Major Microvascular Events Research Articles

Study Design and Protocol for a Randomized Controlled Trial to Assess Long-Term Efficacy and Safety of a Triple Combination of Ezetimibe, Fenofibrate, and Moderate-Intensity Statin in Patients with Type 2 Diabetes and Modifiable Cardiovascular Risk Factors (ENSEMBLE).

Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined. This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months. This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.

Association of RASGRP1 polymorphism with vascular complications in Chinese diabetic patients with glycemic control and antihypertensive treatment

BackgroundStudies have shown that RASGRP1 was potently associated with the onset of type 2 diabetes mellitus (T2DM), and RASGRP1 rs7403531 was significantly correlated with islet function in T2DM patients. However, the effect of RASGRP1 polymorphism on blood glucose and blood pressure in T2DM patients after continuous treatment has yet to be fully elucidated.ObjectiveThis study aimed to explore the association between RASGRP1 genetic polymorphism and cardiovascular complications in T2DM patients, so as to provide more evidence for the individualized treatment of T2DM patients.MethodsWe retrospectively analyzed a large-scale multicenter drug clinical study cohort that based on a 2 × 2 factorial (glucose control axis and blood pressure lowering axis) randomized controlled design, with follow-up for 5 years. The major vascular endpoint events included cardiovascular death, non-fatal stroke, coronary heart disease, new-onset or worsening renal disease, and diabetic retinopathy. RASGRP1 rs12593201, rs56254815 and rs7403531 were finally selected as candidate single nucleotide polymorphisms. Mixed linear model and Cox hazard ratio (HR) model were used for data analysis with IBM SPSS (version 20.0 for windows; Chicago, IL).ResultsOur study enrolled 1357 patients with high-risk diabetes, with a mean follow-up duration of 4.8 years. RASGRP1 rs7403531 was associated with vascular events in hypoglycemic and antihypertensive therapy. Specifically, compared with CC carriers, patients with CT/TT genotype had fewer major microvascular events (HR = 0.41, 95% confidence interval (CI) 0.21–0.80, P = 0.009), and reduced the risk of major eye disease events (HR = 0.44, 95% CI 0.20–0.94, P = 0.03). For glucose lowering axis, CT/TT carriers had a lower risk of secondary nephropathy (HR = 0.48, 95% CI 0.25–0.92, P = 0.03) in patients with standard glycemic control. For blood pressure lowering axis, all cerebrovascular events (HR = 2.24, 95% CI 1.11–4.51, P = 0.025) and stroke events (HR = 2.07, 95% CI 1.03–4.15, P = 0.04) were increased in patients with CC genotype compared to those with CT/TT genotype in the placebo group, respectively. Furthermore, patients with CC genotype showed a reduced risk of major cerebrovascular events in antihypertensive group (HR = 0.36, 95% CI 0.15–0.86, P = 0.021). For RASGRP1 rs56254815, compared with the AA genotype carriers, the systolic blood pressure of AG/GG carriers in the antihypertensive group decreased by 1.5mmhg on average (P = 0.04). In the placebo group, the blood pressure of AG/GG carriers was 1.7mmHg higher than that of AA carriers (P = 0.02).ConclusionWe found that patients with G allele of RASGRP1 (rs56254815) showed a better antihypertensive therapy efficacy in T2DM patients. The rs7403531 T allele could reduce the risk of major microvascular events and major eye diseases in T2DM patients receiving either hypoglycemic or antihypertensive therapy. Our findings suggest that RASGRP1 genetic polymorphism might predict the cardiovascular complications in T2DM patients.

Increased Derived Time in Range Is Associated with Reduced Risk of Major Adverse Cardiovascular Events, Severe Hypoglycemia, and Microvascular Events in Type 2 Diabetes: A Post Hoc Analysis of DEVOTE.

Time spent in glycemic target range (time in range [TIR]; plasma glucose 70-180 mg/dL [3.9-10.0 mmol/L]) as a surrogate endpoint for long-term diabetes-related outcomes requires validation. This post hoc analysis investigated the association between TIR, derived from 8-point glucose profiles (derived TIR [dTIR]) at 12 months, and time to cardiovascular or severe hypoglycemic episodes in people with type 2 diabetes in the DEVOTE trial. At 12 months, dTIR was significantly negatively associated with time to first major adverse cardiovascular event (P = 0.0087), severe hypoglycemic episode (P < 0.0001), or microvascular event (P = 0.024). A nonsignificant trend was seen toward association between 12-month hemoglobin A1c (HbA1c) and these outcomes, but this was no longer seen after addition of dTIR to the model. The results support targeting TIR >70% and suggest dTIR could be used in addition to, or in some instances in place of, HbA1c as a clinical biomarker. Trial registration details: ClinicalTrials.gov, NCT01959529.

