Microvascular Events Research Articles

Abstract 17121: Predictors of Death and Major Adverse Cardiovascular Events in the ACCORD Trial Identified by Random Survival Forest Based Machine-Learning

Background: Patients with type 2 diabetes (T2D) are at high risk of cardiovascular (CV) morbidity/mortality. The ACCORD trial (NCT00000620) tested intensive glycemic, lipid and blood pressure interventions on major CV events in 10,251 T2D patients with baseline HbA1c concentration >7.5%. Despite its landmark findings, a data-driven systematic evaluation of predictors for major cardiovascular events among hundreds of ACCORD variables has not been conducted. Methods: Random Survival Forest (RSF), a machine-learning method for survival analysis, identified important predictors for total mortality (TM), CV death (CVd), hospitalization/death due to heart failure (hdHF), fatal/non-fatal stroke (CVA), non-fatal myocardial infarction (MI) and MACE (composite of CVd, MI and CVA). Among 378 risk factors, including some highly correlated features, the top-ranked predictors (collected at baseline or derived from repeated measures prior to events) were selected, resulting in a hierarchy of predictive variables. Effects of RSF-selected predictors were then evaluated by multivariate Cox Proportional Hazards Models. Results: Table 1 presented the top ten predictors for six major events. Variables associated with changes in renal function predicted TM, CVd, and hdHF with ~90% accuracy. Insulin use was an important predictor along with predefined composite renal microvascular events for MI, CVA and MACE (74-79% accuracy). The Cox regression models based on RSF variable selection yielded similar findings for these important predictors of events. Conclusions: RSF approach revealed that insulin use and overt renal microvascular events were predictors for the occurrence of MI, stroke, and MACE in T2D patients. Moreover, dynamic changes in urinary renal function biomarkers had additional predictive values for fatal events. These results provide important clinical insights for reducing CV events in Type 2 diabetes patients.

Type-2 diabetes mellitus and cardiovascular disease.

The global prevalence of diabetes has risen in adults from 4.7% in 1980 to 8.5% in 2014. 90-95% of adults with diabetes have Type 2 diabetes (T2D). This paper focuses on the diagnosis and treatment of T2D patients who have or are at risk for cardiovascular disease. Hyperglycemia, insulin resistance and excess fatty acids increase oxidative stress, disrupt protein kinase C signaling and increase advanced glycation end-products that result in vascular inflammation, vasoconstriction, thrombosis and atherogenesis. Intensive T2D treatment produces a ≥10% risk reduction in major macrovascular and microvascular events. Glucose-lowering therapies must be individualized. Metformin is an optimal drug for monotherapy. If hemoglobin A1c is not at goal, a sodium-glucose cotransporter-2 inhibitor or a dipeptidyl peptidase-4 inhibitor should be considered for therapy with metformin. Coronary angioplasty/stenting is recommended for diabetic patients with acute myocardial infarctions. Coronary artery bypass grafting is recommended for symptomatic diabetic patients with multivessel disease.

The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (The Diabetes & Aging Study).

OBJECTIVETo examine for a legacy effect of early glycemic control on diabetic complications and death.RESEARCH DESIGN AND METHODSThis cohort study of managed care patients with newly diagnosed type 2 diabetes and 10 years of survival (1997–2013, average follow-up 13.0 years, N = 34,737) examined associations between HbA1c <6.5% (<48 mmol/mol), 6.5% to <7.0% (48 to <53 mmol/mol), 7.0% to <8.0% (53 to <64 mmol/mol), 8.0% to <9.0% (64 to <75 mmol/mol), or ≥9.0% (≥75 mmol/mol) for various periods of early exposure (0–1, 0–2, 0–3, 0–4, 0–5, 0–6, and 0–7 years) and incident future microvascular (end-stage renal disease, advanced eye disease, amputation) and macrovascular (stroke, heart disease/failure, vascular disease) events and death, adjusting for demographics, risk factors, comorbidities, and later HbA1c.RESULTSCompared with HbA1c <6.5% (<48 mmol/mol) for the 0-to-1-year early exposure period, HbA1c levels ≥6.5% (≥48 mmol/mol) were associated with increased microvascular and macrovascular events (e.g., HbA1c 6.5% to <7.0% [48 to <53 mmol/mol] microvascular: hazard ratio 1.204 [95% CI 1.063–1.365]), and HbA1c levels ≥7.0% (≥53 mmol/mol) were associated with increased mortality (e.g., HbA1c 7.0% to <8.0% [53 to <64 mmol/mol]: 1.290 [1.104–1.507]). Longer periods of exposure to HbA1c levels ≥8.0% (≥64 mmol/mol) were associated with increasing microvascular event and mortality risk.CONCLUSIONSAmong patients with newly diagnosed diabetes and 10 years of survival, HbA1c levels ≥6.5% (≥48 mmol/mol) for the 1st year after diagnosis were associated with worse outcomes. Immediate, intensive treatment for newly diagnosed patients may be necessary to avoid irremediable long-term risk for diabetic complications and mortality.

