Major Macrovascular Events Research Articles

Intensive Glucose Lowering and Its Effects on Vascular Events and Death According to Age at Diagnosis and Duration of Diabetes: The ADVANCE Trial.

To compare the vascular effects of pursuing more versus less glucose lowering in patients with younger or older age at diabetes diagnosis, and with shorter or longer diabetes duration. We studied 11,138 participants from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial, classified into subgroups defined by age at diabetes diagnosis (≤50, >50-60, and >60 years) and diabetes duration (≤5, >5-10, and >10 years). Intensive glucose lowering significantly lowered the risk of the primary composite outcome of major macrovascular and microvascular events (hazard ratio 0.90, 95% CI 0.82-0.98) with no evidence of heterogeneity in the proportional effects across subgroups defined by age at diagnosis or diabetes duration (P for heterogeneity = 0.86 and 0.47, respectively). Similar consistent treatment effects were also observed for all-cause death, cardiovascular death, and the components of major vascular events. Intensive glucose lowering may be recommended irrespective of age at diagnosis or diabetes duration.

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.

Variability in estimated glomerular filtration rate and the risk of major clinical outcomes in diabetes: Post hoc analysis from the ADVANCE trial

There are limited data on whether estimated glomerular filtration rate (eGFR) variability modifies the risk of future clinical outcomes in type 2 diabetes (T2D). We assessed the association between 20-month eGFR variability and the risk of major clinical outcomes in T2D among 8241 participants in the ADVANCE trial. Variability in eGFR (coefficient of variation [CVeGFR ]) was calculated from three serum creatinine measurements over 20 months. Participants were classified into three groups by thirds of CVeGFR : low (≤6.4; reference), moderate (>6.4 to ≤12.1) and high (>12.1). The primary outcome was the composite of major macrovascular events, new or worsening nephropathy and all-cause mortality. Cox regression models were used to estimate hazard ratios (HRs). Over a median follow-up of 2.9 years following the 20-month period, 932 (11.3%) primary outcomes were recorded. Compared with low variability, greater 20-month eGFR variability was independently associated with higher risk of the primary outcome (HR for moderate and high variability: 1.07, 95% CI: 0.91-1.27 and 1.22, 95% CI: 1.03-1.45, respectively) with evidence of a positive linear trend (p = .015). These data indicate that eGFR variability predict changes in the risk of major clinical outcomes in T2D.

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.

How Significant Is Severe Hypoglycemia in Older Adults With Diabetes?

Severe hypoglycemia is a devastating event in the lives of people with diabetes treated with insulin and/or insulin secretogogues. Severe hypoglycemia is defined as an episode in which the person with diabetes requires the assistance of another to increase blood glucose, usually by administration of glucagon or contacting a medical professional. These occurrences are not rare. More than 10% of adult patients in the T1D Exchange registry reported at least one episode of severe hypoglycemia over the past 12 months (1). These events elicit profound fear in patients with diabetes. By depriving the brain of glucose, severe hypoglycemia acutely alters brain function, resulting in neuroglycopenic symptoms, seizures, or even death. The impact extends beyond the acute event. The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial reported that patients with type 2 diabetes who experience severe hypoglycemia were at higher risk for a major macrovascular event or death over the subsequent 12 months (2). As the population ages, there remains a critical need to understand the significance and impact of severe hypoglycemia in older patients with diabetes. In this issue of Diabetes Care , complementary articles provide new insights into the consequences of severe hypoglycemia in older adults. Lacy et al. (3) report that severe hypoglycemia is associated with reduced cognitive function in older adults with type 1 diabetes, and Standl et al. (4) confirm the bidirectional nature of the association between severe hypoglycemia and cardiovascular (CV) events in adults with type 2 diabetes. Both investigations …

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 relationship between eGFR slope and subsequent risk of vascular outcomes and all-cause mortality in type 2 diabetes: the ADVANCE-ON study