Association of visit-to-visit HbA1c variability with cardiovascular diseases in type 2 diabetes within or outside the target range of HbA1c.

Although a growing attention has been recently paid to the role of HbA1c variability in the risk of diabetic complications, the impact of HbA1c variability on cardiovascular diseases (CVD) in type 2 diabetes is still debated. The aim of the study is to investigate the association of HbA1c variability with CVD in individuals within or outside the target range of HbA1c. Using data from Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE), we enrolled 855 patients with type 2 diabetes in China. The primary outcomes included major macrovascular events and major microvascular events. Visit-to-visit HbA1c variability was expressed as the coefficient of variation (CV) of five measurements of HbA1c taken 3-24 months after treatment. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR). Among 855 patients in the intensive glucose treatment group, 563 and 292 patients were assigned to the group of "within the target range of HbA1c" (WTH) (updated mean HbA1c ≤ 7.0%) and "outside the target range of HbA1c" (OTH) (updated mean HbA1c > 7.0%), respectively. HbA1c variability was positively associated with the risk of major microvascular events in all patients and both the subgroups during a median follow-up period of 4.8 years. Particularly, the risk related to HbA1c variability was higher in patients in WTH group for the new or worsening nephropathy [aHR: 3.35; 95% confidence interval (CI): 1.05-10.74; P = 0.042]. This retrospective cohort study confirmed the positive correlation between HbA1c variability and major microvascular events, especially in subjects in WTH or OTH.

Short-Term Changes in Serum Potassium and the Risk of Subsequent Vascular Events and Mortality: Results from a Randomized Controlled Trial of ACE Inhibitors.

Hyperkalemia after starting renin-angiotensin system inhibitors has been shown to be subsequently associated with a higher risk of cardiovascular and kidney outcomes. However, whether to continue or discontinue the drug after hyperkalemia remains unclear. Data came from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, which included a run-in period where all participants initiated angiotensin-converting enzyme inhibitor-based therapy (a fixed combination of perindopril and indapamide). The study population was taken as patients with type 2 diabetes with normokalemia (serum potassium of 3.5 to <5.0 mEq/L) at the start of run-in. Potassium was remeasured 3 weeks later when a total of 9694 participants were classified into hyperkalemia (≥5.0 mEq/L), normokalemia, and hypokalemia (<3.5 mEq/L) groups. After run-in, patients were randomized to continuation of the angiotensin-converting enzyme inhibitor-based therapy or placebo; major macrovascular, microvascular, and mortality outcomes were analyzed using Cox regression during the following 4.4 years (median). During active run-in, 556 (6%) participants experienced hyperkalemia. During follow-up, 1505 participants experienced the primary composite outcome of major macrovascular and microvascular events. Randomized treatment of angiotensin-converting enzyme inhibitor-based therapy significantly decreased the risk of the primary outcome (38.1 versus 42.0 per 1000 person-years; hazard ratio, 0.91; 95% confidence interval, 0.83 to 1.00; P=0.04) compared with placebo. The magnitude of effects did not differ across subgroups defined by short-term changes in serum potassium during run-in (P for heterogeneity =0.66). Similar consistent treatment effects were also observed for all-cause death, cardiovascular death, major coronary events, major cerebrovascular events, and new or worsening nephropathy (P for heterogeneity ≥0.27). Continuation of angiotensin-converting enzyme inhibitor-based therapy consistently decreased the subsequent risk of clinical outcomes, including cardiovascular and kidney outcomes and death, regardless of short-term changes in serum potassium. Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), NCT00145925.