P2528Visit to visit variability of hba1c and glucose and the risk of macro-and microvascular events in the general population

P2528Visit to visit variability of hba1c and glucose and the risk of macro-and microvascular events in the general population

Polygenic Risk Testing at the Time of Diagnosis of Diabetes Could Help Prevent Its Micro- and Macrovascular Complications

Cardiovascular and renal complications of T2D represent a human and societal burden. Early detection of susceptibility to complications could help their prevention. Clinical scores are useful to predict hard outcomes but genomic score can be applied earlier than a risk factor based score and thus save morbidity. We have constructed a polygenic risk score (PRS) based on genetic variants associated to risk factors and outcomes of T2D available from GWAS catalog and tested it on 5,000 genotyped Caucasian subjects with T2D of ADVANCE trial and its 5 year extension in ADVANCE-ON. We selected 620 SNPs which in combination with geo-ethnic principal component, age of onset and diabetes duration achieved a highly significant prediction of outcomes, including cardiovascular (AUC=0.80) and total mortality (AUC=0.77), equalling and surpassing such clinical scores as Framingham and UKPDS. The highest positive predictive values for micro- and macro-vascular prevalent cases were 81% and 78%, respectively. Individuals within the highest tertile of genetic risk for total prevalence of both microvascular and macrovascular events, had significantly higher cardiovascular death than subjects with the lowest genetic score (p=2.02x10-12). The number needed to treat to prevent one CV death over 5 years by ADVANCE therapies, was 12 in subjects with high PRS (p=0.0045) compared to 45 (p=0.14) in subjects with low PRS. Cox cumulative hazard plots demonstrated persistence of benefits for all cause and cardiovascular mortality in high PRS tertile over 10 years of intensive blood pressure control, while for glucose intensive therapy the benefit was restricted to the high PRS group for end-stage renal disease. We conclude that the use of a PRS that detects the risk of micro- and macrovascular complications at the time of T2D diagnosis could effectively assist in preventive and therapeutic measures to attenuate diabetes complications. Disclosure P. Hamet: Consultant; Self; Servier. F. Harvey: None. M. Haloui: None. M. Woodward: None. R. Tahir: None. F. Marois-Blanchet: None. C. Long: None. M. Marre: Board Member; Self; Abbott. Consultant; Self; AstraZeneca. Board Member; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Eli Lilly and Company. Board Member; Self; Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S. Research Support; Self; Sanofi. Board Member; Self; Servier. S. Harrap: Research Support; Self; Servier. J. Chalmers: Research Support; Self; Servier. Other Relationship; Self; Servier. J. Tremblay: Consultant; Self; Servier.

