Predictive factors and the management of hyperglycemia in patients with acromegaly and Cushing's disease receiving pasireotide treatment: post hoc analyses from the SOM230B2219 study.

Introduction: Pasireotide, a somatostatin receptor ligand, is approved for treating acromegaly and Cushing's disease (CD). Hyperglycemia during treatment can occur because of the drug's mechanism of action, although treatment discontinuation is rarely required. The prospective, randomized, Phase IV SOM230B2219 (NCT02060383) trial was designed to assess optimal management of pasireotide-associated hyperglycemia. Here, we investigated predictive factors for requiring antihyperglycemic medication during pasireotide treatment. Methods: Participants with acromegaly or CD initiated long-acting pasireotide 40 mg/28 days intramuscularly (acromegaly) or pasireotide 600 µg subcutaneously twice daily during pre-randomization (≤16 weeks). Those who did not need antihyperglycemic medication, were managed with metformin, or received insulin from baseline entered an observational arm ending at 16 weeks. Those who required additional/alternative antihyperglycemic medication to metformin were randomized to incretin-based therapy or insulin for an additional 16 weeks. Logistic-regression analyses evaluated quantitative and qualitative factors for requiring antihyperglycemic medication during pre-randomization. Results: Of 190 participants with acromegaly and 59 with CD, 88 and 15, respectively, did not need antihyperglycemic medication; most were aged <40 years (acromegaly 62.5%, CD 86.7%), with baseline glycated hemoglobin (HbA1c) <6.5% (<48 mmol/mol; acromegaly 98.9%, CD 100%) and fasting plasma glucose (FPG) <100 mg/dL (<5.6 mmol/L; acromegaly 76.1%, CD 100%). By logistic regression, increasing baseline HbA1c (odds ratio [OR] 3.6; P=0.0162) and FPG (OR 1.0; P=0.0472) and history of diabetes/pre-diabetes (OR 3.0; P=0.0221) predicted receipt of antihyperglycemic medication in acromegaly participants; increasing baseline HbA1c (OR 12.6; P=0.0276) was also predictive in CD participants. Investigator-reported hyperglycemia-related adverse events were recorded in 47.9% and 54.2% of acromegaly and CD participants, respectively, mainly those with diabetes/pre-diabetes. Conclusion: Increasing age, HbA1c, and FPG and pre-diabetes/diabetes were associated with increased likelihood of requiring antihyperglycemic medication during pasireotide treatment. These risk factors may be used to identify those who need more vigilant monitoring to optimize outcomes during pasireotide treatment.

Short, frequent, light-intensity walking activity improves postprandial vascular-inflammatory biomarkers in people with type 1 diabetes: The SIT-LESS randomized controlled trial.

AIM: To examine the effect of interrupting prolonged sitting with short, frequent, light-intensity activity on postprandial cardiovascular markers in people with type 1 diabetes (T1D). MATERIALS AND METHODS: In a randomized crossover trial, 32 adults with T1D (mean ± SD age 28 ± 5 years, glycated haemoglobin 67.9 ± 12.6 mmol/mol, 17 women) completed two 7-h laboratory visits separated by >7 days. Participants either remained seated for 7 h (SIT) or interrupted sitting with 3-min bouts of self-paced walking at 30-min intervals commencing 1 h after each meal (SIT-LESS). Physical activity, insulin regimen, experimental start times, and meal consumption were standardized during each arm. Plasma levels of interleukin (IL)-1ß, tumour necrosis factor (TNF)-α, plasminogen activator inhibitor (PAI)-1 and fibrinogen were sampled at baseline, 3.5 and 7 h, and assessed for within- and between-group effects using a repeated measures ANOVA. The estimated glucose disposal rate was used to determine the insulin resistance status. RESULTS: Vascular-inflammatory parameters were comparable between SIT and SIT-LESS at baseline (p > .05). TNF-α, IL-1ß, PAI-1 and fibrinogen increased over time under SIT, whereas these rises were attenuated under SIT-LESS (p < .001). Specifically, over the 7 h under SIT, postprandial increases were detected in TNF-α, IL-1ß, PAI-1 and fibrinogen (+67%, +49%, +49% and +62%, respectively; p < .001 for all). Conversely, the SIT-LESS group showed no change in IL-1ß (-9%; p > .50), whereas reductions were observed in TNF-α, PAI-1 and fibrinogen (-22%, -42% and -44%, respectively; p < .001 for all). The intervention showed enhanced effects in insulin-resistant individuals with T1D. CONCLUSIONS: Interrupting prolonged sitting with light-intensity activity ameliorates postprandial increases in vascular-inflammatory markers in T1D. TRIAL REGISTRATION: The trial was prospectively registered (ISRCTN13641847).