CLINICAL OUTCOMES AND PATIENT CHARACTERISTICS ACCORDING TO THE COMBINATION OF TEN-YEAR RISK OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE AND SYSTOLIC BLOOD PRESSURE

Abstract Objective: Improving the efficiency of hypertension management has driven treatment indications to be based on cardiovascular disease risk calculations instead of blood pressure or cholesterol management. The aim of this study was to explore the relationship between ten-year risk of atherosclerotic cardiovascular disease (ASCVD) and systolic blood pressure (SBP) in individuals with type 2 diabetes and describe the characteristics of individuals according to their ASCVD risk and SBP cross-classification. The secondary aim was to model the association of ASCVD risk and SBP at study baseline with clinical outcomes (major macrovascular, major microvascular and death). Design and method: This current study used 7,426 individuals from the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) randomised clinical trial, that were free from macrovascular disease at baseline. ASCVD risk and SBP were categorised into approximate thirds, reflecting clinically meaningful cut points, defined as intermediate risk: ASCVD &lt; 20 or SBP &lt; 130, high risk: ASCVD 20 -34 or SBP 130–149, and very high risk: ASCVD &gt; = 35 or SBP &gt; = 150. Individuals were cross-classified according to their ASCVD and SBP categories. Characteristics of individuals among the categories were summarised using descriptive statistics. Cox proportional hazards models were fitted to model the association of ASCVD and SBP cross-classification with clinical outcomes. Results: There was a high proportion of women for ASCVD &lt; 20 across the three sequential SBP categories (67.3%, 80.3% and 87.6%). Mean age increased through increasing ASCVD risk categories, in all risk categories the mean age was highest for SBP &lt; 130 and lowest for SBP &gt; = 150. The risk of death increased as ASCVD increased; though there was no significant association of SBP within the ASCVD categories. The risk of major macrovascular events increased sequentially through the combined effect of ASCVD and SBP (see figure). The highest risk of major microvascular events was for SBP &gt; = 150 across all ASCVD categories. Conclusions: The cross-classification of ASCVD and SBP yielded varying associations with death, major macrovascular and major microvascular events, thus indicating that using ASCVD and /or SBP as predictors produces a non-uniform pattern for adverse clinical outcomes.

The comparative effects of intensive glucose lowering in diabetes patients aged below or above 65 years: Results from the ADVANCE trial.

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. 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). 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. 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.

Cost-Effectiveness of Gliclazide-Based Intensive Glucose Control vs. Standard Glucose Control in Type 2 Diabetes Mellitus. An Economic Analysis of the ADVANCE Trial in Vietnam.

Introduction: ADVANCE was a large, multinational clinical study conducted over 5 years in type 2 diabetes mellitus (T2DM). In all, 11,140 patients were randomly assigned to receive gliclazide-based intensive glucose control (IGC) or standard glucose control (SGC). IGC was shown to significantly reduce the incidence of major macrovascular and microvascular events (composite endpoint) or major microvascular events compared with SGC, primarily by enhancing renal protection. We assessed the cost-effectiveness of IGC vs. SGC, based on the ADVANCE results, from a Vietnamese healthcare payer perspective.Materials and Methods: A partitioned survival times model across five health states (no complications, myocardial infarction, stroke, end-stage renal disease [ESRD], and diabetes-related eye-disease) was designed. Time-to-event curves were informed by the cumulative incidence of events and corresponding hazard ratios from the ADVANCE study. Health outcomes were expressed in terms of ESRD avoided and quality-adjusted life years (QALYs). Costs (in US $) comprised treatment costs and health state costs. Utility weights and costs were documented from literature reporting Vietnamese estimates. For sensitivity analyses, all parameters were individually varied within their 95% confidence interval bounds (when available) or within a ±30% range.Results: Over a 5-year horizon, IGC avoided 6.5 additional ESRD events per 1,000 patients treated compared with SGC (IGC, 3.5 events vs. SGC, 10.0 events) and provided 0.016 additional QALYs (IGC, 3.570 QALYs vs. SGC, 3.555 QALYs). Total costs were similar for the two strategies (IGC, $3,786 vs. SGC, $3,757). Although the total drug costs were markedly higher for IGC compared with SGC ($1,703 vs. $873), this was largely offset by the savings from better renal protection with IGC (IGC, $577 vs. SGC, $1,508). The incremental cost-effectiveness ratio (ICER) of IGC vs. SGC was $1,878/QALY gained, far below the threshold recommended by the World Health Organization (i.e., 1–3 × gross domestic product per inhabitant ≈$7,500 in Vietnam). The ICER of IGC vs. SGC per ESRD event avoided was $4,559/event. The findings were robust to sensitivity analysis.Conclusion: In Vietnam, gliclazide-based IGC was shown to be cost-effective compared with SGC from a healthcare payer perspective, as defined in the ADVANCE study.