Urocortin-2 Gene Transfer Effectively Treats Type 1 Diabetes in Mice

Type 1 diabetes (T1D) affects 1.3 million U.S. patients. Tight glucose control reduces microvascular complications and adverse cardiovascular events. Insulin therapy is essential but has shortcomings: a) only 1 in 3 patients achieve targeted glucose control; b) aggressive insulin use increases hypoglycemia; c) 25% of T1D patients develop insulin resistance. We previously reported that urocortin-2 (UCn2) gene transfer increases insulin sensitivity and release in mouse models of type 2 diabetes. In the present study, 3m-old male Akita mice with T1D (due to Ins2 mutation) received IV saline, AAV8. Null or AAV8.UCn2 (2x1012 gc/kg). Ten weeks after UCn2 gene transfer we saw normalization of fasting glucose, HbA1c and glucose tolerance (Table). Increased body weight and reduced water intake was seen after UCn2 gene transfer. Hyperinsulinemic euglycemic clamps showed increased insulin sensitivity and skeletal muscle glucose uptake. There was reduced nephropathy and retinopathy and increased survival (Table). Echocardiography showed improved ejection fraction (p&amp;lt;.001), end-systolic dimension (p&amp;lt;.001) and diastolic function (p&amp;lt;.0001). Data acquisition and analyses were blinded. The mechanisms for beneficial effects include increased insulin release and sensitivity. Thus, UCn2 gene transfer may be a viable therapy both for new onset T1D with detectable endogenous insulin, and for later stage T1D to reduce exogenous insulin needs. UCn2 Gene Transfer in Akita Mice (Type 1 Diabetes)Saline or AAV8.Null (n)AAV8.UCn2 (n)pPlasma UCn2 (ng/mL)1±.2 (14)12±.9 (14)&amp;lt;.0001Urine Output (ml/hr).43±.06 (8).24±.06 (8).0412hr Fasting Glucose (mg/dL)272±25 (8)106±12 (8)&amp;lt;.0001HbA1c (%)8.2±.4 (5)5.5±.4 (5)&amp;lt;.002Glucose Tolerance Test (AUC)3128±215 (8)2062±286 (8)&amp;lt;.0001Insulin Release 2h post gluc (ng/ml).15±.01 (8).29±.4 (8).004Glucose Infusion Rate (mg/kg/min)12±2.89 (6)33.6±5.3 (5).001Vast Lat Glu Uptake (µM/m/100g)8.2±.4 (7)23.2±2.6 (6)&amp;lt;.0001Glomerulus Expansion Score1.7±.04 (8)1.5±.04 (8).01Urine Albumin/Creatinine (3hr)28±3 (8)17±3 (8).01Retinal Vascular Leak (%)43±1 (5)19±5 (4).001200-day Survival (%)0 (17 of 17 died)82 (3 of 17 died)&amp;lt;.0001Mean ± SE; p from Student’s t-test (unpaired, 2 tails); AAV8, Adeno-Associated Virus Type 8 Disclosure M. Gao: None. N. Lai: None. D. Giamouridis: None. T.Y. Guo: None. B. Xia: None. Y. Kim: None. M.V. Estrada: None. V. Nguyen Huu: None. D. Skowronska-Krawczyk: None. H. Hammond: Stock/Shareholder; Self; Renova Therapeutics.

The Burden of Uncontrolled Glycemia—A Systematic Literature Review

The objective of this systematic literature review (SLR) was to understand the consequences of uncontrolled glycemia in patients with type 2 diabetes mellitus (T2DM) in terms of mortality, macro- or microvascular complications, as well as economic burden in terms of healthcare resource utilization (HCRU) and cost. A predefined search strategy was used in Medline, EMBASE, Cochrane CENTRAL, EconLit and NHS-EED, limited to the last five years, according to PRISMA guidelines. In terms of mortality and clinical data, twenty-two studies met our inclusion criteria. Five studies reported significantly increased risk of mortality for A1C greater than 7.5% (Hazard ratio (HR) ranged from 1.41-13.16). Three studies reported an increased risk of mortality for every 1% increase in A1C above 7% (HR from 1.10-1.40). In one landmark trial (ACCORD), however, comparing intensive (A1C target &amp;lt;6.0%) to standard glycemic control (A1C target 7.0-7.9%), a higher risk of all-cause mortality in the intensive group was reported. Six studies showed that A1C higher than 7% was associated with an increased risk of macrovascular complications (HR / odds ratio (OR) from 1.13-2.26) and three studies reported that every 1% increase in A1C above 7% resulted in an increased risk of different macrovascular complications (HR / OR from 1.05-1.38). Three studies reported higher risk (HR / OR from 1.13-1.40) of microvascular events at A1C higher than 7%. For the economic data, 1 U.S. study reported increased healthcare cost (OR 1.73 (95% CI 1.00-3.01) for T2DM patients with A1C greater than 10%. In another U.S. study, 1% increase in A1C between 7-10.5% was associated with additional diabetes-related pharmacy/medical cost burden of $1586 ($133-$3537) per patient per year. Three non-U.S. studies also reported similar results on the association of A1C and economic burden. Our SLR showed an association between high A1C and increased risk of clinical outcomes, including mortality. Furthermore, poor glycemic control was also associated with increased HCRU and costs. Disclosure G. Fernandes: Employee; Self; Merck &amp; Co., Inc.. Employee; Spouse/Partner; Janssen Research &amp; Development. Stock/Shareholder; Self; Merck &amp; Co., Inc.. Stock/Shareholder; Spouse/Partner; Janssen Research &amp; Development. J. Iff: None. O. Ovcinnikova: None. M. Nassim: None. L. Sun: None. M.S. Richards: None. S. Rajpathak: Employee; Self; Merck &amp; Co., Inc..