Plasma levels of mannan-binding lectin-associated serine proteases are increased in type 1 diabetes patients with insulin resistance.

Activation of the lectin pathway of the complement system, as demonstrated by elevated levels of mannan-binding lectin proteins (MBL), contributes to vascular pathology in type 1 diabetes (T1D). Vascular complications are greatest in T1D individuals with concomitant insulin resistance (IR), however, whether IR amplifies activiation of the lectin pathway in T1D is unknown. We pooled pretreatment data from two RCTs and performed a cross-sectional analysis on 46 T1D individuals. We employed estimated glucose disposal rate (eGDR), a validated IR surrogate with cut-points of: <5.1, 5.1-8.7, and > 8.7 mg/kg/min to determine IR status, with lower eGDR values conferring higher degrees of IR. Plasma levels of MBL-associated proteases (MASP-1, MASP-2, and MASP-3) and their regulatory protein MAp44 were compared among eGDR classifications. In a subset of 14 individuals, we assessed change in MASPs and MAp44 following improvement in IR. We found that MASP-1, MASP-2, MASP-3, and MAp44 levels increased in a stepwise fashion across eGDR thresholds with elevated MASPs and MAp44 levels conferring greater degrees of IR. In a subset of 14 patients, improvement in IR was associated with significant reductions in MASPs, but not MAp44, levels. In conclusion, IR in T1D amplifies levels of MASP-1/2/3 and their regulator MAp44, and improvement of IR normalizes MASP-1/2/3 levels. Given that elevated levels of these proteins contribute to vascular pathology, amplification of the lectin pathway of the complement system may offer mechanistic insight into the relationship between IR and vascular complications in T1D.

Progression of insulin resistance in individuals with type 1 diabetes: A retrospective longitudinal study on individuals from Thailand.

AIMS: To investigate temporal changes in glycaemic control and weight contributing to insulin resistance (IR), in Thai individuals with type 1 diabetes (T1D). METHODS: Longitudinal data of 69 individuals with T1D were retrospectively collected over a median follow-up of 7.2 years. The estimated glucose disposal rate (eGDR), a marker of IR, was calculated using an established formula. Individuals were assigned as insulin-sensitive T1D (the latest eGDR≥8 mg/kg/min), or insulin-resistant T1D/double diabetes (the latest eGDR<8 mg/kg/min). Generalised linear mixed model was employed to compare the temporal patterns of HbA1c, BMI, and eGDR between the two groups. RESULTS: 26 insulin-resistant T1D had a gradual decline in eGDR, corresponding with increased weight and HbA1c. In contrast, 43 insulin-sensitive T1D had stable insulin sensitivity with an improvement in HbA1c over time, associated with a modest weight gain. Fluctuations of glucose levels were observed during the early diabetes course leading to unstable eGDR, thus limiting the use of eGDR to classify insulin-resistant T1D. CONCLUSION: T1D individuals who eventually develop IR are likely to experience early increasing IR over time. In contrast, those who ultimately do not have IR, maintain their insulin sensitivity throughout their course at least in the medium term.

The Cellular and Protein Arms of Coagulation in Diabetes: Established and Potential Targets for the Reduction of Thrombotic Risk.

Diabetes is a metabolic condition with a rising global prevalence and is characterised by abnormally high blood glucose levels. Cardiovascular disease (CVD) accounts for the majority of deaths in diabetes and, despite improvements in therapy, mortality and hospitalisations in this cohort remain disproportionally higher compared to individuals with normal glucose metabolism. One mechanism for increased CVD risk is enhanced thrombosis potential, due to altered function of the cellular and acellular arms of coagulation. Different mechanisms have been identified that mediate disordered blood clot formation and breakdown in diabetes, including dysglycaemia, insulin resistance, and metabolic co-morbidities. Collectively, these induce platelet/endothelial dysfunction and impair the fibrinolytic process, thus creating a prothrombotic milieu. Despite these abnormalities, current antithrombotic therapies are largely similar in diabetes compared to those without this condition, which explains the high proportion of patients experiencing treatment failure while also displaying an increased risk of bleeding events. In this narrative review, we aimed to summarise the physiological functioning of haemostasis followed by the pathological effects of diabetes mellitus on platelets and the fibrin network. Moreover, we carefully reviewed the literature to describe the current and future therapeutic targets to lower the thrombosis risk and improve vascular outcomes in diabetes.