Alternative kidney filtration markers and the risk of major macrovascular and microvascular events, and all-cause mortality in individuals with type 2 diabetes in the ADVANCE trial.

Creatinine-based estimated glomerular filtration rate (eGFR) is biased in the setting of obesity and other conditions. Alternative kidney filtration markers may be useful in adults with diabetes, but few studies examined the associations with risk of clinical outcomes. In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, we evaluated whether baseline levels and change in eGFR based on creatinine (Cr), cystatin c (Cys), β2 -microglobulin (B2M), eGFRCr-Cys , and the average of three estimates (eGFRCr-Cys-B2M ) assessed in 7217 participants at baseline and a random sample of 640 participants at the 1-year visit are associated with clinical outcomes. We examined associations with major macrovascular and microvascular events together and separately and all-cause mortality using Cox regression models, adjusting for established risk factors. Over a median follow-up of 5 years, 1313 major macrovascular (n = 748) and microvascular events (n = 637), and 743 deaths occurred. Lower levels of eGFR based on all filtration markers individually and combined were associated with 1.4 to 3.0 times higher risk of major macrovascular and microvascular events (combined and separately) and all-cause mortality. Per 30% decline in eGFRCys , eGFR Cr-Cys , and eGFRCr-Cys-B2M were associated with a >2-fold higher risk of all clinical outcomes. In adults with type 2 diabetes, baseline levels of eGFR based on alternative filtration markers and per 30% decline in eGFRCys , eGFR Cr-Cys , and eGFRCr-Cys-B2M were associated with clinical outcomes. Measurement of alternative filtration markers, particularly B2M in adults with type 2 diabetes may be warranted.

Effects of Intensive Glycemic Control on Clinical Outcomes Among Patients With Type 2 Diabetes With Different Levels of Cardiovascular Risk and Hemoglobin A1c in the ADVANCE Trial

To study whether the effects of intensive glycemic control on major vascular outcomes (a composite of major macrovascular and major microvascular events), all-cause mortality, and severe hypoglycemia events differ among participants with different levels of 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and hemoglobin A1c (HbA1c) at baseline. We studied the effects of more intensive glycemic control in 11,071 patients with type 2 diabetes (T2D), without missing values, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, using Cox models. During 5 years' follow-up, intensive glycemic control reduced major vascular events (hazard ratio [HR] 0.90 [95% CI 0.83-0.98]), with the major driver being a reduction in the development of macroalbuminuria. There was no evidence of differences in the effect, regardless of baseline ASCVD risk or HbA1c level (P for interaction = 0.29 and 0.94, respectively). Similarly, the beneficial effects of intensive glycemic control on all-cause mortality were not significantly different across baseline ASCVD risk (P = 0.15) or HbA1c levels (P = 0.87). The risks of severe hypoglycemic events were higher in the intensive glycemic control group compared with the standard glycemic control group (HR 1.85 [1.41-2.42]), with no significant heterogeneity across subgroups defined by ASCVD risk or HbA1c at baseline (P = 0.09 and 0.18, respectively). The major benefits for patients with T2D in ADVANCE did not substantially differ across levels of baseline ASCVD risk and HbA1c.

Abstract P274: Kidney Filtration Markers and the Risk of Clinical Outcomes in Individuals With Type 2 Diabetes in the Advance Trial