Circulating amino acids and the risk of macrovascular, microvascular and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE trial

Aims/hypothesesWe aimed to quantify the association of individual circulating amino acids with macrovascular disease, microvascular disease and all-cause mortality in individuals with type 2 diabetes.MethodsWe performed a case-cohort study (N = 3587), including 655 macrovascular events, 342 microvascular events (new or worsening nephropathy or retinopathy) and 632 all-cause mortality events during follow-up, in a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. For this study, phenylalanine, isoleucine, glutamine, leucine, alanine, tyrosine, histidine and valine were measured in stored plasma samples by proton NMR metabolomics. Hazard ratios were modelled per SD increase in each amino acid.ResultsIn models investigating associations and potential mechanisms, after adjusting for age, sex and randomised treatment, phenylalanine was positively, and histidine inversely, associated with macrovascular disease risk. These associations were attenuated to the null on further adjustment for extended classical risk factors (including eGFR and urinary albumin/creatinine ratio). After adjustment for extended classical risk factors, higher tyrosine and alanine levels were associated with decreased risk of microvascular disease (HR 0.78; 95% CI 0.67, 0.91 and HR 0.86; 95% CI 0.76, 0.98, respectively). Higher leucine (HR 0.79; 95% CI 0.69, 0.90), histidine (HR 0.89; 95% CI 0.81, 0.99) and valine (HR 0.79; 95% CI 0.70, 0.88) levels were associated with lower risk of mortality. Investigating the predictive ability of amino acids, addition of all amino acids to a risk score modestly improved classification of participants for macrovascular (continuous net reclassification index [NRI] +35.5%, p < 0.001) and microvascular events (continuous NRI +14.4%, p = 0.012).Conclusions/interpretationWe report distinct associations between circulating amino acids and risk of different major complications of diabetes. Low tyrosine appears to be a marker of microvascular risk in individuals with type 2 diabetes independently of fundamental markers of kidney function.

Novel Risk Engine for Diabetes Progression and Mortality in USA: Building, Relating, Assessing, and Validating Outcomes (BRAVO).

There is an urgent need to update diabetes prediction, which has relied on the United Kingdom Prospective Diabetes Study (UKPDS) that dates back to 1970s' European populations. The objective of this study was to develop a risk engine with multiple risk equations using a recent patient cohort with type 2 diabetes mellitus reflective of the US population. A total of 17 risk equations for predicting diabetes-related microvascular and macrovascular events, hypoglycemia, mortality, and progression of diabetes risk factors were estimated using the data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (n = 10,251). Internal and external validation processes were used to assess performance of the Building, Relating, Assessing, and Validating Outcomes (BRAVO) risk engine. One-way sensitivity analysis was conducted to examine the impact of risk factors on mortality at the population level. The BRAVO risk engine added several risk factors including severe hypoglycemia and common US racial/ethnicity categories compared with the UKPDS risk engine. The BRAVO risk engine also modeled mortality escalation associated with intensive glycemic control (i.e., glycosylated hemoglobin < 6.5%). External validation showed a good prediction power on 28 endpoints observed from other clinical trials (slope = 1.071, R2 = 0.86). The BRAVO risk engine for the US diabetes cohort provides an alternative to the UKPDS risk engine. It can be applied to assist clinical and policy decision making such as cost-effective resource allocation in USA.