Interrupting prolonged sitting with frequent short bouts of light-intensity activity in people with type 1 diabetes improves glycaemic control without increasing hypoglycaemia: The SIT-LESS randomised controlled trial.

AIM: To examine the impact of interrupting prolonged sitting with frequent short bouts of light-intensity activity on glycaemic control in people with type 1 diabetes (T1D). MATERIALS AND METHODS: In total, 32 inactive adults with T1D [aged 27.9 ± 4.7 years, 15 men, diabetes duration 16.0 ± 6.9 years and glycated haemoglobin 8.4 ± 1.4% (68 ± 2.3 mmol/mol)] underwent two 7-h experimental conditions in a randomised crossover fashion with >7-day washout consisting of: uninterrupted sitting (SIT), or, interrupted sitting with 3-min bouts of self-paced walking at 30-min intervals (SIT-LESS). Standardised mixed-macronutrient meals were administered 3.5 h apart during each condition. Blinded continuous glucose monitoring captured interstitial glucose responses during the 7-h experimental period and for a further 48-h under free-living conditions. RESULTS: SIT-LESS reduced total mean glucose (SIT 8.2 ± 2.6 vs. SIT-LESS 6.9 ± 1.7 mmol/L, p = .001) and increased time in range (3.9-10.0 mmol/L) by 13.7% (SIT 71.5 ± 9.5 vs. SIT-LESS 85.1 ± 7.1%, p = .002). Hyperglycaemia (>10.0 mmol/L) was reduced by 15.0% under SIT-LESS (SIT 24.2 ± 10.8 vs. SIT-LESS 9.2 ± 6.4%, p = .002), whereas hypoglycaemia exposure (<3.9 mmol/L) (SIT 4.6 ± 3.0 vs. SIT-LESS 6.0 ± 6.0%, p = .583) was comparable across conditions. SIT-LESS reduced glycaemic variability (coefficient of variation %) by 7.8% across the observation window (p = .021). These findings were consistent when assessing discrete time periods, with SIT-LESS improving experimental and free-living postprandial, whole-day and night-time glycaemic outcomes (p < .05). CONCLUSIONS: Interrupting prolonged sitting with frequent short bouts of light-intensity activity improves acute postprandial and 48-h glycaemia in adults with T1D. This pragmatic strategy is an efficacious approach to reducing sedentariness and increasing physical activity levels without increasing risk of hypoglycaemia in T1D.

Repeated recurrence of bilateral gigantomastia after subcutaneous mastectomy caused by tumoral pseudoangiomatous stromal hyperplasia: a case report and review of literature.

Pseudoangiomatous stromal hyperplasia (PASH) is an uncommon benign proliferative mesenchymal lesion of the breast with a hormonal-sensitive nature. Various manifestations of PASH, ranging from an incidental microscopic finding in a tissue biopsy to a large palpable mass or bilateral gigantomastia, have been described. For tumoral PASH, surgical excision is indicated for a growing and symptomatic mass with a small chance of recurrence. A recurrence of bilateral gigantomastia after surgical excision or reduction mammoplasty is not common but has been occasionally reported, leading to further mastectomy. Repeated recurrence of bilateral gigantomastia is extremely rare. Herein, we report a case of a 13-year-old girl who presented with the third recurrence of bilateral gigantomastia caused by tumoral PASH, after undergoing bilateral reduction mammoplasty, and later subcutaneous mastectomy. Precocious puberty occurred early in this child at the age of 9 years, which may have been a factor unmasking PASH at this young age. The incomplete removal of the PASH could also have been a recurrence risk in our case as extended masses underneath the pectoralis muscle were later identified on the MRI study. This highlights the advantage of preoperative imaging in cases with a very large tumoral PASH in order to maximize the chance of complete tumor removal.

Dietary fat intake is associated with insulin resistance and an adverse vascular profile in patients with T1D: a pooled analysis.