Introduction: Creatinine-based estimated glomerular filtration rate (eGFR) is biased in the setting of obesity and other conditions. Alternative kidney filtration markers may be particularly useful in adults with diabetes, but few studies examined the risk of clinical outcomes associated with filtration markers in adults with type 2 diabetes. Objective: We evaluated whether baseline levels and change in eGFR based on creatinine (Cr), cystatin C (Cys), and B 2 -microglobulin (B2M) were associated with the risk of clinical outcomes among individuals with type 2 diabetes. Methods: In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, Cr, Cys, and B2M were measured in 7,217 participants at baseline and a random sample of 640 participants at the 1 year visit. We categorized baseline eGFR Cr , eGFR Cys , eGFR B2M , and the average across the 3 eGFR estimates (eGFR avg ) into quarters, and examined associations with major macrovascular and microvascular events together, and separately, and all-cause mortality using Cox regression models, adjusting for established risk factors. We also examined associations with continuous eGFR decline and increase (per 30%). Results: Over a median follow-up of 5 years, 1,313 combined major macrovascular (n=748) and microvascular events (n=637), and 743 deaths occurred. Lower levels of eGFR based on all three filtration markers individually and combined were associated with 1.5 to 2.2 times higher risk of combined major macrovascular and microvascular events, with similar patterns for other outcomes ( Table ). Per 30% decline in eGFR Cys and eGFR avg were associated with a &gt;2-fold higher risk of all clinical outcomes, after additional adjustment of baseline eGFR. Conclusions: In adults with type 2 diabetes, baseline levels of eGFR based on alternative filtration markers and per 30% decline in eGFR Cys and eGFR avg were consistently associated with all clinical outcomes.

Association of RASGRP1 Polymorphism with Vascular Complications in Chinese Diabetic Patients with Glycemic Control and Antihypertensive Treatment

Background: Studies have shown that RASGRP1 was strongly associated with the onset of type 2 diabetes, and RASGRP1 rs7403531 was significantly correlated with islet function in type 2 diabetes (T2DM) patients. However, the effect of RASGRP1 polymorphism on blood glucose and blood pressure in T2DM patients after continuous treatment is still unclear. Methods: We retrospectively analyzed a large multicenter drug clinical study cohort that based on a 2×2 factorial (glucose control axis and blood pressure lowering axis) randomized controlled design, and follow-up for 5 years. The major vascular endpoint events in our study included cardiovascular death, non-fatal stroke, coronary heart disease, new or worsening kidney disease, and diabetic retinopathy. Mixed linear model and Cox hazard ratio model were used for data analysis with SPSS. Findings: A total of 1357 patients were included in our research with an average follow-up time of 4.8 years. RASGRP1 rs7403531 T allele could reduce the risk of major microvascular events (HR=0.41, 55%CI 0.21-0.80, P =0.009) and major eye diseases(HR=0.44, 95% CI 0.20-0.94, P =0.03) in T2DM patients . In the group based on antihypertensive therapy, active antihypertensive therapy for CC patients reduced the risk of all cerebrovascular events (placebo vs. antihypertensive: HR=2.35, 95% CI 1.06-5.12, P =0.035). For RASGRP1 (rs56254815), compared with the AA genotype carriers, the SBP of AG/GG carriers in the hypotensive group decreased by 1.5mmhg on average ( P =0.04). In the placebo group, the blood pressure of AG/GG carriers was 1.7mmHg higher than that of AA carriers ( P =0.02). Interpretation: Our findings suggest that RASGRP1 genetic polymorphism might predict the cardiovascular complications in T2DM patients. Trial Registration: (Registration number NCT00145925). Funding Statement: Supported by the National Natural Science Foundation of China (NSFC, No 81573511, 81874329, 81522048), the National Key R&D Plan of China (No. 2016YFC0905000). Declaration of Interests: All authors declare no conflict of interest relevant to the subject matter or materials discussed in the article. Ethics Approval Statement: Approval to conduct the trial was obtained from the ethics committee of each study center, and all participants provided written informed consent.

The Risks of Cardiovascular Disease and Mortality Following Weight Change in Adults with Diabetes: Results from ADVANCE.

Weight loss is strongly recommended for overweight and obese adults with type 2 diabetes. Unintentional weight loss is associated with increased risk of all-cause mortality, but few studies have examined its association with cardiovascular outcomes in patients with diabetes. To evaluate 2-year weight change and subsequent risk of cardiovascular events and mortality in established type 2 diabetes. The Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation was an international, multisite 2×2 factorial trial of intensive glucose control and blood pressure control. We examined 5 categories of 2-year weight change: >10% loss, 4% to 10% loss, stable (±<4%), 4% to 10% gain, and >10% gain. We used Cox regression with follow-up time starting at 2 years, adjusting for intervention arm, demographics, cardiovascular risk factors, and diabetes medication use from the 2-year visit. Among 10 081 participants with valid weight measurements, average age was 66 years. By the 2-year examination, 4.3% had >10% weight loss, 18.4% had 4% to 10% weight loss, and 5.3% had >10% weight gain. Over the following 3 years of the trial, >10% weight loss was strongly associated with major macrovascular events (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.26-2.44), cardiovascular mortality (HR, 2.76; 95% CI, 1.87-4.09), all-cause mortality (HR, 2.79; 95% CI, 2.10-3.71), but not major microvascular events (HR, 0.91; 95% CI, 0.61-1.36), compared with stable weight. There was no evidence of effect modification by baseline body mass index, age, or type of diabetes medication. In the absence of substantial lifestyle changes, weight loss may be a warning sign of poor health meriting further workup in patients with type 2 diabetes.