Contrasting effects on the risk of macrovascular and microvascular events of antihyperglycemic drugs that enhance sodium excretion and lower blood pressure.

Three classes of anti-hyperglycaemic medications are distinguished by their urinary sodium excretion-enhancing and blood pressure-lowering actions: long-acting glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors. Yet, these drugs exert different effects on macrovascular risk. Glucagon-like peptide-1 receptor agonists reduce atherosclerotic thromboembolic events, but have little effect on heart failure; sodium-glucose co-transporter-2 inhibitors decrease the occurrence of heart failure, but have minimal effect on myocardial infarction and stroke; and dipeptidyl peptidase-4 inhibitors do not ameliorate either atherosclerotic thromboembolic events or heart failure. Similarly, the three classes of drugs differ in their early effects on renal function. Dipeptidyl peptidase-4 inhibitors produce a small decrease in renal function that persists for the duration of treatment, and they do not prevent serious adverse renal events. For glucagon-like peptide-1 receptor agonists, a small early decrease in renal function persists for 2 years and is superseded by a small improvement in renal function, with no effect on renal outcomes. In contrast, an initial decrease in glomerular filtration with sodium-glucose co-transporter-2 inhibitors persists for only 1 year and is superseded by a durable improvement in renal function and a reduced risk of serious adverse renal events. These differences may be related to different actions on the proximal tubular reabsorption of sodium, and thereby, on glomerular hyperfiltration. Anti-hyperglycaemic drugs that have natriuretic actions differ markedly in their ability to modulate macrovascular and microvascular risk. These contrasting profiles cannot be predicted by their effects on blood glucose or blood pressure.

Cardiovascular Protection in People With Diabetes.

Cardiovascular Protection in People With Diabetes.

Type 2 Diabetes Diabetes in Older Adults: Example for Patient-Centered Drug Therapy

Diabetes in older adults has a high prevalence and is frequently associated with comorbidities of the cardiovascular system, dysfunction of cognition as well as depression and impaired mobility or increased frailty. Furthermore, impaired renal function, heart failure, risk for hypoglycemia and polypharmacy has to be considered in the decision about the diabetes treatment strategy. The goal of blood glucose management is driven by patient relevant issues and patient self-esteem, quality of life defined by the patient, preservation of physical and social mobility rather than potential long-term effects on reduction of cardio- and microvascular events in the future, which is limited by patient-inherent reduced life expectancy of the aged individual. Therefore, long-term diabetes medication should avoid hypoglycemia and prevent acute hyperglycemia or short-term complications on morbidity and clinical course of geriatric syndromes associated with regular blood glucose levels above 200 mg/dl (11.1 mmol/l). The therapy should be safe, easy to handle for the patient and possibly affect co-morbidities positively. However, there are limited data available about efficacy, safety and pharmacokinetics of drugs in patients over 75years of age or older. Since more than 5 % of the population in Germany is older than 80 years means that more than 1 million of these individuals suffer from diabetes. It is time to ask for data in these elderly subpopulations by policy makers in health care.

Efficacy and safety of glucagon-like peptide-1 agonists on macrovascular and microvascular events in type 2 diabetes mellitus: A meta-analysis