BACKGROUND: Insulin resistance (IR) increases vascular risk in individuals with Type 1 Diabetes (T1D). We aimed to investigate the relationship between dietary intake and IR, as well as vascular biomarkers in T1D. METHODS: Baseline data from three randomised controlled trials were pooled. Estimated glucose disposal rate (eGDR) was used as an IR marker. Employing multivariate nutrient density substitution models, we examined the association between macronutrient composition and IR/vascular biomarkers (tumour necrosis factor-α, fibrinogen, tissue factor activity, and plasminogen activator inhibitor-1). RESULTS: Of the 107 patients, 50.5% were male with mean age of 29 ± 6 years. Those with lower eGDR were older with a longer diabetes duration, higher insulin requirements, and an adverse vascular profile (p < 0.05). Patients with higher degrees of IR had higher total energy intake (3192 ± 566 vs. 2772 ± 268 vs. 2626 ± 395 kcal/d for eGDR < 5.1 vs. 5.1-8.6 vs. ≥ 8.7 mg/kg/min, p < 0.001) and consumed a higher absolute and proportional amount of fat (47.6 ± 18.6 vs. 30.4 ± 8.1 vs. 25.8 ± 10.4%, p < 0.001). After adjusting for total energy intake, age, sex, and diabetes duration, increased carbohydrate intake offset by an isoenergetic decrease in fat was associated with higher eGDR (ß = 0.103, 95% CI 0.044-0.163). In contrast, increased dietary fat at the expense of dietary protein intake was associated with lower eGDR (ß = - 0.119, 95% CI - 0.199 to - 0.040). Replacing fat with 5% isoenergetic amount of carbohydrate resulted in decreased vascular biomarkers (p < 0.05). CONCLUSION: Higher fat, but not carbohydrate, intake is associated with increased IR and an adverse vascular profile in patients with T1D.

Plasmin Inhibitor in Health and Diabetes: Role of the Protein as a Therapeutic Target.

The vascular obstructive thrombus is composed of a mesh of fibrin fibers with blood cells trapped in these networks. Enhanced fibrin clot formation and/or suppression of fibrinolysis are associated with an increased risk of vascular occlusive events. Inhibitors of coagulation factors and activators of plasminogen have been clinically used to limit fibrin network formation and enhance lysis. While these agents are effective at reducing vascular occlusion, they carry a significant risk of bleeding complications. Fibrin clot lysis, essential for normal hemostasis, is controlled by several factors including the incorporation of antifibrinolytic proteins into the clot. Plasmin inhibitor (PI), a key antifibrinolytic protein, is cross-linked into fibrin networks with higher concentrations of PI documented in fibrin clots and plasma from high vascular risk individuals. This review is focused on exploring PI as a target for the prevention and treatment of vascular occlusive disease. We first discuss the relationship between the PI structure and antifibrinolytic activity, followed by describing the function of the protein in normal physiology and its role in pathological vascular thrombosis. Subsequently, we describe in detail the potential use of PI as a therapeutic target, including the array of methods employed for the modulation of protein activity. Effective and safe inhibition of PI may prove to be an alternative and specific way to reduce vascular thrombotic events while keeping bleeding risk to a minimum. Key Points Plasmin inhibitor (PI) is a key protein that inhibits fibrinolysis and stabilizes the fibrin network.This review is focused on discussing mechanistic pathways for PI action, role of the molecule in disease states, and potential use as a therapeutic target.

Glucose variability is associated with an adverse vascular profile but only in the presence of insulin resistance in individuals with type 1 diabetes: An observational study.

AIMS/HYPOTHESIS: We hypothesised that the detrimental effect of high glucose variability (GV) in people with type 1 diabetes is mainly evident in those with concomitant insulin resistance. METHODS: We conducted secondary analyses on continuous glucose monitoring (CGM) using baseline observational data from three randomised controlled trials and assessed the relationship with established vascular markers. We used standard CGM summary statistics and principal component analysis to generate individual glucose variability signatures for each participant. Cluster analysis was then employed to establish three GV clusters (low, intermediate, or high GV, respectively). The relationship with thrombotic biomarkers was then investigated according to insulin resistance, assessed as estimated glucose disposal rate (eGDR). RESULTS: Of 107 patients, 45%, 37%, and 18% of patients were assigned into low, intermediate, and high GV clusters, respectively. Thrombosis biomarkers (including fibrinogen, plasminogen activator inhibitor-1, tissue factor activity, and tumour necrosis factor-alpha) increased in a stepwise fashion across all three GV clusters; this increase in thrombosis markers was evident in the presence of low but not high eGDR and at a threshold of eGDR <5.1 mg/kg/min. CONCLUSION: Higher GV is associated with increased thrombotic biomarkers in type 1 diabetes but only in those with concomitant insulin resistance.