The first harmonic of radial pulse wave predicts major adverse cardiovascular and microvascular events in patients with type 2 diabetes

This brief report take a further look on the first harmonic of radial pulse wave (C1) after the 1.8 ± 0.5 years follow-up and demonstrated that the quartile level of C1 independently predicts the risk of cardiovascular death, major adverse cardiovascular events, and microvascular outcomes in 2324 patients with type 2 diabetes.

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.

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.

Absence of Peripheral Pulses and Risk of Major Vascular Outcomes in Patients With Type 2 Diabetes.

The burden of vascular diseases remains substantial in patients with type 2 diabetes, requiring identification of further risk markers. We tested the absence of dorsalis pedis and posterior tibial pulses as predictors of major macrovascular and microvascular events, death, and cognitive decline in this population. Data were derived from 11,120 patients with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) study. Absent peripheral pulses at baseline were defined as absence of at least one dorsalis pedis or posterior tibial pulse. Absent compared with present peripheral pulses (n = 2,218) were associated with increased 5-year risks for major macrovascular events (hazard ratio 1.47 [95% CI 1.28-1.69], P < 0.0001), myocardial infarction (1.45 [1.13-1.87], P = 0.003), stroke (1.57 [1.23-2.00], P = 0.0003), cardiovascular death (1.61 [1.33-1.95], P < 0.0001), heart failure (1.49 [1.21-1.84], P = 0.0002), all-cause mortality (1.48 [1.29-1.71], P < 0.0001), major microvascular events (1.17 [1.00-1.36], P = 0.04), nephropathy (1.24 [1.00-1.54], P = 0.04), end-stage renal disease or renal death (2.04 [1.12-3.70], P = 0.02), and peripheral neuropathy (1.13 [1.05-1.21], P = 0.0008) after multiple adjustment. Participants with absent dorsalis pedis or posterior tibial pulses had comparable hazard ratios. Risks increased proportionally with the number of absent peripheral pulses, with the highest risks observed in patients with three or four absent pulses. Every additional absent pulse increases the risk of all outcomes. Absent dorsalis pedis and/or posterior tibial pulses are independent predictors of major vascular outcomes in patients with type 2 diabetes. These simple clinical indicators should be used to improve risk stratification and treatment of these patients.

Presentations of major peripheral arterial disease and risk of major outcomes in patients with type 2 diabetes: results from the ADVANCE-ON study.

BackgroundPeripheral arterial disease (PAD) is known to be associated with high cardiovascular risk, but the individual impact of PAD presentations on risk of macrovascular and microvascular events has not been reliably compared in patients with type 2 diabetes. We aimed to evaluate the impact of major PAD, and its different presentations, on the 10-year risk of death, major macrovascular events, and major clinical microvascular events in these patients.MethodsParticipants in the action in diabetes and vascular disease: PreterAx and DiamicroN modified-release controlled evaluation (ADVANCE) trial and the ADVANCE-ON post-trial study were followed for a median of 5.0 (in-trial), 5.4 (post-trial), and 9.9 (overall) years. Major PAD at baseline was subdivided into lower-extremity chronic ulceration or amputation secondary to vascular disease and history of peripheral revascularization by angioplasty or surgery.ResultsAmong 11,140 participants, 516 (4.6 %) had major PAD at baseline: 300 (2.7 %) had lower-extremity ulceration or amputation alone, 190 (1.7 %) had peripheral revascularization alone, and 26 (0.2 %) had both presentations. All-cause mortality, major macrovascular events, and major clinical microvascular events occurred in 2265 (20.3 %), 2166 (19.4 %), and 807 (7.2 %) participants, respectively. Compared to those without PAD, patients with major PAD had increased rates of all-cause mortality (HR 1.35, 95 % CI 1.15–1.60, p = 0.0004), and major macrovascular events (1.47 [1.23–1.75], p < 0.0001), after multiple adjustments for region of origin, cardiovascular risk factors and treatments, peripheral neuropathy markers, and randomized treatments. We have also observed a trend toward an association of baseline PAD with risk of major clinical microvascular events [1.31 (0.96–1.78), p = 0.09]. These associations were comparable for patients with a lower-extremity ulceration or amputation and for those with a history of peripheral revascularization. Furthermore, the risk of retinal photocoagulation or blindness, but not renal events, increased in patients with lower-extremity ulceration or amputation [1.53 (1.01–2.30), p = 0.04].ConclusionsLower-extremity ulceration or amputation, and peripheral revascularization both increased the risks of death and cardiovascular events, but only lower-extremity ulceration or amputation increased the risk of severe retinopathy in patients with type 2 diabetes. Screening for major PAD and its management remain crucial for cardiovascular prevention in patients with type 2 diabetes (ClinicalTrials.gov number, NCT00949286).Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0446-x) contains supplementary material, which is available to authorized users.