AimsGlucagon-like peptide-1 (GLP-1) agonists improve glycaemic control in type 2 diabetes mellitus (DM). Outcome trials investigating macro and microvascular effects of GLP-1 agonists reported conflicting results. The aim of this study was to assess, in a meta-analysis, the effects of GLP-1 agonists on mortality, major nonfatal cardiovascular (CV) events, renal and retinal events. Data synthesisMEDLINE, Cochrane, ISI Web of Science, SCOPUS and ClinicalTrial.gov databases were searched for articles published until June 2017. Randomized trials enrolling more than 200 patients, comparing GLP-1 versus placebo or active treatments in patients with DM, and assessing outcomes among all-cause death, CV death, MI, stroke, HF, diabetic retinopathy and nephropathy were included. 77 randomized trials enrolling 60,434 patients were included. Compared to control, treatment with GLP-1 significantly reduced the risk of all-cause death (RR: 0.888; CI: 0.804–0.979; p = 0.018) and the risk of CV death (RR: 0.858; CI: 0.757–0.973; p = 0.017). GLP-1 agonists did not affect the risk of MI (RR: 0.917; CI: 0.830–1.014; p = 0.092) as well as the risk of stroke (RR: 0.882; CI: 0.759–1.023; p = 0.097), HF (RR: 0.967; CI: 0.803–1.165; p = 0.725), retinopathy (RR: 1.000; CI: 0.807–1.238; p = 0.997) and nephropathy (RR: 0.866; CI: 0.625–1.199; p = 0.385). ConclusionsTreatment with GLP-1 agonists in DM patients is associated with a significant reduction of all cause and CV mortality.

The Long-Term Effects of Bariatric Surgery on Type 2 Diabetes Remission, Microvascular and Macrovascular Complications, and Mortality: a Systematic Review and Meta-Analysis.

This systematic review aimed to evaluate the long-term (≥5years) outcomes of bariatric surgery on diabetes remission, microvascular and macrovascular events, and mortality among type 2 diabetes (T2D) patients. Ten articles (one randomized controlled trial and nine cohorts) met the inclusion criteria and were included in this review. Pooled estimates of nine cohort studies showed that surgery significantly increased the diabetes remission (relative risk (RR)=5.90; 95% CI 3.75-9.28), reduced the microvascular (RR=0.37; 95% CI=0.30-0.46) and macrovascular events (RR=0.52; 95% CI 0.44-0.61), and mortality (RR=0.21; 95% CI 0.20-0.21) as compared to non-surgical treatment. Available evidence suggests better remission and lower risks of microvascular and macrovascular disease and mortality in the surgery group as compared to non-surgical treatment group in T2D patients after at least 5years of follow-up.

Development and validation of Risk Equations for Complications Of type 2 Diabetes (RECODe) using individual participant data from randomised trials

In view of substantial mis-estimation of risks of diabetes complications using existing equations, we sought to develop updated Risk Equations for Complications Of type 2 Diabetes (RECODe). To develop and validate these risk equations, we used data from the Action to Control Cardiovascular Risk in Diabetes study (ACCORD, n=9635; 2001-09) and validated the equations for microvascular events using data from the Diabetes Prevention Program Outcomes Study (DPPOS, n=1018; 1996-2001), and for cardiovascular events using data from the Action for Health in Diabetes (Look AHEAD, n=4760; 2001-12). Microvascular outcomes were nephropathy, retinopathy, and neuropathy. Cardiovascular outcomes were myocardial infarction, stroke, congestive heart failure, and cardiovascular mortality. We also included all-cause mortality as an outcome. We used a cross-validating machine learning method to select predictor variables from demographic characteristics, clinical variables, comorbidities, medications, and biomarkers into Cox proportional hazards models for each outcome. The new equations were compared to older risk equations by assessing model discrimination, calibration, and the net reclassification index. All equations had moderate internal and external discrimination (C-statistics 0·55-0·84 internally, 0·57-0·79 externally) and high internal and external calibration (slopes 0·71-1·31 between observed and estimated risk). Our equations had better discrimination and calibration than the UK Prospective Diabetes Study Outcomes Model 2 (for microvascular and cardiovascular outcomes, C-statistics 0·54-0·62, slopes 0·06-1·12) and the American College of Cardiology/American Heart Association Pooled Cohort Equations (for fatal or non-fatal myocardial infarction or stroke, C-statistics 0·61-0·66, slopes 0·30-0·39). RECODe might improve estimation of risk of complications for patients with type 2 diabetes. National Institute for Diabetes and Digestive and Kidney Disease, National Heart, Lung and Blood Institute, and National Institute on Minority Health and Health Disparities, National Institutes of Health, and US Department of Veterans Affairs.