The relative contribution of diurnal and nocturnal glucose exposures to HbA1c in type 1 diabetes males: a pooled analysis.

Purpose: The exact contribution of daily glucose exposure to HbA1c in people with type 1 diabetes (T1D) remains controversial. We examined the contribution of pre- and postprandial glycaemia, nocturnal and early-morning glycaemia, and glycaemic variability to HbA1c levels in T1D. In this analysis, we used clinical data, namely age, BMI and HbA1c, as well as glycaemic metrics (24-h glycaemia, postprandial, nocturnal, early-morning glycaemia, wake-up glucose, and glycaemic variability) obtained over a four-week period of continuous glucose monitoring (CGM) wear in thirty-two males with T1D. Methods: The trapezoid method was used estimate the incremental area under the glucose curve (iAUC) for 24-h, postprandial (3-h period following breakfast, lunch, and dinner, respectively), nocturnal (between 24:00-04:00 AM), and early-morning (2-h period 2-h prior to wake-up) glycaemia. Linear regression analysis was employed whereby CGM-derived glycaemic metrics were explanatory variables and HbA1c was the outcome. Results: Thirty-two T1D males (mean ± SD: age 29 ± 4 years; HbA1c 7.3 ± 0.9% [56 ± 13 mmol/mol]; BMI 25.80 ± 5.01 kg/m2) were included in this analysis. In linear models adjusted for age and BMI, HbA1c was associated with 24-h mean glucose (r 2 = 0.735, p < 0.001), SD (r 2 = 0.643, p = 0.039), and dinner iAUC (r 2 = 0.711, p = 0.001). CGM-derived metrics and non-glycaemic factors explained 77% of the variance in HbA1c, in which postprandial glucose accounted for 32% of the variance explained. The single greatest contributor to HbA1c was dinner iAUC resulting in 0.6%-point (~7 mmol/mol) increase in HbA1c per SD increase in dinner iAUC. Conclusions: Using comprehensive CGM profiling, we show that postprandial glucose, specifically evening-time postprandial glucose, is the single largest contributing factor to HbA1c in T1D. Trial registration number: NCT02204839 (July 30th 2014); NCT02595658 (November 3rd 2015).

Application of Machine Learning to Assess Interindividual Variability in Rapid-Acting Insulin Responses After Subcutaneous Injection in People With Type 1 Diabetes.

OBJECTIVES: Circulating insulin concentrations mediate vascular-inflammatory and prothrombotic factors. However, it is unknown whether interindividual differences in circulating insulin levels are associated with different inflammatory and prothrombotic profiles in type 1 diabetes (T1D). We applied an unsupervised machine-learning approach to determine whether interindividual differences in rapid-acting insulin levels associate with parameters of vascular health in patients with T1D. METHODS: We re-analyzed baseline pretreatment meal-tolerance test data from 2 randomized controlled trials in which 32 patients consumed a mixed-macronutrient meal and self-administered a single dose of rapid-acting insulin individualized by carbohydrate counting. Postprandial serum insulin, tumour necrosis factor (TNF)-alpha, plasma fibrinogen, human tissue factor (HTF) activity and plasminogen activator inhibitor-1 (PAI-1) were measured. Two-step clustering categorized individuals based on shared clinical characteristics. For analyses, insulin pharmacokinetic summary statistics were normalized, allowing standardized intraindividual comparisons. RESULTS: Despite standardization of insulin dose, individuals exhibited marked interpersonal variability in peak insulin concentrations (48.63%), time to peak (64.95%) and insulin incremental area under the curve (60.34%). Two clusters were computed: cluster 1 (n=14), representing increased serum insulin concentrations; and cluster 2 (n=18), representing reduced serum insulin concentrations (cluster 1: 389.50±177.10 pmol/L/IU h-1; cluster 2: 164.29±41.91 pmol/L/IU h-1; p<0.001). Cluster 2 was characterized by increased levels of fibrinogen, PAI-1, TNF-alpha and HTF activity; higher glycated hemoglobin; increased body mass index; lower estimated glucose disposal rate (increased insulin resistance); older age; and longer diabetes duration (p<0.05 for all analyses). CONCLUSIONS: Reduced serum insulin concentrations are associated with insulin resistance and a prothrombotic milieu in individuals with T1D, and therefore may be a marker of adverse vascular outcome.

Geographical inequality in service utilization for primary aldosteronism screening: spatial epidemiological study in Southern Thailand.