Aims/hypothesisSome studies have reported that annual change in eGFR (eGFR slope) is associated with the future risk of end-stage kidney disease, cardiovascular disease and death in general or chronic kidney disease cohorts. However, the benefits of using eGFR slopes for prediction of major clinical outcomes in diabetes are unclear.MethodsWe used data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial and the ADVANCE Post-Trial Observational Study (ADVANCE-ON). After excluding the first 4 months during which an acute fall in eGFR was induced by the initiation of an ACE inhibitor and diuretic combination agent, eGFR slopes were estimated by linear mixed models, using three measurements of eGFR at 4, 12 and 24 months after randomisation over 20 months, and categorised according to quartiles. Cox regression models were used to evaluate adjusted HRs for the study’s primary outcome, a composite of major renal events, major macrovascular events and all-cause mortality during the subsequent follow-up from 24 months after randomisation.ResultsA total of 8,879 participants (80%) were included in this cohort. The mean age was 65.6 years (SD 6.3), the mean eGFR was 75 ml min−1 (1.73 m)−2 (SD 17) and the median urinary albumin/creatinine ratio was 14 μg/mg (interquartile range 7–38). The mean eGFR slope was −0.63 ml min−1 (1.73 m)−2 year−1 (SD 1.75). Over a median follow-up of 7.6 years following the 20-month eGFR slope ascertainment period, 2,221 participants (25%) met the primary outcome. An annual substantial decrease in eGFR (lowest 25%, <−1.63 ml min−1 [1.73 m]−2 year−1) was significantly associated with the subsequent risk of the primary outcome (HR 1.30 [95% CI 1.17, 1.43]) compared with a stable change in eGFR (middle 50%, −1.63 to 0.33). An annual substantial increase in eGFR (highest 25%, >0.33) had no significant association with the risk of the primary outcome (HR 0.96 [95% CI 0.86, 1.07]).Conclusions/interpretationOur study supports the utility of eGFR slope in type 2 diabetes as a surrogate endpoint for renal outcomes, as well as a prognostic factor for identifying individuals at high risk of cardiovascular disease and all-cause mortality.Trial registry numberClinicalTrials.gov registration no. NCT00145925 and no. NCT00949286

SAT-287 eGFR SLOPE AND THE SUBSEQUENT RISK OF CLINICAL OUTCOMES IN TYPE 2 DIABETES

Diabetic kidney disease (DKD) develops in approximately 40% of patients with diabetes and can lead to poor prognosis. Evaluating DKD progression is critical for identifying patients at high risk of clinical outcomes for both clinical and research purposes. Recent studies have suggested that an annual change in eGFR, defined as an eGFR slope, is associated with the subsequent risk of end-stage kidney disease (ESKD), cardiovascular disease (CVD) and mortality. However, the benefits of using eGFR slopes in diabetes are unclear. The aim of the study was to determine whether eGFR slopes are useful to predict the risk of clinical outcomes in type 2 diabetes. We used data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) and ADVANCE Post-Trial Observational Study (ADVANCE-ON). Excluding the first 4 months in which an acute fall in eGFR was induced by the initiation of a renin-angiotensin-aldosterone-system blocker, eGFR slopes were estimated by linear mixed models, using 3 measurements of eGFR at 4th, 12th, and 24th month after randomisation over the 20-month baseline period and categorised according to quartiles. The risk factors associated with eGFR slopes were assessed in multivariable analyses using linear mixed models. Cox proportional hazards models were used to evaluate adjusted hazard ratios (HRs) of the study’s primary outcome, a composite of major renal events, major macrovascular events, and all-cause mortality. Secondary outcomes included the individual components of the primary outcome. A total of 8879 participants (80%) were included. The mean eGFR slope was -0.63 mL/min/1.73 m2/year (SD 1.75). Overall, 127 (1%), 298 (3%), 695 (8%), 1595 (18%), and 3408 (38%) participants had experienced an annual change in eGFR of -5, -4, -3, -2, and -1 mL/min/1.73 m2/year, respectively. In the multivariable analyses, the mean eGFR slope was steeper in participants with older age, higher albuminuria and HbA1c, and lower HDL cholesterol, while the mean eGFR slope was flatter in patients with lower eGFR. Over a median follow-up of 7.6 years, 2221 participants (25%) developed 1395 major macrovascular events (16%), 117 major renal events (1%), and 1450 deaths (16%). An annual decrease in eGFR (1st quarter, <-1.63 mL/min/1.73 m2/year) was significantly associated with the subsequent risk of primary outcome (HR 1.25; 95%CI 1.13–1.38) compared with a stable change in eGFR (2nd and 3rd quarters, -1.63 to 0.33 mL/min/1.73 m2/year) and showed 301%, 22%, and 32% higher risk of major renal events, major macrovascular events, and all-cause mortality, respectively. An annual increase in eGFR (4th quarter, >0.33 mL/min/1.73 m2/year) had no significant association with the risk of primary outcome. The greater annual declines in eGFR were associated with higher risk of study outcomes compared with no change in eGFR. An annual decrease in eGFR over the 20-month baseline period was strongly associated with future risk of clinical events and death in type 2 diabetes, supporting the potential of using eGFR slopes as a surrogate endpoint for predicting adverse kidney outcomes. The present analysis suggests that monitoring eGFR over time is beneficial to identify diabetic patients at high risk of ESKD, CVD and death.