Impact of age, age at diagnosis and duration of diabetes on the risk of macrovascular and microvascular complications and death in type 2 diabetes.

Data are inconsistent regarding the associations between age, age at diagnosis of diabetes, diabetes duration and subsequent vascular complications. The associations between age (or age at diagnosis), diabetes duration and major macrovascular events, all-cause death and major microvascular events were examined in 11,140 patients with type 2 diabetes randomly allocated to intensive or standard glucose control in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Rates were calculated by 5 year baseline age (or age at diagnosis) and diabetes duration strata. Risks were estimated using Cox models adjusted for treatment assignment and HbA1c. The mean age (±SD) was 65.8 ± 6.4 years, age at diagnosis was 57.8 ± 8.7 years and diabetes duration was 7.9 ± 6.4 years. Diabetes duration was associated with the risk of macrovascular events (HR 1.13 [95% CI 1.08, 1.17]), microvascular events (1.28 [1.23, 1.33]) and death (1.15 [1.10, 1.20]) whereas age (or age at diagnosis) was only associated with the risk of macrovascular events (1.33 [1.27, 1.39]) and death (1.56 [1.48, 1.64]). No interaction was observed between diabetes duration, age and the risk of macrovascular events or death (both p > 0.4). However, an interaction was observed between diabetes duration, age and the risk of microvascular events (p = 0.002), such that the effects of increasing diabetes duration were greatest at younger rather than older age. In patients with type 2 diabetes, age or age at diagnosis and diabetes duration are independently associated with macrovascular events and death whereas only diabetes duration is independently associated with microvascular events and this effect is greater in the youngest patients.

Effects of Visit-to-Visit Variability in Systolic Blood Pressure on Macrovascular and Microvascular Complications in Patients With Type 2 Diabetes Mellitus

Recent evidence suggests that visit-to-visit variability in systolic blood pressure (SBP) and maximum SBP are predictors of cardiovascular disease. However, it remains uncertain whether these parameters predict the risks of macrovascular and microvascular complications in patients with type 2 diabetes mellitus. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) was a factorial randomized controlled trial of blood pressure lowering and blood glucose control in patients with type 2 diabetes mellitus. The present analysis included 8811 patients without major macrovascular and microvascular events or death during the first 24 months after randomization. SBP variability (defined as standard deviation) and maximum SBP were determined during the first 24 months after randomization. During a median 2.4 years of follow-up from the 24-month visit, 407 major macrovascular (myocardial infarction, stroke, or cardiovascular death) and 476 microvascular (new or worsening nephropathy or retinopathy) events were observed. The association of major macrovascular and microvascular events with SBP variability was continuous even after adjustment for mean SBP and other confounding factors (both P<0.05 for trend). Hazard ratios (95% confidence intervals) for the highest tenth of SBP variability were 1.54 (0.99-2.39) for macrovascular events and 1.84 (1.19-2.84) for microvascular events in comparison with the lowest tenth. For maximum SBP, hazard ratios (95% confidence intervals) for the highest tenth were 3.64 (1.73-7.66) and 2.18 (1.04-4.58), respectively. Visit-to-visit variability in SBP and maximum SBP were independent risk factors for macrovascular and microvascular complications in type 2 diabetes mellitus. http://www.clinicaltrials.gov.