BACKGROUND: Primary aldosteronism (PA), the most common cause of secondary hypertension is considered as a "major public health issue" due to higher risk of cardiovascular complications compared to blood-pressure-match hypertension and increase in prevalence around the world. In Thailand, though PA screening is provided under the universal health coverage, the service can be offered only at some centers. Hence, the service availability affects an accessibility of health care in patients. Our study aimed to evaluate the service utilization in PA screening and diagnosis in terms of geographical inequality in health resources in Southern Thailand. METHODS: Data of 688 patients who underwent PA screening from 2011 to 2017 were obtained from the electronic database of Songklanagarind Hospital, a super-tertiary center in this region. The patients' residence in the province, district and subdistrict were transformed to a 6-digit numbers corresponding to the global one (GADM©). The areas with PA screening and diagnosis were visualized by disease mapping procedures. A general log linear model was used to identify the factors affecting patient's service accessibility. RESULTS: From the geographic distribution, patients living in or near the area of the super-tertiary center (Songkhla) had high probability of receiving PA screening. The analysis of factors contributing to PA screening by multivariate log-linear model demonstrated that the distance from the super-tertiary center was a predictive factor for screening while the presence of endocrinologists and cultural differences were not. The chance of patients living in Songkhla, living less than 200 km, and more than 200 km from Songkhla to receive PA screening was 100, 82, and 66%, respectively. The crude incidence rate of PA in Southern Thailand was 1.66/106 person-years. The provinces located adjacent to the Andaman Sea had the highest incidences of PA (3.62-5.17 patients/106 person-years). CONCLUSIONS: There is still geographical inequality and the strategy to decrease the barrier should be resolved. The policymaker should develop a transfer system of blood tests for PA investigation from the local hospital to reduce the burden such as transportation costs in patients who live far away from the super-tertiary hospital. In addition, PA screening should be implemented in hypertension care plan.

Risk factors associated with mortality in individuals with type 2 diabetes following an episode of severe hypoglycaemia. Results from a randomised controlled trial.

BACKGROUND: Severe hypoglycaemia may pose significant risk to individuals with type 2 diabetes (T2D), and evidence surrounding strategies to mitigate this risk is lacking. METHODS: Data was re-analysed from a previous randomised controlled trial studying the impact of nurse-led intervention on mortality following severe hypoglycaemia in the community. A Cox-regression model was used to identify baseline characteristics associated with mortality and to adjust for differences between groups. Kaplan-Meier curves were created to demonstrate differences in outcome between groups across different variables. RESULTS: A total of 124 participants (mean age = 75, 56.5% male) were analysed. In univariate analysis, Diabetes Severity Score (DSS), age and insulin use were baseline factors found to correlate to mortality, while HbA1C and established cardiovascular disease showed no significant correlations. Hazard ratio favoured the intervention (0.68, 95% CI: 0.38-1.19) and in multivariate analysis, only DSS demonstrated a relationship with mortality. Comparison of Kaplan-Meier curves across study groups suggested the intervention is beneficial irrespective of HbA1c, diabetes severity score or age. CONCLUSION: While DSS predicts mortality following severe community hypoglycaemia in individuals with T2D, a structured nurse-led intervention appears to reduce the risk of death across a range of baseline parameters.

Fibrinolysis in Acute and Chronic Cardiovascular Disease.

The formation of an obstructive thrombus within an artery remains a major cause of mortality and morbidity worldwide. Despite effective inhibition of platelet function by modern antiplatelet therapies, these agents fail to fully eliminate atherothrombotic risk. This may well be related to extensive vascular disease, beyond the protective abilities of the treatment agents used. However, recent evidence suggests that residual vascular risk in those treated with modern antiplatelet therapies is related, at least in part, to impaired fibrin clot lysis. In this review, we attempt to shed more light on the role of hypofibrinolysis in predisposition to arterial vascular events. We provide a brief overview of the coagulation system followed by addressing the role of impaired fibrin clot lysis in acute and chronic vascular conditions, including coronary artery, cerebrovascular, and peripheral vascular disease. We also discuss the role of combined anticoagulant and antiplatelet therapies to reduce the risk of arterial thrombotic events, addressing both efficacy and safety of such an approach. We conclude that impaired fibrin clot lysis appears to contribute to residual thrombosis risk in individuals with arterial disease on antiplatelet therapy, and targeting proteins in the fibrinolytic system represents a viable strategy to improve outcome in this population. Future work is required to refine the antithrombotic approach by modulating pathological abnormalities in the fibrinolytic system and tailoring therapy according to the need of each individual.