Higher heart rates increase risk of diabetes and cardiovascular events: A prospective cohort study among Inner Mongolians

AimThe study examined the association between resting heart rate and risk of type 2 diabetes (T2D) and cardiovascular events in an Inner Mongolian population. MethodsBased on a cross-sectional survey carried out in 2003, 2530 participants were reinvestigated between 2013 and 2014. All participants were classified into four groups (quartiles) according to heart rate. Primary outcomes were hypertension, T2D, major macrovascular events and all-cause deaths. Logistic regression models were used to estimate odds ratios (ORs), and shape-restricted cubic spline regressions were conducted to investigate the associations between resting heart rate and study outcomes. ResultsDuring the 10-year follow-up, 502 (41.6%) patients developed hypertension, 200 (10.4%) had diabetes, 464 (18.3%) experienced major macro-vascular events and 306 (14.3%) died. Resting heart rate was significantly associated with an increased risk of hypertension, T2D, major macro-vascular events and all-cause deaths: adjusted ORs (95% CI) for the highest vs lowest quartiles of heart rate were 1.51 (1.06–2.15), 2.44 (1.54–3.85), 1.55 (1.14–2.10) and 1.57 (1.05–2.34), respectively. Multivariable-adjusted restricted cubic spline regression models showed a linear association between heart rate and the four outcomes (all P < 0.05 for linearity). The addition of heart rate to basic risk factors improved the prediction of risk of diabetes and all-cause deaths [indices of continuous net reclassification improvement and of integrated discrimination improvement were 21.92% (P = 0.002) and 22.69% (P < 0.001), and 0.72% (P = 0.01) and 0.58% (P = 0.03), respectively]. ConclusionHigher heart rates were associated with an increased risk of hypertension, T2D, major macro-vascular events and all-cause deaths among Inner Mongolians, suggesting that heart rate measurement may be of value as a potential clinical and diagnostic marker.

Acute Increases in Serum Creatinine After Starting Angiotensin-Converting Enzyme Inhibitor-Based Therapy and Effects of its Continuation on Major Clinical Outcomes in Type 2 Diabetes Mellitus.

Discontinuation of angiotensin-converting enzyme (ACE) inhibitor is recommended if patients experience ≥30% acute increase in serum creatinine after starting this therapy. However, the long-term effects of its continuation or discontinuation on major clinical outcomes after increases in serum creatinine are unclear. In the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation), 11 140 diabetes mellitus patients were randomly assigned to perindopril-indapamide or placebo after a 6-week active run-in period. The current study included 11 066 participants with 2 serum creatinine measurements recorded before and during the active run-in period (3 weeks apart). Acute increase in creatinine was determined using these 2 measurements and classified into 4 groups: increases in serum creatinine of <10%, 10% to 19%, 20% to 29%, and ≥30%. The primary study outcome was the composite of major macrovascular events, new or worsening nephropathy, and all-cause mortality. An acute increase in serum creatinine was associated with an elevated risk of the primary outcome ( P for trend <0.001). The hazard ratios were 1.11 (95% CI, 0.97-1.28) for those with an increase of 10% to 19%, 1.34 (1.07-1.66) for 20% to 29%, and 1.44 (1.15-1.81) for ≥30%, compared with <10%. However, there was no evidence of heterogeneity in the benefit of randomized treatment effects on the outcome across subgroups defined by acute serum creatinine increase ( P for heterogeneity=0.94). Acute increases in serum creatinine after starting perindopril-indapamide were associated with greater risks of subsequent major clinical outcomes. However, the continuation of angiotensin-converting enzyme inhibitor-based therapy reduced the long-term risk of major clinical outcomes, irrespective of acute increase in creatinine. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00145925.

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.

Acute Increase in Creatinine after Starting ACE Inhibitor and Vascular Events and Premature Death in Patients with Type 2 Diabetes—The ADVANCE Trial