Comparative effects of microvascular and macrovascular disease on the risk of major outcomes in patients with type 2 diabetes

BackgroundMicrovascular 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.MethodsParticipants 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.ResultsAll-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.ConclusionsMicrovascular 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.

142 Intravital imaging of leukocyte, platelet and stem cell trafficking in vivo in the cardiac microcirculation following myocardial ischaemia-reperfusion injury

BackgroundThe clinical success of stem cell (SC) therapy for myocardial infarction is compromised by poor cardiac homing following systemic delivery. As such therapy may depend on beneficial paracrine effects, it...

Effect of intensive glucose control on microvascular events in people with type 2 diabetes

Effect of intensive glucose control on microvascular events in people with type 2 diabetes ● Febrile seizures in children: benefits and risks of prophylactic drug management More on gastric acid...

Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials

Intensive glucose control is understood to prevent complications in adults with type 2 diabetes. We aimed to more precisely estimate the effects of more intensive glucose control, compared with less intensive glucose control, on the risk of microvascular events. In this meta-analysis, we obtained de-identified individual participant data from large-scale randomised controlled trials assessing the effects of more intensive glucose control versus less intensive glucose control in adults with type 2 diabetes, with at least 1000 patient-years of follow-up in each treatment group and a minimum of 2 years average follow-up on randomised treatment. The prespecified and standardised primary outcomes were kidney events (a composite of end-stage kidney disease, renal death, development of an estimated glomerular filtration rate <30 mL/min per 1·73m2, or development of overt diabetic nephropathy), eye events (a composite of requirement for retinal photocoagulation therapy or vitrectomy, development of proliferative retinopathy, or progression of diabetic retinopathy), and nerve events (a composite of new loss of vibratory sensation, ankle reflexes, or light touch). We used a random-effects model to calculate overall estimates of effect. We included four trials (ACCORD, ADVANCE, UKPDS, and VADT) with 27 049 participants. 1626 kidney events, 795 eye events, and 7598 nerve events were recorded during the follow-up period (median 5·0 years, IQR 4·5-5·0). Compared with less intensive glucose control, more intensive glucose control resulted in an absolute difference of -0·90% (95% CI -1·22 to -0·58) in mean HbA1c at completion of follow-up. The relative risk was reduced by 20% for kidney events (hazard ratio 0·80, 95% CI 0·72 to 0·88; p<0·0001) and by 13% for eye events (0·87, 0·76 to 1·00; p=0·04), but was not reduced for nerve events (0·98, 0·87 to 1·09; p=0·68). More intensive glucose control over 5 years reduced both kidney and eye events. Glucose lowering remains important for the prevention of long-term microvascular complications in adults with type 2 diabetes. None.

The impact of level of education on vascular events and mortality in patients with type 2 diabetes mellitus: Results from the ADVANCE study.

The relationship between educational level and the risk of all-cause mortality is well established, whereas the association with vascular events in individuals with type 2 diabetes is not well described. Any association may reflect a link with common cardiovascular or lifestyle-based risk factors. The relationships between the highest level of educational attainment and major cardiovascular events, microvascular complications and all-cause mortality were explored in a cohort of 11,140 individuals with type 2 diabetes. Completion of formal education before the age of 16 was categorized as a low level of education. Regional differences between Asia, East Europe and Established Market Economies were also assessed. During a median of 5years of follow up, 1031 (9%) patients died, 1147 (10%) experienced a major cardiovascular event and 1136 (10%) a microvascular event. After adjustment for baseline characteristics and risk factors, individuals with lower education had an increased risk of cardiovascular events (hazard ratio (HR) 1.31, 95% CI 1.16-1.48, p<0.0001), microvascular events (HR 1.23, 95% CI 1.08-1.39, p=0.0013) and all-cause mortality (HR 1.34, 95% CI 1.18-1.52, p<0.0001). In regional analyses the increased risk of studied outcomes associated with lower education was weakest in Established Market Economies and strongest in East Europe. A low level of education is associated with an increased risk of vascular events and death in patients with type 2 diabetes, independently of common lifestyle associated cardiovascular risk factors. The effect size varies between geographical regions.