Antithrombotic therapy in diabetes: which, when, and for how long?

Cardiovascular disease remains the main cause of mortality in individuals with diabetes mellitus (DM) and also results in significant morbidity. Premature and more aggressive atherosclerotic disease, coupled with an enhanced thrombotic environment, contributes to the high vascular risk in individuals with DM. This prothrombotic milieu is due to increased platelet activity together with impaired fibrinolysis secondary to quantitative and qualitative changes in coagulation factors. However, management strategies to reduce thrombosis risk remain largely similar in individuals with and without DM. The current review covers the latest in the field of antithrombotic management in DM. The role of primary vascular prevention is discussed together with options for secondary prevention following an ischaemic event in different clinical scenarios including coronary, cerebrovascular, and peripheral artery diseases. Antiplatelet therapy combinations as well as combination of antiplatelet and anticoagulant agents are examined in both the acute phase and long term, including management of individuals with sinus rhythm and those with atrial fibrillation. The difficulties in tailoring therapy according to the variable atherothrombotic risk in different individuals are emphasized, in addition to the varying risk within an individual secondary to DM duration, presence of complications and predisposition to bleeding events. This review provides the reader with an up-to-date guide for antithrombotic management of individuals with DM and highlights gaps in knowledge that represent areas for future research, aiming to improve clinical outcome in this high-risk population.

Body mass index, estimated glucose disposal rate and vascular complications in type 1 diabetes: Beyond glycated haemoglobin.

AIMS: To understand the relationship between insulin resistance (IR), assessed as estimated glucose disposal rate (eGDR), and microvascular/macrovascular complications in people with type 1 diabetes. MATERIALS AND METHODS: Individuals with a confirmed diagnosis of type 1 diabetes were included in this cross-sectional study. BMI was categorised into normal weight (18.0-24.9 kg m-2 ), overweight (25.0-29.9 kg m-2 ) and obese groups (≥30.0 kg m-2 ). We categorised eGDR into four groups: eGDR >8, 6-7.9, 4-5.9 and <4 mg kg-1  min-1 . Multiple logistic regression was used to identify associations with vascular complications, after adjusting for relevant confounders. RESULTS: A total of 2151 individuals with type 1 diabetes were studied. Median [interquartile range (IQR)] age was 41.0 [29.0, 55.0] with diabetes duration of 20.0 [11, 31] years. Odds ratio (OR) for retinopathy and nephropathy in obese compared with normal weight individuals was 1.64 (95% CI: 1.24-2.19; p = 0.001) and 1.62 (95% CI: 1.10-2.39; p = 0.015), while the association with cardiovascular disease just failed to reach statistical significance (OR 1.66 [95% CI: 0.97-2.86; p = 0.066]). Comparing individuals with eGDR ≥8 mg kg-1  min-1 and <4 mg kg-1  min-1 showed OR for retinopathy, nephropathy and macrovascular disease of 4.84 (95% CI: 3.36-6.97; p < 0.001), 8.35 (95% CI: 4.86-14.34; p < 0.001) and 13.22 (95% CI: 3.10-56.38; p < 0.001), respectively. Individuals with the highest eGDR category (≥8 mg kg-1  min-1 ) had the lowest complication rates irrespective of HbA1c levels. CONCLUSIONS: Obesity is prevalent in type 1 diabetes and diabetes complications are not only related to glucose control. IR, assessed as eGDR, is strongly associated with both microvascular and macrovascular complications, regardless of HbA1c levels.

Estimated glucose disposal rate demographics and clinical characteristics of young adults with type 1 diabetes mellitus: A cross-sectional pilot study.

BACKGROUND: Estimated glucose disposal rate (eGDR) is a practical measure of Insulin Resistance (IR) which can be easily incorporated into clinical practice. We profiled eGDR in younger adults with type 1 diabetes mellitus (T1DM) by their demographic and clinical characteristics. METHODS: In this single centre study, medical records of TIDM were assessed and eGDR tertiles correlated with demographic and clinical variables. RESULTS: Of 175 T1DM individuals, 108 (61.7%) were males. Mean age (±SD) was 22.0 ± 1.6 years and median time from diagnosis 11.0 years (range 1-23). Individuals were predominantly Caucasian (81.7%), with 27.4% being overweight (BMI: 25-30 kg/m2) and 13.7% obese (BMI > 30 kg/m2). Mean total cholesterol (TC) levels were significantly lower in high and middle eGDR tertiles (4.4 ± 1 and 4.3 ± 0.8 mmol/l, respectively) compared with low eGDR tertile (4.8 ± 1, p < 0.05 for both). Triglyceride (TG) levels showed a similar trend at 1.1 ± 0.5 and 1.1 ± 0.5 mmol/l for high and middle eGDR tertile compared to low eGDR tertile (1.5 ± 1 mmol/l, p < 0.05 for both). Renal function was similar across eGDR tertiles and no difference in retinopathy was detected. CONCLUSION: TC and TG are altered in individuals with T1DM and low eGDR, suggesting that this subgroup requires optimal lipid management to ameliorate their vascular risk.