Background: An acute increase in serum creatinine (AICr) after starting ACE inhibitor is frequently observed, and consideration of discontinuation has been recommended if creatinine values increased 30% or more. However, the long term effect of continuation or discontinuation of that therapy is unclear. Objective: To examine the association of AICr after starting a fixed combination of perindopril-indapamide and its continuation or discontinuation, with clinical outcomes using data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Research Design and Methods: A total of 11,140 diabetes patients were randomly assigned to a fixed combination of perindopril-indapamide or placebo after a 6-week active run-in period. These analyses included 11,066 patients with 2 measurements of serum creatinine, before and during the active run-in period (3 weeks apart). AICr was determined using these 2 measurements, classified into 4 groups: &amp;lt;10%, 10-19%, 20-29%, and ≥30%. Results: AICr after starting perindopril-indapamide in the run-in period was subsequently associated with an increased risk of a composite of major macrovascular events, new or worsening nephropathy, all-cause mortality, in both randomized groups (P for trend &amp;lt;0.for each). However, a consistent benefit of randomized treatment for the outcome was observed across subgroups defined by AICr, with no heterogeneity in the magnitude of the effects (P for heterogeneity = 0.94). Similar results were observed for major macrovascular events alone, new or worsening nephropathy alone, and all-cause mortality alone. Conclusions: AICr after starting ACE inhibitor was associated with an increased risk of clinical outcomes, irrespective of continuation or discontinuation of the therapy. However, randomized treatment effects are consistent and beneficial across subgroups defined by AICr. Disclosure T. Ohkuma: None. M. Jun: None. M. Woodward: None. J. Chalmers: Research Support; Self; Servier. Other Relationship; Self; Servier. V. Perkovic: Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Advisory Panel; Self; Merck Sharp &amp; Dohme Corp.. Consultant; Self; AbbVie Inc.. Advisory Panel; Self; Janssen Global Services, LLC.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novartis Pharmaceuticals Corporation, AstraZeneca, Gilead Sciences, Inc.. Consultant; Self; Servier. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Eli Lilly and Company. A. Rodgers: Other Relationship; Self; George Health Enterprises.

Changes in Albuminuria and the Risk of Major Clinical Outcomes in Diabetes: Results From ADVANCE-ON.

To assess the association between 2-year changes in urine albumin-to-creatinine ratio (UACR) and the risk of clinical outcomes in type 2 diabetes. We analyzed data from 8,766 participants in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Post-Trial Observational Study (ADVANCE-ON). Change in UACR was calculated from UACR measurements 2 years apart, classified into three groups: decrease in UACR of ≥30%, minor change, and increase in UACR of ≥30%. By analyzing changes from baseline UACR groups, categorized into thirds, we repeated these analyses accounting for regression to the mean (RtM). The primary outcome was the composite of major macrovascular events, renal events, and all-cause mortality; secondary outcomes were these components. Cox regression models were used to estimate hazard ratios (HRs). Over a median follow-up of 7.7 years, 2,191 primary outcomes were observed. Increases in UACR over 2 years independently predicted a greater risk of the primary outcome (HR for ≥30% UACR increase vs. minor change: 1.26; 95% CI 1.13-1.41), whereas a decrease in UACR was not significantly associated with lower risk (HR 0.93; 95% CI 0.83-1.04). However, after allowing for RtM, the effect of "real" decrease in UACR on the primary outcome was found to be significant (HR 0.84; 95% CI 0.75-0.94), whereas the estimated effect on an increase was unchanged. Changes in UACR predicted changes in the risk of major clinical outcomes and mortality in type 2 diabetes, supporting the prognostic utility of monitoring albuminuria change over time.

Prognostic Value of Variability in Systolic Blood Pressure Related to Vascular Events and Premature Death in Type 2 Diabetes Mellitus: The ADVANCE-ON Study.

Visit-to-visit variability in systolic blood pressure (SBP) is a risk factor for cardiovascular events. However, whether it provides additional predictive information beyond traditional risk factors, including mean SBP, in the long term is unclear. The ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) was a randomized controlled trial in patients with type 2 diabetes mellitus; ADVANCE-ON (ADVANCE-Observational) followed-up patients subsequently. In these analyses, 9114 patients without major macrovascular or renal events or death during the first 24 months were included. Data on SBP from 6 visits during the first 24 months after randomization were used to estimate visit-to-visit variability in several ways: the primary measure was the standard deviation. Events accrued during the following 7.6 years. The primary outcome was a composite of major macrovascular and renal events and all-cause mortality. Standard deviation of SBP was log-linearly associated with an increased risk of the primary outcome (P<0.001) after adjustment for mean SBP and other cardiovascular risk factors. The hazard ratio (HR; 95% confidence interval [CI]) in the highest, compared with the lowest, tenth of the standard deviation was 1.39 (1.15-1.69). Results were similar for major macrovascular events alone and all-cause mortality alone (both P<0.01). Addition of standard deviation of SBP significantly improved 8-year risk classification (continuous net reclassification improvement, 5.3%). Results were similar for other measures of visit-to-visit variability, except maximum SBP. Visit-to-visit variability in SBP is an independent predictor of vascular complications and death, which improves risk prediction beyond that provided by traditional risk factors, including mean SBP.