately. These advantages include its simplicity of use and global application. [ABSTRACT FROM AUTHOR]

Objective We hypothesize that in type 1 diabetes vasa vasorum (VV) are affected by microangiopathic changes. For this purpose, we assessed the status of the VV signal in patients with type 1 diabetes. Methods The VV signal at the arterial adventitia of the common carotid artery was evaluated by contrast-enhanced ultrasound imaging. The VV contrast agent signal was quantified in an plaque-free arterial segment as the ratio of the adventitial signal and that of the lumen of the artery. We studied 113 type 1 diabetic patients, 60 with and 53 without retinopathy and without known cardiovascular disease, and a group of 78 non-diabetic subjects free of cardiovascular risk factors. All study subjects underwent a clinical evaluation. Results The mean ± standard deviation VV signal of healthy subjects was 0.562 ± 0.135. Type 1 diabetic patients showed a higher adventitial VV signal (0.723 ± 0.128) than non-diabetic subjects (P < 0.0001). After adjustment for cardiovascular risk confounders, this difference remained significant. No differences in VV signal, or common carotid intima-media thickness, between subjects with and without retinopathy were found. Conclusions Type 1 diabetic patients, independently of their retinopathy status, show an increased angiogenesis of the VV of the common carotid artery compared with non-diabetic subjects. Diabetic microangiopathy, that according to our results would also affect the wall of the large arteries, could be a factor contributing to atherosclerosis in type 1 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Aims To compare diabetes-associated secondary healthcare utilization in patients with type 2 diabetes ( T2DM) prescribed sulphonylureas ( SUs) versus other oral antihyperglycaemic agents ( OHAs) as an add-on to metformin monotherapy (metformin + SU vs metformin + OHA). Methods This retrospective cohort study used data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics. Adults with T2DM initiated on metformin + SU or metformin + OHA from April 2003 to March 2012 were identified. Patients were matched using propensity scores. Diabetes-associated secondary healthcare visits were counted from >6 months post-initiation of dual therapy until treatment change or end of follow-up. Outcomes were calculated as rate ratios, adjusted for over-dispersion using negative binomial regression and propensity score for covariates. Results After propensity score matching, 1704 patients were included in each cohort. For the primary objective (diabetes-associated inpatient and outpatient visits combined), the metformin + SU cohort had a directionally higher rate of diabetes-associated secondary healthcare utilization than the metformin + OHA cohort [adjusted rate ratio 1.12, 95% confidence interval ( CI) 0.97-1.29]. For the secondary outcomes, the adjusted rate ratio was 1.38 (95% CI 0.95-2.00) for inpatient admissions and 1.10 (95% CI 0.95-1.28) for outpatient visits. Macrovascular complications, accounting for 77.2% of inpatient admissions, occurred at a statistically significantly higher rate in the metformin + SU cohort than in the metformin + OHA cohort (adjusted rate ratio 1.77, 95% CI 1.15-2.71). Conclusions This study found a statistically significant higher rate of inpatient admissions for macrovascular complications and cardiology outpatient visits and, overall, a directionally higher rate of secondary healthcare utilization for patients prescribed metformin + SU than for those prescribed metformin + OHA. This adds to the evidence that long-term and health economic outcomes should be considered in treatment decisions for patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims To report baseline characteristics and cardiovascular ( CV) risk management by region, age, sex and CV event type for 14 724 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin ( TECOS), a randomized, double-blind, placebo-controlled trial exploring whether sitagliptin added to usual type 2 diabetes ( T2DM) care affects time to first event in the composite endpoint of CV death, non-fatal myocardial infarction ( MI), non-fatal stroke or unstable angina hospitalization. Methods TECOS enrolled patients aged ≥50 years, with T2DM and CV disease from 38 countries in five regions: North America, Eastern Europe, Western Europe, Asia Pacific and Latin America. Participants had a glycated haemoglobin concentration of 6.5-8.0% (48-64 mmol/mol) and were receiving oral and/or insulin-based antihyperglycaemic therapy. Analysis of variance or logistic regression was used to compare regional CV risk factors and treatments, referenced to North America. Results Patients had a mean [1 standard deviation (SD)] age of 66 (8) years, a median (interquartile range) diabetes duration of 9.4 (4.9, 15.3) years, and a mean (SD) body mass index 30.2 (5.7) kg/m2. Compared with North America, blood pressure and lipids were higher in all regions. Statin use was lowest in Latin America (68%) and Eastern Europe (70%) and aspirin use was lower compared with North America in all regions except Asia Pacific. Achievement of treatment targets did not differ by age group or insulin usage, but men and participants with previous MI were more likely than women or those with previous stroke or peripheral arterial disease to reach most treatment goals. Conclusion The CV risk factors of participants in TECOS are reasonably controlled, but differences in CV risk management according to region, sex and history of disease exist. This diversity will enhance the generalizability of the trial results. [ABSTRACT FROM AUTHOR]

Diabetes is associated with the development of premature atherosclerotic disease, including coronary heart disease and acute coronary syndromes. A late consequence of this process is the development of chronic heart failure, which contributes to the increased cardiovascular ( CV) morbidity and mortality associated with diabetes. Reduction of cholesterol with statins and intensive blood pressure control significantly reduce vascular events in people with diabetes. Intensive treatment of glycaemia reduces microvascular complications, especially retinopathy and nephropathy, but has only a modest effect in reducing macrovascular complications. Attention has therefore focused on individual antidiabetic drugs or drug classes to determine if these have effects in reducing CV events beyond the reduction of blood glucose. Glucagon-like peptide 1 ( GLP-1) receptor agonists are a class of injected therapies that enhance the incretin effect, increasing insulin release from the pancreas and reducing glucagon production. They also have a central effect, increasing satiety, and in routine clinical use are associated with reductions in body weight. Another possibly beneficial effect of these drugs is a slight but significant reduction in systolic blood pressure. Data from cohort studies have indicated no increase in CV events with GLP-1 receptor agonists, and perhaps some reductions in CV events. The safety and possible CV benefit of these drugs is now being tested in large, multicentre, randomized, placebo-controlled trials. [ABSTRACT FROM AUTHOR]