Performance of the unilateral AV/IVC index in primary hyperaldosteronism subtype prediction: A validation study in a single tertiary centre.

BACKGROUND: Failure of cannulation of the right adrenal vein is frequent during AVS for investigation of primary aldosteronism (PA). The aldosterone:cortisol ratio of either adrenal vein compared with the inferior vena cava (AV/IVC index) has been proposed to differentiate between unilateral and bilateral disease, and aid in lateralization of unilateral disease. METHODS: Sixty-two patients with unilateral or bilateral PA identified by either successful bilateral (45 patients) or unilateral (17 patients) adrenal vein cannulation, and with biochemical remission following surgery were enrolled into the analysis. The diagnostic performances of the previously identified AV/IVC index cut-offs of ≥5.5 to predict ipsilateral disease and ≤0.5 to predict contralateral disease were validated using data from the entire cohort. RESULTS: Fifty-three patients had unilateral PA and 9 patients bilateral PA. The area under ROC curve (AUROC) of the AV/IVC cut-off ≤0.5 for identifying unilateral aldosterone secretion from the contralateral adrenal was 0.95 (95% CI; 0.88-0.99), whereas the AUROC of the AV/IVC cut-off ≥5.5 for identifying unilateral aldosterone secretion from ipsilateral adrenal was 0.96 (95% CI; 0.92-0.99). The AV/IVC index cut-off value of 0.5 had 93% sensitivity and 91% specificity, and the AV/IVC index cut-off value of 5.5 had 21% sensitivity and 100% specificity. The optimal AV/IVC cut-offs to achieve 100% specificity for our cohort were >2.4 and <0.1 to predict ipsilateral and contralateral disease. CONCLUSION: Our data confirm that the AV/IVC index is a potential tool for subtype classification and lateralization in patients with PA in the setting of failed bilateral, but successful unilateral, adrenal vein cannulation during AVS.

Construction of a predictive scoring system as a guide to screening and confirmation of the diagnosis of primary aldosteronism.

BACKGROUND: Primary aldosteronism (PA) is the most frequent cause of secondary hypertension. In Southern Thailand, the aldosterone-renin ratio (ARR) is only available within a small number of tertiary centres, necessitating need for a simple clinical assessment to determine the requirement for ARR. OBJECTIVE: This study aimed to identify predictive factors for the diagnosis of PA and generate a predictive scoring system (PSS) for use in screening and diagnosis of PA. PATIENTS AND METHODS: A total of 420 patients aged >15 years with paired plasma aldosterone concentration and plasma renin activity values allowing calculation of ARR were identified from the electronic hospital database between 2011 and 2016. RESULTS: The overall prevalence of PA was 16.7% (range; adrenal incidentaloma 5.6% to hypokalaemia 30%). Predictive factors for diagnosis of PA were as follows: age <60 years, BMI < 25 kg/m2 , presence of diabetes, ≥3 antihypertensive agents, serum sodium ≥ 141 mmol/L and serum potassium < 3.5 mmol/L. A predictive scoring system (PSS) (range -2 to 13) was generated by the coefficients of the variables with ROC curve AUC 0.87 [95% CI: 0.83-0.91]. Using the PSS, a total score <4 provided a robust negative predictive value (sensitivity, 0.97; specificity, 0.48; NPV, 0.99; PPV, 0.27) for PA. In patients at high risk of PA (PAC > 15 ng/dL and PRA < 1.0 ng/mL/hr), a PSS score > 9 had specificity and PPV of 100%, essentially confirming PA in these individuals. CONCLUSION: The proposed PSS for PA will enable more focused and cost-effective use of ARR screening and confirmatory testing. In our cohort, 40% and 42% of patients would not require ARR screening or confirmatory tests, respectively.